Figure 19.5 Pulmonary toxicity. Persistent ALT but < twice upper limit of normal ALT > twice upper limit of normal Stop leflunomide and monitor response Reduce leflunomide dose and monitor Persists Persistent problem Resolved Stop leflunomide and monitor response Hepatitis serology Colestyramine or Activated charcoal Washout Consider Retreatment at Lower dose Persists Resolved Assessment with Hepatologist Hepatitis serology Hepatic ultrasound Liver biopsy Consider Retreatment at Lower dose Colestyramine or Activated charcoal Washout Figure 19.6 Hepatic toxicity. ANTI-MALARIALS (HYDROXYCHLOROQUINE AND CHLOROQUINE) 544 Anti-malarials (hydroxychloroquine and chloroquine) Trade name Hydroxychloroquine = Plaquenil. Although there is some in vitro data to support an anti- thrombotic effect of HCQ in antiph ospholipid antibody syndrome there is a lack of good quality trial data to sup- port it \200\231s routine use. History \200 Antiquity: bark of the cinchona tree of South America (found in the Andes Mountains); recog nized as having bene \201 ts in treating fever. 1600s: Spanish Jesuits introduce the cinch ona bark to Europe. 1670s: powder of cinchona bark used to treat fever in King Charles II. 1820: quinine (the active compound) isolated from cin- chona bark. 1895: Dr Thomas Payne (P hysician, St Thomas \200\231 Hospital London), successfully uses quinine for patients with lupus erythematosus. 1931: quinacrine (mepacrine), the \201 rst synthetic quinine derivat ive is synthesized (Bayer, Germany). 1934: chloroquine; the \201 rst synthetic aminoquino lone is synthesized (Bayer, Germany). Hydroxychloroquine, another aminoquinolone, is synthe sized soon after. 1951: Page publishes evidence for mepacrine in SLE in Lancet 1957: data p ublished on the ef \201 cacy of chloroquine in SLE. 1959: data published on the ef \201 c acy of hydroxychloro- quine in SLE. 1960s: retinal toxicity of the anti-malarials (particul arly chloroquine) highlighted. 1970s: hydroxychloroquine is found to be as ef \201 cacious as chloroquine, but associated with less retinal toxicity. 1980s: monitoring protocols dev eloped for hydroxy- chloroquine. There is good quality trial evidence for HCQ, particu- larly in combination with MTX (+/- S ulfasalazine) in rheu- matoid arthritis SLE The Canadian Hydroxychloroquine Study Group (1991) A randomized study of the effect of withdrawing hydroxy- chloroquine sulfate in systemic lupus erythematosus. N Engl J Med. 324 (3): 150 \200\2234. Withdrawal of hydroxychloro- quine is associated with an increased prev alence of lupus \202 ares. Drugs for discoid lupus erythematosus (2001) Cochrane Database Syst Rev 1:CD002954. A review of the trials in discoid lupus concluding that hydroxychloro quine is ef \201 ca- cious. Williams HJ, Egger MJ, Singer JZ, et al. (1994) Comparison of hydroxychloroquine and placebo in the treatment of the arthropathy of mild systemic lupus e rythematosus. J Rheu- matol 21: 1457 \200\22362. A small study (71 patients) that showed mi nimal bene \201 ts for hydroxychloroquine in treating the arthropathy of SLE. Rheumatoid arthritis HCQ monotherapy The HERA Study (1995) A randomized trial of hydroxy- c hloroquine in early rheumatoid arthritis: the HERA Study. Am J Med. 98: 156 \200\22368. A D BPCS of 120 rheumatoid patients showing the ef \201 cacy of hydroxychloroquine as monother apy in early rheumatoid arthritis (<2 years dura- tion). A subsequent follow-up study showe d that the treat- ment had long term bene \201 t. Possible mechanisms of action Inhibition of antigen presentation The aminoquinolones increa ses the pH within a number of cytoplasmic compartments. This is likely to interfere with th e antigen presentation function of B cells and macro- phages by affecting the assembly of M HC Class II molecules with peptide. This may be an important effect of antima- larials when used in combination treatments in rheumatoid arthritis. HCQ combination therapy Hydroxychloroquine is ef \201 cacious in combination with MTX. HCQ and methotrexate O \200\231Dell JR, Leff R, Paulsen G, et al. (2002) Treatment of rheum atoid arthritis with methotrexate and hydroxychlo- roquine, methotrexate and sulfasalazine, or a combination of the three medications: results of a two-year, random- ized, double-bli nd, placebo-controlled trial. Arthritis Rheum 46: 1164 \200\22370. Mottonen T, Hannonen P, Leirsalo-Repo M, et al. (1999) Comparison of combination therapy with single-drug ther- apy in early rheumatoid arthritis: a randomized trial. FIN- RACo trial group. Lancet 353(9164) : 1568 \200\22373. Triple com- bination treatment with MTX, hydroxychloroquine and sulfasal azine (or MTX and hydroxychloroquine) is better than MTX and sulfasalazine in combination. Induction of apoptosis Aminoquinolones have been shown to increase apoptosis in certain cel l types. Given the proposed defect in apopto- sis in SLE this may be an important mechanism in SLE. Reduced levels of B-cell activating factor BAFF is a serum factor (part of the TNF family) that appear to be important in autoantibody production in SLE. The quinolones appear to red uce the levels of BAFF. Evidence base: the clinical trials with HCQ and what they showed Summary Despite widespread usage, there is a relative lack of good quality trial evidence to support the use of anti- malarials in SLE. There is some evidence to support HCQ treatment of the mucocutaneous mani festations of SLE and evidence that HCQ treatment reduces the frequency of \202 ares in m ild/moderate disease. There is a lack of good evidence for the articular manifestations. Prescribing considerations What do I need to do before starting the treatment? \200 Patient education re: dosing, side effects, monitoring, drug interactions, etc. It is parti cularly important to discuss visual considerations (see below). CHAPTER 19 DMARDs and immunosuppressive drugs 545 Important drug interactions Amiodarone and moxi \202 oxacin: there is a signi \201 cant i ncreased risk of ventricular arrhythmias when used with either of these drugs concomitantly . Record at baseline FBC LFTs ESR or CRP Renal function Allows monitoring of changes Adjust dose if impaired Monitor disease activity Adjust dose i f impaired Monitoring of HCQ Blood tests There is no requirement for regular blood test monitoring. Baseline visual assessment, Royal College of Ophthalmologists 2004 Visual monitoring See Royal College of Ophthalmologists 2004. \200 Ask about visual impairment. Record near visual acuity of each eye (with glasses where appr opriate). Hydroxychloroquine is consider safe in pregnancy, with no evidence of fetal toxic ity at therapeutic doses. In SLE studies have shown that there is a signi \201 cantly grea ter risk of \202 ares, if the treatment is discontinued. In SLE it is there- fore reasona ble to continue treatment. See College of Op- thalmologists website: http://www.rcophth.ac. uk/docs/ publications/Oculartoxicity2004.pdf \200 Ask patient about visual symptoms and monitor visual acuity annually using the reading char t http://www.rcophth. ac.uk/docs/publications/Oculartoxicity2004.pdf. This can be undertake n by either a rheumatologist or an optometrist. Refer to ophthalmologist if: Visual acuity changes: treatment should be stopped. Vision rep orted blurred. \200 Side effects and what to discuss with your patients Common Nausea, abdominal discomfort, he adache, skin reactions. If no abnormality is detected with the above, treatment with HCQ can be commenced. If visua l impairment is present an assessment, initially by an optometrist, is advised. If chloroqu ine is being prescribed ALL patients require regular ocular examinations by an ophthalmolog ist and liaison with the local ophthalmologists is required before commencing treatment Rare Prolonged QT syndrome and predisposition to ventricular arrhythmias. FAQs How