Immunosuppressants

  Immunosuppressant drugs
Classification
 

1.       Calcineurin inhibitors (Specific T cell inhibitors)

                            Cyclosporine, Tacrolimus

2.       m-TOR inhibitors

                            Sirolimus, Everolimus

3.       Anti-proliferative drugs (Cytotoxic drugs)

Azathioprine, Methotrexate

Cyclophosphamide, Chlorambucil

Mycophenolate mofetil (MMF)

4.       Glucocoticoids

                             Predisolone and others

5.       Biological agents

a.       TNFα inhibitors: Etanercept, Infliximab, Adalimumab

b.      IL-1 receptor antagonist: Anakinra

c.       IL-2 receptor antagonists: Daclizumab (anti CD-25 antibodies), Basiliximab

d.      Anti CD-3 antibody: Muromonab CD3

e.      Polyclonal antibodies: Antithymocyte antibody (ATG), Rho (D) immuneglobulin

 
 
Calcineurin inhibitors (Specific T cell inhibitors)
 
Cyclosporine
  • It profoundly and selectively inhibits T lymphocyte proliferation, IL-2 and other cytokine production as well as response to inducer T cells to IL-1, without any effect on suppressor T cells
  • Lymphocytes are arrested in G0 or G1 phase
  • Cyclosporine selectively suppresses cell mediated immunity (CMI), prevents graft rejection 
  • It is free of toxic effects on the bone marrow and RE system
  • Humoral immunity remains intact
  • It is concentrated in WBCs and RBCs, metabolized in liver by CYP3A4 and excreted in bile
  • The plasma t ½ is biphasic 4-6 hr and 12-18 hr
  • Adverse effects
  • Nephrotoxic
  • Impairs liver function
  • Sustained rise in BP
  • Precipitation of diabetes
  • Anorexia, lethargy
  • Hyperkalemia
  • Hyperuricemia
  • Opportunistic infections
  • Hirsutism
  • Gum hyperplasia
  • Tremor and seizures
  • Uses
  • Most effective drug in prevention and treatment of graft rejection reaction
  • Routinely used in renal, hepatic, cardiac, bone marrow and other transplantations
  • Second line drug in autoimmune diseases like severe rheumatoid arthritis, uveitis, bronchial asthma, inflammatory bowel disease, dermatomyositis etc.
  • It is generally used along with corticosteroids and methotrexate
  • Used in treatment of aplastic anemia
  • Drug interactions
  • All nephrotoxic drugs like aminoglycosides, vancomycin, amphotericin B, NSAIDs enhance toxicity
  • Phenytoin, phenobarbitone, rifampicin and other enzyme inducers lower its blood levels so transplant rejection may result
  • CYP3A4 inhibitors erythromycin, ketoconazole and related drugs inhibit its metabolism to increase bioavailability and cause toxicity
  • Potassium supplements and K+ sparing diuretics can produce hyperkalemia in patients on cyclosporine 
  • Cyclosporin A is a powerful immunosuppressive agent which lack myelotoxicty. It has been used in recipients of kidney, liver, bone marrow and pancreas transplants. It may also have clinical application in the treatment of autoimmune disorders. (1)
  • The administration of cyclosporine at the time of reperfusion is associated with a smaller infarct by some measures. (2)
  • In an anesthetized animal preperation, the vasoconstrictor and blood pressure-raising effects of cyclosporine are caused by sympathetic neural activation. (3)
  • Immunosuppressants like cyclosporine can promote cancer progression by a direct cellular effect that is independent of its effect on the host's immune cells and that cyclosporine induced TGF-beta production is involved in this. (4)
  • Cyclosporine is an effective treatment for chronic urticaria (CU) and a history of hives, shorter duration of disease and CU index ≥ 10 predict a successful response. (5)
  • Cyclosporine is a calcineurin inhibitor that act selectively on T cells. It can be used in various dermatological disorders like psoriasis, atopic dermatitis, blistering disorders and connective tissue diseases. (6)
  • Cyclosporine is not useful in the treatment of Crohn's disease. (7)
  • Cyclosporine 0.05% ophthalmic emulsion is shown to be effective in the management of posterior blepharitis, ocular rosacea, post-LASIK dry eye, contact lens intolerance, atopic keratoconjunctivitis, graft versus host disease and herpetic stromal keratitis. (8)
  • Cyclosporine is used in the treatment of psoriasis, atopic dermatitis, bullous disorders, pyoderma gangrenosum, lichen planus, dermatomyositis, systemic lupus erythematosus and varioud forms of vasculitis. It is an effective disease modifying agent in psoriatic arthritis. The long term risks of cyclosporine therapy include renal toxic effects, hypertension and increased risk of malignancy. (9)
  • Cyclosporine has a encouraging role in the management of uncomplicated cases of Steven Johnson syndrome (SJS), Steven Johnson syndrome-Toxic epidermal necrolysis (TEN) overlap or TEN. (10)
  • Cyclosporine inhibits the direct interactions between cyclophilins and hepatitis C NS5A. (11)
  • Corticosteroids remain the mainstay of the treatment of chronic sarcoidosis. When these drugs have not been successful for the skin manifestations of the disease, a trial of cyclosporine may be justified. (12)
  • The use of chylomicron-cleared plasma for therapeutic drug monitoring of cyclosporine in type V hyperlipoproteinemic patients is strongly recommended. (13)
  • Thromboxane receptor blockade attenuates chronic cyclosporine nephrotoxicity and improves survival in rat model with renal isograft. (14)
  • Cyclosporine levels have been correlated with risk of nephrotoxicity and to a lesser extent hepatotoxicity. Low cyclosporine levels is one factor contributing to the risk of acute graft-versus-host disease in patients with allogenic bone marrow transplantation. Cyclosporine concentration monitoring in blood can assist the clinician in maximising the chances of graft versus host disease prevention while reducing the risks of cyclosporine side effects. (15)
  • Cyclosporine stimulates endothelial cells synthesis of endothelin which in turn causes smooth muscle cell proliferation. This action is inhibited by the coincubation of a specific antibody to endothelin or a calcium channel antagonist. These findings may help in the inderstanding of cyclosporin induced hypertension and vasculopathy. (16)
  • Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most common syndrome among acute encephalopathies and is associated with high incidence of neurologic sequelae. Cyclosporine could improve the neurological prognosis of patients with AESD except for those with frontal lobe predominant type. (17)
  • The clinical and radiologic findings in patients showing the neurotoxic effects of cyclosporine appear to be identical to those with hypertensive encephalopathy. Other associated factors such as cyclosporine induced vasculopathy or hypoalbuminemia may also play a role in the condition and intracranial hemorrhage may occur owing to associated thrombocytopenia. Symptoms generally resolve after reduction of blood pressure and follow up is usually unnecessary in uncomplicated cases. (18)
  • Oral cyclosporine therapy is successful in the treatment of refractory severe vernal keratoconjunctivitis. (19)
  • Cyclosporine modulation in poor risk acute myeloid leukemia results in a significant decrease in residual disease following induction therapy. The long term significance regarding relapse free survival and overall survival appears to be a matter of speculation. (20)
  • Conversion to tacrolimus may represent a useful therapeutic strategy to reduce cyclosporine- associated renal failure in recipients of orthotopic heart transplants. (21)
  • Therapeutic doses of cyclosporine induce reversible glucose intolerance due, in part, to inhibition of insulin secretion and also possibly inhibition of synthesis, though peripheral effect is not exluded. This hyperglycemic effect of cyclosporine has implications for its potential use in type I diabetes mellitus, transplantation and other autoimmune disease. (22)
  • In patients with de novo cardiac transplantation, early Cyclosporine A dose reduction is not associated with renal benefit at 12 months. The strategy may benefit patients with high creatinine levels before transplantation. (23)
  • Topical cyclosporine could be an effective and safe treatment method for allergic conjunctivitis. (24)
  • Cyclosporin A seems to be a promising treatment against dry eye disease. (25)
  • Intravenous cyclosporin may be used in the treatment of severe refractory ulcerative colitis. (26)
  • Cyclosporin induces the biochemical remission of the hepatic inflammatory/ necrotic process in children with autoimmune hepatitis, with few and well tolerated adverse effects. (27)
  • Hypoxia-reoxygenation induces ERK 1/2 phophorylation, as well as transactivation of the transcription factors NFkB and EGR-1 in pulmonary artery endothelial cells (PAEC). Cyclosporine selectively reduces proinflammatory mediator secretion, likely by transcriptional regulation through NFkB and EGR-1. Thus, it modulates the response to hypoxia-reoxygenation in pulmonary artery endothelial cells. (28)
  • Immunosuppression with cyclosporin A affects host defense mechanisms which are operative against superficial candidiasis but appear superfluous in resistance to the invasive form of this mycosis, an indication for the divergent nature of the host defense against the two forms of candidiasis. (29)
  • If mycophenolate mofetil (MMF) treatment is combined with cyclosporine, mycophenolic acid (MPA) plasma concentrations decrease, mycophenolic acid glucuronide (MPAG) increases and the second peak in the MPA pharmacokinetic profile disappears. (30)
  • Chlorhexidene mouthwash used twice daily may reduce the severity of cyclosporine induced gingival overgrowth. (31)
  • Vitamin C administration provides protection against cyclosporine induced injury in rat liver function and may have hepatoprotective role in the patients experiencing cyclosporine treatment. (32)
  • Topical 0.05% cyclosporine A is a safe and effective alternative treatment in patients with subepithelial infiltrates after epidemic keratoconjunctivitis who do not respond to other treatment modalities or have undesired side effects from topical steroids. (33)
Tacrolimus
 
  • 100 times more potent than cyclosporine
  • It binds with FK 506 binding protein (FKBP) and cause inhibition of helprt T cell via calcineurin
  • It is administered orally as well as by iv infusion
  • Oral absorption is variable and decreased by food
  • It is metabolized by CYP3A4 and excreted in bile with a t ½ of 12 hours
  • The nephrotoxic potential of tacrolimus and cyclosporine are equivalent in pancreas transplant recipients. (34)
  • Chronic tacrolimus nephrotoxicity can be nonreversible. This effect can be minimized by the use of low dose regimens. Observed and projected long term graft survivals wuth tacrolimus now equal or exceed those obtainable with alternative immunosuppresive drugs. (35)
  • Tacrolimus combined therapy with mycophenolate mofetil is effectiv ein the prevention of organ rejection in kidney transplant patients. (36)
  • Tacrolimus is effective in the treatment of pyoderma gangrenosum. This allows reductio of severe adverse effects associated with systemic administration of immunosuppressants, including the complications of prolonged glucocorticosteroid treatment. (37)
  • The stable kidney transplant patients treated with prograf can be converted to tacrolimus sandoz if trough concentrations of tacrolimus and plasma creatinine levels are closely monitored. (38)
  • The ability of tacrolimus to reverse steroid resistant rejection in patients who have undergone renal transplantation and are receiving primary cyclosporin immunosuppression suggests that tacrolimus is a more potent immunosuppressant than cyclosporin. (39)
  • Tacrolimus has more advantage than cyclosporin in prevention of liver allgraft rejection. (40)
  • Tacrolimus induced chronic hypertension is mediated largely by NCC (renal sodium chloride cotransporter) activation and inexpensive and well tolerated thiazide diuretics may be especially effective in preventing the complications of tacrlimus treatment. (41)
  • Immunosuppressive regimens based on tacrolimus and cyclosporine are comparable in terms of patients and graft survival. Tacrolimus is associated with significantly fewer episodes of acute, corticosteroid resistant or refractory rejection but substantially more adverse events requiring discontinuation of the drug. (42)
  • Propanolol can be used in the treatment of tacrolimus induced tremors. (43)
  • Vitiligo can be successfully treated with 0.1% tacrolimus ointment. (44)
  • Topical tacrolimus 0.03% monotherapy can be used for the treatment of vernal keratoconjunctivitis. (45)
  • Cutaneous lupus mucinosis can be successfully treated with systemic corticosteroid and systemic tacrolimus combination therapy. (46)
  • During the first 2 weeks after liver transplant, tacrolimus trough concentration between 7 and 10 ng/ml are safe in terms of acute rejection and are associated with longer graft survival. (47)
  • Prion diseases such as Cruetzfeldt Jakob disease (CJD) are incurable and rapidly fatal neurodegenerative diseases. Tacrolimus and Astemizole are antiprion agents which can be used in the treatment of Prion disease. (48)
  • Multitarget therapy combining glucocorticoid, mizoribine and tacrolimus may have the potential to become a treatment option which is effective and safe for systemic lupus erythematosus with or without active nephritis. (49)
  • Tacrolimus associated arrhythmia after kidney transplantation may be life threatening and so patients should be carefully monitored. (50)
  • Solitary mastocytoma can be successfully treated with topical tacrolimus. (51)
  • Ingestion of tacrolimus by infants via breast milk is negligible. Women taking tacrolimus should not be discouraged from breastfeeding if monitoring of infant levels is available. (52)
  • Topical tacrolimus ointment for facial lesions of chronic actinic dermatitis appears to be effective and well tolerated and may provide long term benefits. (53)
  • Short term administration of phenytoin facilitates reversal of elevated tacrolimus concentrations and severe renal impairment. Phenytoin appears to be a potential treatment in severe cases of tacrolimus toxicity. (54)
  • Tacrolimus is safe and effective in the treatment of varity of skin disorders like atopic dermatitis, eczema, disorders of cornification, papulosquamous disorders, connective tissue diseases, rosacea, vitiligo and follicular disorders.It is quite safe, has no potential of skin atrophy and the most common adverse effect being a transient sensation of burning at the site of application. (55)
  • Tacrolimus is effective for the maintenance of refractory ulcerative colitis and can deliver sustained improvement in mucosal inflammation. (56)
  • Application of topical tacrolimus on eyelid skin may be effective for treatment of severe atopic dermatitis of the eyelid, and may have secondary benefits for atopic keratoconjunctivitis. (57)
  • Tacrolimus might affect RANKL (receptor activator of NF-kB ligand) expression in IL-6 stimulated FLS (fibroblast like synoviocytes) through STAT3 (signal transducer and activator of transcription-3) suppression together with up-regulation of SOCS3 (suppressor of cytokine signalling). (58)
  • Oral tacrolimus 0.2 mg/kg/day is effective for fistula improvement, but not fistula remission in patients with perianal Crohn's disease. (59)
  • Tacrolimus is an immunosuppressive agent that can show a wide variety of neurologic side effects including leukoencephalopathy. The prognosis is good, after cessation or dose reduction, complete recovery usually occurs. (60)
  • Tacrolimus inhibit the revascularisation of isolated pancreatic islets without affecting the characteristics of the transplanted grafts. Further refinement of this immunosuppressive regimen, especially regarding the revascularisation of islet grafts, could improve the outcome of islet allotransplantation. (61)
  • Takayasu arteritis can be successfully treated with tacrolimus. (62)
  • Generalized morphea can be successfully treated with tacrolimus 0.1% ointment. (63)
  • Tacrolimus and low dose prednisolone therapy induces complete remission rapidly and effectively in adult patients with minimal change nephrotic syndrome. (64)
  • Uses
  • It is preferred drug in organ transplantation
  • Particularly useful in liver transplantation because its absorption is not dependent on bile
  • It is suitable for suppressing acute rejection
  • Fistulating crohn’s disease
  • Adverse effects
  • Neurotoxicity
  • Alopecia
  • Diarrhea
  • Hypertension, hirsutism, gum hyperplasia and hyperuricemia are less marked 
 
mTOR inhibitors
 
Sirolimus
  • Sirolimus arrest immune response at a later stage than cyclosporine
  • It is absorbed orally, fatty meal reduces absorption
  • It is extensively metabolized, mainly by CYP3A4.
  • Bioavailability is only 15-20%
  • Elimination occur primarily by the biliary route; the t ½ is 60 hours
  • Inhibitors and inducers of CYP3A4 significantly alters its blood level
  • Sirolimus has been a drug looking for a dominant role in immunosuppression regimens. Its long term use has been limited by its profound effect on hematopoeisis as well as lipid metabolism, proteinuria. (65)
  • Switching from calcineurin inhibitors to sirolimus has an antitumoral effect among kidney transplant recipients with previous squamous cell carcinoma. (66)
  • Ultrathin biodegradable polymer sirolimus eluting stents are non inferior to durable polymer everolimus eluting stents in combined safety and efficacy for percutaneous coronary revascularisation. (67)
  • Sirolimus eluting coronary stents have a dramatically improved patient outcomes after percutaneous intervention. (68)
  • Sirolimus, a water insoluble immunosuppressant, has been formulated into an oral solid dosage form by using NanoCrystal technology to increase the water solubility and therby the bioavailability. It is more cost effective treatment in renal transplantation than cyclosporine and tacrolimus. (69)
  • Sirolimus appears to be useful in the treatment of patients with steroid refractory autoimmune hepatitis. (70)
  • Sirolimus (rapamycin) is a lipophillic macrocytic lactine with immunosuppressive, antitumor, and antoviral properties. Because of its multiple modes of activities, it is being increasingly used in the management of graft versus host disease. (71)
  • Sirolimus improves pain in neurofibromatosis 1 patients with severe plexiform neurofibromas. (72)
  • Stent fracture in sirolimus eluting stents is associated with a higher major adverse coronary event rate up to 1 year. There is no significant increase in major adverse coronary event rate of fractures stents between years 1 and 4. (73)
  • There are chances of occurance of very late stent thrombosis after sirolimus eluting stent implantation. Thus long term antiplatelet medication should be prescribed among patients receiving sirolimus eluting stents. (74)
  • Sirolimus combined with low dose calcineurin inhibitors appears to be a safe and effective alternative immunosuppressive therapy to sirolimus alone in lung transplant recipients with renal failure. (75)
  • Low dose sirolimus increases the risk of menstrual cycle disturbances and ovarian cysts and monitoring of sirolimus associated ovarian toxicity is warranted. (76)
  • Topical sirolimus can used for the treatment of oral pemphigus vulgaris. (77)
  • Sirolimus (Rapamycin) inhibits proliferating cell nuclear antigen expression and blocks cell cycle in the G1 phase in human keratinocyte stem cells. (78)
  • Sirolimus induced lung toxicity may manifest as alveolar proteinosis and granulomatous lung disease. Interleukin-12 (IL-12) and transforming growth factor (TGF B) may play a role in pulmonary macrophage dysfunction leading to decreased clearance of surfactant and formation of granulomas. (79)
  • Severe radiation induced esophagitisat an early stage of radiation therapy can occur with concurrent use of sirolimus. (80)
  • Sirolimus is a promising alternative for the maintenance immunosuppression after renal transplantation. (81)
  • Sirolimus is more effective in improving GFR in patients without preexisting diabetes and adequate MMF (mycophenolate mofetil) doses are needed for sirolimus conversion. (82)
  • Sirolimus and everolimus are members of a relatively new class of immunosuppressants that impair cell cycle proliferation by inhibition of the mammalian target of rapamycin. (83) 
  • Sirolimus alters the insulin signalling pathway so as to increase adipose tissue lipase activity and/ or decrease lipoprotein lipase activity, resulting in increased hepatic synthesis of triglyceride, increased secretion of VLDL and increased hypertriglyceridemia. (84) 
  • Topical sirolimus can be used for the treatment of facial angiofibromas. (85)
  • Sirolimus can induce interstitial pneumonitis in patients. Patients present with cough, dyspnea, fever, hemoptysis and eyelid edema. CRP is elevated, chest radiograph reveal bilateral basal opacities and bronchoalveolar lavage shows lymphocytosis. Histopathology shows lymphoplasmocytic interstitial inflammation, scattered intra-alveolar epitheloid granulomas and focal organizing pneumonia. Withdrawal of sirolimus results in resolution of symptoms, radiographic opacities in chest and CRP. (86)
  • Due to potential for sirolimus toxicity and excessive immunosuppression, the concurrent use of dronedarone and sirolimus should be avoided when possible. (87)
  • Lymphangioleiomyomatosis (LAM) is a rare lung disease that predominantly affects young females and generally progresses to respiratory failure. Sirolimus can be used for its treatment. (88)
  • Sirolimus is a immunosuppressant isolated from macrolide antibiotic. It may have a beneficial role in prophylaxis of rejection as well as treatment of refractory rejection. It also has antifungal, antitumor and antismooth muscle proliferative roles. (89)
  • The inhibitory effects of sirolimus on circulating endothelial progenitor cells potently may affect re-endotheliazation after sirolimus eluting stent implantation. (90)
  • The use of sirolimus should be restricted in liver transplantation. (91)
  • An "angiographic late catch up" phenomenon and a trend toward increased incidence of coronary artery aneurysm and stent fracture is found after sirolimus eluting stent implantation. (92)
  • Sirolimus appears to enhance the cytotoxicty of cisplatin in malignant pleural mesothelioma cell lines through the mammalian target of rapamycin pathway. Thus combined sirolimus and cisplatin chemotherapy can be used in malignant pleural mesothelioma. (93)
  • There is reversal of tamoxifen resistance by addition of sirolimus in metastatic breast cancer. (94)
  • Hemolytic Uremic Syndrome can occur due to sirolimus in a heart transplant recipient. (95)
  • Sirolimus has an anti-proliferation effect on the T24 bladder carcinoma cell line. (96)
  • Sirolimus therapy is effective for chylous effusions in lymphangioleiomyomatosis. (97)
  • Sirolimus is effective in prevention of development of Bronchiolitis Obliterans in lung transplant recipient patients. (98)
  • Neoadjuvant treatment with sirolimus may be considered to facilitate surgery and allow early control of potentially metastatic disease in patients with large hepatic perivascular epitheloid cell tumor (PEComa). (99)
  • Uses
  • Prophylaxis and therapy of graft rejection reaction
  • Used in steroid refractory cases
  • Not recommended in liver transplant patient
  • Sirolimus coated stents are used to reduce the incidence of coronary artery restenosis, by inhibiting endothelial proliferation at the site
  • Side effects 
  • Bone marrow depression
  • Not nephrotoxic
  • Thrombocytopenia
  • Rise in serum lipids
  • Diarrhea
  • Liver damage
  • Pneumonitis 
 
