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- 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• Useso Renal and other transplant rejection reaction
• Used in maintenance regimen for maintenance of graft Anti-CD3 antibodyMuromonab CD3
• Murine monoclonal antibody against CD3 glycoprotein expressed near to the T cell receptor on helper T cell
• Useso Acute transplant rejection reaction, particularly in steroid resistant caseso Used to deplete T cells from the donor bone marrow before transplantation
• Adverse effectso Initial doses are associated with cytokine release syndrome with flu like symptoms: chills, rigor, fever, wheezing, malaise etco Aseptic meningitiso Intragraft thrombosiso Life threatening pulmonary edemao Seizureo Shock like states Polyclonal antibodiesAntithymocyte 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
• Useso Acute allograft rejection episodes, especially in steroid resistant cases  o Also used in induction regimens• Adverse effectso Serum sicknesso 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 transplantation1. 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/azathioprineo 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: 

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