long does it take to work? A clinical response is usually seen within 3 months wit h both hydroxychloroquine and chloroquine What dose should I prescribe? \200 The maximum daily dose of hydroxychloroquine is 6.5 mg/kg/day. The usual treatment dose in both rheumatoid arthritis and SLE is 200 mg bd. This can be reduced to 200 mg od once a res ponse has occurred or if side effects are problematic. The maximum daily dose of chloroquin e is 2.5 mg/kg/ day. The usual treatment dose in both rheumatoid arthritis and SLE is 150 m g od. What do I do if I want to get pregnant? Rheumatoid improves in pregnancy, HCQ treatment is frequently discontinued and restarted post-delivery. Do I have to take other anti-malarials if I am traveling? Yes \200\223 hydroxychloroquine is not an effective monotherapy for malaria. Other anti-malarial quinolones should generall y be avoided. GOLD: INTRAMUSCULAR (SODIUM AUROTHIMALATE) AND ORAL (AURANOFIN) 546 Gold: intramuscular (sodium aurothimalate) and oral (aurano \201 n) Trade names: Myocrisin, Intramuscular Gold, Ridaura, Oral Gold. Antigen presentation Gold salts inhibit the differentiation of dendritic cells from their p recursor cells thereby interfering with antigen pre- sentation. This effect on maturation m ay be secondary to gold salts actions on Toll-like receptors or Class II MHC function. History \200 2000 BC: records suggest that the Egyptians and Chinese ingested solid gold for medicinal purposes. 1300s: the Islamic alchemist Geber produces \200\230aqua regia \200\231 \200 \223 soluble gold salts (using nitric and hydrochloric acid to dissolve gold). 1500s: parac elsus uses soluble gold salts as a treatment for melancholy. 1700s: gold salts included in Culpepper \200\231s pharmacopeia for general malaise. 1800s: gold salt use re-emerges as a treatment of syphilis. 1905: Robert Koch awarded the Nobel Prize for Medicine for identi \201 cation of Mycobacterium tuberculosis as the cause of tuberculosis. Koch also demonstra ted that Gold cyanide inhibited the growth of Mycobacterium in vitro. 1920s: gold salts use d to treat pulmonary tuberculosis despite a lack of clinical evidence of ef \201 cacy, on the basis of Koch \200\231s in vitro \201 ndings. 1920s: gold salts used to treat rheumat oid arthritis on the basis that the mycobacterium may be important in the etiology. 1927: a German study demonstrates the ef \201 cacy of gold treatment in rheumatoid arthritis. 197 6: oral gold (aurano \201 n) introduced for treatment of rheumatoid arthritis. 1970s/1980s : most commonly used DMARD in rheuma- toid arthritis. T cell activation Gold salts have been shown to interfere with peptide pre- sentation by Cl ass II MHC molecules and impair subse- quent T cell activation. Cytokine production (TNFA, IL-12, IL-1 and IL-10) Gold salts inhibit TNFA and IL-12 secretion by activated monocytes. Gold salts also inhibit IL-1 converting enzyme activity thereby reducing IL-1 secretion. Fu rthermore, gold salts have been shown, in vivo, to increase serum levels of IL-10, an anti- in \202 ammatory cytokine that reduces TNFA, IL-1 and IL-6 expression by monocytes. Metalloproteinases Gold salts can react with the thiol groups in metallopro- teinases, such as collagenase, to inhibit their activity. Evidence base: the main clinical trials with gold salts and what they showed Summary IM gol d is more effective than PO gold. There is evidence of short-term bene \201 t in rheumatoi d arthritis, as mono- therapy or in combination with methotrexate. Side effects limit it \200\231s utility. Rheumatoid arthritis Gold monotherapy Clark P, Tugwell P, Bennett K, et al. (1989) Meta-ana lysis of injectable gold in rheumatoid arthritis. J Rheumatol. 16: 442 \200\2237. A meta-an alysis of trials with injectable gold as monotherapy showing a signi \201 cant improvement in active synovitis, function and in \202 ammatory markers. 