 
Everolimus 
  • Everolimus can be used in HR positive advanced breast cancer. Median progression free survival in patients receiving everolimus is 6.9 months according to radiologic assessment by local investigators and 10.6 months according to central assessment. (100)
  • Everolimus combined with an aromatase inhibitor improves progression free survival in patients with hormone receptor positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. (101)
  • The addition of everolimus to exemestane markedly prolongs progression free survival in patients with HR positive advanced breast cancer with disease recurrence/ progression following prior non stroidal aromatase inhibitors. (102)
  • Compared with best supportive care, everolimus does not significantly improve overall survival for advanced gastric cancer that progressed after one or two lines of previous systemic chemotherapy. (103)
  • Inpatients with advanced hepatocellular carcinoma, the everolimus maximum tolerated dose in combination with standard dose sorafenib is 2.5 mg once daily. (104)
  • Everolimus and carboplatin combination is effective in patients with triple negative metastatic breast cancer. (105)
  • Everolimus has a key role to play in renal transplantation. The synergism between everolimus and cyclosporine permits cyclosporine dose reduction enabling nephrotoxicity to be minimized without compromising efficacy. (106)
  • The mTORC1 inhibitor everolimus prevents and treats Eµ-Myc lymphoma by restoring oncogene induced senescence. (107)
  • Everolimus seems to provide comparable short term outcome to enetric coated mycophenolate sodium (EC-MPS) when combined with low dose tacrolimus/ steroids and dual induction therapy in simultaneous pancreas and kidney transplantation. (108)
  • Everolimus can induce severe pulmonary toxicity in patients with diffuse alveolar hemorrhage. (109)
  • In patients with renal cell carcinoma, the addition of zoledronic acid to everolimus significantly reduces bone resorption markers and may prolong tumor control. (110)
  • Dovitinib and everolimus has modest activity in vasular endothelial growth factor refractory clear cell renal cancer. (111)
  • In patients with cancer, everolimus is associated with a small but significant increase in the odds of a treatment related fatal events. (112)
  • Everolimus, a potent anto-proliferative agent in drug eluting stents and bioresorbable vascular scaffolds, may inhibit atheroma progression and/ or promote atheroma stabilization through diminished viability of foam cell, decreased matrix degradation and reduced pro-inflammatory cytokine secretion. (113)
  • Everolimus lowers plasma activity and cellular production of Lp-PLA2 (lipoprotein-associated phospholipase A2) and thereby dampens oxidative stress, These efefcts may additonally contribute to the reduced CAV incidence observed in heart transplant recipients receiving everolimus therapy. (114)
  • Everolimus can cause severe hypertriglyceridemia and acute pancreatitis. (115)
  • In addition to anemia, leukopenia and thrombocytopenia, everolimus consistently induces red cell microcytosis and reduced hemoglobin content. Lymphopenia may contribute to immune suppression and increased risk of infection. (116)
  • Everolimus reduced 89Zr-Bevacizumab tumor uptake in patients with neuroendocrine tumors. (117)
  • mTOR inhibitor everolimus can be successfully used in the treatment of perivascular epitheloid cell tumor. (118)
  • The safety profile of everolimus is not influenced by previous treatment with peptide receptor radiotherapy. (119)
  • Head and neck cancer patients tolerate everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. (120)
  • Everolimus once daily dosing shoyld be 7.5 mg and 5 mg in patients with mild and moderate hepatic impairment respectively. Everolimus is not recommended in patients with severe hepatic impairment unless benefits outweigh risks; in that case 2.5 mg once daily should not be exceeded. (121)
  • There is reduction in the size of renal angiomyolipoma after treatment with everolimus in lung transplantation due to lymphangioleiomyomatosis. (122)
  • Everolimus can cause severe steatohepatis in a patient. (123)
  • Everolimus can be used in the treatment of patients with inoperable cardiac rhabdomyomas. (124)
  • STAT3 activity may be biomarker of everolimus induced dermatological toxicity. (125)
  • Everolimus administration after heart transplantation id associated with plaque regression. (126)
  • The addition of everolimus may have beneficial effects on bone turnover and progressive disease in bone in patients with metastatic breast cancer. (127)
  • Everolimus appears to be a new effective treatment for patients with metastatic insulinoma and refractory hypoglycemia. Tolerance should be carefully monitored. (128)
  • verolimus reduces angiomyolipoma volume with an acceptable safety profile. It could be a potential treatment for angiomyolipomas associated with tuberous sclerosis. (129)
 
Antiproliferative drugs (Cytotoxic immunosuppressants)
 
Azathioprine
 
  • It selectively affects differentiation and function of T cells and inhibits cytolytic lymphocytes
  • CMI is primarily depressed
  • Uses
  • Prevention of renal and other graft rejection
  • Lower doses (1-2 mg/kg/day) are used in progressive rheumatoid arthritis
  • Used in maintaining remission in inflammatory bowel disease
  • Azathioprine is used in dermatology on the basis of steroid saring effect when used together with corticoteroids. It is used for immunobullous disorders. (130)
  • Azathioprine can be used in the treatment of atopic dermatitis. (131)
  • Patients with moderate to severe Crohn's disease who are treated with infliximab plus azathioprine or infliximab monotherapy are more likely to have a corticosteroid free clinical remission than thise receiving azathioprine monotherapy. (132)
  • The administration of azathioprine within 6 months of diagnosis of crohn's disease is no more effective than conventional management in increasing time of clinical remission. (133)
  • Patients with moderate to severe ulcerative colitis treated with infliximib plus azathioprine is more likely to achieve corticosteroid free remission at 16 weeks than those receiving either monotherapy. Combination tehrapy led to significantly better mucosal healing than azathioprine monotherapy. (134)
  • Long term use of azathioprine in patients with air borne contact dermatitis can lead to severe drug induced side effects of gastrointestinal and hepatic origin. (135)
  • In recipients of cadaver kidney transplants given ciclosporin microemulsion, mycophenolate mofetil offers no advantages over azathioprine in preventing acute rejections and is about 15 times more expensive. Standard immunosuppression regimens for transplantation should perhaps include azathioprine rather than mycophenolate mofetil at least for kidney grafts. (136)
  • Azathioprine and 6-mercaptopurine are therapeutic options for patients with moderate to severe inflammatory Crohn's disease. Patients who do not respond to azathioprine therapy may benefit from the addition of biologic therapy or methotrexate. (137)
  • Lymphomatoid granulomatosis is associated with azathioprine therapy give to patients with Crohn's disease. (138)
  • Patients with steroid insensitive glomerulonephritis can be treated with azathioprine and prednisolone in sustained low dosages. Hypocomplementemia and hyperalpha2-globulinemia in the face of steroid unresponsiveness are considered to be indications for antimetabolite therapy. (139)
  • The mechanism of azathioprine toxicity to hepatocytes involves depletion of GSH leading to mitochondrial injury with profound depletion of ATP and cell death by necrosis. Cell death can be prevented by potent antioxidants, glycine and blocking the mitochondrial permeability transition pore. (140)
  • Prescribers should be aware that monitoring liver enzymes when initiating azathioprine may be warranted within the first week, especially if the patient is taking corticosteroids or other high risk medications that cause hepatotoxicity. (141)
  • < 1.0 mg/kg was effective as 1.0-2.0 mg/kg in maintaining remission among chinese patients with Crohn's disease. (142)
  • Azathioprine can induce sweet syndrome which may be underdiagnosed because it can be easily misinterpreted as inflammatory bowel disease associated skin eruption. Patients with inflammatory bowel disease may be at higher risk of this condition. Early recognition and drug withdrawal can decrease morbidity of the patients. (143)
  • Switching from azathioprine (AZA) to mycophenolate mofetil (MMF) is most often due to azathioprine failure whike switching from MMF to AZA is mostly due to side effects and pregnancy in lupus patients. When reason for switch is drug failure improvement in disease activity occurs and there is a reduction in steroids dose after 6 months. When reason for switching is other than drug failure, there is no deterioration in global disease activity. Switching for side effects usually results in elimination of the side effects. (144)
  • Azathioprine can be used in the treatment of autoimmune hemolytic anemia in children. (145)
  • Azathioprine is generally effective and well tolerated in patients with neuromyelitis optica (NMO). Early initiation, adequate dosing and hematologic parameter monitoring may optimize efficacy. (146)
  • When azathioprine is used in combination with corticosteroids, it is a safe and acceptable option for treating patients with active serpiginous choroiditisa. Side effects and recurrences while on AZA therapy can occur, requiring either replacement of the drug or addition of another immunosuppressive agent. (147)
  • Azathioprine can be a causative factor for inducing liver cirrhosis. Thus, treating inflammatory bowel disease effectively while trying to limit iatrogenic disease is a continuous struggle. (148)
  • Varicella can develop in children receiving azathioprine and steroids for immunosuppression after renal homotransplantation. (149)
  • Azathioprine and methotrexate are appropriate options for the treatment of severe atopic eczema. (150)
  • Liver plays a major role in the metabolism of azathioprine through the interaction of the drug with glutathione. (151)
  • Although increased risk of atrial or ventricular septal defects with azathioprine exposure, this should be weighed against possible consequences of dicontinuing azathioprine and possible disease relapse or transplant rejection during pregnancy. There is no evidence that AZA exposure is associated with congenital malformations, spontaneous abortions or stillbirth. (152) 
  • Azathioprine, infliximab, certolizumab, adalimumab are effective in maintaining remission in Crohn's disease. (153)
  • Cyclosporin A induces substantial impairment of fibrinolytic activity, which is recovered after conversion to azathioprine. The impaired fibrinolysis observed during Cyclosporin A treatment may be caused by modulation of eicosanoid production or metabolism in vascular endothelial cells and poosibly contributes to the high incidence of cardiovascular disease after kidney transplantation. (154)
  • Azathioprine can be of benefit in the treatment of recalcitrant pediatric atopic dermatitis. Repeat assessment of TPMT activity may be helpful for evaluation of non response or change in response. (155)
  • Azathioprine pulse therapy regimen produces prolonged remission in psoriasis. (156)
  • Azathioprine can be used in the treatment of refractory lymphocytic colitis. (157)
  • Multiple cutaneous neutropenic ulcers may develop in patients of pemphigus vulgaris treated with azathioprine. (158)
  • Azathioprine can induce nodular regenerative hyperplasia in inflammatory bowel disease patients. (159)
  • Azathioprine can induce severe cholestatic hepatitis in crohn's disease patient. (160)
  • Azathioprine can a possible alternative to corticosteroid in the treatment of chronic beryllium disease. (161)
  • Erythema nodosum can occue as a poosible azathioprine hypersensitivity reaction in a patient with bullous pemphigoid. (162)
  • Low dose corticosteroid and azathioprine are successful treatment of long term severe progressive interstitial pneumonia in a patient with diffuse systemic sclerosis. (163)
Methotrexate
 
  • It markedly depresses cytokine production and cellular immunity
  • Has anti-inflammatory property
  • Uses
  • Rapidly progressing rheumatoid arthritis
  • Severe psoriasis
  • Pemphigus
  • Myasthenia gravis
  • Uveitis
  • Chronic active hepatitis 
  • Side effects of high dose methotrexate may be life threatening. Bone marrow, gastrointestinal mucosa and hair are particularly vulnerable to effects of methotrexate. Because methotrexate concentration is inversely proportional to the renal clearance, renal toxiciy is frequent with high dose methotrexate. (164)
  • Rheumatoid arthritis and psoriatic arthritis patients on methotrxate should be closely monitored with Methotrexate intolerance severity score (MISS) for early detection of methotrexate intolerance in order to intervene timely and avoid discontinuation of an effective treatment. (165)
  • Low dose methotrexate is considered as a mainstay in the treatment of rheumatoid arthritis. There are severeal mechanism including inhibition of T cell proliferation via its effects on purine and pyrimidine metabolism, inhibition of transmethylation reactions required for the prevention of T cell cytotoxicity, interference with glutathione metabolism leading to alterations in recruitment of monocytes and other cells to the inflamed joint and promotion of the release of the endogenous anti-inflammatory mediator adenosine. (166)
  • Triple therapy with sulfasalazine and hydroxychloroquine added to methotrexate is noninferior to etanercept plus methotrexate in patients with rheumatoid arthritis who had active disease despite methotrexate therapy. (167)
  • The early administration of carboxypeptidase-G2 (CPDG2) in addition to leucovorin (LV) may be beneficial for patients with methotrexate induced renal dysfunction and significantly elevates the plasma methotrexate concentrations. (168)
  • Methotrexate is well tolerated in the medium and long term and is recommended to the patients with inflammatory arthritis. The incidence of life threatening side effects is 1.7% with one death (0.15%) directly due to methotrexate. (169)
  • Intralesional methotrexate is effective in the treatment of invasive squamous cell carcinoma in a patient taking vemurafenib for the treatment of metastatic melanoma. (170)
  • Low dose methotrexate appears to be safe in the treatment of rheumatoid arthritis in elderly patients. Routine determination of serum liver enzymes and renal function may reduce individual risk. (171)
  • Methotrexate given intramuscularly has improved clinical efficacy with fewer side efefcts than given orally. Intramuscular methotrexate administration should be considered when rheumatoid arthritis remains active in spite of high dose oral methotrexate. (172)
  • The nurotoxicity of methotrexate must be taken into account in evaluating the risks and benefits of the therapy for meningeal leukemia. (173)
  • Subacute methotrexate neurotoxicity may be mediated by adenosine and relieved by aminophylline. (174)
  • Large doses of methotrexate and folinic acid may be effective in the treatment of leukemia. (175)
  • Although methotrexate is most widely used medication for psoriatic arthritis, it has failed to show disease modifying effects. (176)
  • The combination of infliximab and methotrexate, although sfae, is no more effective than infliximab in patients with Crohn's disease receiving treatment with prednisone. (177)
  • Erroneous diagnosis of intrauterine pregnancies as ectopic with subsequent first trimester exposure to methotrexate may result in the birth of severely malformed babies or fetal demise. (178)
  • Hyaluronic acid-methotrexate conjugate can be used as a targeted therapy for rheumatoid arthritis. Owing to pH-sensitive nature of the conjugate, methotrexate is rapidly released inder the mildly acidic conditions, similar to the environment of inflamed synovial tissue in rheumatoid arthritis. (179)
  • Methotrexate can be used for the treatment of cutaneous dermatomyositis. (180)
  • Methotrexate may provide a substantial survival benefit largely by reducing cardiovascular mortality. This survival benefit of methotrexate would set a standard against which new disease modifying antirheumatic drugs could be compared. (181)
  • Acute pneumonitis is an uncommon but serious adverse effect of low dose methotrexate treatment for refractory rheumatoid arthritis. The initial presentation is non specific and a high index of suspicion is required as respiratory failure may develop rapidly. Management depends on exclusion of infection, withdrawal of methotrexate and high dose corticosteroid treatment. (182)
  • Methotrexate is a promising new agent for the treatment of inflammatory bowel disease. (183)
  • There is a interaction of dihydrofolate reductase with methotrexate. (184)
  • There is a time limited and reversible impact of methotrexate on oocyte yield. This may impact the management of ectopic gestation in the patient with a history of infertility or the timing of subsequent treatments. (185)
  • Methotrexate can induce cerebellar leukoencephalopathy in patients. (186)
  • Low dose methotrexate has a significant steroid sparing effect in steroid dependent asthmatic patients. The greatest effect is evident in patients in whom an effort was made to reduce baseline steroid dosage and in whom methotrexate is used for 24 weeks. (187)
  • The actual fetal exposure to methotrexate released from maternal organs is considered to be minimal, the outcomes of pregnancies conceived shortly after methotrexate therapy for extrauterine pregnancy are more likely to be favourable and similar to those conceived after 6 months. A recommendation of at least 3 month waiting perios for women whi are planning pregnancy seems to be prudent. (188)
  • Methotrexate decreases humoral response to pneumococcal vaccination and may impair response to influenza vaccination. (189)
  • Methotrexate therapy is effective in maintaining remission and reducing corticosteroid exposure in pediatric ulcerative colitis. (190)
  • Long term use of methotrexate is well tolerated and relatively safe after thiopurine therapy in patients with Crohn's disease. (191)
  • Methotrexate suppresses the immune system and may complicate the management of bisphosphonate related osteonecrosis of the jaw (BRONJ). (192)
  • During the treatment with methotrexate in rheumatoid arthritis, drug drug interactions play an important role in both the development of adverse drug reactions and therapeutic failure. (193)
  • Methotrexate is recommended for the treatment of sarcoidosis. (194)
  • Methotrexate hepatotoxicity is a common complication of long term treatment with methotrexate. It is associated with liver enzyme elevation and is related to duration of therapy. (195)
  • Transcatheter intraarterial methotrexate infusion combined with uterine artery embolization may be a feasible, effective and safe option for cervical pregnancy. (196)
  • Methotrexate therapy is a safe and effective alternative for the management of unruptured ectopic pregnancies with minimal or no side effects and associated advantage of avoiding invasive surgery. (197)
  • Devic's disease, which is characterized by attacks of optic neuritis and myelitis, can be treated with methotrexate and prednisone. (198) 
Cyclophosphamide
 
  • Cytotoxic drug which has more marked effect on B cells and humoral immunity compared to T cell and CMI
  • Uses
  • Bone marrow transplantation
  • Rheumatoid arthritis
  • Maintenance therapy in pemphigus
  • Systemic lupus erythematosus
  • Idiopathic thrombocytopenic purpura 
  • Sequential therapy of oral cyclophosphamide follwed by azathioprine or mycophenolate mofetil is comparable to iv cyclophosphamide regimens in the treatment of lupus glomerulonephritis. The efficacy may not be affected by race. (199)
  • Cyclophosphamide can be a very useful drug in the right setting with sufficient monitoring. There is increased evidence to support IV cyclophosphamide therapy is equally as effective as oral therapy and is associated with less toxicity in patients with systemic vasculitis. (200)
  • Cyclophosphamide treatment in patients with systemic sclerosis related interstitial lung disease does not result in clinically significant improvement of pulmonary function. (201)
  • Ibrutinib is well tolerated when added to R-CHOP (Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and could improve responses in patients with B cell non-Hodgkin lymphoma. (202)
  • Cyclophosphamide therapy causes suppression of B cell function at multiple points in the B cell cycle. This may be responsible for the efficacy of cyclophophamide therapy in certain antibody and immune complex mediated diseases. (203)
  • Paclitaxel is noninferior and less toxic in comparison to doxorubicin and cyclophosphamide as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes. (204)
  • Cyclophosphamide may be able to replace ifosfamide in consolidation treatment of standard risk Ewing Sarcoma. (205)
  • An extended course of pulse cyclophosphamide is more effective than 6 months of pulse methylprednisolone in preserving renal function in patients with severe lupus nephritis. Addition of a quaterly maintenance regimen to monthly pulse cyclophosphamide reduces the rate of exacerbations. (206)
  • High dose, posttransplantation cyclophosphamide (PTCy) is an effective strategy for preventing graft versus host disease (GVHD) after allogenic blood or marrow transplantation (alloBMT). Treg resistance to Cy through expression of aldehyde dehrogenase may contribute to the clinical activity of PTCy in preventing GVHD. (207)
  • Rituximab therapy is non inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA associated vasculitis and may be superior in relapsing disease. (208)
  • Mycophenolate mofetil (MMF) may offer advantage over intravenous cyclophophamide for the treatment of lupus nephritis. (209)
  • Cyclophophamide is increasingly used to treat various types of cancers and autoimmune conditions. Higher doses of this drug may produce significant cardiac toxicity including fatal hemorrhagic myocarditis. (210)
  • Pulse therapy with cyclophosphamide and methylprednisolone may be effective in preventing respiratory failure and reducing mortality in patients with moderate to severe paraquat poisoning. (211)
  • Metronomic cyclophosphamide could be proposed as a new therapeutic option to treat metastatic hepatic epitheloid hemangioendothelioma. (212)
  • Single doses of cyclophosphamide can regularly induce bladder damage in rats and dogs. Changes develop rapidly and within 24 hours, consist of ulceration of the mucosal epithelium, hemorrhage and edema in all bladder tissues and necrosis in smooth muscle and small arteries. The epithelium and submucosa of the renal pelvis are similarly affected. Renal tubular necrosis is seen in a minority of the affected animals. (213)
  • Genetic variability in cyclophosphamide metabolism independently impacts outcome from adjuvant chemotherapy for breast cancer. (214)
  • Low dose of cyclophosphamide can be used as a strategy against tuour progression after standard chemotherapy in patients with advanced epithelial ovarian cancer who are platinum resistant with poor performance status. (215)
  • Cyclophosphamide can limit proliferation without impairing intermitotic functions of sensitized lymhocytes, such as the release of MIF. It does not impair development of a population of specifically sensitized T type lymphocytes. (216)
  • Administration of high dose cyclophosphamide over several days in pediatric patients results in an increase in metabolism, possibly by induction of the activation pathway. This induction is effectively reversed following a four week period between cyclophosphamide doses. (217)
  • Cyclophosphamide alters the gene expression profile in patients treated with high doses prior to stem cell transplantation. (218)
  • Hematologic malignancy patients receiving personalized cyclophosphamide have significantly lower postconditioning peak total serum bilirubin, a 38% reduction in the hazard of acute kidney injury and similar nonrelapse and overall survival rates. (219)
  • Antioxidants, iNOS inhibitors, peroxynitrite scavengers, anti-inflammatory agents as well as HBO therapy may be added to mesna administration in order to improve quality of comfort in patients with cyclophosphamide and ifosfamide induced hemorrhagic cystitis. (220)
  • Almost all the patients of systemic lupus erythematosus have a good response after 3-4 cycles of dexamethasone-cyclophosphamide pulse therapy. Fever, malar rash and oral ulceration respond early but photosensitivity, discoid rash, alopecia and joint pains take some more time. (221)
  • Daily oral cyclophosphamide is associated with increased risk of both hemorrahgic cystitis and bladder cancer in a dose dependent and/or duration dependent manner. IV cyclophosphamide carries low risk of hemorrhagic cystitis and bladder cancer. Mesna is effective in the prevention of cystitis, but there is no evidence of effectiveness of mesna in prevention of bladder cancer in humans. (222)
  • Intravenous pulse cyclophosphamide may be an alternative treatment option in patients with pemphigus recalcitrant to standard therapy. (223)
  • Lupus psychosis can be effectively treated with oral cyclophosphamide followed by azathioprine maintenance. (224)
  • Dexamethasone cyclophosphamide pulse therapy causes prolonged remission of rheumatoid arthritis. (225)
  • Post transplantation cyclophophamide is used for tolerance induction in HLA Haploidentical bone marrow transplantation. (226)
  • Immunoablative high dose cyclophosphamide therapy can be used in the treatment of pemphigus vulgaris. (227)
  • Cyclophosphamide can be used in ocular inflammatory diseases. It is effective in most patients for controlling ocular inflammation and allowing tapering of systemic corticosteroids to 10 mg prednisone or less, although 1 year of therapy may be needed to achieve these goals. (228)
  • 3 Indian medicinal plants Asparagus racemosus, Withania somnifera and Tinospora cordfolia protects against cyclophosphamide induced neutropenia. (229)
  • Cyclophosphamide improves survival in cases of severe pulmonary alveolar hemorrhage due to leptospirosis. (230)
  • The combination of hyperbaric oxygen therapy and intravesical sodium hyaluronate instillation may be useful in severe hemorrhagic cystitis caused by cyclophosphamide. (231)
  • Cyclophosphamide and prednisone can be used in the treatment of castration-resistant prostate cancer. (232)
  • Corticosteroid and cyclophosphamide pulse therapy can be used in the treatment of exacerbations of idiopathic pulmonary fibrosis. (233)
  • Cyclophosphamide can be used in the treatment of patients of multiple sclerosis (MS) not controlled by beta-interferon or glatiramer acetate as well as those with rapidly worsening MS. Outpatient IV pulse therapy is given with or without corticosteroids every 4 to 8 weeks. (234)
Mycophenolate mofetil (MMF)
 
