Anti-TNF and azathioprine Perdriger A, Mariette X, Kuntz JL, et al. (2006) Safety of in \202 iximab used in combination with le \202 unomide or aza- thioprine in daily clinical p ractice. J Rheumatol 33: 865 \200\2239. One of several observational studies suggesting aza thio- prine combination therapy with anti-TNF is not associated with any less ef \201 cacy or any more adverse events than combination treatment with le \202 unomide or methotrex- ate. PMR/GCA De Silva M and Hazleman BL (1986) Azathioprine in giant cell arteritis/polymyalgia rheumatica: a double-blind study. Ann Rheum Dis. 45: 136 \200\2238. A small double blind st udy (31 patients) showing that treatment with azathioprine (2.5 mg/kg/day) enabled a signi \201 cantly greater reduction in ste- roid requirements at 1 year than placebo treatment. Inhibition of CD28 co-stimulation AZA (through 6-MP) interferes in vitro with T cell co-sti m- ulation through CD28. This is analogous to the effects of CTLA4-Ig and may, in part, exp lain the immunosuppressant properties of azathioprine. Beh et \200\231s disease Yazici H, Pazarli H, Barnes CG, et al. (1990) A controlled trial of azathioprine in Beh et \200\231s syndrome. N Engl J Med. 322(5): 281 \200\2235. A doubl e blind study (73 patients) showing that treatment with azathioprine (2.5 mg/kg/day) reduce d the occurrence and recurrence of eye disease and reduced orogenital ulceration compared w ith placebo. Antigen presentation AZA has been shown to inhibit in vitro antigen presenta- tion by antig en presenting cells, another possible immuno- modulatory mechanism of action. Inhibition of activated T cells Genomic studies have shown that AZA and 6-MP have ef- fects on the expression of a variety of potentially relevant genes in activated T cells (but not quiescent T cells), includ- ing a number of TNF receptor related genes. ANCA associated vasculitis (AAV) Jayne D, Rasmussen N, Andrassy K, et al. (2003) A random- ized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 349: 36 \200\22344. A controlled study of 144 patients who ha d achieved disease remission with cyclophosphamide. Patients were randomly assigned to trea tment with either azathioprine (2 mg/kg/day) or continued cyclophospha- mide. There was no signi \201 cant difference in relapse rates in the two groups. Evidence base: the main clinical trials with AZA and what they showed Summary \200 AZA is effective as monotherapy in rheumatoid arthritis, systemic lupus erythematosus, and Behcet \200\231s. CHAPTER 19 DMARDs and immunosuppressive drugs 553 6-MP becomes preferentially metabolized via the IMPDH route (see Figure 19.7). Systemic lupus erythematosus (SLE) Although there is good trial evidence to support the use of azathioprine to maintain remiss ion, post-cyclophospha- mide, in patients with lupus nephritis, there is a lack of good tri al data to support it \200\231s use in other patients with SLE. Houssiau FA, Vasconcelos C, D \200\231Cruz D, et al. (2002) Immunosuppressive therapy in lupus nephritis: the Euro- Lu pus Nephritis Trial, a randomized trial of low dose ver- sus high dose intravenous cyclopho sphamide. Arthritis Rheum 46: 2121 \200\22331. A controlled study of 90 patients showing th at azathioprine maintenance treatment, follow- ing remission induction with cyclophosphamid e, was not significantly different to continued cyclophosphamide treatment. Both the availability and the use of TPMT screening is variable and whether it alters clini cal decision making is debated, since all patients treated with AZA are closely monitored f or marrow toxicity. Furthermore, TPMT screening does not allow assessment of the risks of p oten- tial hepatic toxicity. What dose should I prescribe? Usual protocol for AZA prescription (local protocols may vary ): \200 \200 The dose can be increased to 3 or 3.5 mg/kg/day if necessary. Week 1: 50 mg od \200\223 then if tolerated Week 2: 2.5 mg/kg/day (usually 100 \200\223150 mg/day) Important drug interactions \200 \200 \200 Prescribing considerations What do I need to do before starting the treatment? \200 \200 Allopurinol: increased risk of all toxicity. Captopril: increased risk of marrow suppressio n. Trimethoprim/cotrimoxazole: increased risk of mar- row suppression. Phenytoin: interfere s with absorption of azathioprine. Patient education re: dosing, side effects and monitoring. Ensure your patient has a patien t held monitoring booklet Record at baseline FBC LFTs ESR or CRP Renal function Monitoring of AZA \200 Allows monitoring of changes Allows monitoring of changes Monitor disease activity Monitori ng if renal disease activity (reduce dose if signi \201 cantly impaired) FBC & LFTs: example monitoring regime (local guide- lines may vary). Fortnightly for the \201 rst 4 weeks. Monthly thereafter. ESR: useful for monitoring response to treatment Side effects and what to discuss with your patients Common Nausea, abdominal