The two initial anti-TNF studies (with etanercept and in \202 iximab) showing that combina tion treatment with MTX and anti-TNF is ef \201 cacious in MTX non-responders Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. (2005). Clinical and radiogr aphic outcomes of four different treatment strategies in patients with early rheu- matoid a rthritis (the BeSt study): a randomized controlled trial. Arthritis Rheum 52: 3381 \200\223 90. The BeSt study showing that early combination treatment with methotrexate and anti-TNF, or methotrexate, sulfasalazine, and prednisolone, resulted in more rapid improvement clini cally and joint damage suppression than sequential monotherapy or step- up combination ther apy. Record at baseline FBC LFTs ESR or CRP Renal function Allows monitoring of changes Allows monitoring of changes Monitor disease activity Impaired renal function increases MTX levels Either history or serology Allows comparison in pulmon ary toxicity Psoriatic arthritis MTX monotherapy Willkens RF, Williams HJ, Ward JR, et al. (1984) Random - ized, double-blind, placebo controlled trial of low-dose pulse methotrexate in psoriatic arthritis. Arthritis Rheum 27: 376 \200\22381. Showed that MTX is more ef \201 cacious tha n pla- cebo \200\223 in the Cochrane systematic review of 2000 it was concluded: \200\230 The magnitude of the effect seen with \200 oral low dose methotrexate suggests that it ma y be effective, but that further multicentre clinical trials are required to establish its ef \201 cacy \200\231. Sulfasalazine and parenteral high dose MTX were seen to be more ef \201 cacious Varicella status CXR An abnormal CXR is not a contraindication to treat- ment, but the patient should be monitor ed carefully, since there is an increased risk of MTX pneumonitis in patients with pre-exis ting lung disease. Some clinicians advocate pre-treatment pulmonary func- tion to facilitat e monitoring in the event of pneumonitis (see below under pneumonitis), but this is not uni versal Liaise with the patients GP represcribing and appropri- ate monitoring of the treatm ent MTX combination therapy In psoriatic arthritis the only good evidence is for ciclospo- rin and MTX combination treatment: Fraser AD, van Kuijk AW, Westhovens R, et al. (2005) A rando mized, double blind, placebo controlled, multicentre trial of combination therapy with meth otrexate plus ciclo- sporin in patients with active psoriatic arthritis. Ann Rheum Dis 64: 859 \200\22364. Showed that patients responding inade- quately to MTX alone bene \201 ted from additional DMARD treatment with ciclosporin. What dose should I prescribe? \200 \200 \200 Oral methotrexate: 7.5 \200\22325 mg/week. Methotrexate should not be crushed or chewed. Me thotrexate is a weekly treatment, e.g. M is for Methotrexate on a Monday. Various protocols are used for dosage escalation. S ome use a more rapidly escalating regime than others. Giant cell arteritis There is no evidence for the use of methotrexate in GCA. Hoffman GS, C id MC, Hellmann DB, et al. (2002) A multi- center, randomized, double-blind, placebo-contro lled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum. 46 : 1309 \200\22318. One of several good quality studies that have failed to show any bene \201 t for MTX in giant cell arteritis. METHOTREXATE 534 Note: MTX does not appear to cause pulmonary \201 brosis Warn patients to report new: dry cough +/- dyspnoea. Example regime: \200 10 mg/week starting dose increasing at 6 weeks (if blood test monitoring satisfactory) to 1 5 mg/week. Thereafter, 3 monthly increases of 2.5 mg/week (if blood test monitoring satisfa ctory) until dose of 25 mg/week or disease adequately controlled. In vasculitis the usual s tarting dose in 15 mg/week. Hepatic toxicity \200 \200 \200 \200 MTX can cause hepatic \201 brosis and cirrhosis. More problematic in patients with psoria tic arthritis. Alcohol exacerbates this problem. Warn patients to avoid alcohol (psoriatic) and to