  • It selectively inhibits inosine monophosphate dehydrogenase, enzyme essential for de novo synthesis of guanosine nucleotides in the T and B cells
  • Lymphocyte proliferation, antibody production and CMI are inhibited
  • MMF is rapidly absorbed orally and quickly converted  to the active metabolite mycophenolic acid
  • This is then slowly inactivated by glucuronidation with a t ½ of 16 hours
  • The glucuronide is excreted in urine
  • Adverse effects
  • Vomiting, diarrhea
  • Leucopenia
  • Predisposition to CMV infection
  • Gi bleeds
  • It is add on drug to cyclosporine + glucocorticoid in renal transplantation 
  • MMF is a prodrug of mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase (IMPDH). It can induce apoptosis of activated T lymphocytes which may eliminate clones of cells responding to antigenic stimulation. It suppresses glycosylation and the expression of some adhesion molecules, thereby decreasing the recruitment of lymphocytes and monocytes into the sites of inflammation and graft rejection. It depletes tetrahydrobiopterin, a cofactor for the inducible form of nitric oxide synthase (iNOS). It suppresses the production by iNOS of NO and consequent tissue damage mediated by peroxynitrite. (235)
  • MMF may offer advantages over intravenous cyclophsphamide for the treatment of lupus nephritis. (236)
  • MMF should be considered as an effective and well tolerated alternative to cyclophosphamide for remission induction in non life threatening MPO-ANCA (myeloperoxidase-anti neutrophill cytoplasmic antibodies) positive microscopic polyangiitis with mild to moderate renal involvement. (237)
  • MMF is more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis and has a more favorable safety profile. (238)
  • Enetric coated mycophenolate sodium (EC-MPS) can be used as an alternative immunosuppresive agent in kidney transplant recipients with efficacy and safety profile similar to MMF. (239) 
  • Mycophenolate is associated with reduction in relapse frequency and stable or reduced disability in patients with Neuromyelitis Optica spectrum disorders. (240)
  • Mycophenolate mofetil can be used in the treatment of pemphigus vulgaris. (241)
  • MMF can be effective in the treatment of hepatopulmonary syndrome due to inhibition of angiogenesis and nitric oxide (NO) production. (242)
  • Mycophenolate mofetil is effective in the management of treatment resistant asthma. (243)
  • Mycophenolate mofetil can be used as an adjuvant in the treatment of pemphigus vulgaris. (244)
  • Mycophenolate mofetil and hydroxychloroquine are effective treatment for recalcitrant cutaneous lupus erythematosus. (245)
  • Mycophenolate mofetil is effective in the treatment of neuropsychiatric systemic lupus erythematosus. (246)
  • Mycophenolate mofetil is a safe and promising immunosuppressant in neuromusclar diseases. (247)
  • MMF appears to be safe and effective alternative immunosuppressant for extra renal and renal disease in SLE not responding to conventional immunosuppressant treatment. (248)
  • The use of MMF apparently increases the incidence of cytomegalovirus disease in renal transplant patients. (249)
  • MMF is a potentially teratogenic drug. The most consistent characteristics of MMF embryopathy include cleft lip and palate, microtia and aural atresia and ocular anomalies (hypertelorism, arching eyebrows). (250)
  • Mycophenolate mofetil induces caspase- dependent apoptosis and cell cycle inhibition in multiple myeloma cells. It attenuates G1-S phase cycle progression and activates the pathway of mitochondrial dysfunction, leading to cytochrome c release followed by activation of caspases. (251)
  • Mycophenolate mofetil is effective in the treatment of scleroderma associated interstitial lung disease. (252)
  • MMF may enhance the negative effects of tacrolimus on kidney function and may even display nephrotoxic properties when combined with sirolimus. (253)
  • Addition of mycophenolate mofetil to tacrolimus is associated with decreases in food specific IgE levels in a pediatric patient with liver transplantation associated food allergy. (254)
  • MMF can be considered as an alternative for the treatment of inflammatory bowel disease. (255)
  • MMF appears to be efficacious and safe as maintenance treatment for proliferative lupus nephritis. (256)
  • MMF can be used in the treatment of variety of inflammatory skin conditions like in psoriasis, autoimmune blistering disorders, dermatitides and connective tissue disorders. (257)
  • Drug interaction is seen between intravenous ciprofloxacin and mycophenolate mofetil in bone marrow transplant recipients. Ciprofloxacin should be used with caution in patients receiving mycophenolate mofetil. If this antiinfective must be used, therapeutic drug monitoring should be performed to guide dosage adjustments. (258)
  • Mycophenolate mofetil may represent a promising treatment for inducing and maintaining remission in inflammatory bowel disease patients intolerant to thiopurines. It may be of more value and relevance in ulcerative colitis. (259)
  • Mycophenolate mofetil has produced excellent results in patients with chronic relapsing erythema nodosum leprosum reaction where long use of systemic steroid produce complications or are contraindicated. (260)
  • Fetal mycophenolate mofetil syndrome includes arched eyebrows, hypertelorism, epicanthic folds, micrognathia, thick everted lower lip, cleft palate, bilateral microtia with aural atresia and brachydactyly. (261) 
  • Mycophenolate mofetil may have a protective role against Pneumocystis carinii pneumonia in renal transplant patients. (262)
 
Glucocorticoids
 
  • Have potent immunosuppressant and anti-inflammatory action
  • It inhibit MHC expression and activation/ proliferation of T lymphocytes
  • Expression of several IL and other cytokine genes is regulated by corticosteroids and production of adhesion molecules is depressed
  • They have marked effect on CMI and little effect on humoral immunity
  • Uses
  • Used as companion drug to cyclosporine or other immunosuppressants in various organ transplants
  • Large dose of steroids are given iv for short periods in graft rejection
  • Used in severe autoimmune diseases, especially during exacerbation 
  • Glucocorticoids are most widely used and effective treatments to control inflammatory and autoimmune diseases. Their clinical efficacy is compromised by the metabolic effects of long term treatment which include osteoporosis, hypertension, dyslipidemia and insulin resistance/ type 2 diabetes mellitus. (263)
  • Glucocorticoids have a therapeutic use in rheumatic disorders, renal diseases, thrombocytopenia, organ transplantation, Grave's ophthalmopathy. It has an important role in immune disorders, including reduction of immune response in autoimmune diseases and organ transplantation. (264)
  • The number of patientstaking immunosuppressive drugs for the management of autoimmune inflammatory conditions is increasing. Monitoring is required because immunosuppressive drugs increase the risks of infectiomn, malignancy, cardiovascular disease and bone marrow suppression. Vigilance is needed as adverse effects may have atypical clinical presentations. (265)
  • Glucocorticoids are the most widely used anti-inflammatory and immunomodulatory agents, whose mechanism of action is based mainly on interference with the activity of transcription factors such as nuclear factor kB (NF-kB) and activator protein-1 (AP-1). (266)
  • In patients with type 1 diabetes, the islet transplantation can result in insulin independence with excellent metabolic control when glucocorticoid free immunosuppression is combined with the infusion of an adequate islet mass. (267)
  • Glucorticoids have remained an important component of induction, maintenance and rejection regimens in heart transplant recipients. (268)
  • Immunosuppressants that affect cytokine synthesis (glucocorticoids, cyclosporin-CsA, tacrolimus-FK506 and Sirolimus-RAPA) interfere in bone metabolism and may influence tooth movement. Interference in bone metabolism is dependent on the force applied, dose and duration of immunosuppressant therapy, in addition to the individual response to each patient, except to azathioprine and Mycophenolate mofetil that have shown no deleterious effect on bone density. (269)
  • Despite limited evidence for the effectiveness of corticosteroids and immunosuppresive agents in systemic sclerosis, these potentially harmful drugs are frequently prescribed to patients with all forms of systemic sclerosis. (270)
  • Corticosteroids measurably affect both lymphocyte cell numbers and function in infants with infantile hemangioma. Prophylaxis with the combination of trimethoprim and sulfamethoxazole should be considered in infants treated with corticosteroids for infantile hemangioma. Tetanus and diphtheria antibodies should be checked in patients who receive oral corticosteroids during the immunization period and that additional immunization be administered if the titers are not protective after corticosteroid therapy. (271)
  • Pentoxyfylline have a steroid sparing effects and contribute to improved clinical outcomes from immunosuppressive treatment of renal diseases. It potentiates in vitro lymphocyte suppression by glucorticoids and immunosuppressive drugs. (272)
  • Rifampicin does not have glucocorticoids like immunosuppressive properties. (273)
  • Defalazacort is a synthetic glucorticoid that has few adverse effects on glucose and calcium metabolism and fewer deleterious effects on the neuronal population. It plays a crucial role in the treatemnt of patients with autoiimune disorders associated with central nervous system or metabolic affectations. It increases the risk of acquiring opportunistic infection compared with other synthetic glucocorticoids. (274)
  • Methylprednisolone and betamethasone are very potent, dexamethasone, hydrocortisone and prednisolone are of intermediate potency and aldosterone, prednisone and the metabolites of hydrocortisone are of low immunosuppresive potency. (275)
  • Glucocorticoid medication in adult renal transplant patients is associated in a dose dependent manner with increased cystatin C, leading to systematic underestimation of GFR. (276)
  • Rapid immunosuppressive effects of glucocorticoids is through inhibition of Lck and Fyn kinases mediated via glucocorticoid receptor dependent pathway. (277)
  • There is a increased risk of bladder cancer from systemic use of gucocorticoids and a potential role if immune surveillance in bladder cancer aetiology. (278)
  • Mild to moderate psoriasis can be controlled with topical corticosteroid therapy. Topical therapy should be administered with adjunctive therapy in severe and extended psoriasis. (279)
  • Immunosuppression by glucorticoid is mediated through inhibition of NF-kB activity through induction of IkB synthesis. (280)
  • All patients with Wegener's granulomatosis should be given chemoprophylaxis against P carinii while they are receiving daily glucocorticoids. (281)
  • Both tacrolimus + MMF and Tacrolimus + MMF + Pred could provide effective immunosuppression in allogenic islet transplantation. The combined glucocorticoid free immunosuppressive strategy of low dose tacrolimus and MMF could protect islet grafts in islet transplantation with diabetogenic side effects. (282)
  • A substance(s) can be extracted from the serum of AIDS patients that attenuates the inhibitory effect of cortisol on thymocyte proliferation and interferes with the binding of cortisol to the glucocorticoid receptor. (283)
  • Patient with polymyositis and interstitial lung disease responds well to corticosteroids and methotrexate. (284)
  • Endogenous glucocorticoids are required for a robust adaptive immune response because of their promotion of the selection of T cells that have sufficient affinity for self and the absence of thymocyte glucocorticoid signalling results in an immunocompromised state. (285)
  • Standard therapy for granulomatosis with polyangiitis and other asculitides is a combination of cyclophosphamide and glucocorticoids. Although most patients achieve remission, relapses and treatment related morbidities are common. (286)
  • Systemic corticosteroids play an integral rle in the management of many inflammatroy and immunologic conditions. Osteoporosis, adrenal suppression, hyperglycemia, dysplipidemia, cardiovascular disease, Cushing's syndrome, psychiatric disturbances and immunosuppression are serious side effects noted with systemic corticosteroid therapy particularly when used at high doses for prolonged periods. (287)
  • Septic shock is characterized by uncontrolled systemic inflammation that contributes to the progression of organ failures and eventually death. With sepsis, via nongenomic and genomic effects, corticosteroids restore cardiovascular homeostasis, terminate systemic and tissue inflammation, restore organ function and prevent death. (288)
  • Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. (289)
Biological agents
 
TNF α inhibitors
 
Etanercept
 
  • It neutralizes both TNF α and TNF β. It prevents activation of macrophages and T cells during immune reaction
  • Uses
  • In combination of methotrexate in treatment of rheumatoid arthritis
  • Severe/ refractory ankylosing spondylitis
  • Polyarticular idiopathic juvenile arthritis
  • Plaque psoriasis 
  • Etanercept is significantly better than methotrexate in slowing the rate of radiographic erosions in patients with rheumatoid arthritis. In patients with severe psoriatic arthritis, etanercept is effective in reducing disease activity. (290)
  • The anti-TNFα agent etanercept is well tolerated, safe and effective in elderly patients of rheumatoid arthritis. (291)
  • Conventional or reduced doses of etanercept withg methotrexate in patients with moderately active rheumatoid arthritis more effectively maintain low disease activity than does methotrexate alone after withdrawal of etanercept. (292)
  • The treatment of psoriasis with etanercept led to a significant reduction in the severity of disease over a period of 24 weeks. (293)
  • Etanercept monotherapy ameliorates disease activity in glucocorticoid naive patients withg polymyalgia rheumatica. However, the effect is modest, indicating a minor role of TNFα in polymyalgia rheumatica. (294)
  • Perispinal administration of etanercept could provide sustained improvement in cognitive function for Alzheimer's patients. (295)
  • Rapid and sustained improvement in chronic post stroke neurological and cognitive dysfuntion following perispinal administration of etanercept. (296)
  • etanercept therapy is effective in the treatment of toxic epidermal necrolysis. (297)
  • Ocular hypertension triggers an inflammatory response characterized by the appearance of activated microglia around optic nerve head that express TNF-α. Etanercept inhibits this microglial response and prevents axonal degenration and loss of retinal ganglion cells. (298)
  • Fatal sepsis in a patient with rheumatoid arthritis can be treated with etanercept. (299)
  • Etanercept can be used in the treatment of latent autoimmune diabetes of adults (LADA), which is a subtype of type 1 diabetes mellitus. (300)
  • Etanercept can be used in the treatment of juvenile idiopathic arthritis. (301)
  • In patients with nonradiographic axial spondyloarthritis, etanercept treatment is associated with rapid, significant improvement in symptomatic disease activity, function and systemic and skeletal inflammation over 12 weeks; clinical/ functional improvement is sustained over 24 weeks. (302)
  • Treatment with etanercept for 3 months is safe and well tolerated in patients with advanced heart failure. It results in a significant dose-dependent improvement in LV structure and function and a trend toward improvement in patients functional status. (303)
  • Infliximab, etanercept and adalimumab can be effective in the treatment of ankylosing spondylitis. (304)
  • Etanercept is effective as a therapeutic agent for subacute lung injury after allogenic stem cell transplantation. (305)
  • Etanercept is able to maintain cell viability of osteochondral allografts significantly better than the current storage paradigm after 28 days of storage. (306)
  • Although both infliximab and etanercept shows powerful TNFα neutralization, only infliximab is able to bind to peripheral blood lymphocytes and lamina propria T cells and subsequently induce apoptosis of activated lymphocytes in patients with Crohn's disease. (307)
  • Etanercept may suppress the clinical signs of Grave's ophthalmopathy. (308)
  • Etanercept given for 24 weeks as adjuvant therapy to interferon and ribavarin significantly improves virologic response at the end of the etanercept randomization period among patients with hepatitis C virus (HCV) and is associated with decreased incidence of most adverse effects associated with interferon and ribavarin. (309)
  • Aseptic meningitis is a rare complication in a patients taking etanercept for rheumatoid arthritis. (310)
  • Lymphopenia can occur in a patient taking etanercept. (311)
  • Infertility improves by etanercept in a patients with ankylosing spondylitis. (312)
  • Ocular inflammation is a potential adverse event following the use of etanercept both in previously uninvolved eyes and in previously inflamed eyes subjected to rechallenge. Careful surveillance of patients on etanercept is warranted to determine the true risk and associated factors related to their occurence. (313)
  • Dose reductions of etanercept is cost effective in treating patients with rheumatoid arthritis when remission is achieved. (314)
  • Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signalling, not immediate response TNF genes. (315)
  • Etanercept does have some antiangiogenic and anti-inflammatory effects in treatment of corneal neovascularization. The combination of bevacizumab and etanercept may be promising approach in the treatment of corneal neovascularization. (316)
  • Etanercept appears to be safe, effective and well tolerated in children with Kawasaki disease. (317)
  • Etanercept levels in breast milk are extremely low, providing reassurance to rheumatlogists who are tempted to encourage high risk patients of rheumatoid arthritis to start or reinitiate etanercept while breast feeding. (318)
  • Leukopenia and thrombocytopenia can be induced by etanercept. (319)
  • At 24 weeks, a single course of rituximab and etanercept provides a significant and clinically meaningful improvements in disease activity in patients with active, longstanding rheumatoid arthritis who had an inadequate response to 1 or more nonbiologic DMARDS. (320)
  • Patients with rheumatoid arthritis, psoriatic arthritis and seronegative inflammatory arthritis who are treated with etanercept may develop venous thromboembolism. Clinicians must keep this in mind during therapy with antitumor necrosis factor agents in order to prevent, detect and treat potential conequences such as deep vein thrombosis and pulmonary embolism. (321)
  • Etanercept is slowly absorbed and slowly eliminated after subcutaneous administration. DOsing at the recommended rate of 25 mg twice weekly would be expected to result in concentrations of approximately 3 mg/l. Intersubject variability for apparent clearance in healthy volunteers is 64%. (322)
  • Both clinical remission and radiographic non-progression are acheivable goals in patients with early rheumatoid arthritis within 1 year of combined treatment with etanercept plus methotrexate. (323)
  • Progressive autoimmune inner ear disease (AIED) may respond well to TNFα inhibition (etanercept), whilst more diffcult cases could benefit from combining such therapy with methotrexate. (324)
  • etanercept is effective in the treatment of isiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation. (325)
  • Articular listerosis may develop in a patient with rheumatoid arthritis receiving treatment with etanercept. (326)
  • Etanercept is most effective in suppressing Candida albicans water soluble fractions CAWS-induced vasculitis and can be a new therapeutic intervention for Kawasaki disease. (327)
  • Patients with amyloidosis secondary to rheumatoid arthritis with renal and intestinal involvement, responds well to treatment with etanercept. (328)
  • Etanercept has a better retention rate than adalimumab and infliximab as first line biotherapy in rheumatoid arthritis, and than adalimumab as second line biotherapy. (329)
  • Besides a rapid suppression of disease activity, serum sCAM and VEGF concentrations are downregulated following anti-tumor necrosis factor alpha therapy (etanercept) combined with methotrexate. Prolonged treatment wit etanercept sustained or even more remarkably diminished the sCAM and VEGF serum concentrations in patients with rheumatoid arthritis. (330)
Infliximab
 
  • Monoclonal antibody against TNFα which binds and inactivates TNFα
  • Used by sc injection 4-8 weeks along with methotrexate
  • Uses
  • Refractory rheumatoid arthritis
  • Fistulating crohn’s disease
  • Ulcerative colitis
  • Psoriasis
  • Ankylosing spondylitis 
  • Patients with moderate to severe Crohn's disease who are treated with infliximab plus azathioprine or infliximab monotherapy are more likely to have a corticosteroid free clinical remission than those receiving azathioprine monotherapy. (331)
  • Patients with moderately to severely active ulcerative colitis treated with infliximab are less likely to undergo colectomy. (332)
  • Pediatric patients with crohn's disease responding to an induction regimen of infliximab are more likely to be in clinical response and remission at week 54 without dose adjustment when their maintenance theraoy was given every 8 weeks rather than every 12 weeks. Allowing for dose intensification in the case of relapse, remission rates but not response rates at week 54 were superior with every 8 week dosing compared with every 12 week dosing. (333)
  • Infliximab induces complete mucosal healing and reduces the rates of hospitalisation and surgery in patients with Crohn's disease. Based on disease related risk factors, a treatment algorithm for infliximab is dilineated in favor of a rapid step up approach in patients at high risk for a disabling course of disease. (334)
  • The addition of infliximab to primary treatment in acute Kawasaki disease does not reduce treatment resistance. It is safe and well tolerated and reduces fever duration, some markers of inflammation, left anterior descending coronary artery Z score and intravenous immunoglobulin reaction rates. (335)
  • Infliximab is approved for induction and maintenance of remission of pediatric ulcerative colitis. It provides expansion of available treatment options, may eliminate the need for corticosteroids and can delay colectomy. (336)
  • Dose escalation optimizes the durability of infliximab in psoriatic patients. The probabaility of maintaining response is enhanced by concomitant methotrexate and increasing the infusion frequency before increasing the dose. (337)
  • Infliximab is safe and effective in the treatment of patients with rheumatoid arthritis. Infections, principally tuberculosis are increased in treated patients and the risk is greater at higher dose. Patients treated with infliximab should be closely monitored. (338)
  • The administration of infliximab for the treatment of several disease like rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and Crohn's disease can induce autoantibodies and subsequent onset of systemic lupus erythematosus (SLE). (339) 
  • Infliximab is effective as a thrid line therapeutic for severe sarcoidosis. The majority of patients that discontinued infliximab therapy relapsed. Thus close monitoring of the patients is recommended when they discontinue infliximab treatment. (340)
  • Infliximab reduces the cytokine mediated inflammation but does not suppress cellular infilteration of the vessel wall in refractory Kawasaki disease. (341)
  • Postoperative therapy with infliximab prevents long term Crohn's disease recurrence. (342)
  • Infliximab is effective in the treatment of Crohn's disease and Type 1 diabetes mellitus. (343)
  • Immunogenecity to infliximab and adalimumab may be associated with both acute anaphylactoid reactions and delayed hypersensitivity reactions. Reactions may be precipitated by newly induced specific anti-drug antibodies rather than by cross reactivity of previously generated antibodies. (344)
  • In severe alcoholic hepatitis, single dose infliximab is associated with improvement in parameters of severity and survival. (345)
  • Infliximab infusion results in rapid resolution of episcleritis in patient with Crohn disease, psoriasis and enteropathic arthropathy. (346)
  • The combination treatment with mycophenolate mofetil and infliximab is a promising therapeutic approach for neurosarcoidosis. (347)
  • Infliximab intensification is necessary for long term maintenance of remission and to prevent colectomy in patients with refractory ulcerative colitis. (348)
  • The High concentrations of infliximab duing treatment initiation reduce the development of antibodies toward infliximab (ATI), and the absence of ATI may be associated with prolonged maintenance of infliximab. Thus trough serum infliximab concentration should be monitored early in patients wit rheumatic diseases. (349)
  • Infliximab is used in the treatment of rheumatoid arthritis and Crohn's disease. It can cause serious hematologic events in some patients like leukopenia, neutropenia, thrombocytopenia and pancytopenia. (350)
  • Infliximab adds minial potential benefit to corticosteroids for pulmonary sarcoidosis at doses above 15-20 mg/day of prednisone. (351)
  • Infliximab, etanercept and adalimumab can be used for the treatment of ankylosing spondylitis. (352)
  • Infliximab is found to be alternative treatment with a relatively acceptable toxicity profile in established rheumatoid arthritis, despite that patient may develop pulmonary tuberculosis. (353)
  • Infliximab has been recommended for the treatment of moderate to severe plaque psoriasis in adults who have failed to respond to methotrexate, cyclosporine, acitretin or ultraviolet radiation or who cannot tolerate them. (354)
  • Adding infliximab to gemcitabine to treat cachexia in advanced pancreatic cancer patients is not associated with statistically significant safety or efficacy. (355)
  • Through week 50, the respinse is best maintained with continuous infliximab therapy in comparison to intermittent inflixima maintenance regimen in the treatment of moderate to severe plaque psoriasis. Infliximab is generally well tolerated in most patients. (356)
  • Local injection of infliximab into the patients with Crohn's disease recurrence is feasible and safe, requiring a low dose. (357)
  • Infliximab reduces the frequency of ocular attacks and improves visual acuity in patients with Behcet's disease related uveitis and is generally well tolerated with few serious adverse events. (358)
  • Infliximab induced psoriasis developed in a patient treated for Crohn's disease associated ankylosing spondylitis. (359)
  • Chronic ulcerative colitis patients treated with infliximab before total proctocolectomy and ileal pouch anal anastamosis (IPAA) have substantially increased the odds of postoperative pouch related and infectious complications. (360)
  • Anti-neutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) is associated with endothelial dysfunction. Infliximab alone or in combination with standard treatment results in clinical remission, reduced inflammation and improved endothelium dependent vasomotor responses. (361)
  • Disseminated nocardiosis developed in a patient on infliximab and methylprednisolone for treatment resistant Sweet's syndrome. (362)
  • Higher dose infliximab (10 mg/kg) in combination with methotrexate appears to be more effective than the standard 3 mg/kg dose in the treatment of rheumatoid arthritis, particularly for patients with severe disease activity. (363)