discomfort, he adache, anorexia. dsDNA in SLE Allows monitoring of changes ANCA in AAV Allows monitoring of changes Uncommon Interstitial nephritis, pancreatitis, pneumonitis. What about checking TPMT status? Hematological toxicity \200 \200 \200 TPMT converts 6-MP to both active and inactive metabo- lites. The active metabolites produc ed by this route seem to correlate with hepatotoxicity. IMPDH metabolizes 6-MP to an active metabolite associated with more marrow tox- icity. TPMT has signi \201 cant genetic polym orphism. TPMT activity can be graded, with appropriate screening, as high, intermediate or low. Low levels of TPMT activity are as- sociated with signi \201 cantly more marrow toxic ity because Neutropenia, thrombocytopenia, pancytopenia. Warn patients to report infections/sore throat /bruising. These usually occur within the \201 rst 6 months of starting treatment with az athioprine. Sperm toxicity \200 A small, but significant increased risk of congenital abnormalities and spontaneous abortio n is seen in men taking thiopurines within 3 months of conception. Advise male patients to discontinue AZA for 3 months prior to conception azathioprine FAQs How long does it take to work? A clinical response is usually seen after 3 months of t reat- ment with AZA 6-mercaptopurine What do I do if I want to get pregnant? AZA is generally considered reasonably safe in preg nancy, although some studies have shown a small, but signi \201 cant increase in congenita l abnormalities and pre-term birth. Given the risks to patients of activation of SLE and va sculi- tis during pregnancy, the risk bene \201 t ratio is often in favor of continuing tr eatment in these patients. IMPDH TPMT Active metabolites with potential marrow toxicity Active metabolites with potential hepatotoxicity Inactive metabolites What about breastfeeding? Although listed as a contraindication in the BNF, AZA appears to be relatively safe to use during lactation. Studies have shown that the active metabolites are only detectable at signi \201 cantly sub-therapeutic levels in the breast milk of moth ers taking therapeutic doses of AZA. Furthermore, TPMT = thio-purine methyltransferase IMPDH = inosine monophosphate dehydrogenase Figure 19.7 AZATHIOPRINE 554 cannot tolerate, reduce the dose of AZA, and try to increase a few weeks later. WBC <3.5 \227 109/l. Stop AZA and review. Platelets <150 \227 109/l. Stop AZA and review. ALT > twi ce upper limit. Stop AZA and review. neonatal blood levels are undetectable and the infants show no evidence of immunosuppressio n. Does azathioprine cause cancer? There is some data to suggest a small increased risk of lym phoma amongst patients taking azathioprine. However, there is also an increased risk associ ated with the autoim- mune rheumatic diseases. Overall, the risk with azathio- prine appear s to be slightly greater, but the data is incon- clusive. Hypersensitivity reactions \200 \200 Dizziness, vomiting, diarrhea, myalgia, rash, hypotension. Stop AZA and treat as appropriat e. Interstitial nephritis Stop AZA and treat as appropriate. Can I drink alcohol? There is no evidence that alcohol interferes with azathio- prine, alth ough signi \201 cant hepatic impairment would be a relative contraindication and dose adju stment would be required. Pancreatitis Stop AZA and treat as appropriate. Pneumonitis Stop AZA and treat as appropriate. What about immunizations? \200 Live vaccines should be avoided: live polio, rubella, vari- cella, and yellow fever. In \202 uenza vaccination is recommended and is safe. What to do if side effects occur Common side effects These frequently resolve if the patien t can continue with treatment for 2 \200\2233 weeks. If they fail to resolve and patient This page intentionally left blank MYCOPHENOLATE MOFETIL 556 Mycophenolate mofetil Trade name: CellCept. Systemic lupus erythematosus (SLE) Ginzler EM, Dooley MA, Aranow C, et al. (2005) Mycophe- nolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 353: 2219 \200\22328. A large randomized open label study of 140 patients comparing oral MMF with IV pulsed cyclophosphamide in remission induction in renal SLE. The study showed that MMF is m ore effective and better tolerated than cyclophosphamide. Karim MY, Alba P, Cuadrado MJ, et al. (2002) Mycopheno- late mofetil for systemic lupus erythematosus refractory to other im munosuppressive agents. Rheumatol (Oxf) 41: 876 \200\22382. An open label study of 21 patie nts with refractory disease showing bene \201 t for MMF in both renal and non- renal disea se History \200 1800s: mycophenolic acid is identified in Penicillium fungus. 1969: mycophenolic acid is sh own to inhibit inosine monophosphate dehydrogenase (IMPDH). 1980s: mycophenolate mofetil (a pro-drug of mycophe- nolic acid) is developed and used in renal transplanta- tion. 1990s: placebo-controlled studies (PCS) con \201 rm the ef \201 cacy of mycophenolate mofetil in renal transplanta- tion. 1999: open pilot study of mycophenolate shows ef \201 cacy in SL E nephritis. 