minimize alcohol (rheumatoid). Oral versus parenteral treatment \200 Above 20 mg/week the bioavailability of oral meth- otrexate is variable and partial respond ers may ben- e \201 t from a change to parenteral (usually subcutaneous) treatment Overall dose should be adjusted on conversion due to improved bioavailability 20 mg/week of oral M TX = 15 mg/week of SC. MTX FAQs How long does it take to work? A clinical response is usually seen after 3 months of treat- ment with methotrexate What if I want to get pregnant? Methotrexate is teratogenic, and should be avoided before and during pregnancy. It can have effects on both sperm and ova. It can also cause miscarriage. Methotrexate should be disco ntinued at least 3 months prior to planned con- ception by men and women Folic acid prescription? \200 Folic acid supplementation reduces side effects (muco- cutaneous and hepatic) without affec ting ef \201 cacy and is generally prescribed routinely. It should not be given the same d ay and is usually given weekly like MTX, e.g. F for Folic Acid on a Friday What about fertility? Methotrexate may affect fertility in both and men and women although this has not been exte nsively studied. What about injections? \200 Important drug interactions \200 Live attenuated vaccines need to be avoided by patients taking methotrexate: yellow fever, MMR and rubella, BCG, oral polio, oral typhoid. Other vaccines will not be a problem. Patie nts should be advised to have an annual in \202 uenza immunization since they are at an in creased risk of in \202 u- enza. Trimethoprim and Cotrimoxazole (Septrin) can cause acute pancytopenia and should be avoided . Phenytoin can increase the anti-folate effects of MTX. Probenecid decreases MTX excretion . NSAIDs do not signi \201 cantly interfere with MTX at the doses used rheumatologically \200 \200 \200 What if I miss a dose? Methotrexate can be taken at the normal dose up to 48 h after the us ual time of the weekly dose. If later than 48 h the dose for that week should be omitted an d the normal dose taken the following week. Monitoring \200 FBC & LFTs: the British National Formulary advises weekly until therapy is stabilized and t hereafter 2 \200\2233 monthly. ESR: useful for monitoring response to treatment Can I drink alcohol? Patients with psoriatic arthritis should be advised to avoid alcohol. Patients with rheumatoid arthritis should be ad- vised to minimize alcohol consumption Side effects and what to discuss with your patients Common Nausea, abdominal discomfort, di arrhea, anorexia, oral ulceration. What to do if side effects occur Common side effects \200 \200 Hematological toxicity Neutropenia, thrombocytopenia, pancytopenia. Warn patients to report infections/sore throat/bruising Reduce the dose of MTX. Consider increasing folic acid dose. Pulmonary toxicity \200 \200 Acute interstitial pneumonitis (an acute presentation). This is a hypersensitivity reaction to methotrexate. CHAPTER 19 DMARDs and immunosuppressive drugs 535 ASYMPTOMATIC PATIENT SYMPTOMATIC PATIENT Persistent Neutropenia (<1.5x109/L) or Thrombocytopenia (<150x109/L) Neutropenia (<1.5x109/L) or Thrombocytopenia (<150x109/L) Stop MTX Give appropriate antibiotics for neutropenic sepsis Give folinic acid rescue (calc ium folinate) (IV bolus 30mg followed by 15mg qds orally x2/7) Monitor response Consider G- CSF if recalcitrant Stop MTX and monitor response Persists Resolved Persists Patient improves Consider Retreatment at Lower dose Assessment with Hematologist Consider Retreatment at Lower dose Assessment with Hematologist Figure 19.1 Hematological toxicity. Acute Respiratory Illness (Dry Cough +/-dyspnoea and fever) Stop MTX CXR (look for diffuse interstitial shadowing) \200\223 compare with baseline CXR FBC (looking for eosinophilia) ABGs (looking for hypoxia) Blood and sputum cultures Pulmona ry Function Test (decrease TLCO and VC suggestive) Suspicious of pneumonitis No evidence of pneumonitis Consider HRCT and