 

Adalimumab
  • Fully human recombinant anti TNFα
  • Used in autoimmune diseases
  • Adalimumab can be used in a number of arthritic disease states including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis. It has a rapid onset of action, sustained efficacy with long term treatment and is well tolerated. (364)
  • Tocilizumab monotherapy was superior to adalimumab monotherapy for reduction of signs and symptoms of rheumatoid arthritis in patients for whom methotrexate is deemed inappropriate. (365)
  • Patients with ankylosing spondylitis or psoriatic arthritis previously treated with infliximab and/or etanercept experiences clinically relevant improvements of their disease after 12 weeks of adalimumab. (366)
  • Adalimumab is safe and effective in long term in patients with rheumatoid arthritis. (367)
  • Adalimumab is approved by the US FDA for the treatment of moderate to severe rheumatoid arthritis. (368)
  • Adalimumab is safe in long term in the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn's disease. (369)
  • Adalimumab induces and maintains clinical remission of children with Crohn's disease, with a safety profile comparable to that of adult patients with Crohn's disease. (370)
  • Adalimumab is effective in the treatment of rheumatoid arthritis in monotherapy and when associated with DMARD, but the evidence for combined use is more robust. (371)
  • Adalimumab can induce mononeuritis multiplex in patients with refractory rheumatoid arthritis. (372)
  • Adalimumab is effective in the treatment of cutaneous sarcoidosis. (373)
  • Factor XI deficiency may develop in patients using long term adalimumab leading to increased risk of bleeding. (374)
  • Myelodysplastic syndrome can be successfully treated with adalimumab. (375)
  • Adalimumab acts by TNFα inhibition and may have clinical advantage compared with infliximab. (376)
  • There is no significant difference between infliximab and adalimumab in the treatment of Crohn's disease (CD) across 3 primary outcome measures: persistence on therapy without surgery or use of steroids, hospitalization because of CD or need fr surgery. (377)
  • In patients with ankylosing spondylitis, a significant reduction in the number of anterior uveitis attacks, as well as in the number of attacks per patient is observed during adalimumab treatment. (378)
  • Thoracic myelopathy due to hypertrophic pachymeningitis may develop in patients secondary to adalimumab therapy. (379)
  • Severe hidradenitis suppurativa can be treated with adalimumab therapy. (380)
  • Interstitial granulomatous drug reaction may occue due to adalimumab. (381)
  • Decreased clinical response to adalimumab in ankylosing spondylitis is associated with antibody formation. (382)
  • Transaminase elevation is seen secondary to the use of adalimumab. (383)
  • Patients who had a suboptimal response to etanercept, methotrexate or narrow band ultraviolet B (NB-UVB) phototherapy, there is a clinically relevant response to adalimumab therapy. (384) 
  • There is a better efficacy of adlimumab when used as first anti TNFα treatment in childhood chronic uveitis. (385)
  • Adalimumab is an effective and safe treatment for patients with rheumatoid arthritis. (386)
  • Macrophage activation syndrome may occue following initiation of adalimumab in a patient with adult onset still's disease. (387)
  • Tocilizumab monotherapy is superior to adlimumab monotherapy for reduction of signs and symptoms of rheumatoid arthritis in patients for whom methotrexate is deemed inappropriate. (388)
  • Adalimumab is used for the treatment of moderate to severe hidradenitis suppurativa. (389)
  • Among patients with active rheumatoid arthritis who had not had adequate response to methotrexate, addition of adalimumab acheived statistically significant, long term improvement. (390)
  • Subacute thyroiditis in a psoriatic patient can be treated with adalimumab. (391)
  • Adalimumab is effective in the treatment of pediatric uveitis. (392)
  • Both infliximab and adalimumab seems to be effective and safe in long term outpatient treatment of Crohn's disease. (393)
  • Severe neuropathy and tetraparesis can be induced by adalimumab. (394)
  • isceral leishmaniasis may develop in a patient taking adalimumab for rheumatoid arthritis. (395)
  • Drug induced liver injury can occur in a patient taking adalimumab. (396)
  • Adalimumab improves health related quality of life in patients with moderate to severe plaque psoriasis. (397)
  • Adalimumab is not associated with complement dependent cytotoxicity (CDC) reactions and the death of human cells from healthy volunteers or rheumatoid arthritis patients nor human cell lines. (398)
  • Adalimumab is effective in the treatment of immune mediated diseases like rheumatoid arthritis (RA), psoriatic arthritis (PsA), plaque psoriasis, inflammatory bowel disease (Crohn's disease, ulcerative colitis, pediatric Crohn's disease and intestinal Behcet's disease), ankylosing spondylitis (AS), axial spondyloarthritis (SpA) and juvenile idiopathic arthritis. (399)
  • Hypersensitivity reaction may develop during treatment with infliximab, etanercept and adalimumab. (400)
  • Adalimumab is a potent therapeutic option for psoriatic arthritis patients with chronic renal failure on hemodialysis. (401)
  • Pulmonary tuberculosis is associated with the use of adalimumab. (402)
  • Adalimumab is used in the management of palmoplantar psoriasis. (403)
  • Adalimumab induces clinical remission in refractory and long standing systemic juvenile idiopathic arthritis. (404)
  • Adalimumab is safe and effective in re-inducing clinical remission after post-surgcal relapse of Crohn's disease. (405)
  • Etanercept, infliximab and adalimumab are effective in the treatment of psoriatic arthritis. (406)

 

IL-1 receptor antagonist
 
Anakinra
 
  • Recombinant human IL-1 receptor antagonist prevents IL-1 binding to its receptor
  • Used in treatment of rheumatoid arthritis
  • Anakinra may be efficient in gouty arthritis, is relatively well tolerated with short term use and could be a relevant option in managing gouty arthritis when conventional therapies are ineffective or contraindicated. Its long term use could be limited by infectious complications. (407)
  • Anakinra is effective in the treatment of corticosteroid resistant autoimmune inner ear disease. (408)
  • Chronic infantile neurologial cutaneous articular (CINCA) syndrome, also known as neonatal onset multisystem inflammatory disease, is a rare congenital inflammatory disease characterised by cardinal signs including a variable congenital maculopapular urticarial rash, chronic non inflammatory arthropathy with abnormal cartilage proliferation and chronic meningitis with progressive neurological impairment associated with polymorphonuclear and occasionally eosinophilic infiltration. The CINCA syndrome is associated with childhood uveitis and papillitis with chronic disc swelling. Anakinra is successfully used in the treatment of a patient with refractory CINCA- associated uveitis. (409)
  • Anakinra is an effective drug for treating rheumatoid arthritis. It is less effective than adalimumab, etanercept and infliximab. It also seems to be associated with comparably high rates of injection site reactions. (410)
  • Anakinra can be used for the management of resistant idiopathic recurrent pericarditis. (411)
  • CRP level changes during anakinra treatment in systemic onset juvenile idiopathic arthritis (SJIA) patients. A prospective dosage adjustment is proposed based on a -.4 mg/L in order to obtain a CRP decrease to 10 mg/L or below. (412)
  • Schnitzler syndrome is a rare disorder that mimics chronic idiopathic urticaria. Anakinra is effective in the treatment of urticaria of Schnitzler syndrome. (413)
  • Anakinra is efficacious and well tolerated by most patients with rheumatoid arthritis. (414)
  • Anakinra is safe, well tolerated in patients with Familial Mediterranean fever in whom colchicine treatment is not successful or leads to side effects. The most common side effect is local skin reaction at the injection site. (415)
  • In patients with idiopathic refractory pericarditis (IRP) refractory to initial treatment, anakinra should be considered as a potential therapy. (416)
  • Anakinra (Interleukin-1 Receptor Antagonist) has positive effects on function and quality of life in patients with rheumatoid arthritis. (417)
  • Systemic inflammation is often present in patients with heart failure (HF). Anakinra improves cardiopulmonary exercise testing (CPX) performance in patients with heart failure reduced ejection fraction (HFrEF) as well as in patients with heart failure preserved ejection fraction (HFpEF). (418)
  • Anakinra is effective in the treatment of moderate to severe hidradenitis suppurativa. (419)
  • The administration of anakinra within 24 hours of acute myocardial infarction significantly ameliorates the remodelling process by inhibiting cardiomyocyte apoptosis in 2 different experimental animal models of acute myocardial infarction. (420)
  • The combination therapy of Abatacept and Anakinra is effective in children with refractory systemic juvenile idiopathic arthritis. (421)
  • High dose anakinra is effective in a case of medically refractory macrophage activation syndrome. (422)
  • An abnormal lipopolysaccharide (LPS) induced inflammatory cytokines production is seen in Schnitzler syndrome (SS), which can be decreased or even normalized by in vitro and in vivo anakinra. (423)
  • Anakinra protects cultured human islets from IL-1β- mediated β-cell dysfunction and apoptosis. IL-1 receptor blockers may provide a new approach to enhance islet survival and function during pretransplant culture therby increase the success rate of islet transplantation. (424)
  • The 
IL-2 receptor antagonist
 
Daclizumab
 
  • Highly humanized chimeric monoclonal anti CD-25 antibody which binds to and acts as IL-2 receptor antagonist
  • Used in Renal and other transplant rejection reaction, also used in combination regimen for maintenance of graft. 
  • Daclizumab high yield process is safe and effective in the treatment of relapsing-remitting multiple sclerosis. (425)
  • Daclizumab is effective in the treatment of moderately to severely active ulcerative colitis. (426)
  • Daclizumab induced monocyte mediated trogocytosis of CD25 from T cells appears to be an additional mechanism contributing to daclizumab inhibition of IL-2 signalling. (427)
  • Subcutaneous daclizumab high yield process administered every 4 weeks leads to clinically important effects on multiple sclerosis disease activity during 1 year of treatment. It has a potential as an additional treatment option for relapsing-remitting disease. (428)
  • Daclizumab is effective in the treatment of acute graft versus host disease. (429)
  • Daclizumab inhibits disease activity in multiple sclerosis patients failing to respond to interferon β. (430)
  • The 
Basiliximab
• Another anti CD-25 antibody with higher affinity for IL-2 receptor
• Shorter plasma t ½ of 1 week
• Uses
o Renal and other transplant rejection reaction
o Used in maintenance regimen for maintenance of graft
 
Anti-CD3 antibody
Muromonab CD3
• Murine monoclonal antibody against CD3 glycoprotein expressed near to the T cell receptor on helper T cell
• Uses
o Acute transplant rejection reaction, particularly in steroid resistant cases
o Used to deplete T cells from the donor bone marrow before transplantation
• Adverse effects
o Initial doses are associated with cytokine release syndrome with flu like symptoms: chills, rigor, fever, wheezing, malaise etc
o Aseptic meningitis
o Intragraft thrombosis
o Life threatening pulmonary edema
o Seizure
o Shock like states
 
Polyclonal antibodies
Antithymocyte globulin (ATG)
• Polyclonal antibody purified from horse or rabbit immunized with human thymic lymphocytes which contains antibodies against many CD antigens as well as HLA antigens
• It binds with T lymphocytes and depletes them
• Uses
o Acute allograft rejection episodes, especially in steroid resistant cases  
o Also used in induction regimens
• Adverse effects
o Serum sickness
o Anaphylaxis
 
Anti-D immune globulin
• It is human IgG having a high titer of antibodies against Rh (D) antigen
• It is used for prevention of post partum/ post abortion formation ofantibodies in Rho-D negative, DU negative women who have delivered or aborted an Rho-D positive DU positive baby/ fetus
• Higher doses (1000-2000 mcg) are needed for Rh negative recipients of inadvertently administered Rh positive blood
 
 
 
 
 
 
 
Immunosuppression in organ transplantation
1. Induction regimen
• It is given in the peri-operative period: starting just before the transplant to about 2-12 weeks after it
• Most common regimen are:
o Cyclosporine/tacrolimus/sirolimus + prednisolone + MMF/azathioprine
o Sirolimus + prednisolone + MMF combination
• If no rejection develops, the doses are gradually reduced after 2 weeks and this phase merges imperceptibly with maintenance phase
 
2. Maintenance regimen
• Given over long period, usually life long
• Triple drug regimen include any of the following:
o Cyclosporine/ tacrolimus, sirolimus, prednisolone, azathioprine/MMF
• Nephrotoxicity occurs with cyclosporine/ tacrolimus
• 2 drug and 1 drug regimen are used but are associated with more episodes of acute rejection
• Second line drugs used are:
o Cyclophosphamide, Chlorambucil, daclizumab
 
3. Anti rejection regimen
• This is given to suppress the episode of acute rejection
• Steroid pulse therapy (methylprednisolone 0.5-1 g iv daily for 3-5 days)
• In case of no response, muromonab CD3/ ATG is given as rescue therapy ot the antibodies are combined with steroids
 
Adverse effects
• Increased risk of bacterial, fungal, viral (especially CMV) as well as opportunistic infections
• Development of lymphomas and related malignancies after a long latency.
 
References:
 