2000s: increasing evidence of ef \201 cacy in both renal and non-renal SLE. 2 004: evidence for mycophenolate in remission mainte- nance in vasculitis. ANCA associated vasculitis (AAV) Open label studies and anecdotal reports show ef \201 cac y in remission maintenance \200\223 less robust evidence for remis- sion induction. Langfo rd CA, Talar-Williams C, Sneller MC (2004) Myco- phenolate mofetil for remission maintenanc e in the treat- ment of Wegener \200\231s granulomatosis. Arthritis Rheum 51: 278 \200\2238 3. Stassen PM, Cohn Tervaert JW, Stegeman CA (2007) In- duction of remission in active anti -neutrophil cytoplasmic antibody-associated vasculitis with mycophenolate mofetil in patien ts who cannot be treated with cyclophosphamide. Ann Rheum Dis 66: 798 \200\223802. Two smal l open label studies (14 and 32 patients, respec- tively) showing ef \201 cacy for mycophe nolate in vasculitis [both remission maintenance and induction (in patients who could not b e treated with cyclophosphamide)]. Possible mechanisms of action Mycophenolate mofetil (MMF) is a pro-drug which is de- esteri \201 ed to mycophenolic acid (MPA). MPA is an inhibitor of the inducible inosine monophos phate dehydrogenase (IMPDH -2), which is particularly important in T and B lym- phocyte gua nine nucleotide synthesis. It has less effect on the constitutively expressed isoform (IMPD H-1). Enteric- coated mycophenolate sodium is an alternative pro-drug that has been develop ed and used more recently in the \201 eld of transplantation. The enteric-coated sodium s alt ap- pears to have less gastrointestinal side effects (see below), but similar ef \201 cacy. However, there is, as yet, very little data on its use in rheumatology. Dermatomyositis Majithia V, Harisdangkul V. (2005) Mycophenolate mofetil (CellCept): an alt ernative therapy for autoimmune in \202 am- matory myopathy. Rheumatol (Oxf) 44: 386 \200 \2239. One of several small open studies showing potentially bene \201 cial results in pat ients with dermatomyositis. As well as inhibiting T and B cell proliferation MMF has a number of other potentially bene \201 cial immunomodulatory effects. \200 \200 \200 Induction of T cell apoptosis. Inhibition of dendritic cell maturation. Inhibition of adhes ion molecule expression. Rheumatoid arthritis Mycophenoloate monotherapy Unpublished clinical trials have been under taken with MMF, but have failed to show bene \201 t Evidence base: the main clinical trials with MMF and what they showed Summary Apart from in renal SLE there is a relative lack of good randomized controlled studies, but \200 Beh et \200\231s disease Adler YD, Mansmann U, Zouboulis CC (2001) Mycophe- nolate mofetil is ineffective in the treatment of mucocuta- neous Adamantiades \200\223Behcet \200\231s d isease. Dermatology 203(4): 322 \200\2234. A prospective open label study of 30 patients sh ow- ing that treatment with MMF is ineffective in Behcet \200\231s. MMF is as effective as pulsed IV cyclophosphamide in remission induction in renal SLE. MMF appears effective in non-renal SLE. MMF appears effective in remission maintenance in ANCA associated vasculitis. MMF may be an alternative to cyclophosphamide in remission induction in certain patient with vasculitis. MMF may be effective in dermatomyositis. MMF is not ef fective in rheumatoid arthritis or Behcet \200\231s disease. \200 Prescribing considerations What do I need to do before starting the treatment? \200 \200 Patient education re: dosing, side effects and monitoring. Ensure your patient has a monito ring booklet \200 CHAPTER 19 DMARDs and immunosuppressive drugs 557 These usually occur within the \201 rst 6 months of starting treatment with MMF. Record at baseline FBC LFTs ESR or CRP Monitor disease activity Renal function Monitoring i f renal disease activity (reduce dose if signi \201 cantly impaired; MMF is 95% renally ex creted so if in doubt measure creatinine clearance) Although recommended the rationale is u nclear \200\223 some animal models actu- ally suggest favorable effects of MMF on atheroge nesis. It may re \202 ect the post-transplant effects of other immu- nosuppressants dsDNA in SLE Allows monitoring of changes ANCA in AAV Allows monitoring of changes BP Allows monitoring of changes Allows monitoring of changes Gastrointestinal toxicity \200 The gastrointestinal side effects are the most trouble- some with MMF, and can be reduced b y slowly increasing the dose or by splitting the dose from bd to qds. The new enteric-coate d mycophenolate sodium may be less problematic and similarly ef \201 cacious but has not y et been extensively studied in non-transplant use Lipid pro \201 le Contraception Mycophenolate is potentially toxic in pregnancy and ap- propriate contracepti on should be advised. What