11% of trial patients discont inued due to side effects. Ward JR, Williams HJ, Egger MJ, et al. (1983) Comparison of aura no \201 n, gold sodium thiomalate, and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum 26: 1303 \200\22315. A placebo controlled study (193 patients) showing that both oral and injectable gold salts are ef \201 cacious. The oral preparation (aurano \201 n) was less ef \201 cacious, but better tolerated than the inject- able preparation. Possible mechanisms of action Sodium aurothiomalate (intramuscular gold) is a water soluble gold thiolate salt. Aurano \201 n is an orally bioavailable lipophilic gold salt (also a thiolate salt) developed in the 1980s. Serum gold levels with aurano \201 n are lower than those with aurothiomalate (probably accounting for both the improved side effect pro \201 le and the reduced ef \201 cacy). Nevertheless, the presumed mechanisms of action of both gold salts are presumed to be similar. Gold thiolate salts appear to have potentially impo rtant actions at every stage of immune activation \200\223 potential effects at the differ ent levels are indicated below. These effects appear to be pre- dominantly mediated by inte ractions of the gold thiolate salts with thiols (compounds containing an \200\223SH group) such as cysteine. These thiol-mediated effects are probably also important in the etiology of the side effects of gold salt treatment. Gold combination therapy 1. Gold and methotrexate Lehman AJ, Esdaile JM, Klinkhoff AV, et a l. (2005) A 48-week, randomized, double-blind, double-observer, placebo-con- trolled multic enter trial of combination methotrexate and intramuscular gold therapy in rheumatoid arthri tis: results of the METGO study. Arthritis Rheum 52: 1360 \200\22370. The METGO study: IM g old is statistically better than placebo as step-up combination in MTX partial responders. Innate immune system Toll-like receptor 4 (TLR4) is part of the recognition arm of the inna te immune system. Gold salts have been shown to interfere with TLR4 activation, thereby int erfering with NFkB activation in antigen presenting cells and reduced expression of COX-2. CHAPTER 19 DMARDs and immunosuppressive drugs 547 Prescribing considerations What do I need to do before starting the treatment? \200 \200 Approximately every 2 \200\2233 months: ESR or CRP: useful for monitoring response to treatment. An annual Chest X-ray is advised o n gold treatment Patient education re: dosing, side effects, and monitoring. Ensure your patient has a patie nt held monitoring booklet Oral gold Every 2 weeks for 2 months then monthly thereafter: \200 \200 For either oral or intramuscular gold: Urinalysis: look for developing proteinuria/haematuria. FBC: look for evidence or bone marr ow suppression. Look for eosinophilia \200\223 it may precede a skin reaction. LFTs/CRP/ES R: every 2 \200\2233 months. Record at baseline FBC Urinalysis ESR or CRP Renal function Avoid if signi \201 cantly imp aired Avoid if signi \201 cantly impaired Liver function Allows monitoring of changes Ches t X-ray Allows monitoring of changes Allows monitoring of changes Monitor disease activity Side effects and what to discuss with your patients Approximately 1/3 of patients experienc e side effects with IM gold salts. Oral gold (aurano \201 n) has a wider therapeutic index with less side effects, but lower ef \201 cacy. Although the side effects below are more common with intramuscular gold, they can still occur with the oral preparation. Common Nausea, abdominal discomfort, skin rashes, malaise, head- ache, anorexia, oral ulcer ation. What dose should I prescribe? Intramuscular gold (either deltoid or gluteal) Initial treatm ent is weekly \200 Week 1 \200\223 10 mg: this is a test dose to ensure no immedi- ate hypersensitivity react ion (ideally, this should be undertaken in hospital and patient observed for 1 h). Thereaft er, 50 mg weekly until a total dose of 1000 mg (excluding the test dose). Then