  1. A Laupacis, PA Keown, RA Ulan, N McKenzie, CR Stiller. Cyclosporin A: a powerful immunosuppressanr. Can Med Assoc J. May 1982;126(9):1041-1046. 
  2. Christophe Plot. Plerre Crolslle, Patrick Staat, Helene Thibault, Gilles Rloufol et al. Effect of cyclosporine on reperfusion inhury in acute myocardial infarction. N Engl J Med. 2008;359:473-481. 
  3. BJ Morgan, T Lyson,U Scherrer, RG Victor. Cyclosporine causes sympathetically mediated elevations in arterial pressure in rats. Hypertension. 1991;18:458-466. 
  4. Minoru Hojo, Takashi Morimoto, Mary Maluccio, Tomohiko Asano et al. Cyclosporine induces cancer progression by a cell autonomous mechanism. Nature. Feb 1999;397:530-534. 
  5. Seth M Hollander, Shirley S Joo, H James Wedner. Factors that predict the success of cyclosporine treatment for chronic urticaria. Annals of allergy, Asthma & Immunology. Dec 2011;107(6):523-528. 
  6. Karrie T Amor, Caitriona Ryan, Alan Menter. The use of cyclosporine in dermatology: Part I. Journal of teh American Academy of Dermatology. Dec 2010;63(6):925-946. 
  7. Brian G Feagan, John WD McDonald. Cyclosporin in Crohn's disease. The Lancet. May 1997;349(9061):1328. 
  8. Eric Donnenfeld, Stephen C Pflugfelder. Topical Ophthalmic Cyclosporine: pharmacology and clinical uses. Survey of Ophthalmology. May-June 2009;54(3):321-338. 
  9. Hugh Zachariae. Long term use of cyclosporine in dermatology. Arch Dermatol. 1996;132(6):692-694. 
  10. GK Singh, Manas Chatterjee, Rajesh Verma. Cyclosporine in Stevens Johnson syndrome and toxic epidermal necrolysis and retrospective comparison with systemic corticosteroids. Indian Journal of dermatology, venereology and leprology. 2013;79(5):686-692. 
  11. Fiona Fernandes, Israr-ul H Ansari, Rob Striker. Cyclosporine inhibits a direct interaction between cyclophilins and hepatitis C NS5A. PLOS One. March 23, 2010. DOI: 10.1371/journal.pone.0009815. 
  12. EL York, T Kovithavongs, SF Man, AS Rebuck, BJ Sproule. Cyclosporine and chronic sarcoidosis. Chest 1990;98(4):1026-1029. 
  13. HL Verrill, RE Girgis, RE Easterling, BS Malhi et al. Distribution of cyclosporine in blood of a renal transplant recipient with type V hyperlipoproteinemia. Clinical Chemistry. March 1987;33(3):423-428.
  14. N Perico, M Rossini, O Imberti, B Malanchini, RP Cornejo, et al. Thromboxane receptor blockade attenuates chronic cyclosporine nephrotoxicity and improves survival in rats with renal isografts. JASN. March 1992;2(9):1398-1404. 
  15. Rod Quilitz. Cyclosporine monitoring in allogenic bone marrow transplantation. J Oncol Pharm Pract. March 1996;2(1):27-32. 
  16. TE Bunchman, CA Brookshire. Cyclosporine induced synthesis of endothelin by cultured human endothelial cells. J Clin Invest. 1991;88(1):310-314. 
  17. Yoshihiro Watanabe, Hirotaka Motoi, Yoshitaka Oyama, Kazushi Ichikawa et al. Cyclosporine for acute encephalopathy with biphasic seizures and late reduced diffusion. Pediatrics International. May 2014. doi: 10.1111/ped.12288. 
  18. RB Schwartz, SM Bravo, RA Klufas, L Hsu et al. Cyclosporine neurotoxicty and its relationship to hypertensive encephalopathy: CT and MR findings in 16 cases. American Journal of Roentgenology. 1995;165:627-631. 
  19. Nikhil S Gokhale, Rohini Samant, Vishnu Sharma. Oral cyclosporine therapy for refractory severe vernal keratoconjunctivitis. Indian Journal of Ophthalmology. 2012;60(3):220-223. 
  20. Jim V Beattie, Paul J Petruska. Cyclosporine modulation in poor risk acute myeloid leukemia. Blood. July 2002;100(1). 
  21. Ajay Israni, Susan Brozena, Oleh Pankewycz, Robert Grossman, Roy Bloom. Conversion to tacrolimus for the treatment of cyclosporine associated nephrotoxicty in heart transplant recipients. American Journal of Kidney Diseases. March 2002;39(3):e16.1-e16.5. 
  22. JF Yale, RD Roy, M Grose, TA Seemayer, GF Murphy, EB Marliss. Effects of cyclosporine on glucose tolerance in the rat. Diabetes. Dec 1985;34(12):1309-1313. 
  23. Pascale Boissonnat, Segolene Gaillard, Catherine Mercier, Michel Redonnet et al. Impact of the early reduction of cyclosporine on renal function in heart transplant patients: a French randomised controlled trial. Trials 2012;13:231. 
  24. Kelvin Ho-Nam Wan, Li Jia Chen, Shi Song Rong, Chi Pui Pang, Alvin L Young. Topical cyclosporine in the treatment of allergic conjunctivitis. Ophthalmology. Nov 2013;120(11):2197-2203. 
  25. George D Kymionis, Dimitrios I Bouzoukis, Vassilios F Diakonis, Charalambos Siganos. Treatment of chronic dry eye: focus on cyclosporine. Clinical Ophthalmology. August 2008;2(4):829-836.  
  26. CG Loftus, EV Loftus Jr, WJ Sandborn. Cyclosporin for refractory ulcerative colitis. Gut 2003;52:172-73. 
  27. Fernando Alvarez, Mirta Ciocca, Cristina Canero-Velasco, Margarita Ramonet, Maria TG de Davila et al. Short term cyclosporine induces a remission of autoimmune hepatitis in children. Journal of Hepatology. Feb 1999;30(2):222-227. 
  28. Alexander S Farivar, Brendan C Mackinnon-Patterson, Andrew D Barnes, Anton S McCourtie, Michael S Mulligan. Cyclosporine modulates the response to hypoxia-reoxygenation in pulmonary artery endothelial cells. The Annala of Thoracic Surgery. March 2005;79(3):1010-1016. 
  29. MW Krause, A Schaffner. COmparison of immunosuppressive effects of cyclosporin A in a murine model of systemic candidiasis and of localized thrushlike lesions. Infect Immun. Nov 1989;57(11):3472-3478. 
  30. Dennis A Hesselink, Teun van Gelder. The influence of cyclosporine on mycophenolic acid plasma concentrations: a review. Transplantation Reviews. July 2003;17(3):158-163. 
  31. Ching Hwa Gau, Hsiao Pei Tu, Yu Tang Chin, Rebecca YA Chen et al. Can chlorhexidene mouthwash twice daily ameliorate cyclosporine induced gingival overgrowth? Journal of the Formosan Medical Association. March 2013;112(3):131-137. 
  32. Maryam Mohsenikia, Babak Hajipour, Mohammad Hossein Somi, Ali Khodadadi, Mehran Noori. Prophylactic effect of vitamin C on cyclosporine A induced liver toxicity. Thrita. Sept 2012;1(1):24-6. 
  33. Seydi Okumus, Erol Coskun, Mehmet Gurkan Tatar, Erdal Kaydu et al. Cyclosporine A 0.05% eye drops for the treatment of subepithelial infiltrates after epidemic keratoconjunctivitis. BMC Ophthalmology 2012;12:42. 
  34. Paolo Fioretto, Behzad Najafian, Michael Mauer. Tacrolimus and cyclosporine nephrotoxicity in native kidneys of pancreas transplant recipients. Clin J Am Soc Nephrol. Jan 2011;6(1):101-106. 
  35. Parmjeet S Randhawa, Thomas E Starzl, Anthony Jake Demetris. Tacrolimus (FK506) associated renal pathology. Adv Anat Pathol. Jul 1997;4(4):265-276. 
  36. P Dalal, G SHah, D Chhabra et al. Role of tacrolimus combination therapy with mycophenolate mofetil in the prevention of organ rejection in kidney transplant patients. International Journal of Nephrology and Renovascular disease. August 2010;3:107-115. 
  37. Hans Christian Schuppe, Bernhard Homey, Till Assmann, Roya Martens, Thomas Ruzicka. Topical tacrolimus for pyoderma gangrenosum. The Lancet. March 1998;351(9105):832. 
  38. Staffan Rosenborg, Annica Nordstrom, Tora Almquist, Lars Wennberg, Peter Barany. Systemic conversion to generic tacrolimus in stable kidney transplant recipients. Clin Kidney J. 2014;7(2):151-155. 
  39. Bernhard K Kramer, Frank Schweda. DIffering proteinuria control with cyclosporin and tacrolimus. The Lancet. March 1997;349(9056):953-954. 
  40. European FK506 Multicentre Liver Study Group. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rajection. The Lancet. August 1994;344(8920):423-428. 
  41. Ewout J Hoorn, Stephen B Walsh, James A McCormick et al. The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension. Nature Medicine. 2011;17:1304-1309. 
  42. The US Multicenter FK506 Liver Study Group. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. N Engl J Med. 1994;331:1110-1115. 
  43. Timothy Yoon, Brian M Kelly, Joseph Hornyak. Use of propanolol for treating tacrolimus induced tremors: A case report. Archives of physical medicine and rehabilitation. Sept 2007;88(9):E19. 
  44. Lisa B Travis, Jeffrey M Weinberg, Nanette B Silverberg. Successful treatment of vitiligo with 0.1% tacrolimus ointment. Arch Dermatol. 2003;139(5):571-574. 
  45. PMK Tam, AL Young, PTH Lam. Topical tacrlimus 0.03% monotherapy for vernal keratoconjunctivitis- case series. Br J Ophthalmol. 2010;94:1405-1406. 
  46. Kazumitsu Sugiura, Kana Tanahashi, Yoshinao Muro, Masashi Akiyama. Cutaneous lupus mucinosis successfully treated with systemic corticosteroid and systemic tacrolimus combination therapy. Journal of the American Academy of Dermatology. October 2013;69(4):e200-e202. 
  47. Manuel Rodriguez-Peralvarez, Giacomo Germani, Vasilios Papastergiou, Emmanuel Tsochatzis et al. Early tacrolimus exposure after liver transplantation: Relationship with moderate/ severe acute rejection and long term outcome. Journal of Hepatology. Feb 2013;58(2):262-270. 
  48. Yervand Eduard Karapetyan, Gian Franco Sferrazza, Minghai Zhou, Gregory Ottenberg et al. Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents. Proceedings of National Academy of Sciences of the United States of America. March 2013;110(17):7044-7049. 
  49. A Nomura, H Shimizu, M Kishimoto, Y Suyama et al. Efficacy and safety of multitarget therapy with mizoribine and tacrolimus for systemic lupus erythematosus with or without active nephritis. Lupus. Nov 2012;21(131):1444-1449. 
  50. Bo-Ra Kim, Ho-Sik Shin, Yeon-Soon Jung, Hark Rim. A case of tacrolimus induced supraventricular arrhythmia after kideny transplantation. Sao Paulo Med J. 2013;131(3). 
  51. Sukesh MS, Dandale A, Dhurat R et al. Case Report: SOlitary mastocytoma treated successfully with topical tacrolimus. F1000Research 2014;3:181. doi: 10.12688/f1000research.3253.1.  
  52. Kate Bramham, Gary Chusney, Janet Lee, Liz Lightstone, Catherine Nelson-Piercy. Breastfeeding and tacrolimus: serial monitoring in breast fed and bottle fed infants. CJASN. Jan 2013. DOI: 10.2215/CJN.06400612. 
  53. Naoko Uetsu, Hiroyuki Okamoto, Keiko Fujii, Risa Doi, Takeshi Horio. Journal of the American Academy of Dermatology. Dec 2002;47(6):881-884. 
  54. Arin S Jantz, Samir J Patel, Wadi N Suki et al. Treatment of acute tacrolimus toxicity with phenytoin in solid organ transplant recipients. Case Reports in Transplantation. 2013, Article ID 375263, 6 pages. 
  55. Nitin D Chaudhari, Hemant V Talaniker, Sanjeev Gupta et al. Topical tacrolimus: a boon to dermatology. Int J Pharm Biomed Sci. 2012;3(4):188-192. 
  56. Jonathan Landy, Mahmood Wahed, Simon TC Peake, Mohammed Hussein et al. Oral tacrolimus as maintenance therapy for refractory ulcerative colitis- an analysis of outcomes in two London tertiary centres. Journal of Crohn's and Colitis. Dec 2013;7(11):e516-e521. 
  57. Sarah M Rikkers, Gary N Holland, Gail E Drayton, Franz K Michel et al. Topical tacrolimus treatment of atpopic eyelid disease. AMerican Journal of Ophthalmology. March 2003;135(3):297-302. 
  58. Jung Yoon Choe, Ki Yeun Park, Sung Hoon Park, Sang Il Lee, Seong Kyu Kim. Regulatory effect of calcineurin inhibitor, tacrolimus, on IL-6/sIL-6R-mediated RANKL expression through JAK2-STAT3-SOCS3 signalling pathway in fibroblast like synoviocytes. Arthritis Research & Therapy. 2013;15:R26. 
  59. Willaim J Sandborn, Daniel H Present, Kim L Isaacs et al. Tacrolimus for the treatment of fistulas in patients with crohn's disease: a randomized, placebo controlled trial. Gastroenterology. Aug 2003;125(2):380-388. 
  60. Janneke Schuuring, Pieter Wesseling, Aad Verrips. Severe Tacrolimus Leukoencephalopathy after liver transplantation. AJNR 2003;24:2085-2088. 
  61. Ryuichi Nishimura, Sho Nishioka, Ikuma Fujisawa et al. Tacrolimus inhibits the revascularization of isolated pancreatic islets. PLOSone. April 2013. DOI: 10.1371/journal.pone.0056799. 
  62. Hayato Yamazaki, Toshihiro Nanki, Masayoshi Harigai. Successful treatment of refractory takayasu arteritis with tacrolimus. The Journal of Rheumatology. 2014;39(7):1487-1488. 
  63. Carmen Cantisani, Emanuele Miraglia, Antonio G Richetta et al. Generalized morphea successfully treated with tacrolimus 0.1% ointment. Journal of drugs in dermatology. Jan 2013;12(1). 
  64. Yong Chul Kim, Tae Woo Lee, Hajeong Lee, Ho Suk Koo et al. Complete remission induced by tacrolimus and low dose prednisolone in adult minimal change nephrotic syndrome: a pilot study. Kidney Research and Clinical Practice. June 2012;31(2):112-117. 
  65. Stephen J Tomlanovich, Flavio Vincenti. SIrolimus: Defining nephrotoxicity in the renal transplant recipient. CJASN. March 2007;2(2):198-199. 
  66. Sylvle Euvrard, Emmanuel Morelon, Llonel Rostalng et al. Sirolimus and secondary skin cancer prevention in kidney transplantation. N Engl J Med. 2012;367:329-339.
  67. Thomas Pilgrim, Dik Heg, Marco Roffi, David Tuller et al. Ultrathin strut biodegradable polymer sirolimus eluting stent versus durable polymer everolimus eluting stent for percutaneous coronary revacularisation (BIOSCIENCE): a randomised, single blind, non-inferiority trial. The Lancet. Sept 2014. doi: 10.1016/S0140-6736(14)61038-2. 
  68. Alexandre Abizaid. SIrolimus eluting coronary stents: a review. Vasc Health Risk Manag. Apr 2007;3(2):191-201. 
  69. Li Jiuan Shen, Fe Lin Lin Wu. Nanomedicines in renal transplant rejection- focus on sirolimus. Int J Nanomedicine. Mar 2007;2(1):25-32. 
  70. Hemant Chatrath, Larissa Allen, Thomas D Boyer. Use of sirolimus in the treatment of refractory autoimmune hepatitis. The American Journal of Medicine. June 2014. doi: 10.1016/j.amjmed.2014.06.016
  71. Ahmed Abouelnasr, Jean Roy, Sandra Cohen, Thomas Kiss, Silvy Lachance. Defining the role of sirolimus in the management of graft versus host disease: From prophylaxis to treatment. Biology of Blood and Marrow Transplant. Jan 2013;19(1):12-21. 
  72. Camille Hua, Ouidad Zehou, Stphane Ducassou et al. Sirolimus improves pain in NF1 patients with severe plexiform neurofibromas. Pediatrics. June 2014;133(6):e1792-e1797. 
  73. Marc Vorpahl, Jason R Foerst. Impact of sirolimus eluting stent fracture on 4 year clinical outcomes. Circulation: Cardiovascular Interventions. 2011;4:e54. 
  74. E Karvouni, S Korovesis, DG Katritsis. Very late thrombosis after implantation of sirolimus eluting stent. Heart 2005;91:e45. doi: 10.1136/hrt.3004.056341. 
  75. David Shitrit, Ruth Rahaminov, Sahar Gidon et al. Use of sirolimus and low dose calcineurin inhibitor in lung transplant recipients with renal impairment: Results of a controlled pilot study. Kidney International. 2005;67:1471-1475. 
  76. Matthias Braun, James Young, Cacilla S Reiner, Diane Poster et al. Low dose oral sirolimus and the risk of menstrual cycle disturbances and ovarian cysts: Analysis of th randomized controlled SUISSE ADPKD trial. PLOSone. Oct 2012. doi: 10.1371/journal.pone.0045868. 
  77. Angelique M Poot, Marcel F Jonkman. Topical sirolimus for oral pemphigus vulgaris: 3 unresponsive cases. Journal of the American Academy of Dermatology. Nov 2012;67(5):e228-e229. 
  78. AF Javier, Z Bata-Csorgo, CN Ellis, S Kang, JJ Voorhees, KD Cooper. Rapamycin (sirolimus) inhibits proliferating cell nuclear antigen expression and blocks cell cycle in the G1 phase in human keratinocyte stem cells. J Clin Invest. 1997;99(9):2094-2099. 
  79. Harish Seethamraju, Thomas S Kaleekal, Remzi Bag. Pulmonary toxicity of sirolimus in lung transplant patients. Chest 2003;124(4_MeetingAbstracts):101S. 
  80. Adil S Akthar, Daniel W Golden, Rita Nanda et al. Early and severe radiation esophagitis associated with concurrent sirolimus. Journal of Clinical Oncology. 2014;32. doi: 10.1200/JCO.2013.50.1643. 
  81. Christian Morath, Wolfgang Arns, Vedat Schwenger et al. Sirolimus in renal transplantation. Nephrol. Dial Transplant. 2007;22(suppl 8):viii61-viii65.
  82. A Zuckermann, H Eisen, S See Tai, H Li et al. Sirolimus conversion after heart transplant: Risk factors for acute rejection and predictors of renal function response. American Journal of Transplantation. Sept 2014;14(9):2048-2054. 
  83. Christopher JE Watson, J Andrew Bradley. Sirolimus and everolimus: inhibitors of mammalian target of rapamycin in liver transplantation. Transplantation Reviews. April 2006;20(2):104-114. 
  84. Joel D Morrisett, Ghada Abdel Fattah, Ron Hoogeveen et al. Effects of sirolimus on plasma lipids, lipoprotein levels and fatty acid metabolism in renal transplant patients. The Journal of Lipid Research. AUg 2002;43:1170-1180. 
  85. Bhushan Madke. Topical rapamycin (sirolimus) for facial angiofibromas. Indian dermatology online journal. 2013;4(1):54-57. 
  86. RN Bankar, S Kumar, A Kohnke. Sirolimus induced interstitial pneumonitis. Journal of postgraduate medicine. 2006;52(4):329. 
  87. Eric M Tichy, Andrew J Medwid, Elizabeth A Mills et al. Significant sirolimus and dronedarone interaction in a kidney transplant recipient. Ann Pharmacother. July 2010;44(7-8):1338-1341. 
  88. Alvaro Casanova, Rosa Maria Giron, Orlando Acosta et al. Lymphangioleiomyomatosis treatment with sirolimus. Arch Bronconeumol. 2011;47(9):470-2. 
  89. T Mukherjee, BV Shah. Sirolimus: a new immunosuppressant. JAPI. Oct 2005;53. 
  90. Toshio Imanishi, Katsunobu Kobayashi, Shintaro Kuki et al. Sirolimus accelerates senescence of endothelial progenitor cells through telomerase inactivation. Atherosclerosis. Dec 2006;189(2):288-296. 
  91. Omar Massoud, Russell H Wiesner. The use of sirolimus should be restricted in liver transplantation. Journal of Hepatology. Jan 2012;56(1):288-290. 
  92. Tae-HyunYang, Doo-II Kim, Han-Young Jin et al. "Angiographic late catch-up" phenomenon after sirolimus-eluting stent implantation. International Journal of Cardiology. Sept 2012;160(1):48-52. 
  93. Mor-Li Hartman, John Matthew Esposito, Beow Yong Yeap, David John Sugerbaker. Combined treatment with cisplatin and sirolimus to enhance cell death in human mesothelioma. The Journal of Thoracic and Cardiovascular Surgery. May 2010;139(5):1233-1240. 
  94. GS Bhattacharvva, J Biswas, JK Singh, M SIngh, K Govindbabu. Reversal of tamoxifen resistance (Hormone resistance) by addition of sirolimus (mTOR inhibitor) in metastatic breast cancer. European Journal of Cancer. Sept 2011;47(2):9. 
  95. Maria T Izquierdo, Luis Almenar, Luis Martinez-Dolz, Jose A Moro. Hemolytic Uremic syndrome due to sirolimus in a heart transplant recipient. Case Report. Rev Esp Cardiol. 2007;60:85-6. 
  96. Rosario Pinto-Leite, Pedro Botelho, Eufemia Ribeiro et al. Effect of sirolimus on urinary bladder cancer T24 cell line. Journal of Experimental & Clinical Cancer Research 2009;28:3. 
  97. Pilar Barrera, Sami O Simons, Bart Luijk, Marion JC Wessels, Yvonne F Heijdra. Efficacy of sirolimus therapy for chylous effusions in lymphangioleiomyomatosis. Annals of the American Thoracic Society. 2013;10(4):408-409. 
  98. Vikas Y Sacher, Debra Fertel, Karan Srivastava, Anthony Panos et al. Effects of prophylactic use of sirolimus on bronchiolitis obliterans syndrome development in lung transplant recipients. The Annals of Thoracic Surgery. Jan 2014;97(1):268-274. 
  99. Francesca Bergamo, Marco Maruzzo, Umberto Basso, Maria Cristina Montesco et al. Neoadjuvant sirolimus for a large hepatic perivascular epitheloid cell tumor (PEComa). World Journal of Surgical Oncology. 2014;12:46. 
  100. Suleiman Massarweh, Jessica Croley, Heidi Weis. Everolimus in HR positive advanced breast cancer. N Engl J Med 2012;366:1738-1740. 
  101. Jose Baselga, Marlo Campone, Martine Piccart, Howard A Burris et al. Everolimus in postmenopausal hormone receptor positive advanced breast cancer. N Engl J Med 2012;366:520-529. 
  102. Denise A Yardley, Shinzaburo Noguchi, Kathleen I Pritchard, Howard A Burris III et al. Everolimus plus exemestane in post menopausal patients with HR+ Breast cancer: BOLERO-2 final progression free survival analysis. Advances in Therapy. Oct 2013;30(10):870-884. 
  103. Atsushi Ohtsu, Jaffer A Ajani, Yu-Xian Bai, Yung-Jue Bang et al. Everolimus for previously treated advanced gastric cancer: Results of the randomized, double-blind, phase III GRANITE-1 study. Journal of clinical oncology. Sept 16, 2013. doi: 10.1200/JCO.2012.48.3552. 
  104. Richard S Finn, Ronnie TP Poon, Thomas Yau, Heinz-Josef Klumpen et al. Phase I study investigating everolimus combined with sorafenib in patients with advanced hepatocellular carcinoma. Journal of Hepatology. Dec 2013;59(6):1271-1277. 
  105. Jasmeet Chadha Singh, Yelena Novik, Stacey Stein, Matthew Volm, Marlene Meyers et al. Phase 2 trial of everolimus and carboplatin combination in patients with triple negative metastatic breast cancer. Breast Cancer Research. 2014;16:R32. 
  106. Julio Pascual. The use of everolimus in renal transplant patients. International Journal of Nephrology and Renovascular Disease. June 2009;2:9-21. 
  107. Meaghan Wall, Gretchen Poortinga, Kym L Stanley, Ralph K Lindemann et al. The mTORC1 inhibitor everolimus prevents and treats Eµ-Myc lymphoma by restoring oncogene induced senescence. Cancer Discovery. Jan 2013;3:82. 
  108. Junichiro Sageshima, Gaetano Ciancio, Linda Chen, Takehiko Dohi, Ashraf Ei-Hinnawi et al. Everolimus with low dose tacrolimus in simultaneous pancreas and kidney transplantation. Clinical Transplantation. July 2014;28(7):797-801. 
  109. Parichart Junpaparp, Bhavna Sharma, Ambiga Samiappan, Ji Hyun Rhee, K Randall. Everolimus induced severe pulmonary toxicity with diffuse alveolar hemorrhage. Annals of the American Thoracic Society. 2013;10(6):727-729. 
  110. Reuben J Brrom, Victoria Hinder, Katrina Sharples, Janie Proctor et al. Everolimus and zoledronic acid in patients with renal cell carcinoma with bone metastases: A randomized first line phase II trial. Clinical genitourinary cancer. July 2014. doi: 10.1016/jclgc.2014.07.002.  
  111. Thomas Powles, Shah-Jalal Foreshew, Jonathan Shamash et al. A phase Ib stusy investigating the combination of everolimus and dovitinib in vascular endothelial growth factor refractory clear cell renal cancer. European Journal of Cancer. Aug 2014;50(12):2057-2064. 
  112. Robert Wesolowski, Mahmoud Abdel Rasoul, Maryam Lustberg, Maria Paskell et al. Treatment related mortality with everolimus in cancer patients. The Oncologist. May 2014. doi: 10.1634/theoncologist.2013-0355. 