to do if side effects occur Common side effects \200 The gastrointestinal effects are discussed above. Other minor side effects frequently resol ve if the patient can continue with treatment for 2 \200\2233 weeks. If they fail to resolv e and patient cannot tolerate, one can consider dose reduction or try a qds, rather than a bd regime. Mycophenolate can cause hypertensive changes What dose should I prescribe? Usual protocol for MMF prescription (local protocols may vary ): \200 \200 \200 \200 Hypertension \200 \200 Consider dose reduction in \201 rst instance. If necessary treat with appropriate anti-hy pertensive. Week 1: 500 mg od, then if tolerated Week 2: 500 mg bd Week 3: 1 g morning, 500 mg evening From week 4: 1 g bd. The dose can be increased to 1.5 g bd if necessary Hematological toxicity \200 \200 \200 WBC <3.5 \227 109/l: stop MMF and review. Platelets < 150 \227 109/l: stop MMF and review . ALT > twice upper limit: stop MMF and review. Note: mycophenolate sodium: 720 mg is approximately equivalent to 1 g of MMF. FAQs How long does it take to work? A clinical response is usually seen after 3 months of t reat- ment with MMF. Important drug interactions \200 Antacids and colestyramine: reduce the absorption of MMF by 1/3. Phenytoin: absorption is reduced by MMF. Aciclovir/ganciclovir: increased plasma concentrations with MMF. What do I do if I want to get pregnant? The transplant literature shows an increased preval ence of congenital abnormalities, premature birth and low birth weight amongst babies born of patients taking MMF. Ideally, MMF should therefore be discontinued at least 6 weeks prio r to conception. However, this decision need to be balanced with the potential risk of stop ping or changing treatment, and needs careful discussion with the patient. \200 Monitoring of MMF FBC, renal function, and LFTs and BP Example monitoring regime \200 Weekly for the \201 rst month. \200 Fortnightly for th e next 2 months. \200 Monthly thereafter. What about breastfeeding? There is a lack of good data with which to advise in this area, b ut the general guidance is to avoid the use of myco- phenolate if breast feeding Does MMF cause cancer? There is con \202 icting data on whether MMF is associated with an increased risk of lymphoma and skin malignancy. Indeed, some studies suggest an anti-tumor effect. Pa- tients should generally be advised to use high factor suntan cream and avoid ex cessive sunlight exposure. ESR or CRP Useful for monitoring response to treatment (check monthly) Side effects and what to discuss with your patients Common Nausea, abdominal discomfort, di arrhea, headache, an- orexia. Can I drink alcohol? There is no evidence that alcohol interferes with MMF, although given the potentially hepatotoxic and pancreatitic effects of MMF moderation should be advised. Uncommon Rash (rarely Stevens \200\223Johnson syndrome), pancreatitis. What about immunizations? \200 Live vaccines should be avoided: live polio, rubella, varicella and yellow fever. In \202 uenza vaccination is recommended and is safe Hematological toxicity \200 \200 Neutropenia, thrombocytopenia, pancytopenia. Warn patients to report infections/sore throat /bruising. CICLOSPORIN (PREVIOUSLY CYCLOSPORIN A) 558 Ciclosporin (previously cyclosporin A) History \200 methotrexate alone in patient inadequately responding to methotrexate. Hetland ML, Stengaar d-Pedersen K, Junker P, et al. (2006) Combination treatment with methotrexate, cyclosporine , and intraarticular betamethasone compared with metho- trexate and intra-articular betamet hasone in early active rheumatoid arthritis: an investigator-initiated, multicenter, random ized, double-blind, parallel-group, placebo- controlled study. Arthritis Rheum. 54: 1401 \200\2239. The CIMES- TRA Study: a randomized controlled trial in 160 patients showing bene \201 t from the addition of ciclosporin to metho- trexate and intraarticular steroids in patients with early rheumatoid. 1971: ciclosporin is identi \201 ed as an 11 amino acid peptide product of the soil fungus Tolypocladium In \202 atum, itself identi \201 ed as part of a program at Sandoz (subse- quently Novartis) to identify fungally derived antibiotics. 1972: animal studies demonstra te immunosuppressive effects of ciclosporin, subsequently shown to be due to T cell mediate d effects, as well as nephrotoxicity. 1979: ciclosporin use, in preventing organ transplant rejection, is published by Prof Sir Roy Calne. 1983: ciclosporin approved by the FDA for u se in trans- plantation. 1984: synthetic ciclosporin produced. 1991: ciclosporin is identi \201 ed (in an open label study) as being ef \201 cacious in rheumatoid arthritis, but wi th signi \201 - cant renal toxicity. 