reduce dose to 50 mg every 2 \200\2234 weeks dependent on response (usually monthly). A response will u sually take 12 \200\22315 weeks and should not be expected before at least 500 mg total dos e has been achieved. If a patient fails to signi \201 cantly respond after a total dose of 1 g the treatment should be discontinued. A maximum duration of 5 years of treatment with intra- muscular gold is advised by some. Hematological toxicity \200 \200 \200 Neutropenia, thrombocytopenia, pancytopenia. Warn patients to report infections/sore throat /bruising. These usually occur within the \201 rst 6 months of starting treatment with su lfasalazine. Dermatological toxicity Can cause local pruritis to severe exfoliative dermatitis. In addit ion, long-term treatment with gold can cause a persis- tent blue-gray photosensitive skin p igmentation (chrysia- sis). Patients should be advised to inform their doctor of any skin r ashes developing on gold treatment. Renal toxicity In approximately 10% of patients, gold can cause protein- uria (usually reve rsible) and, rarely, haematuria, secondary to membranous glomerulonephritis. This can progr ess to nephrotic syndrome and renal impairment. Patients should be aware of the importance of urine dipstick monitoring Oral gold The normal starting dose is 3 mg od increasing to 3 mg bd after 1 month if tolera ted. The dose should then be increased at 6 months to 9 mg (3 mg tds) if inadequate respons e. Dis- continue after 9 months if no signi \201 cant response. Hepatic toxicity Gold can cause hepatotoxicity with cholestatic jaundice. Patients should b e aware that liver function is monitored as part of the regular blood testing Why do you give the test dose for intramuscular gold? Approximately 5% of patients develop an acute vasomotor reaction to intramuscular gold, within the \201 rst hour of the \201 rst dose (a nitritoid reaction). This may include a rash, \202 ushing, hypotension, and collapse. It should be managed as an anaphylactic reaction according to the clinical severi ty. The test dose should therefore be given where appropriate facilities for management./re suscitation are available \200\223 usually this is within hospital. Pulmonary toxicity Gold can cause a progressive pulmonary \201 brosis. This is monitored with an annual chest X-ray. FAQs How long does it take to work? A clinical response is usually seen after 3 \200\2234 months of treatment with gold What do I do if I want to get pregnant? There is evidence of transplacental transfer of gold to the fetus. Although there are no speci \201 c data on t eratogenic- ity, it is advisable to discontinue gold treatment 3 month prior to a planned c onception. Important drug interactions ACE inhibitors: there appears to be an increased risk of a \201 rst dose reactions in patients on ACE inhibitors. Monitoring of gold Intramuscular gol d Before every dose of intramuscular gold check: \200 \200 Urinalysis: look for developing proteinuria/haematuria. FBC: look for evidence of bone marr ow suppression. Look for eosinophilia \200\223 it may precede a skin reaction. Renal funct ion: look for worsening renal function. LFTs: look for developing hepatotoxicity. Skin: ins pect for developing skin rash. What about breastfeeding? Weight adjusted serum gold levels in a breastfeeding child have b een shown to be higher than those in the mother. Gold treatment should be avoided during br east feeding. \200 \200 GOLD: INTRAMUSCULAR (SODIUM AUROTHIMALATE) AND ORAL (AURANOFIN) 548 Can I drink alcohol? There is no evidence that alcohol interferes with gold Renal toxicity Proteinuria \200 + on dipstick on 1 occasion \200\223 continue treatment and monitor. ++ or greater on urin e dipstick or + on more than 2 occasions. Check MSU to exclude infection. Arrange 24-h urin e collection. If 24-h protein excretion >0.1, but <0.5 g/24 h \200\223 continue treatment and monitor. If 24-h protein excretion >0.5 g/24 h, stop treatment. What to do if side effects occur Common side effects \200 Mouth ulcers can be improved with a regular mouth wash. Abdominal pain can be improved with a high \201 bre diet. Mild skin rashes can improve with anti-histamines or 1% hydrocorti sone. Mild side effects may improve with a reduction in the dose or frequency of gold treat ment. \200 \200 \200 Haematuria ++ or greater on urine dipstick \200\223 stop treatment, check MSU, consider ot her causes. Hematological toxicity \200 WBC <3.5 \227 109/l. \200 Platelets < 150 \227 109/l Stop gold and review. \200 Eosinophilia This may precede a skin rash. If it occurs reduce dos e or frequency of gold and observe. Hepatic toxicity \200 Acute jaundice or persistent elevation of ALT >twice upper limit of normal. Stop treatment, Dermatological toxicity \200 Dependent on severity of skin reaction reduce dose or frequency or discontinue. Try with 1% hydrocortisone with or without antihista- mines. Chrysiasis is generally irreversible, but gold should be discontinued if it develops. This page intentionally left blank PENICILLAMINE 550 Penicillamine Trade name: Distamine . Rheumatoid arthritis Penicillamine monotherapy Van Jaarsveld CH, Jacobs JW, van der Veen MJ , et al. (2000) Aggressive treatment in early rheumatoid arthritis: a ran- domised controll ed trial. On behalf of the Rheumatic Re- search Foundation Utrecht, The Netherlands. Ann Rh eum Dis 59(6): 468 \200\22377. A randomized trial of several treatments showing that penici llamine was less ef \201 cacious and associ- ated with more toxicity than other treatments including methotrexate, sulfasalazine and hydroxychloroquine. History \200 1943: penicillamine is identi \201 ed as a degradation product of penicillin. 1956: Dr J W alshe identi \201 es penicillamine as a heavy metal chelator and describes it \200\231s us e as a copper chela- tor in the treatment of Wilson \200\231s disease. 1950s/60s: D and L i soforms of penicillamine are studied \200\223 L-isoforms are identi \201 ed as toxic in r ats [due to greater pyridoxine (vitamin B6) antagonism], whilst D isoforms emerge as therap eutic agents. D-penicillamine is used to treat cystinuria, Wilson \200\231s disease, and pr imary biliary cir- rhosis. 1963: penicillamine is identi \201 ed as being ef \201 cacious in rheumatoid arthritis when used as a possible chelator of rheumatoid factor. 1966: penic illamine is identi \201 ed as having potentially favorable effects on collagen in systemic sclerosis. Systemic sclerosis Penicillamine monotherapy Clements PJ, Furst DE, Wong WK, et al. (1999) High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis: analysis of a two-year, double-blind, randomized, controlled clinical trial. Arthritis Rheum. 42: 1194 \200\223203. A 2- year trial of 134 patients with systemic sclerosis comparing high dose (7 50 \200\2231000 mg/day) with low dose (125 mg alt days) penicillamine. No signi \201 cant difference was demon- strated. There was no placebo arm so it is possible that low dose pen icillamine may be effective, but there is no trial data to support that assumption. Possible mechanisms of action Penicillamine is a cysteine analog that contains a free thiol group. Like the gold thiolate salts, penicillamine can there- fore interact with compounds containing an \200\223SH group, such as the amino acid cysteine These thiol mediated ef - fects are likely to important in the mechanism of action and the side effects of penicill amine, as they are with gold. Like gold penicillamine may have effects on the immune system at multiple levels. There are relatively few studies of the mechanism of action of penicil lamine, but there is evi- dence for cytokine effects (but not on TNF) and effects on metall oproteinases. 