  113. Steven Hsu, Eugen Koren, Yen Chan, Mima Koscec et al. Effects of everolimus on macrophage derived foam cell behaviour. Cardiovascular revascularization Medicne. July-August 2014;15(5):269-277.  
  114. Katharine Rosing, Manfred Fobker, Frank Kannenberg, Stefan Gunai et al. Everolimus therapy is associated with reduced lipoprotein-associated phospholipase A2 (Lp-Pla2) activity and oxidative stress in heart transplant recipients. Atherosclerosis. Sept 2013;230(1):164-170. 
  115. Somasundaram Subramaniam, Jason A Zell, Pamela L Kunz. Everolimus causing severe hypertriglyceridemia and acute pancreatitis. J Natl Compr Canc Netw. 2013;11:5-9. 
  116. Amy Chen, Li Chen, Abeer Al-Qaisi, Edward Romond et al. Everolimus induced hematologic changes in patients with metastatic breast cancer. August 2014. doi: 10.1016/j.clbc.2014.07.002. 
  117. Sophie J van Asselt, Sjoukje F Oosting, Adrienne H Brouwers, Alfons HH Bongaert et al. Everolimus reduced 89Zr-Bevacizumab tumor uptake in patients with neuroendocrine tumours. J Nucl Med. July 2014. doi: 10.2967/jnumed.113.129056. 
  118. Constantine Gennatas, Vasiliki Michalaki, Paraskevi Vasilatou Kairi et al. Successful treatment with the mTOR inhibitor everolimus in a patient with perivascular epitheloid cell tumor. World Journal of Surgical Oncology. 2012;10:181. 
  119. Kimberly Kamp, Brenda Gumz, Richard A Feelders et al. Safety and efficacy of everolimus in gastrointestinal and pancreatic neuroendocrine tumors after 177Lu-octreotate. Endocr Relat Cancer. December 2013;20:825-831. 
  120. Matthew G Fury, Nancy Y Lee, Eric Sherman, Alan L Ho et al. A phase 1 study of everolimus + weekly cisplatin + intensity modulated radiation therapy in head and neck cancer. International Journal of radiation oncology, biology, physics. Nov 2013;87(3):479-486. 
  121. Jan Peveling-Oberhag, Stefan Zeuzem, Wei Peng Yong, Tiffany Kunz et al. Effects of hepatic impairment on the pharmacokinetics of everolimus: A single dose, opne label, parallel group study. Clinical Therapeutics. March 2013;35(3):215-225. 
  122. Carlos Bujalance-Cabrera, Jose Manuel Vaquero-Barrios, Javier Redel-Montero et al. Reduction in size of renal angiomyolipoma after treatment with everolimus in lung transplantation due to lymphangioleiomyomatosis. Arch Bronconeumol. 2012;48:479-81. 
  123. Gisela Schieren, Edwin Bolke, Axel Scherer, Andreas Raffel et al. Severe everolimus induced steatohepatis: a case report. European Journal of Medical Research. 2013;18:22. 
  124. Haci Ahmet Demir, Filiz Ekici, Arzu Yazal Erdem, Suna Emir, Bahattin Tunc. Everolimus: a challanging drug in the treatment of multifocal inoperable cardiac rhabdomyoma. Pediatrics. July 2012;130(1):e243-e247. 
  125. Kazuhiro Yamamoto, Atsushi Uda, Akira Mukai et al. everolimus induced human keratinocyte toxicity is mediated by STAT3 inhibition. Journal of Experimental & Clinical cancer research. 2013;32:83. 
  126. Daisaku Nakatani, Jun-ichi Kotani, Koichi Tachibana, Yasuhiro Ichibori et al. Plaque regression associated with everolimus administration after heart transplantation. Journal of cardiology cases. June 2013;7(6):e155-e157. 
  127. Peyman Hadji, Robert Coleman, Michael Gnant. Bone effects of mammalian target of rapamycin (mTOR) inhibition with everolimus. Critical reviews in oncology/hematology. August 2013;87(2):101-111. 
  128. Valerie Bernard, Catherine Lombard-Bohas, Marie-Caroline Taquet et al. Efficacy of everolimus in patients with metastatic insulinoma and refractory hypoglycemia. Eur J Endocrinol. May 2013;168:665-674. 
  129. John J Bissler, J Christopher Kingswood, Elzbieta Radzikowska, Bernard A Zonnenberg, Michael Frost et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double blind, placebo controlled trial. The Lancet. Jan 11, 2013. doi: 10.1016/S0140-6736(12)61767-X. 
  130. A Anstey. Azathioprine in dermatology: a review in the light of advances in understanding methylation pharmacogenetics. J R Soc Med. Mar 1995;88(3):155P-160P. 
  131. Schram ME, Borgonjen RJ, Bik CM, van der Schroeff JG, van Everdingen JJ et a;. Off label use of azathioprine in dermatology: a systematic review. Arch Dermatol. Apr 2011;147(4):474-88. 
  132. Jean Frederic Colombel, William J Sandborn, Walter Reinisch et al. Infliximab, azathioprine or combination therapy for Crohn's disease. N Engl J Med. 2010;362:1383-1395. 
  133. Jacques Cosnes, Anne Bourrier, David Laharie, Stephane Nahon et al. Early administration of azathioprine vs conventional management of Crohn's disease: A randomized controlled trial. Gastroenterology. Oct 2013;145(4):758-765. 
  134. Remo Panaccione, Subrata Ghosh, Stephen Middleton, Juan R Marquez et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. Feb 2014;146(2):392-400. 
  135. Kaushal K, Y Manchanda. Long term safety and toxicity of azathioprine in patients with air borne contact dermatitis. IJDVL. 2001;67(2):75-77. 
  136. Giuseppe Remuzzi, Mariadomenica Lesti, Eliana Gotti, Maria Ganeva et al. Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial. The Lancet. August 2004;364(9433):503-512. 
  137. Barrett G Levesque, Edward V Loftus. Initiating azathioprine for Crohn's disease. May 2012;10(5):460-465. 
  138. William Connors, Cameron Griffiths, Jay Patel, Paul J Belletrutti. Lymphomatoid granulomatosis associated with azathioprine therapy in Crohn's disease. BMC Gastroenterology 2014;14:127. 
  139. Emil J Bardana, George A Porter, Bernard Pirofsky, Richard T Gourley, Cemil Bayrakci. Azathioprine in steroid-insensitive nephropathy. The American Journal of Medicine. Dec 1970;49(6):789-800. 
  140. Alice U Lee, Geoffrey C Farrell. Mechanism of azathioprine induced injury to hepatocytes: roles of glutathione depletion and mitochondrial injury. Journal of Hepatology. Dec 2001;35(6):756-764. 
  141. Kristin Horning, Chelsea Schmidt. Azathioprine induced rapid hepatotoxicty. Journal of Pharmacy Technology. Feb 2014;30(1):18-20. 
  142. The Jianghong Wu, Yan Gao, Chuanhua Yang et al Low dose azathioprine is effective in maintaining remission among chinese patients with Crohn's disease. Journal of Translational Medicine. 2013;11:235. 
  143. Charoen Choonhakarn, Suteeraporn Chaowattanapanit. Azathioprine induced Sweet's syndrome and published work review. The Journal of Dermatology. April 2013;40(4):267-271. 
  144. Hesham Al Maimouni, Dafna D Gladman, Dominique Ibanez, Murray B Urowitz. Switching treatment between myophenolate mofetil and azathioprine in lupus patients: Indications and outcomes. Arhtritis Care & Research 2014. DOI: 10.1002/acr.22364. 
  145. WH Hitzig, L Massimo. Treatment of autoimmune hemolytic anemia in children with azathioprine (Imuran). Blood Dec1966;28(6). 
  146. C Costanzi, M Matiello, CF Lucchinetti, BG Weinshenker, SJ Pittock, J Mandrekar et al. Azathioprine. Tolerability, efficacy and predictors of benefit in neuromyelitis optica. Neurology. August 16, 2011;77(7):659-666. 
  147. Raul NG Vianna, Pinar C Ozdal, Jean Deschenes, Miguel N Burnier. Combination of azathioprine and corticosteroids in the treatment of serpiginous choroiditisa. Canadian Journal of Ophthalmology. April 2006;41(2):183-189. 
  148. Aida Ben Slama Trabelsi,Eya Hamami, Ahlem Souguir et al. The Pan African Medical Journal. 2014;17:174. 
  149. Richard N Fine, Harry T Wright, Ellin Lieberman, Arthur Gordon. Azathioprine and varicella. JAMA. 1969;207(1):147-148. 
  150. Mandy Elvira Schram, Evelien Roekevisch, Mariska Maria Geertruida Leeflang et al. A randomized trial of methotrexate versus azathioprine for severe atopic eczema. Journal of allergy and clinical immunology. August 2011;128(2):353-359. 
  151. N Kaplowitz. Interaction of azathioprine and glutathione in the liver of the rat. JPET. March 1977;200(3):479-486. 
  152. Aniket Natekar, Anna Pupco, Pina Bozzo, Gideon Koren. Safety of azathioprine use during pregnancy. Canadian Family Physician. Dec 2011;57(12):1401-1402. 
  153. John K Marshall. Review: azathioprine, infliximab, certolizumab and adalimumab are effective for maintaining remission in Crohn's disease. Evid Based Med. 2008;13:115. 
  154. Marinus A van den Dorpel, Arie J Man in't Veld, Marcel Levi et al. Beneficial effects of conversion from cyclosporine to Azathioprine on fibrinolysis in renal transplant recipients. Arteriosclerosis, Thrombosis and vascular biology. 1999;19:1555-1558. 
  155. Maura Caufield, Wynnis L Tom. Oral azathioprine for recalcitrant pediatric atopic dermatitis: Clinical response and thiopurine monitoring. Journal of teh American Academy of Dermatology. Jan 2013;68(1):29-35
  156. Ramji Gupta. Prolong remission of psoriasis with azathioprine pulse therapy. Apollo Medicine. August 2014. DOI: 10.1016/japme.2014.07.005. 
  157. Soussan E Ben, Savoye G, Lemoine F, Ducastelle P, Colin R. Azathioprine as a treatment of refractor lymphocytic colitis. European Journal of Gatroenterology & Hepatology. April 2001;13(4):457-458. 
  158. Baisakhi Laha, Rajib Guha, Avijit Hazra. Multiple cutaneous neutropenic ulcers associated with azathioprine. Indian Journal of Pharmacology. 2012;44(5):646-648. 
  159. Fady Daniel, Jean Francois Cadranel, Philippe Seksik et al. Azathioprine induced nodular regenerative hyperplasia in IBD patients. Gastroenterologie Clinique et Biologique. 2005;29(5):600-603. 
  160. H Wani, A al Omair, N Hassan, B Ahmed. Azathioprine induced severe cholestatic hepatitis in a Crohn's disease patient. The Internet Journal of Gastroenterology. 2009;9(2). 
  161. Helene Salvator, Thomas Gille, Aurelie Herve et al. Chronic beryllium disease: azathioprine as a possible alternative to corticosteroid treatment. European Respiratory Journal. Jan 1, 2013;41(1):234-236. 
  162. Jose Antonio Vargas-Hitos, Jose Mario Sabio, Jesus Tercedor et al. Erythema nodosum as azathioprine hypersensitivity reaction in a patient with bullous pemphigoid. Indian Journal of dermatology. 2013;58(5):406. 
  163. Takuya Kotani, Tohru Takeuchi, Shigeki Makino, Toshiaki Hanafusa. Successful treatment of long term severe progressive interstitial pneumonia with low dose corticosteroid and azathioprine in a patient with diffuse systemic sclerosis. Case reports in rheumatology. 2012, Article ID 143927, 4 pages. doi: 10.1155/2012/143927. 
  164. Emna Gaies, Nadia Jenanli, Sameh Trabelsi et al. Methotrexate side effects: Review article. J Drug Metab Toxicol. 2012;3:4. 
  165. Maja Bulatovic Calasan, Oscar FC van den Bosch, Marjonne CW Creemers et al. Prevalence of methotrexate intolerance in rheumatoid arthritis and psoriatic arthritis. Arthritis Research & Therapy. 2013;15:R217. 
  166. Bruce N Cronstein. Low dose methotrexate: A mainstay in the treatment of rheumatoid arthritis. Pharmacological Reviews. June 2005;57(2):163-172. 
  167. James R O'Dell, Ted Mlkuls, Thomas H Taylor, Vandana Ahluwalia et al. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med. 2013;369:307-318. 
  168. Brigitte C Widemann, Peter C Adamson. Understanding and managing methotrexate nephrotoxicity. The Oncologist. JUne 2006;11(6):694-703. 
  169. AJ Kiner, AB Hassell, J Brand, A Brownfield, M Grove, MF Shadforth. The treatment of inflammatory arthritis with methotrexate in clinical practice: treatment duration and incidence of adverse drug reactions. Rheumatology. 2005;44(1):61-66. 
  170. Molly S oye, Ashlynne H Clark, Allison A Legler, Mohammed M Milhem et al. Intralesional methotrexate for treatment of invasive squamous cell carcinoma in a patient taking vemurafenib for treatment of metastatic melanoma. JCO. April 21, 2014. doi: 10.1200/JCO.2013.50.2880. 
  171. B Hirshberg, M Muszkat, O Schlesinger, A Rubinow. Safety of low dose methotrexate in elderly patients with rheunatoid arthritis. Postgrad Med J. Dec 2000;76(902):787-789. 
  172. J Wegrzyn, P Adeleine, P Miossec. Better efficacy of methotrexate given intramuscular injection than orally in patients with rheumatoid arthritis. Ann Rheum Dis, Oct 2004;63(10):1232-1234. 
  173. M Julian Duttera, W Archie Bleyer, Thomas C Pomeroy, Carl M Leventhal et al. Irradiation, methotrexate toxicity and the treatment of meningeal leukemia. The Lancet. Sept 1973;302(7831):703-707. 
  174. JC Bernini, DW Fort, JC Griener et al. Aminophylline for methotrexate induced neurotoxicity. The Lancet. March 1995;345(8949):544-547. 
  175. William M Hryniuk, Joseph R Bertino. Treatment of leukemia with large doses of methotrexate and folinic acid: clinical-biochemical correlates. J Clin Invest. 1969;48(11):2140-2155. 
  176. Philip J Mease. Spondyloarthritis: Is methotrexate effective in psoriatic arthritis? Nature Reviews Rheumatology. May 2012;8:251-252. 
  177. Brian G Feagan, John WD McDonald, Remo Panaccione, Robert A Enns et al. Methotrexate in combination with infliximab is no more effective than infliximab alone in patient with Crohn's disease. Gastroenterology. March 2014;146(3):681-688. 
  178. Laila Nurmohamed, Myla E Moretti, Tal Schechter et al. Outcome following high dose methotrexate in pregnancies misdiagnosed as ectopic. American Journal of Obstetric & Gynecology. Dec 2011;205(6):533.e1-533.e3. 
  179. Jung Min Shin, Seol-Hee Kim, Thavasyappan Thambi et al. A hyaluronic acid-methotrexate conjugate for targeted therapy of rheumatoid arthritis. Chem Cimmun. 2014;50:7632-7635. 
  180. James W Click, Abrar A Qureshi, Ruth Ann Vleugels. Methotrexate for the treatment of cutaneous dermatomyositis. Journal of the American Academy of Dermatology. June 2013;68(6):1043-1045. 
  181. Hyon K Choi, Miguel A Hernan, John D Seeger et al. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. The Lancet. April 6, 2002;359:1173-77. 
  182. MR Hargreaves, AG Mowat, MK Benson. Acute pneumonitis associated with low dose methotrexate treatment for rheumatoid arthritis: report of five cases and review of published reports. Thorax 1992;47:628-633. 
  183. Laurence J Egan, William J Sandborn. Methotrexate for inflammatory bowel disease: pharmacology and preliminary results. Mayo clinic proceedings. Jan 1996;71(1):69-80. 
  184. PT Ravi Rajagopalan, Zhiquan Zhang, Lynn McCourt et al. Interaction of dihydrofolate reductase with methotrexate: Ensemble and single molecule kinetics. PNAS. 2002;99(21):13481-13486. 
  185. Janet F McLaren, Richard O Burney, amin A Milki et al. Effect of methotrexate exposure on subsequent fertility in women undergoing controlled ovarian stimulation. Fertility and Sterility. Aug 2009;92(2):515-519. 
  186. Christopher Goshgarian, Abdulrahman Alwaki, Anibal Lugo, Kavita Grover. Methotrexate induced cerebellar leukoencephalopathy. Neurology. April 8, 2014;82(10):Supplement P6.009. 
  187. Matthew G Marin. Low dose methotrexate spares steroid usage in steoid dependent asthmatic patients: A meta-analysis. Chest 1997;112(1):29-33. 
  188. Rinat Hackmon, Sachi Sakaguchi, Gideon Koren. Effect of methotrexate treatment of ectopic pregnancy on subsequent pregnancy. Canadian Family Physician. Jan 2011;57(1):37-39. 
  189. Charlotte Hua, Thomas Barnetche, Bernard Combe, Jacques Morel. Effect of methotrexate, anti-tumor necrosis factor α and rituximab on the immune response to influenza and pneumococcal vaccines in patients with rheumatoid arthritis: a systematic review and meta-analysis. Arthritis Care & Research. July 2014;66(7):1016-1026. 
  190. Aloi M, Conte F, Cavallari N, Iacono O et al. Role of methotrexate in pediatric ulcerative colitis. Journal of pediatric gastroenterology & nutrition. April 2009;48:S111-S112. 
  191. Margien L Seinen, Cyriel Y Ponsioen, Nanne KH de Boer et al. Sustained clinical benefit and tolerability of methotrexate monotherapy after thiopurine therapy in patients with Crohn's disease. Clinical Gastroenterology and Hepatology. June 2013;11(6):667-672. 
  192. Fahd Alsalleeh, Jeffrey Keippel, Lyde Adams, Bruce Bavitz. Bisphosphonate associated osteonecrosis of jaw reoccurence after methotrexate therapy: A case report. Journal of Endodontics. Spetember 2014;40(9):1505-1507. 
  193. Marinella Patane, Miriam Ciriaco, Serafina Chimirri et al. Interactions among low dose of methotrexate and drugs used in the treatment of rheumatoid arthritis. Advances in pharmacological sciences. 2013, Article ID 313858, 8 pages. 
  194. Johanna P Cremers, Marjolein Drent, Aalt Bast et al. Multinational evidence based world association of sarcoidosis and other granulomatous disorders recommendations for the use of methotrexate in sarcoidosis: integraing systematic literature research and expert opinion of sarcoidologists worldwide. Curr Opin Pulm Med. 2013;19:545-561. 
  195. Rssol Sotoudehmanesh, B Anvari, K Akhlaghi et al. Methotrexate hepatotoxicity in patients with rheumatoid arthritis. Middle East Journal of Digestive Diseases (MEJDD). 2010;2(2):104-109. 
  196. Zhang Xiaolin, Lu Ling, Yu Chengxin, Tan Yiqing et al. Transcatheter intraarterial methotrexate infusion combined with selective uterine artery embolization as a treatment option for cervical pregnancy. Journal of vacular and interventional radiology. June 2010;21(6):836-841. 
  197. Pankaj Talwar, K Sandeeo, Nikita Naredi, BS Duggal, Tony Jose. Systemic methotrexate: an effective alternative to surgery for management of unruptured ectopic pregnancy. Medical Journal Armed Forces India. April 2013;69(2):130-133. 
  198. Alireza Minagar, William A Sheremata. Treatment of Devic's disease with methotrexate and prednisone. International journal of MS Care. Dec 2000;2(4):43-49. 
  199. Alison McKinley, Edward Park, Brad H Rovin. Oral cyclophosphamide for lupus glomerulonephritis: An underused therapeutic option. Clin J Am Soc Nephrol. Nov 2009;4(11):1754-1760. 
  200. Kenneth S Wu, Chung Kwog, Aishin Lok. Oral versus intravenous administration of cyclophosphamide: a case report. Cases Journal 2008;1:395. 
  201. Carlotta Nannini, Colin P West, Patricia J Erwin, Eric L Matteson. Effects of cyclophosphamide on pulmonary function in patients with scleroderma and interstitial lung disease: systematic review and meta-analysis of randomized controlled trials and observational prospective cohort studies. Arthritis Research & Therapy. 2008;10:R124. 
  202. Anas Younes, Catherine Thieblemont, Franck Morschhauser et al. Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) for treatment naive patients with CD20- positive B cell non-Hodgkin lymphoma: a non-Hodkin lymphoma: a non-randomised, phase 1b study. The Lancet Oncology. Aug 2014;15(9):1019-1026. 
  203. LP Zhu, TR Cupps, G Whalen, AS Fauci. Selective effects of cyclophosphamide therapy on activation, proliferation and differentiation of human B cells. J Clin Invest. 1987;79(4):1082-1090. 
  204. Lawrence N Shulman, Donald A Berry, Constance T Cirrincione et al. Comparison of doxorubicin and cyclophosphamide versus single agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). JCO. June 16, 2014. doi: 10.1200/JCO.2013.53.7142. 
  205. Marie Cecile Le Deley, Michael Paulussen, Ian Lewis et al. Cyclophosphamide compared with ifosfamide in consolidation treatment of standard risk Ewing Sarcoma: Results of randomized noninferiority Euro-EWING99-R1 trial. JCO. June 30, 2014. doi: 10.1200/JCO.2013.54.4833. 
  206. DT Boumpas, HA Austin, JE Balow et al. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. The Lancet. Sept 1992;340(8822):741-745. 
  207. Christopher G Kanakry, Sudipto Ganguly, Marianna Zahurak et al. Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide. Sci Transl Med. 13 Nov 2013;5(211):211ra157. 
  208. John H Stone, Peter A Merkel, Robert Splera, Philip Seo et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010;363:221-232. 
  209. Gerald B Appel, Gabriel Contreras, Mary Anne Dooley, Ellen M Ginzler et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. JASN. May 2009;20(5):1103-1112. 
  210. Sumandeeo Dhesi, Michael P Chu, Gregg Blevins et al. Cyclophosphamide induced cardiomyopathy. A case report, review and recommendations for management. Journal of investigative medicine high impact case reports. Jan-March 2013;1(1). doi: 10.1177/2324709613480346. 
  211. Ja-Liang Lin, Mein-Chung Wei, Yu-Chih Liu. Pulse therapy with cyclophosphamide and methylprednisolone in patients with moderate to severe paraquat poisoning: a preliminary report. Thorax 1996;51:661-663. 
  212. Zaher Lakkis, Stefano Kim, Eric Delabrousse, Marine Jary, Thierry Nguyen et al. Metronomic cyclophosphamide: An alternative treatment for hepatic epitheloid hemangioendothelioma. Journal of Hepatology. June 2013;58(6):1254-1257. 
  213. Frederick S Philips, Stephen S Sternberg, Alice P Cronin, Pedro M Vidal. Cyclophosphamide and urinaru bladder toxicity. Cancer Res. Dec 1961;21:1577. 
  214. Priya P Gor, H Irene Su, Robert J Gray, Phyllis A Gimotty et al. Cyclophosphamide metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node positive breast cancer: a retrospective cohort study. Breast Cancer Research. 2010;12:R26. 
  215. Riccado Samaritani, Giacomo Corrado, Enrico Vizza, Carlo Sbiroli. Cyclophosphamide metronomic chemotherapy for palliative treatment of a young patient with advanced epithelial ovarian cancer. BMC Cancer. 2007;7:65. 
  216. Alan Winkelstein. Mechanisms of immunosuppression: Effects of cyclophosphamde on cellular immunity. Blood. Feb 1, 1973;41(2)
  217. Girish Chinnaswamy, Julie Errington, Annabel Foot et al. Pharmacokinetics of cyclophosphamide and its metabolites in pediatric patients receiving high dose myeloablative therapy. European Journal of Cancer. July 2011;47(10):1556-1563. 
  218. Ibrahim El-Serafi, Manuchehr Abedi-Valugerdi, Zuzana Potacova et al. Cyclophosphamide alters the gene expression profile in patients treated with high doses prior to stem cell transplantation. PLoS ONE. Jan 2014;9(3):e93239. 
  219. JS McCune, A Batchelder, KA Guthrie, R Witherspoon et al. Personalized dosing of cyclophosphamide in the total body irradiation-cyclophosphamide conditioning regimen: A phase II trial in patients with hematologic malignancy. CLinical Pharmacology & Therapeutics. 2009;85(6):615-622. 
  220. Ertan Altayli, Ercan Malkoc, Bilal Firat Alp, Ahmet Korkmaz. Prevention and treatment of cyclophosphamide and ifosfamide induced hemorrhagic cystitis. J Mol Pathophysiol. 2012;1(1):53-62. 