1995: micro-emulsion synthetic ciclosporin developed with improved bio-availability (neoral). \200 2. Ciclosporin and le \202 unomide Karanikolas G, Charnlambopoulos D, Andrianakos A, et al . (2006) Combination of cyclosporine and le \202 unomide ver- sus single therapy in severe rheumatoid arthritis. J Rheuma- tol 33: 486 \200\2239. A randomized controlled trial in 10 6 patients showing that the combination of le \202 unomide (20 mg) and ciclosporin (2.5 \200\2235 mg/kg/day) was better than either treat- ment as monotherapy in chronic rheumatoi d arthritis Possible mechanisms of action Ciclosporin inhibits the early activation of helper T cells ( CD4+ T cells) by inhibition of IL-2 production. Ciclospo- rin binds to an intracellular pro tein (immunophilin) in CD4+ T cells. This complex in turns inhibits the action of calcineur in \200\223 a calcium dependent enzyme that is impor- tant in the regulation of interleuki n 2 (IL-2) expression in T cells. IL-2 is critically important in early T cell activation a nd proliferation. CD4+ T cells are thought to have an impor- tant role in rheumatoid arthri tis \200\223 they are key regulators of both the innate and the acquired immune response, they can be identi \201 ed in the rheumatoid synovium, and there is the Class II MHC assoc iation with HLA-DRB0401. 3. Ciclosporin and hydroxychloroquine Miranda JM, Alvarez-Nemegvei J, Saavedra MA, et al. ( 2004) A randomized, double-blind, multicenter, controlled clini- cal trial of cyclosporine plus chloroquine vs. cyclosporine plus placebo in early-onset rheumatoid arthritis. Arch Me d Res 35: 36 \200\22342. A randomized controlled trial in 149 pa- tients showing that the c ombination of antimalarials and ciclosporin (2.5 \200\2235 mg/kg/day) was no better than ci clospo- rin alone. Psoriatic arthritis Ciclosporin monotherapy Spadaro A, Riccieri V, Sili-Scavalli A, et al. (1995) Compari- son of cyclosporin A and methotrexate in the treatment of psoriatic arthrit is: a one-year prospective study. Clin Exp Rheumatol 13: 589 \200\22393. A small randomized study (35 pa- tients) showing that ciclosporine monotherapy is similarly ef \201 cacious to methotrexate monotherapy in psoriatic arthritis. Evidence base: the main clinical trials with ciclosporin and what they showed Summary Ciclo sporin is ef \201 cacious in both rheumatoid arthritis and psoriatic arthritis. It is more effective as a combination treatment with both methotrexate and le \202 unomide than as m onotherapy. There are no large randomized controlled studies, but a number of small studies show ef \201 cacy in both renal and non-renal SLE, as well as myositis. There is anec- do tal data and small series showing ef \201 cacy in Behcet \200\231s syndrome. Ciclosporin combination therapy 1. Ciclosporin and methotrexate Fraser AD, van Kuijk AW, We sthovens R, et al. (2005) A randomized, double blind, placebo controlled, multicentre trial of combination therapy with methotrexate plus ciclo- sporin in patients with active psoria tic arthritis. Ann Rheum Dis 64: 859 \200\22364. A randomized controlled study in 72 pa- ti ents with psoriatic arthritis only partially responsive to MTX, showing signi \201 cant, b ut limited ef \201 cacy of additional ciclosporin. Rheumatoid arthritis Ciclosporin monotherapy Ahern MJ, Harrison W, Hollingsworth P, et al. (1991) A ran- domised double-blind trial of cyclosporin and azathioprine in refractory rheu matoid arthritis. Aust N Z J Med 21: 844 \200\2239. A randomized study showing that monothe rapy with ciclosporin is similar to azathioprine in terms of ef \201 cacy Systemic lupus erythematosis Caccavo D, Lagana B, Mitterhofer AP, et al. (1997) Long- term treatment of systemic lupus erythematosus with cy- closporine A. Arthritis Rheum 40: 27 \200\22335. An open label prospective study in 30 patients showing ef \201 cacy of ciclo- sporin in non-renal SLE. Tam LS, Li EK, Leung CB, et al. (1998) Long-term treatment of lupu s nephritis with cyclosporin A. QJM. 91(8): 573 \200\22380. A small open label study (17 pa tients) showing ef \201 cacy of ciclosporin in renal SLE (WHO Type IV). Ciclosporin combination therapy 1. Ciclosporin and Methotrexate Tugwell P, Pincus T, Yocum D, et al. (1995) Combination therapy with cyclosporine and methotrexate in severe rheumatoi d arthritis. The Methotrexate-Cyclosporine Combination Study Group. N Engl J Med 333(3): 13 7 \200\22341. A double blind placebo-controlled study in 148 patients showing that step-up combination treatment with ciclosporin and methotrexate was more ef \201 cacious than CHAPTER 19 DMARDs and immunosuppressive drugs 559 Thereafter, monitor monthly. ESR or CRP: useful for monitoring response to treat- ment (che ck monthly). Dermatomyositis/polymyositis Vencovsky J, Jarosova K, Machacek S, et al. (2000) Cy- clospor ine A versus methotrexate in the treatment of polymyositis and dermatomyositis. Scand J Rhe umatol 29: 95 \200\223102. A randomized study of 36 patients with in \202 amma- tory myosi tis showing similar ef \201 cacy for methotrexate and ciclosporin. Side effects and what