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 patie nt held monitoring booklet. Record at baseline FBC Urinalysis ESR or CRP Renal function Avoid if signi \201 cantly imp aired Allows monitoring of changes Allows monitoring of changes Monitor disease activity Cytokine production Penicillamine has been shown in vitro and in animal models to produce a more Th2 type cytokine pro \201 le with in- creased IL-4 production and decreased interfe ron gamma production. What dose should I prescribe? \200 \200 Metalloproteinases Penicillamine has been shown in vivo to inhibit the activity of gelatina se B (MMP-9), a neutrophil and monocyte de- rived metalloproteinase that may be important i n rheuma- toid synovitis. Month 1: 125 \200\223250 mg (usually 250 mg) od. Thereafter: Increasing by 125 \200\223250 mg/month to usual maintenance of 750mg/day [maximum dose 1.5 g/day (1 g/day in the elderly) ]. Important drug interactions \200 Rheumatoid factor Penicillamine has been shown both in vivo and in vitro to reduce rheumato id factor production. Antipsychotics: increased risk of agranulocytosis with clozapine. Iron and antacids: reduce the absorption of penicilla- mine. Penicillamine inhibits collagen cross-linking in vitro, main- taining collagen in a more so luble form. This is probably through thiol mediated effects. This action was the reason pen icillamine treatment was considered in patients with systemic sclerosis. Monitoring of penicillamine Every 2 weeks for \201 rst month and then monthly thereaf- te r: \200 \200 \200 Penicillamine is also a heavy metal chelator and is used for copper chelation in Wilson \200\231s disease and treatment of ar- senic poisoning. This does not seem to be important in it \200\231s mechanism of action in rheumatoid or systemic sclerosis Urinalysis: look for developing proteinuria/haematuria. FBC: look for low platelets or low white cell count. ESR or CRP: useful for monitoring response to treat- ment. Evidence base: the main clinical trials with penicillamine and what they showed Summary Pen icillamine is less effective than other DMARDs in rheu- matoid arthritis and is associated with more toxicity. Trials have failed to demonstrate ef \201 cacy in systemic sclerosis. CHAPTER 19 DMARDs and immunosuppressive drugs 551 Side effects and what to discuss with your patients Penicillamine treatment is associated w ith a wide spectrum of side effects. Approximately 2/3 of patients discontinue penicillamin e in the \201 rst 2 years of treatment and the ma- jority of these are due to side effect s. It is estimated that 50% of patients experience side effects with penicillamine. The mos t important side effects are given below. What about breastfeeding? Penicillamine treatment should be avoided during breast feeding. Can I drink alcohol? There is no evidence that alcohol interferes with penicil- lamine What to do if side effects occur Common side effects Mild side effects may improve with a r eduction in the dose of penicillamine. Common Nausea, abdominal discomfort, skin rashes, taste distur- bance, malaise, headache, a norexia Hematological toxicity \200 WBC <3.5 \227 109/l. \200 Platelets < 150 \227 109/l. Sto p penicillamine and review. Hematological toxicity \200 \200 \200 Occurs in approximately 5% of patients. Neutropenia, thrombocytopenia, pancytopenia all see n. Warn patients to report infections/sore throat/bruising. Renal toxicity \200 Proteinuria. \200 + on dipstick on 1 occasion \200\223 continue tr eatment and monitor. ++ or greater on urine dipstick or + on more than 2 occasions \200 \223 check MSU to exclude infection. Arrange 24- h urine collection. If 24-h protein excret ion >0.1, but <0.5 g/24 h \200\223 continue treatment and monitor. If 24-h protein excreti on >0.5 g/24 h stop treatment. Spontaneous resolution of proteinuria may take >12 months. C onsider corticosteroids treatment for more rapid resolution Renal toxicity Occurs in approximately 10% of patients. Penicillamine can cause proteinuria (usually reversible), and rarely haematu- ria, secondary to membranous