  221. Ravindra Dabhai, G Kalla, MK Singhi, BC Ghiya, Dilip Kachhawa. Dexamethasone-cyclophosphamide pulse therapy in systemic lupus erythematosus. IJDVL 2005;71(1):9-13. 
  222. Paul A Monach, Lindsay M Arnold, Peter A Merkel. Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseases. Arthritis & Rheumatism. Jan 2010;62(1):9-21. 
  223. Mary E Fleischli, Rachel H Valek, AMit G Pandya. Pulse intravenous cyclophosphamide therapy in pemphigus. Arch Dermatol. 1999;135(1):57-61. 
  224. Chi CHi Mok, Chak Sing Lau, Raymond WS Wong. Treatment of lupus psychosis with oral cyclophosphamide followed by azathioprine maintenance: an open label study. The American Journal of Medicine. July 2003;115(1):59-62. 
  225. Ramji Gupta, Sarthak Gupta. Prolonged remission of rheumatoid arthritis with dexamethasone cyclophosphamide pulse therapy: A case series. Indian Journal of Rheumatology. June 2014;9(2):98-100. 
  226. Leo Luznik, Paul V O'Donnell, Ephraim J Fuchs. Post transplantation cyclophosphamide for tolerance induction in HLA-Haploidentical bone marrow transplantation. Seminars in Oncology. Dec 2012;39(6):683-693. 
  227. Carlos H Nousari, Robert Brodsky, Grant J Anhalt. Evaluating the role if immunoablative high dose cyclophosphamide therapy in pemphigus vulgaris. Journal of the american academy of dermatology. July 2003;49(1):148-150. 
  228. Siddarth S Pujari, John H Kempen, Craig W Newcomb. Cyclophosphamide for ocular inflammatory diseases. Ophthalmology. Feb 2010;117(2):356-365. 
  229. Thatte UM, Chhabria SN, Karandikar SM, Dahanukar Sa. Protective effects of Indian medical plants against cyclophosphamide neutropenia. Journal of Postgraduate Medicine. 1987;33(4):185-8. 
  230. Samir V Trivedi, Ashwin H Vasava, Tinkal C Patel, Lovleen C Bhatia. Cyclophosphamide in pulmonary alveolar hemorrhage due to leptospirosis. Indian Journal of Critical Care Medicine. 2009;13(2):79-84. 
  231. Chuo-Jung Tsai, Shian-Shiang Wang, Yen-CHuan Ou. Cyclophosphamide induced intractable hemorrhagic cystitis treated with hyperbaric oxygenation and intravesical sodium hyaluronate. Urological Science. May 2014. doi: 10.1016/j.urols.2014.03.001. 
  232. Nicolas Batty, Naveen Yarlagadda, Roberto Pili. Major response to cyclophosphamide and prednisone in recurrent castration-resistant prostate cancer. J Natl Compr Canc Netw. 2013;11:911-915. 
  233. E Morawiec, I Tillie-Leblond, V Pansini, J Selleron et al. Exacerbations of idiopathic pulmonary fibrosis treated with corticosteroids and cyclophosphamide pulses. European Respiratory Journal. Dec 2011;38(6):1487-1489. 
  234. Francesco Patti, Salvatore Lo Fermo. Lights and shadows of cyclophosphamide in the treatment of multiple sclerosis. Autoimmune diseases. 2011, Article ID 961702, 14 pages. 
  235. Anthony C Allison, Elsie M Eugui. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology. May 2000;47(2-3):85-118. 
  236. Gerald B Appel, Gabriel Contreras, Aspreva Lupus. Mycophenolate Mofetil versus Cyclophosphamide for induction treatment of lupus nephritis. J AM Soc Nephrol. May 2009;20(5):1103-1112. 
  237. Francisco Silva, Ulrich Specks, Fernando C Fervenza. Mycophenolate mofetil for induction and maintenance of remission in microscopic polyangiitis with mild to moderate renal involvement- A preospective, open label pilot trial. Clin J Am Soc Nephrol. March 2010;5(3):445-453. 
  238. Ellen M Glnzier, Mary Anne Dooley, Cynthia Aranow, Mimi Y Klm et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 2005;353:2219-2228. 
  239. Pranav Dalal, Monica Grafals, Darshika Chhabra, Lorenzo Gallon. Mycophenolate mofetil: safety and efficacy in the prophylaxis of acute kidney transplantation rejection. Therapeutic and clinical risk management. Jan 2009;5:139-149. 
  240. Anu Jacob, Marcelo Matiello, Brian G Weinshenker, Dean M Wingerchuk et al. Treatment of neuromyelitis optica with mycophenolate meofetil. Retrospective analysis of 24 patients. Arch Neurol. 2009;66(9):1128-1133. 
  241. Alexander H Enk, Jurgen Knop. Treatment of pemphigus vulgaris with mycophenolate mofetil. The Lancet. August 1997;350(9076):494. 
  242. Helena Moreira Silva, Guilhermina Reis, Margarida Guedes et al. A case of hepatopulmonary syndrome solved by mycophenolate mofetil (an inhibitor of angiogenesis and nitric oxide production). Journal of hepatology. March 2013;58(3):630-633. 
  243. Christopher Grainge, Nivenka Jayasekera, Patrick Dennison et al. Case series reporting the effectiveness of mycophenolate mofetil in treatment resistant asthma. European respiratory journal. October 2013;42(4):1134-1137. 
  244. Nilendu Sarma, Sanjay Ghosh. Mycophenolate mofetil as adjuvant in pemphigus vulgaris. Indian journal of dermatology, venereology and leprology. 2007;73(5):348-350. 
  245. Muriel Sadlier, Brian Kirby, Aoife Lally. Mycophenolate mofetil and hydroxychloroquine: an effective treatment for recalcitrant cutaneous lupus erythematosus. Journal of the American Academy of Dermatology. Jan 2012;66(1):160-161. 
  246. J Jose, BK Paulose, Z Vasuki, D Danda. Mycophenolate mofetil in neuropsychiatric systemic lupus erythematosus. Indian journal of medical sciences. 2005;59(8):353-356. 
  247. V Chaudhry, DR Cornblath, JW Griffin et al. Mycophenolate mofetil: A safe and promising immunosuppressant in neuromuscular diseases. Neurology. Jan 2001;56(1):94-96. 
  248. MY Karim, P Alba, MJ Cuadrado et al. Mycophenolate mofetil for systemic lupus erythematosus refractory to other immunosuppressive agents. Rheumatology. 2002;41(8):876-882. 
  249. Alice Tung Wan Song, Edson Abdala, Patricia Rodrigues Bonazzi et al. Does mycophenolate mofetil increase the risk of cytomegalovirus infection in solid organ transplant recipients? - A mini review. Braz J Infect Dis. Apr 2006;10(2). 
  250. Antonio Perez-Aytes, Ana Ledo, Virginia Boso et al. Immunosuppressive drugs and pregnancy: Mycophenolate mofetil embryopathy. Neoreviews. October 2010;11(10):e578-e589. 
  251. Naoko Takebe, Xiangfei Cheng, Tamer E Fandy, Rakesh K Srivastava et al. IMP dehydrogenase inhibitor mycophenolate mofetil induces caspase dependent apoptosis and cell cycle inhibition in multiple myeloma cells. Mol Cancer Ther. Feb 2006;5:457. 
  252. Ana C Zamora, Paul J Wolters, Harold R Collard, M Kari Connolly et al. Use of mycophenolate mofetil to treat scleroderma associated interstitial lung disease. Respiratory Medicine. Jan 2008;102(1):150-155. 
  253. Klawitter J, Schmitz V, Shokati T, Epshtein E et al. Mycophenolate mofetil enhances the negative effects of sirolimus and tacrolimus on rat kidney cell metabolism. PLoS ONE. 2014;9(1):e86202. doi: 10.1371/journal.pone.0086202. 
  254. Juan Carlos Cardet, Joshua A Boyce. Addition of mycophenolate mofetil to tacrolimus is associated with decreases in food specific IgE levels in a pediatric patient with liver transplantation associated food allergy. The Journal of allergy and clinical immunology: In practice. Jan 2013;1(1):104-106. 
  255. DH Present. Is mycophenolate mofetil a new alternative in the treatment of inflammatory bowel disease? Gut 1999;44:592-593. 
  256. Katerina Laskari, Clio P Mavragani, Athanasios G Tzioufas, Haralampos M Moutsopoulos. Mycophenolate mofetil as maintenance therapy for proliferative lupus nephritis: a long term observational prospective study. Arthritis Research & Therapy. 2010;12:R208. 
  257. Alissa K Orvis, Stanton K Wesson, Thomas S Breza, Ann A hurch, Christina L Mitchell, Shannon W Watkins. Mycophenolate mofetil in dermatology. Journal of the American Academy of Dermatology. Feb 2009;60(2):183-199. 
  258. Sylvian Goutelle, Valerie Mialou, Aurore Gouraud et al. Probable drug interaction between intravenous ciprofloxacin and mycophenolate mofetil in a bone marrow transplant recipient. Pharmacotherapy: The journal of human pharmacology and drug therapy. Jan 2011;31(1):114. 
  259. Matthew R Smith, Sheldon C Cooper. Mycophenolate mofetil therapy in the management of inflammatory bowel disease- A retrospective case series and review. Journal of Crohn's and Colitis. August 2014;8(8):890-897. 
  260. Kalyan Banerjee, Raghubir Banerjee. Management of erythema nodosum leprosum by mtcophenolate mofetil. Indian journal of dermatology. 2008;53(3):142-143. 
  261. Velinov Milen, Zellers Nancy. The fetal mycophenolate mofetil syndrome. Clinical Dysmorphology. Jan 2008;17(1):77-78. 
  262. Luiz Sergio Azevedo, Maria Cristina R Castro, Flavio J Paula et al. Mycophenolate mofetil may protect against Pneumocystis carinii pneumonia in renal transplant patients. Rev Inst Med Trop. May-June 2005;47(3):143-145. 
  263. Agnes E Coutinho, Karen E Chapman. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol. Mar 2011;335(1):2-13. 
  264. Grbovic L, Radenkovic M. Therapeutic use of glucocorticoids and immunosuppressive agents. Srp Arh Celok Lek. Oct 2005;133(Suppl 1):67-73. 
  265. Denise C Hsu, Constance H Katelaris. Long term management of patients taking immunosuppressive drugs. Aust Prescr 2009;32:68-71. 
  266. Karolien De Bosscher, Wim Vanden Berghe, Guy Haegeman. Mechanisms of anti-inflammatory action and of immunosuppression by glucocorticoids: negative interference of activated glucocorticoid receptor with transcription factors. Journal of Neuroimmunology. Sept 2000;109(1):16-22. 
  267. AM James Shaplro, Jonathan RT Lakey, Edmond A Ryan et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid free immunosuppressive regimen. N Engl J Med. 2000;343:230-238. 
  268. JoAnn Lindenfeld, Geraldine G Miller, Simon F Shakar et al. Drug therapy in heart transplant recipient. Circulation. 2004;110:3858-3865. 
  269. Rogerio Lacerda dos Santos, Maria Claudia Mesquita Lacerda, Renato Torres Goncalves et al. Immunosuppressants: implications in orthodontics. Dental Press J Orthod. Mar/Apr 2012;17(2). 
  270. Nicolas Hunzelmann, Pia Moinzadeh, Ekkehard Genth, Thomas Krieg et al. High frequency of corticosteroid and immunosuppressive therapy in patients with systemic sclerosis despite limited evidence for efficacy. Arthritis Research & Therapy 2009;11:R30. 
  271. Michael E kelly, Anna M Juern, William J Grossman, Dennis W Schauer, Beth A Drolet. Immunosuppressive effects in inafnts treated with corticosteroids for infantile hemangiomas. Arch Dermatol. 2010;146(7):767-774. 
  272. William A Briggs, Joseph Eustace, Suresh Mathew, Luis F Gimenez et al. Pentoxifylline potentiates in vitro lymphocyte suppression by glucocorticoids and immunosuppressive drugs. The Journal of clinical pahrmacology. June 1998;38(6):561-566. 
  273. J Visser, JL Hillebrands, J Rozing. No evidence that rifampicin has glucocorticoids like immunosuppressive properties leading to suppression of rat splenocyte proliferation in vitro. J Antimicrob Chemother. 2001;47(6):894-895. 
  274. Oscar Gonzalez Perez, Sonia Luquin, Joaquin Garcia-Estrada, Cesar Ramos-Remus. Deflazacort: A glucocorticoid with few metabilic adverse effects but important immunosuppressive activity. Advances in Therapy. Sept/Oct 2007;24(5):1052-1060. 
  275. E Langhoff, J Ladefoged. Relative immunosuppressive potency of various corticosteroids measured in vitro. European Journal of Clinical Pharmacology. 1983;25(4):459-462. 
  276. Lorenz Risch, Roberto Herklotz, Alfred Blumberg, Andreas R Huber. Effects of glucocorticoid immunosuppression on serum cystatin C concentrations in renal transplant patients. Clinical Chemistry. Nv 2001;47(11):2055-2059. 
  277. Mark Lo wenberg, Jurriaan Tuynman, Joyce Bilderbeek, Timo Gaber et al. Rapid immunosuppressive effects of glucocorticoids mediated through Lck and Fyn. Blood. Spet 2005;106(51703-1710). 
  278. K Dietrich, A Schned, J Fortuny, J Heaney et al. Glucocorticoid therapy and risk of bladder cancer. British Journal of Cancer. 2009;101:1316-1320. 
  279. Luis Uva, Diana Miguel, Catarina Pinheiro et al. Mechanisms of action of topical corticosteroids in psoriasis. International Journal of Endocrinology. 2012, Article ID 561018, 16 pages. 
  280. Nathalie Auphan, Joseph A DiDonato, Caridad Rosette et al. Immunosuppression by glucocorticoids: Inhibition of NF-kB activity through induction of IkB synthesis. Science. Oct 1995;270(5234):286-290.
  281. FP Ognibene, JH Shelhamer, GS Hoffman, GS Kerr, D Reda et al. Pneumocystis carinii pneumonia: a mojor complication of immunosuppressive therapy in patients with Wegener's granulomatosis. American Journal of Respiratpry and Critical Care Medicine. 1995;151(3):795-9. 
  282. Cheng You Du, Er Kan Xu. Protective effect of glucocorticoid free immunosuppressive regimen in allogenic islet transplantation. Hepatobilliary Pancreat Dis Int. Feb 2006;5(1):43-47. 
  283. Charlotte Sumida, Genevieve Vallette, Nicole Thobie, Emmanuel A Nunez. Perturbation of the immunosuppressive action of glucocorticoids in rat thymocytes by liposoluble extracts of serum from AIDS patients. AIDS Research and Human Retroviruses. AUg 1993;9(8):755-760. 
  284. Nieves Hoyos, ALvaro Casanova, Silvia Sanchez et al. Polymyositis and interstitial lung disease with a favorable response to corticosteroids and methotrexate. Arch Bronconeumol. 2007;43:636-9. 
  285. Paul R Mittelstadt, Joao P Monteiro, Jonathan D Ashwell. Thymocyte responsiveness to endogenous glucocorticoids is required for immunological fitness. J Clin Invest. 2012;122(7):2384-2394. 
  286. David Jayne. Treating vasculitis with conventional immunosuppressive agents. Cleveland Clinic journal of medicine. Nov 2012;79(Suppl 3):S46-S49. 
  287. Dora Liu, Alexandra Ahmet, Leanne Ward, Preetha Krishnamoorthy, Efrem D Mandelcorn et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy, Asthma & Clinical Immunology. 2013;9:30. 
  288. Djillali Annane. Corticosteroids for severe sepsis: an evidence based guide for physicians. Annals of Intensive Care 2011;1:7. 
  289. Ali Hafezi Moghadam, Tommaso Simoncini, Zequan Yang, Florian P Limbourg et al. Acute cardiovascular protective effects of corticosteroids are mediated by non transcriptional activation of endothelial nitric oxide synthase. Nature Medicine. May 2002;8(5). 
  290. G Spencer Green. Etanercept (Enbrel): update on therapeutic use. Ann Rheum Dis. Nov 2000;59(Suppl 1):i46-i49. 
  291. Alfredomaria Lurati, Mariagrazia Marrazza, Katia Angela et al. Safety of etanercept in elderly subjects with rheumatoid arthritis. Biologics: Target and therapy. 2009;4:1-4. 
  292. Josef S Smolen, Peter Nash, Patrick Durez, Stephen Hall et al. Maintenance, reduction or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial. The Lancet. March 2013;381(9870):918-929. 
  293. Cragl L Leonardl, Jerold L Powers, Robert T Matheson, Bernard S Goffe et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Me 2003;349:2014-2022. 
  294. Frederik Kreiner, Henrik Galbo. Effect of etanercept in polymyalgia rheumatica: a randomized controlled trial. Arthritis Research & Therapy. 2010;12:R176. 
  295. W Sue T Griffin. Perispinal etanercept: Potential as an Alzheimer therapeutic. Journal of Neuroinflammation. 2008;5:3. 
  296. Tracey A Ignatowski, Robert N Spengler, Krishnan M Dhandapani et al. Perispinal etanercept for post-stroke neurological and cognitive dysfunction: Scientific rationale and current evidence. CNS Drugs. May 2014. DOI: 10.1007/s40263-014-0174-2. 
  297. Andrea Paradisi, Damiano Abeni, Fabio Bergamo, Francesco Ricci et al. Etanercept therapy for toxic epidermal necrolysis. Journal of the AMerican academy of Dermatology. August 2014;71(2):278-283. 
  298. Miin Roh, Yan Zhang, Yusuke Murakami et al. Etanercept, a widely used inhibitor of tumor necrosis factor-α (TNFα), prevents retinal ganglion cell loss in a rat model of glaucoma.  PLoS ONE. July 2012. DOI: 10.1371/journal.pone.0040065. 
  299. Mercedeh Baghai, Douglas R Osmon, Donna M Wolk, Lester E Wold et al. Fatal sepsis in a patient with rheumatoid arthritis reated with etanercept. Mayo clinic proceedings. June 2001;76(6):653-656. 
  300. Vince N Montes, Irl B Hirsch. Treatment of LADA with etanercept. Diabetes Care. May 2012;35(5):e36. 
  301. Hao Pang, Xue-Hui Wu, Jian-Zhong Xu. Response to etanercept in juvenile idiopathic arthritis. JAMA. 2012;307(11):1140-1141. 
  302. Vlaxime Dougados, Desiree van der Heijde, Joachim Sieper, Jurgen Braun et al. Symptomatic efficacy of etanercept and its effects on objective signs of inflammation in early nonradiographic axial spondyloarthritis: A multicenter, randomized, double blind, placebo controlled trial. Arthritis & Rheumatology. August 2014;66(8):2091-2102. 
  303. Biykem Bozkurt, Guillermo Torre-Amione, Marshelle Smith Warren, James Whitmore et al. Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure. Circulation. 2001;103:1044-1047. 
  304. A Wailoo, N Bansback, J Chilcott. Infliximab, etanercept and adalimumab for the treatment of ankylosing spondylitis: cost-effectiveness evidence and NICE guidance. Rheumatology. 2008;47:119-120. 
  305. Gregory A Yanik, Shin Mineishi, John E Levine, Carrie L Kitko et al. Soluble tumor necrosis factor receptor: Enbrel (Etanercept) for subacute pulmonary dysfunction following allogeneic stem cell transplantation. Biology of blood and marrow transplant. July 2012;18(7):1044-1054. 
  306. Michael S Linn, Derek C Chase, Robert M Healey et al. Etanercept enhances preservation of osteochondral allograft viability. AM J Sports Med. July 2011;39(7):1494-1499. 
  307. Jan MH Van der Brande, Henri Braat, Gijs R van den Brink et al. Infliximab but not etanercept induces apoptosis in lamina propria T lymphocytes from patients with Crohn's disease. Gastroeneterology. June 2003;124(7):1774-1785. 
  308. D Paridaens, WA van den Bosch, TL van der Loos et al. The effect of etanercept on Grave's ophthalmopathy: a pilot study. Eye 2005;19:1286-1289. 
  309. Nizar N Zein. Etanercept as an adjuvant to interferon and ribavarin in treatment naive patients with chronic hepatitis C virus infection: a phase 2 randomized, double blind, placebo controlled study. Journal of Hepatology. March 2005;42(3):315-322. 
  310. Matthew J Booker, Julia Flint, Shanmugam Saravana. Aseptic meningitis in a patient taking etanercept for hreumatoid arthritis: a case report. Cases Journal. 2008;1:364. 
  311. Amber N Pepper, Neetu Talreja, Gregory M Cowan, Mark C Glaum, Richard F Lockey. Lymphopenia induced by etanercept. Annals of allergy, asthma & immunology. March 2014;112(3):262-263. 
  312. Aylin Rezvani, Nihal Ozaras. Infertility improved by etanercept in ankylosing spondylitis. Indian Journal of pharmacology. 2008;40(6):276-277. 
  313. M Taban, WJ Dupps, B Mandell, VL Perez. ETanercept (Enbrel) associated inflammatory eye disease: case report and review of literature. Invest Ophthalmol Vis Sci. 2005;46:E-Abstract 2849. 
  314. Gisela Kobelt. Treating to target with etanercept in rheumatoid arthritis: cost effectiveness of dose reduction when remission is achieved. Value in health. July 2014;17(5):537-544. 
  315. Lisa C Zaba, Mayte Suarez-Farinas, Judilyn Fuentes-Duculan, Kristine E Nograles et al. Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signalling, not immediate response TNF genes. Journal of allergy and clinical immunology. Nov 2009;124(5):1022-1030.e395. 
  316. Ozdemir Ozdemir, Ozgul Altintas, Levent Altintas, Demir Kursat Yildiz, Ender Sener, Yusuf Caglar. Effects of subconjunctivally injected bevacizumab, etanercept and the combination of both drugs on experimental corneal neovascularization. Canadian Journal of Ophthalmology. April 2013;48(2):115-120. 
  317. Nadine F Choueiter, AAron K Olson, Danny D Shen, Michael A Portman. Prospective open label trial of etanercept as adjunctive therapy for Kawasaki disease. The Journal of Pediatrics. Dec 2010;157(6):960-966.e1. 
  318. Stephanie Keeling, Gert-Jan Wolbink. Measuring multiple etanercept levels in the breast milk of a nursing mother with rheumatoid arthritis. The Journal of Rheumatology. 2010;37(7):1551. 
  319. Valderilio Feijo Azevedo, Marilia Barreto Gameiro Silva, Debora Karine Marinello et al. Leukopenia and thrombocytopenia induced by etanercept: two case reports and literature review. Rev Bras Reumatol. Jan/Feb 2012;52(1). 
  320. Afrim A Gashi, Sylejman Rexhepi, Idriz Berisha, AVni Kryeziu et al. Treatment of rheumatoid arthritis with biologic DMARDS (Rituximab and Etanercept). Med Arh. 2014;68(1):51-53. 
  321. Ashima Makol, Madhusudan Grover, Carla Guggenheim, Houria Hassouna. Etanercept and venous thromboembolism: a case series. Journal of medical case reports. 2010;4:12. 
  322. Joan M Korth Bradley, Abbe Sue Rubin, Roberta K Hanna et al. The pharmacokinetics of etanercept in healthy volunteers. Ann Pharmacother. Feb 2000;34(2):161-164. 
  323. Paul Emery, Ferdinand C Breedveld, Stephen Hall, Patrick Durez et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active early, moderate to severe rheumatoid arthritis (COMET): a randomised, double blind, parallel treatment trial. The Lancet. August 2008;372. 
  324. I Street, P Jobanputra, DW Proops. Etanercept, a tumor necrosis factor α receptor antagonist and methotrexate in acute sensorimeural hearing loss. The Journal of Laryngology & Otology. Dec 2006;120(12):1064-1066. 
  325. Haydar Frangoul, Tatsuki Koyama, Jennifer Domm, Etanercept for treatment of idiopathic peumonia syndrome after allogeneic hematopoietic stem cell transplantation. Blood, March 2009;113(12). 
  326. Georg Schett, Petra Herak, Winfried Graninger, Josef S Smolen, Martin Aringer. Listeria associated arthitis in a patient undergoing etanercept therapy: case report and review of literature. J Clin Microbiol. May 2005;43(5):2537-2541. 
  327. Ryuji Ohashi, Ryuji Fukazawa, Makoto Watanabe, Hanako Tajima et al. Etanercept suppresses arteritis in a murine model of Kawasaki disease: A comparative study involving different biological agents. International Journal of vascular medicine. 2013, Article ID 543141, 10 pages. DOI: 10.1155/2013/543141. 
  328. Inmaculada Macias Fernandez, Antonia Maria Fernandez Rodriguez, Sergio Garcia Perez. use of etanercept in amyloidosis secondary to rheumatoid arthritis: a report of two cases. Reumatol Clin. 2011;07(06):397-400. 