to discuss with your patients Common Nausea, abdominal discomfort, di arrhea, headache, tremor, paraesthesia Prescribing considerations What do I need to do before starting the treatment? \200 \200 Uncommon Hirsutism and gum hyperplasia, seizures. Advise patients on oral hygiene to preven t gum disease and on cosmetic ap- proaches to any hirsuitism. Patient education re: dosing, side effects, and monitoring. Ensure your patient has a patie nt held monitoring booklet Record at baseline Nephrotoxicity \200 FBC LFTs ESR or CRP Monitor disease activity Renal function (Ciclosporin is nephrotoxic). M easure \2273 serum creatinine (record average baseline creatinine). Measure creati- nine c learance Allows monitoring of changes Treat hypertension before commencing Allows monitoring of changes Allows monitoring of changes Rising serum creatinine and hyperkalaemia: discuss with patients what is being monitored an d why. Warn patients about the interaction of ciclosporin with grapefruit juice, and the im portance of monitoring of renal function and blood pressure What to do if side effects occur Common side effects The common side effects will usually s ubside once treat- ment becomes established. If persistent consider dose re- duction. Urine BP What dose should I prescribe? Usual protocol for ciclosporin prescription (local proto- col s may vary): \200 \200 \200 \200 Hypertension on treatment \200 \200 Consider dose reduction in \201 rst instance. If necessary treat with an appropriate anti -hypertensive and continue treatment. Stop treatment if hypertension remains uncontrolled. Starting dose 2.5 mg/kg/day (twice daily divided dose). After 6 weeks (if tolerated). Incre ase by 25 mg per day every 2 \200\2234 weeks Maximum dose 4 mg/kg/day (in rheumatoid arthri tis/ psoriatic arthritis). In other conditions doses up to 5 mg/kg/day may be used. The bra nd of ciclosporin should be speci \201 ed. Generally neoral (the micro-emulsion of ciclosp orin) is the oral version of ciclosporin that is used. If changing from neural to sandim- m un the bioavailability is less but generally a conversion of 1:1 is reasonable. If converti ng from sandimmun to neoral, an initial small dose reduction should be considered. Nephrotoxicity \200 Nephrotoxicity is monitored with reference to the base- line average creatinine. If there i s a rise in serum creatinine >30% above baseline: consider dose reduction; if failure to improve after 1 month, discontinue. Rise in serum cr eatinine >50% above the average baseline creatinine should trigger discontinuation of treat ment. \200 FAQs How long does it take to work? A clinical response is usually seen after 3 months of t reat- ment with ciclosporin Important drug interactions \200 There is an increased risk of nephrotoxicity and hyper- kalaemia when ciclosporin is given with other nephro- toxic agents (NSAIDs, ACE inhibitors, aminoglycoside antibiotics, amphot ericin, cipro \202 oxacin, melphalan, tri- methoprim, colchicines, potassium sparing diure tics). St John \200\231s Wort also potentiates the action of ciclosporin. Statins: there is an increased risk of myopathy on statins [probably due to effects of ciclosporin on the he patic transportation of statins (+/ \200\223 an effect on the cytochrome P450-mediated meta bolism of the statins)]. Grapefruit juice: grapefruit juice increases the plasma concentrat ion of ciclosporin by interfering with gastroin- testinal cytochrome P450 function. What do I do if I want to get pregnant? The transplant literature suggests an increased pre valence of low birth weight and prematurity amongst babies born of patients taking ciclospo rin (possibly due to interference with fetal uptake of the amino acid taurine). Ideally, ci clo- sporin should therefore be discontinued at least 6 weeks prior to conception. However, the risk appears small and ciclosporin has certainly been used successfully in preg- nancy . The serum concentration of ciclosporin falls during pregnancy so if dose escalation is re quired during preg- nancy, the pre-pregnancy dose should be returned to post- partum to avo id nephrotoxicity. What about breastfeeding? Ciclosporin is excreted in the breast milk so in general it is ad visable to avoid ciclosporin if breast feeding. However, anecdotal data from the transplant ation experience sug- gests that the drug is not signi \201 cantly absorbed by the in- fan t since in one study serum levels in an infant breast feeding, whilst their mother was on c iclosporin were unde- tectable (despite detectable levels in breast milk). Monitoring of ciclosporin Monitor 2-weekly for the \201 rst 3 months: \200 \200 \200 \200 Serum creatinine. FBC. Blood pressure. Urinalysis. CICLOSPORIN (PREVIOUSLY CYCLOSPORIN A) 560 Does ciclosporin cause cancer? There is some data to suggest an increased risk of non- mela noma skin cancer. Patients should generally be advised to use high factor