glomerulonephritis (in ap- proximately 90% of cases). Proteinuria most frequently develops after 4 \200\2236 m onths of treatment (75% of cases within 1 year). This can progress to nephrotic syndrome an d renal impairment if treatment is continued. Patients should be aware of the importance of urine dipstick moni- toring. \200 Systemic reactions Rarely penicillamine can cause a febrile reaction, drug-in- duced lupus, and a myasthenia-like syndrome. Haematuria ++ or greater on urine dipstick \200\223 stop treatment, check MSU, consider ot her causes. FAQs How long does it take to work? A clinical response is usually seen after 3 \200\2234 m onths of treatment with penicillamine. What do I do if I want to get pregnant? Penicillamine is contraindicated in pregnancy. In a nimal models it has adverse effects on lung development. Advise discontinuation 3 months pr ior to conception. AZATHIOPRINE 552 Azathioprine Trade name: Imuran AZA is a weakly effective steroid sparing agent in GCA/ PMR. AZA is effective in maintainin g remission (but not induc- ing remission) in ANCA associated vasculitis and in lupus nephr itis. History \200 1951: Elion and Hitchings (working at the Burroughs Wellcome Research Laboratories) develop 6-mercap- topurine (a thiopurine) as part of a program to design purine analogs to interfe re with nucleic acid synthesis (they are subsequently awarded the Nobel Prize for medicine in 1988 for their work). 1952: 6-mercaptopurine is shown to be ef \201 cacious in childhoo d leukemia. 1963: azathioprine (a pro-drug of 6-mercaptopurine) is developed and found to b e less toxic than 6-mercap- topurine, but similarly ef \201 cacious. 1960s: Professor Sir Roy Calne uses 6-mercaptopurine and subsequently azathioprine as immunosuppressants to prev ent transplant rejection. Reports of azathioprine having ef \201 cacy in a variety of rheu matic diseases accu- mulate. 1969: DBPCS con \201 rm the ef \201 cacy of azathioprine in rheumatoid arthritis and systemic lupus erythematosus. 1986: DBPCS shows ef \201 cacy in P MR/GCA. 1990: DBPCS shows ef \201 cacy in Behcet \200\231s. Rheumatoid arthritis AZA monotherapy Barnes CG, Currey HL, Dunne JF, et al. (1969) Azathio- prine: a controlled double-blind trial in rheumatoid arthri- tis. Ann Rheum Dis 28: 327 \200\2238. A double blind placebo con- trolled study with 49 patients over 1 year showing t hat azathioprine (2.5 mg/kg/day) facilitated a statistically signi \201 - cant reduction i n steroid requirements. Suarez-Almazor ME, Spooner C, Belseck E. (2000) Azathio- prine for treating rheumatoid arthritis. Cochrane Database Syst Rev 2: CD001461. A meta-analysis show ing that aza- thioprine has short-term ef \201 cacy in patients with rheuma- toid arthriti s. Long-term ef \201 cacy could not be assessed due to a lack of data and azathioprine was associated with more toxicity than other DMARDs \200 AZA combination therapy There is some data to suggest azathioprine is a safe alter- native to use in combination with in \202 iximab, but there is no evidence of ef \201 cacy in co mbination with other DMARDs Possible mechanisms of action Azathioprine (AZA) is a pro-drug consisting of the thiopu- ri ne 6-mercaptopurine (6-MP) and a nitro-imadazole ring (6-thioinosinic acid). AZA is metabol ized in vivo to 6-MP that is then further converted into several active metabo- lites by tw o main enzymes \200\223 TPMT (thio-purine methyl- transferase) and IMPDH (inosine monophos phate dehy- drogenase). TPMT also metabolizes 6-MP to an inactive metabolite (see below for the importance of this in toxic- ity). The anti-proliferative effects of AZA and 6-MP are mediated through the purine antagonist properties of 6- MP metabolites, inhibiting DNA repl ication. However, whether this wholly accounts for the immunosuppressive properties is uncl ear. Other possible mechanisms are out- lined below: 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.