  329. Aline Frazier Mironer, Maxime Dougados, Xavier Mariette et al. Retention rates of adalimumab, etanercept and infliximab as first and second line biotherapy in patients with rheumatoid arthritis in daily practice. Joint Bone Spine. Sous presse, Epreuves corrigees par l'auteur. 2014. doi: 10.1016/j.jbspin.2014.02.014. 
  330. PA Klimiuk, S Sierakowski, I Domyslawska, J Chwiecko. Effect of etanercept on serum levels of soluble cell adhesion molecules (sICAM-1, sVCAM-1 and sE-selectin) and vascular endothelial growth factor in patients with rheumatoid arthritis. Scandinavian Journal of rheumatology. 2009;38(6):439-444. 
  331. Jean Frederic Colombel, William J Sandborn, Walter Reinisch, Gerassimos J Mantzaris et al. Infliximab, azatioprine or combination therapy for Crohn's disease. N ENgl J Med. 2010;362:1383-1395 
  332. William J Sandborn, Paul Rutgeerts, Brian G Feagan, Walter Reinisch et al. Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab. Gastroenterology. Oct 2009;137(4):1250-1260. 
  333. Jeffrey Hyams, Wallace Crandall, Subra Kugathasan, Anne Griffiths et al. Induction and maintenance infliximab therapy for the treatment of moderate to severe Crohn's disease in children. Gastroenterology. March 2007;132(3):863-873. 
  334. S Danese, JF Colombel, W Reinisch, PJ Rutgeerts. Review article: infliximab for Crohn's disease treatment- shifting therapeutic strategies after 10 years of clinical experience. Alimentary Pharmacology & Therapeutics. April 2011;33(8):857-869. 
  335. Adriana H Tremoulet, Sonia Jain, Preeti Jaggi et al. Infliximab for intensification of primary therapy for Kawasaki disease: a phase 3 randomised, double blind, placebo controlled trial. The Lancet. May 2014;383(9930):1731-1738. 
  336. Malgorzata Szerszen, Evan R Horton. Infliximab for the treatment of paediatric ulcerative colitis. Eur J Hosp Pharm. August 2014. doi:10.1136/ejhpharm-2013-000440. 
  337. Adam J Luber, Cindy L Tsui, Gillian M Heinecke, Mark G Lebwohi, Jacob O Levitt. Long term durability and dose escalation patterns in infliximab therapy for psoriasis. March 2014;70(3):525-532. 
  338. A Perdriger. Infliximab in the treatment of rheumatoid arthritis. Biologics: Targets and therapy. May 2009;3: 183-191. 
  339. Joao Luiz Pereira Vaz, Carlos Augusto Ferreira Andrade, Alessandra Cardoso Pereira, Maria de Fatima M Martins, Roger Abramino Levy. Systemic review of infliximab induced autoantibodies and systemic lupus erythematosus. Rev Bras Reumatol. Aug 2013;53(4). 
  340. Adriane DM Vorselaars, Anouk Verwoerd, Coline HM van Moorsel et al. Prediction of relapse after discontinuation of infliximab therapy in severe sarcoidosis. European Respiratory Journal. European Respiratory Journal. Feb 2014;43(2):602-609. 
  341. Keiichi Hirono, Yasushi Kemmotsu, Helmut Wittkowski et al. Infliximab reduces the cytokine mediated inflammation but does not suppress cellular infiltration of the vessel wall in refractory Kawasaki disease. Pediatric Research. 2009;65:696-701. 
  342. Miguel Regeuiro, Kevin E Kip, Leonard Baidoo, Jason M Swoger, Wolfgang Schraut. Postoperative therapy with infliximab prevents long term Crohn's disease recurrence. Clinical Gastroenterology and Hepatology. Sept 2014;12(9):1494-1502.e1. 
  343. Katharina Timper, Petr Hruz, Christoph Beglinger, Marc Y Donath. Infliximab in the treatment of Crohn disease and type 1 diabetes. Diabetes Care. July 2013;36(7):e90-e91. 
  344. Casper Steenholdt, Morten Svenson, Klaus Bendtzen et al. Acute and dleayed hypersensitivity reactions to infliximab and adalimumab in a patient with Crohn's disease. Feb 2012;6(1):108-111. 
  345. Praveen Sharma, Ashish Kumar, Barjesh Chander Sharma, Shiv Kumar Sarin. Infliximab monotherapy for severe alcoholic hepatitis and predictors of survival: An open label trial. Journal of hepatology. March 2009;50(3):584-591. 
  346. Shokufeh Tavassoli, Guy T Smith. Infliximab infusion resulting in rapid resolution of episcleritis. JAMA Ophthalmol. 2014;132(8):941. 
  347. Michael Moravan, Benjamin M Segal. Treatment of CNS sarcoidosis with infliximab and mycophenolate mofetil. Neurology. Jan 2009;72(4):337-340. 
  348. Satoshi Yamada, Takuya Yoshino, Minoru Matsuura, Naoki Minami et al. Long term efficacy of infliximab for refractory ulcerative colitis: results from a single center experience. BMC Gastroenterology. 2014;14:80. 
  349. Emilie Ducourau, Denis Mulleman, Gilles Paintaud et al. Antibodies toward infliximab are associated with low infliximab concentration at treatment initiation and poor infliximab maintenance in rheumatic diseases. Arthritis Research & Therapy. 2011;13:R105. 
  350. Cynthia Phelan, Eric Wooltorton. Infliximab and serous hematologic events. CMAJ. Oct 2004;171(9):1045. 
  351. Marc A Judson, Robert P Baughman, Ulrich Costabel, Michael Mack, Elliot S Barnathan. The potential additional benefit of infliximab in patients with chronic pulmonary sarcoidosis already receiving corticosteroids: A retrospective analysis from a randomized clinical trial. Respiratory Mediicne. Jan 2014;108(1):189-194. 
  352. A Wailoo, N Bansback, J Chilcott. Infliximab, etanercept and adalimumab for the treatment of ankylosing spondylitis: cost-effectiveness evidence and NICE guidance. Rheumatology 2008;47:119-120. 
  353. Paraskevi V Voulgari, Yannis Alamanos, Spyros N Nikas et al. Infliximab therapy in established rheumatoid arthritis: An observational study. The American Journal of Medicine. May 2005;118(5):515-520. 
  354. Shehnaz Arsiwala, Infliximab: efficacy in psoriasis. IJDVL 2013;79(7):25-34. 
  355. Bertram Wiedenmann, Peter Malfertheiner, Helmut Friess et al. A multicenter, phase II study of infliximab plus gemcitabine in pancreatic cancer cachexia. J Support Oncol. 2008;6:18-25. 
  356. Alan Menter, Steven R Feldman, Gerald D Weinstein, Kim Papp et al. A randomized comparison of continuous vs intermittent infliximab maintenance regimens over 1 year in the treatment of moderate to severe plaque psoriasis. Journal of the American Academy of Dermatology. Jan 2007;56(1):31.e1-31.e15. 
  357. Livia Biancone, Micaela Cretella, Claudio Tosti, Giampiero Palmieri et al. Local injection of infliximab in the postoperative recurrence of Crohn's disease. Gastroinetstinal Endoscopy. March 2006;63(3):486-492. 
  358. Masaru Takeuchi,Takeshi Kezuka, Sunao Sugita, Hiroshi Keino et al. evaluation of the long term efficacy and safety of infliximab treatment for uveitis in Behcet's disease. Ophthalmology. June 2014. doi: 10.1016/j.ophtha.2014.04.042. 
  359. Shannon Famenini, Jashin J Wu. Infliximab-induced psoriasis in treatment of Crohn's disease- associated ankylosing spondylitis: Case report and review of 142 cases. J Drugs Dermatol. 2013;12(8):939-943. 
  360. Chelliah R Selvasekar, Robert R Cima, David W Larson, Eric J Dozois et al. Effect of infliximab on short term complications in patients undergoing operation for chronic ulcerative colitis. Journal of the American College of Surgeons. May 2007;204(5):956-962. 
  361. AD Booth, DRW Jayne, RK Kharbanda et al. Infliximab improves endothelial dysfunction in systemic vascultis. Circulation 2004;109:1718-1723. 
  362. Elizabeth R Drone, Allison L McCrory, Natalie Lane, Katherine Fiala. Disseminated nocardiosis in a patient on infliximab and methylprednisolone for treatment resistant Sweet's syndrome. Indian dermatology online journal. 2014;5(3):300-302. 
  363. Elias Zintzaras, Issa J Dahabreh, Stavroula Giannouli, Michael Voulgarelis, Haralampos M Moutsopoulos. Infliximab and methotrexate in the treatment of rheumatoid arthritis: A systematic review and meta-analysis of dosage regimens. Clinical Therapeutics. Nov 2008;30(11):1939-1955. 
  364. Philip J Mease. Adalimumab in the treatment of arthritis. Ther Clin Risk Manag. Mar 2007;3(1):133-148. 
  365. Cem Gabay, Paul Emery, Ronald van Vollenhoven, Ara Dikranian et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double blind, contolled phase 4 trial. The Lancet. May 2013;381(9877):1541-1550. 
  366. Martin Rudwaleit, Filip Van den Bosch, Martina Kron et al. Effectiveness and safety of adalimumab in patients with ankylosing spondylitis or psoriatic arthritis and history of anti-tumor necrosis factor therapy. Arthritis Research & Therapy 2010;12:R117. 
  367. Gerd R Burmester, Marco Matucci-Cerinic, Xavier Mariette et al. Safety and effectiveness of adalimumab in patients with rheumatoid arthritis over 5 years of therapy in a phase 3b and subsequent postmarketing observational study. Arthritis Research & Therapy 2014;16:R24. 
  368. Bornadata Bain, Melanie Brazil. Adalimumab. Nature Reviews drug discovery. Sept 2003;2:693-694. 
  369. Gerd R Burmester, Remo Panaccione, Kenneth B Gordon et al. Adalimumab: long term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn's disease. Ann Rheum Dis. May 2012. doi: 10.1136/annrheumdis-2011-201244. 
  370. Jeffrey S Hyams, Anne Griffiths, James Markowitz, Robert N Baldassano et al. Safety and efficacy of adalimumab for moderate to severe Crohn's disease in children. August 2012;143(2):365-374.e2. 
  371. Marina Amaral de Avila Machado, Alessandra Almeida Maciel, Livia Lovato Pires de Lemos et al. Adalimumab in rheumatoid arthritis treatment: a systemic review and meta analysis of randomised clinical trials. Rev Bras Reumatol. Sept/Oct 2-13;53(5). 
  372. Ashima Makol, Madhusudan Grover. Adalimumab induced mononeuritis multiplex in a patient with refrctory rheumatoid arthritis: a case report. Cases Journal 2008;1:287. 
  373. Maxwell B Sauder, Jennifer Beecker, Timothy Ramsay. Comment on 'A double blind randomized placebo controlled trial of adalimumab in the treatment of cutaneous sarcoidosis'. Journal of the American Academy of Dermatology. May 2014;70(5):950-951. 
  374. Guven Cetin, Cumali Karatoprak, Muharrem Kiskac et al. Factor XI deficiency following use of adalimumab. Indian Journal of Pharmacology. 2014;46(5):553-554. 
  375. Anca Prica, Rena Buckstein. Myelodysplatic syndrome successfully treated with adalimumab. Journal of Clinical Oncology. February 24, 2014. doi: 10.1200/JCO.2013.49.4948. 
  376. Shi Hu, Shuaiyi Liang, Huaizu Guo, Dapeng Zhang et al. Comparison of the inhibition mechanisms of adalimumab and infliximab in treating tumor necrosis factor α- associated diseases from a molecular view. The Journal of BIological Chemistry. 2013. doi: 10.1074/jbc.M113.491530. 
  377. Angad S Dhillon, Adam W Harris. Infliximab vs adalimumab for Crohn's disease. Clinical gastroenetrology and Hepatology. June 2014. doi: 10.1016/j.cgh.2014.06.012. 
  378. J Christian van Denderen, Ingrid M Visman, Michael T Nurmohamed et al. Adalimumab significantly reduces the recurrence rate of anterior uveitis in patients with ankylosing spondylitis. The Journal of Rheumatology. Aug 2014;41(9):1843-1848. 
  379. Yefim Yushveyev-Cavalier, Warren Zeigler, Mary Ann McKee et al. Thoracic myelopathy due to hypertrophic pachymeningitis secondary to adalimumab (P4.040). Neurology. April 8, 2014;82(10):Supplement P4.040. 
  380. Danielle K Moul, Neil J Korman. Severe hidradenitis suppurativa treated with adalimumab. Arch Dermatol. 2006;142(9):1110-1112. 
  381. Martorell-Calatayud Antonio, Balmer Nicole, Cardenas Cardona, Luis Fernando, Teague Daniel. Interstitial granulomatous drug reaction to adalimumab. American Journal of Dermatopathology. June 2010;32(4):408-409.  
  382. MK de Vries, E Brouwer, IE van der Horst-Bruinsma et al. Decreased clinical response to adalimumab in ankylosing spondylitis is associated with antibody formation. Ann Rheum Dis. 2009;68:1787-1788. 
  383. Marietta Luz Juan-Guardela, Lisseth Fernanda Marin-Carrillo, Laura Ximena Kattah-Martinez, Daniel G Fernandez-Avila. Transaminase elevation secondary to the use of adalimumab. Reumatol Clin. 2014;10:265-6. 
  384. Bruce E Strober, Yves Poulin, Francisco A Kerdel et al. Switching to adalimumab for psoriasis patients with a suboptimal response to etanercept, methotrexate or phototherapy: Efficacy and safety results from an open label study. Journal of the American Academy of Dermatology. April 2011;64(4):671-681. 
  385. Gabriele Simonini, Andrea Taddio, Marco Cattalini et al. Superior efficacy of adalimumab in treating childhood rfractory chronic uveitis when used as first biologic modifier drug: Adalimumab as starting anti-TNF α therapy in childhood chronic uveitis. Pediatric Rheumatology 2013;11:16. 
  386. Boulos Haraoui, Alfred Cividino, Jacqueline Stewart et al. Safety and effectiveness of adalimumab in a clinical setting that reflects Canadian standard of care for the treatment of rheumatoid arthritis (RA): Results from the CanACT study. BMC Musculoskeletal Disorders 2011;12:261. 
  387. Leila Souabni, Leila Dridi, Kawther Ben Abdelghani et al. Possible macrophage activation syndrome following initiation of adalimumab in a patient with adult onset still's disease. The Pan African Medical Journal. 2014;17:94. 
  388. Cem Gabay, Paul Emery, Ronald van Vollenhovn. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double blind, controlled phase 4 trial. The Lancet. May 2013;381(9877):1541-1550. 
  389. AB Kimball, F Kerdel, D Adams, U Mrowietz et al. Adalimumab for the treatment of moderate to severe hidradenitis suppurativa. A parallel randomized trial. Annals of Internal Medicine. Dec 2012;157:846-855. 
  390. Michael H Weisman, Larry W Moreland, Daniel E Furst et al. Efficacy, pharmacokinetic and safety assessment of adalimumab, a fully human anti tumor necrosis factor alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate: A pilot study. Clinical Therapeutics. June 2003;25(6):1700-1721. 
  391. Anca Chiriac, Liliana Foia, Anca E Chiriac et al. A case of subacute thyroiditis in a patient on adlimumab for treatment of refractory palmo-plantar psoriasis. Muller Journal of Medical Sciences and Research. 2014;5(1):70-73. 
  392. Christoph Deuter, Manfred Zierhut. Effectiveness of adlimumab in the therapy of paediatric uveitis. European Ophthalmic Review. 2009;3(1):85-8. 
  393. Antonio Tursi, Walter Elisei, Marcello Picchio, ANtonio Penna et al. Effectiveness and safety of infliximab and adalimumab for ambulatory Crohn's disease patients in primary gastroenterology centres. European Journal of Internal Medicine. June 2014;25(5):485-490. 
  394. Zeljko Vucicevica, Vesna Degoricijaa, Lidija Dezmalj-Grbeljab. Severe neuropathy and tetraparesis induced by adalimumab. J Neurol Res. 2013;3(2):81-83. 
  395. Catherine E Berry, Jeffrey Tsai, Alexander Tierney, Robert Pickles. Visceral leishmaniasis in a patient taking adalimumab for rheumatoid arthritis. Med J Aust 2013;198(6):331-333. 
  396. Bernardo Frider, Andres Bruno, Marcelo Ponte, Marcelo Amante. Drug induced liver injury caused by adalimumab: A case report and review of bibliography. Case reports in hepatology. 2013, Article ID 406901, 3 pages. 
  397. Dennis A Revicki, Alan Menter, Steven Feldman, Miriam Kimel, Neesha Harnam, Mary K Willian. Adalimumab improves health related quality of life in patients with moderate to severe plaque psoriasis compared with the United States general population norms: Results from a randomized, controlled phase III study. Health and Quality of Lige Outcomes. 2008;6:75. 
  398. KM Grebe, J Salfeld, Z Kaymakcalan. Lack of adlimumab's complement dependent cytotoxicity on human cells expressing complement regulatory proteins. Journal of Translational Medicine. 2010;8(Suppl 1):P9. 
  399. Lapadula G, Marchesoni A, Armuzzi A, Blandizzi C et al. Adalimumab in the treatment of immune mediated diseases. Int J Immunopathol Pharmacol. Jan-Mar 2014;27(1 Suppl):33-48. 
  400. IIaria Puxeddu, Lucia Giori, Valeria Rocchi et al. Hypersensitivity reactions during treatment with infliximab, etanercept and adalimumab. Annals of allergy, Asthma & Immunology. Feb 2012;108(2):123-124. 
  401. Yasuhiro Shimojima, Masayuki Matsuda, Wataru Ishii, Shu-ichi Ikeda. Adalimumab monotherapy in a patient with psoriatic arthritis associated with chronic renal failure on hemodialysis: A case report and literature review. Clinical Medicine Insights: Case Reports 2012;5:13-17. 
  402. Jose J Blanco Perez, Angel Aranda Torres, JOse M Pego Reigosa et al. Pulmonary tuberculosis associated to adalimumab: a study of 3 cases. Arch Bronconeumol. 2010;46:203-5. 
  403. Jayashri V Ghate, Carrie D Alspaugh. Adalimumab in the management of palmoplantar psoriasis. Dermatology Online Journal. 15(7):15. 
  404. Alessandro Consolaro, Stefano Lanni, Alberto Martini, Angelo Ravelli. Adalimumab induced clinical remission in refractory and long standing systemic juvenile idiopathic arthritis: Case report. Ann Paediatr Rheum. 2014;3(1):29-34. 
  405. Flavio Caprioli, Chiara Vigano, Fiorenzo Botti, Ettore Contessini-Avesani. Adalimumab is safe and effective in re-inducing clinical remission after post-surgical relapse of Crohn's disease: A case report. DIgestive and Liver disease supplements. Dec 2010;4(1):14-17. 
  406. M Rodgers, D Epstein, L Bojke, H Yang et al. Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis: a systematic review and economic evaluation. Health Technology Assessment. 2011;15(10). 
  407. Sebastien Ottaviani, Anna Molto, Hang-Korng Ea et al. Efficacy of anakinra in gouty arthritis: a retrospective study of 40 cases. Arthritis Research & Therapy. 2013;15:R123. 
  408. Andrea Vambutas, Martin Lesser, Virginia Mullooly et al. Early efficacy trial of anakinra in corticosteroid resistant autoimmune inner ear disease. J Clin Invest. 2014;124(9):4115-4122. 
  409. SCB Teoh, S Sharma, A Hogan, R Lee, AV Ramanan, AD Dick. Tailoring biological treatment: anakinra treatment of posterior uveitis associated with the CINCA syndrome. Br J Ophthalmol. Feb 2007;91(2):263-264. 
  410. Kylie Thaler, Divya V Chandiramani, Richard A Hansen, Gerald Gartlehner. Efficacy and safety of anakinra for treatment of rheumatoid arthritis: an update of the Oregon Drug Effectiveness Review Project. Biologics. 2009;3:485-498. 
  411. George Lazaros, Panagiotis Vasileiou, Christos Koutsianas et al. Anakinra for the management of resistant idiopathic recurrent pericarditis. Initial experience in 10 adult cases. Ann Rheum Dis. doi: 10.1136/annrheumdis-2014-205990. 
  412. Saik Urien, Christophe Bardin, Brigitte Bader-Meunier et al. Anakinra pharmacokinetics in children and adolescents with systemic- onset juvenile idiopathic arthritis and autoinflammatory syndromes. BMC Pharmacology and Toxicology. 2013;14:40. 
  413. Lisa A Devlin, Gary Wright, J David M Edgar. A rare cause of a common symtom, Anakinra is effective in the urticaria of Schnitzler syndrome: a case report. Cases Journal 2008;1:348. 
  414. RM Fleischmann. Addressing the safety of anakinra in patients with rheumatoid arthritis. Rheumatology. 2003;42(suppl 2): ii29-ii35. 
  415. Sadan Soyyigit, Resat Kendirlinan, Omur Aydin, Gulfem E Celik. Successful desensitization with anakinra in a case with immediate hypersensitivity reaction. Annals of allergy, asthma & immunology. Sept 2014;113(3):325-326. 
  416. Ian C Scott, Vijay Hajela, Philip N Hawkins, Helen J Lachmann. A case series and systemic literature review of anakinra and immunosuppression in idiopathic recurrent pericarditis. Journal of cardiology cases. Oct 2011;4(2):e93-e97. 
  417. Arthur Kavanaugh. Anakinra (Interleukin-1 Receptor Anatgonist) has positive effects on function and quality of life in patients with rheumatoid arthritis. Advances in Therapy. March/April 2006;23(2):208-217. 
  418. Justin M Canada, Benjamin W Van Tassell, Sanah Christopher et al. Clinical predictors of response to anakinra in patients with heart failure. International Journal of Cardiology. May 15, 2014; 173(3):537-539. 
  419. Kieron S Leslie, Shivani V Tripathi, Tien V Nguyen, Mariela Pauli, Michael D Rosenblum. An open label study of anakinra for the treatment of moderate to severe hidradenitis suppurativa. Journal of the American Academy of Dermatology. Feb 2014;70(2):243-251. 
  420. Antonio Abbate, Fadi N Salloum, Elena Vecile et al. Anakinra, a Recombinant Human Interleukin-1 receptor antagonist, inhibits apoptosis in experimantal Acute Myocardial Infarction. Circulation. 2008;117:2670-2683. 
  421. Combination therapy of Abatacept and Anakinra in children with refractory systemic juvenile idiopathic arthritis: a retrospective case series. The Journal of Rheumatology. 2014;38(1):180-181. 
  422. PJ Kahn, RQ Cron. Higher dose anakinra is effective in a case of medically refractory macrophage activation syndrome. The Journal of Rheumatology. May 1, 2013;40(5):743-744. 
  423. David Launay, Virginie Dutoit-Lefevre, Emmanuel Faure et al. Effect of in vitro and in vivo anakinra on cytokines production in Schnitzler syndrome. PLOS one. March 19, 2013. doi: 10.1371/journal.pone.0059327. 
  424. Yoo Jin Park, Yun Zhang, Ziliang Ao, Mark Meloche et al. The IL-1 receptor antagonist anakinra enhances survival and function of human islets during culture: Implications in clinical islet transplantation. Canadian Journal of Diabetes. Oct 2012;36(5):244-250. 
  425. Gavin Giovannoni, Ralf Gold, Krzysztof Selmaj et al. Daclizumab high yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double blind extension trial. The Lancet Neurology. May 2014;13(5):472-481. 
  426. G Van Assche, WJ Sandborn, BG Feagan. Daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), for the treatment of moderately to severely active ulcerative colitis: a randomised, double blind, placebo controlled, dose ranging trial. Gut. Nov 2006;55(11):1568-1574. 
  427. Y Zhang, M McClellan, L Efros et al. Daclizumab reduces CD25 levels on T cells through monocyte mediated trogocytosis. Mult Scler. July 11, 2013. doi: 10.1177/1352458513494488. 
  428. Ralf Gold, Gavin Giovannoni, Krzysztof Selmaj et al. Daclizumab high yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double blind, placebo controlled trial. The Lancet. June 2013;381(9884):2167-2175. 
  429. D Przepiorka, NA Kernan, C Ippoliti et al. Daclizumab, a humanized anti-interleukin-2 receptor alpha chain antibody, for treatment of acute graft versus host disease. Blood. Jan 2000;95(1). 
  430. Bibiana Bielekova, Nancy Richert, Thomas Howard et al. Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon β. 
  431. The