suntan cream and avoid excessive sunlight exposure. Can I drink alcohol? There is no evidence that alcohol interferes with ciclosporin. What about immunizations? \200 Live vaccines should be avoided: live polio, rubella, varicella, and yellow fever. In \202 uenza vaccination is recommended and is safe There does not seem to be an increased risk of other malignancies. This page intentionally left blank CYCLOPHOSPHAMIDE 562 Cyclophosphamide immune tolerance and might, in part, account for it \200\231s ef \201 - cacy in autoimmune diseases like SLE and AAV. Trade name: Endoxana History \200 Evidence base: the clinical trials with cyclophosphamide Summary Overall, the data in SLE w ith renal involvement from con- trolled studies (such as the NIH (National Institute of Hea lth) studies) support the use of IV pulsed cyclophos- phamide (in combination with IV methy lprednisolone) for remission induction in lupus nephritis. The NIH regime uses 0.5 \200\223 1 g/m2 cyclosphosphamide monthly with IV methyl- prednisolone for induction. There is some evidence that lower dose regimens (500 mg IV fortnightly) may be as ef- \201 cacious as t hese higher dose regimens. Maintenance treat- ment with cyclophosphamide also has proven ef \201 cacy in lupus nephritis, but for such longer-term treatment other immunosuppressive regimens (such as azathioprine, metho- trexate or mycophenolate) may be as ef \201 cacious (and less toxic). There is less robust, but nonetheless signi \201 cant, data to support the use of IV cyclophosphamide in other pa- tients with severe non-renal neuropsychiatric S LE. 1958: Brock (working for ASTA Werke pharmaceutical company in Germany) publishes in Nature the develop- ment of a cyclic nitrogen mustard phosphamide ester (cyclophosphamide), which shows selective in vivo acti- vation. This oxazaphosphorine was synthesized in a transporta tion form which is enzymatically activated to the active nitrogen mustard. 1960s: cyclophos phamide is shown to be ef \201 cacious in cancer treatment and in the late 1960s is shown to have immunosuppressive effects (in transplantation). 1960s: urothelial toxicity of cyclo phosphamide is recog- nized as problematic. 1968: animal studies report the bene \201 ts o f cyclophos- phamide in lupus nephritis. 1971: a placebo controlled study shows ef \201 ca cy of oral cyclophosphamide treatment in lupus nephritis. 1978: the protective effects of M ESNA (sodium-2-mer- captoethane-sulfonate) in preventing urothelial toxicity are identi \201 ed. 1980s/90s: randomized controlled studies (the NIH studies) show the ef \201 cacy of IV pulsed cyclophospha- mide (in combination with IV methylprednisolone) in lupus nephri tis. 1990s: randomized controlled studies with cyclosphos- phamide show ef \201 cacy in AN CA associated vasculitides. Cyclophosphamide (particularly intravenous pulsed therapy in combination with intravenous p ulsed steroid) is also effective in both inducing and maintaining remission in ANCA associa ted vasculitis (AAV). The standard regimes in AAV use 10 \200\22315 mg/kg doses of cyclopho sphamide given fortnightly for 6 weeks then 3-weekly for 9 weeks for re- mission induction. This regimen is also known as the CY- CLOPS regimen, since it is the regime that has been stud- ied in an ongoing large multicentre study of pulsed versus oral cyclophosphamide for remission induction Mechanism of action Cyclophosphamide is a pro-drug (an inactive cyclic phos- phamide ester of phosphoramide mustard) that undergoes an in vivo activation process. It is initially hep atically me- tabolized via cytochrome P450 to an equilibrium mixture of 4-hydroxycyclophosp hamide and aldophosphamide. In both AAV and SLE intravenous pulsed treatment is associated with less toxicity than cont inuous oral treat- ment with similar ef \201 cacy. Oral cyclophosphamide shows weak ef \201 cacy as mono- therapy in rheumatoid arthritis, bu t toxicity and side effects are severe. Aldophosphamide can be metabolized to phospho- ramide mustard (the active guanidine alkylat ing agent responsible for the therapeutic effects) and acrolein (the agent responsible for bladder toxicity). Aldophosphamide can also be inactivated via aldehyde dehydrogenase (ALDH ). The therapeutic effects of cyclophosphamide are therefore seen predominantly in cells wi th relatively low levels of ALDH. SLE Steinberg AD, Kaltreider HB, Staples PJ, et al. (1971) Cyclo- phosphamide in lupus neph ritis: a controlled trial. Ann In- tern Med 75: 165 \200\22371. The \201 rst randomized p lacebo con- trolled study of oral cyclophosphamide (3 \200\2234 mg/kg/day \200\223 a relat ively high dose regime) in lupus nephritis. 13 patients treated over 10 weeks \200\223 sig ni \201 cant bene \201 t in cyclophos- phamide treated group relative to placebo Austin H A, Klippel JH, Balow JE, et al. (1986) Therapy of lupus nephritis. N Engl J Med 314: 614 \200\22319. The \201 rst of the NIH studies, in 107 patients, using a variety of regimes. The study showed that IV pulsed cyclophosphamide (0.5 \200\2231 g/ m2) was signi \201 can tly better in proliferative lupus nephritis (reduced rate of end stage renal failure after 5 years) than oral steroids. The other regimes (oral cyclophospha- mide and azathioprine) w ere not shown to be statistically different from IV pulsed cyclophosphamide, but neither we re they shown to be signi \201 cantly better than oral steroids. The phosphoramide mustard moiety causes alkylation of guanidine nucleotides and inhibits DN A polymerization, thereby preventing cell replication in susceptible cell types. It is non- cell cycle phase speci \201 c. The most susceptible cell types are those which are most ra pidly dividing, such as those of the immune system and the bone marrow. The immunoregulatory effects of cyclophosphamide ap- pear to be mediated, in part, through effects on T cell activ- ity. There is some evidence that cyclophosphamide sup- presses Th1 -mediated immune responses whilst enhancing Th2-mediated responses. More recently there has been interest in a possible role of cyclophosphamide in modify- ing immune tolerance. Ther e is evidence, from the trans- plantation literature, that cyclophosphamide reduces CD4+CD2 5+ regulatory T cells which could modulate CHAPTER 19 DMARDs and immunosuppressive drugs 563 Boumpas DT, Austin HA, Vaughan EM, et al. (1992) Con- trolled trial of pulse methylpredniso lone versus two regi- mens of pulse cyclophosphamide in severe lupus nephritis. Lancet 340: 741 \200\2235. The second NIH study, in 65 patients, showing that pulsed IV cyclophosphami de [either over 6 months (0.5 \200\2231 g/m2 monthly) or 30 months (0.5 \200\2231 g/m2 mont hly \2276/12 then 3-monthly \2272 years) was better (as measured by increasing creatinine ) than pulsed IV methylprednisolone. Relapses were more common in the 6-month study group t han the 30-month group, but the 6-month group was not given any treatment to maintain remis sion. Gourley MF, Austin HA, Scott D, et al. (1996) Methylpred- nisolone and cyclophosphami de, alone or in combination, in patients with lupus nephritis. Ann Intern Med 125: 549 \200 \223 57. The third NIH study, in 82 patients, demonstrating the superior ef \201 cacy of c ombination treatment with pulsed IV cyclophosphamide (0.5 \200\2231 g/m2 monthly \2276/12 then 3- monthly \2272 years) and IV methylprednisolone, compared with pulsed IV methylpred nisolone alone. There was a trend to improved ef \201 cacy of combination treatment over p ulsed IV cyclophosphamide alone, but this failed to reach statistical signi \201 cance. Fl anc RS, Roberts MA, Strippoli, et al. (2004) Treatment for lupus nephritis. Cochrane Databa se Syst Rev 1: CD002922. A meta-analysis of all cyclophosphamide studies conclud- ing that cyclophosphamide treatment, in combination with steroids, is ef \201 cacious in proliferat ive lupus nephritis. A sig- ni \201 cant risk of gonadal failure (relative risk 2.18) was also noted. Yee CS, Gordon C, Dostal C, et al. (2004) EULAR random- ized controlled trial o f pulse cyclophosphamide and meth- ylprednisolone versus continuous cyclophosphamide and pr ednisolone followed by azathioprine and prednisolone in lupus nephritis. Ann Rheum Dis 63: 525 \200\2239. A randomized controlled study in 32 patients showing no signi \201 cant dif - ference in ef \201 cacy between pulsed treatment (10 mg/kg IV initially than pulsed oral treatment thereafter) and continu- ous treatment with cyclophosphamide (2 mg/kg/day \227 3 months) in remission induction and maintenance in renal SLE. However, the IV/pulsed regim e was better tolerated. Houssiau FA, Vasconcelos C, D \200\231Cruz D, et al. (2002) Im- mun osuppressive therapy in lupus nephritis: the Euro- Lupus Nephritis Trial, a randomized tria l of low dose ver- sus high dose intravenous cyclophosphamide. Arthritis Rheum 46: 2121 \200\22331. A controlled study of 90 patients showing that fortnightly pulsed low dose IV c yclophospha- mide (500 mg/2 weeks) was as effective in remission induc- tion as high dose t reatment (0.5 g/m2 increasing by 250 mg with each pulse to a maximum of 1500 mg/pulse), but with less infection risk. Barile-Fabris L, Ariza-Andraca R, Olguin-Ortega L, et al. (2005) Controlled clinical trial of IV cyclophosphamide versus IV methylprednisolone in severe ne urological mani- festations in systemic lupus erythematosus. Ann Rheum Dis 64: 620 \200\223 5. A controlled study of 32 patients with severe neurological SLE. The study showed that, a fter an initial 3 g IV methylprednisolone treatment, pulsed IV cyclophospha- mide (0.75 g/m 2 monthly for 1 year and then 3-monthly thereafter for another year) was signi \201 cantly better (>20% neurological improvement) than pulsed IV methylprednis- olone (1 g monthly \2274/12, 2-monthly \2276/12, 3-monthly \227 1 year) alone.