BAL (need to exclude pneumocystis pneumonia) Liaise with respiratory phys icians Restart MTX Assess for other causes Treatment High dose oral prednisolone or IV Methylprednisolone Oxygen +/-Ventilatorysupport Consider IV cyclophosphamide AVOID RETREATMENT IN FUTURE Figure 19.2 Pulmonary toxicity. METHOTREXATE 536 Persistent ALT but < twice upper limit of normal ALT > twice upper limit of normal Reduce methotrexate dose by 2.5mg/week and monitor Hepatitis serology Hepatic ultrasound Stop MTX and monitor response Persistent problem Resolved Persists Stop MTX and monitor response Consider Retreatment at Lower dose Assessment with Hepatologist Hepatitis serology Hepatic ultrasound Liver biopsy Persists Resolved Assessment with Hepatologist ?Liver biopsy Consider Retreatment at Lower dose Figure 19.3 Hepatic toxicity. Surgical considerations It is safe to continue MTX in the perioperative period and stopping the treatment may be associated with worse post-operative outcomes due to impaired rehabil itation. This page intentionally left blank SULFASALAZINE K. HARRIS 538 Sulfasalazine Dougados M, van der Linden S, Leirisalo-Repo M, et al. (1995) Sulfasalazine in the treatmen t of spondylarthropa- thy. A randomized, multicenter, double-blind, placebo- controlled stu dy. Arthritis Rheum 38: 618 \200\22327. Gupta AK, Grober JS, Hamilton TA, et al. (1995) Sul fasala- zine therapy for psoriatic arthritis: a double blind, placebo controlled trial. J R heumatol 22: 894 \200\2238. Clegg DO, Reda DJ, Mejias E, et al. (1996) Comparison of sulfas alazine and placebo in the treatment of psoriatic arthritis. A Department of Veterans Affai rs Cooperative Study. Arthritis Rheum 39: 2013 \200\22320. A selection of the placebo-contr olled trials showing ef \201 - cacy for SSZ in patients with psoriatic arthritis. A review of the evidence in favor of SSZ in psoriatic arthritis was pub- lished by the Cochrane Rev iew Group in 2000. Trade name Salazopyrin History \200 1942: Dr Svartz synthesizes sulfasazaline \200\223 a combina- tion of an anti-in \202 amm atory (5-aminosalicylic acid) and an antibiotic (sulfapyridine). 1973: sulfasalazine shown to have ef \201 cacy in ulcerative colitis. 1983: sulfasalazine shown to have ef \201 cac y in rheumatoid arthritis. 1990: sulfasalazine shown to have ef \201 cacy in psoriatic art hritis. Possible mechanisms of action Sulfasalazine (SSZ) is a combination of 5-amino salicylic aci d and sulfapyridine. The anti-in \202 ammatory, 5-aminosali- cylic acid is produced follow ing metabolism of SSZ in the intestine and is not well absorbed. It is this non-absorbed 5- aminosalicylic acid component that accounts for the ef- \201 cacy of SSZ in in \202 amma tory bowel disease. The sulfapyri- dine moiety is absorbed systemically and probably ac- co unts for much (but not all) of the ef \201 cacy of SSZ in in \202 ammatory arthritis. Rheumatoid arthritis SSZ monotherapy Pullar T, Hunter JA, Capell HA (1983) Sulphasalazine i n rheumatoid arthritis: a double blind comparison of sulphasalazine with placebo and sodium aurothiomalate. Br Med J (Clin Res Ed) 287(6399): 1102 \200\2234. The \201 rst study sho wing the ef \201 cacy of SSZ in rheumatoid arthritis. Inhibition of NFkB activation NFkB is important in T cell activation and can be induced by TNF-A. This mechanism of action may underline the ef- \201 cacy of sulfasalazine in in \202 ammatory arthritis. Sulfapyri- dine in isolation does not appear to have the same effe ct. SSZ combination therapy Sulfasalazine is ef \201 cacious in combination with MTX and ste- roid, particularly when hydroxychloroquine is used as well. SSZ, hydroxychloroquine, and methotrexate O \200\231Dell JR, Leff R, Paulsen G, et al. (200 2) Treatment of rheumatoid arthritis with methotrexate and hydroxychlo- roquine, methotrexa te and sulfasalazine, or a combination of the three medications: results of a two-year, ran dom- ized, double-blind, placebo-controlled trial. Arthritis Rheum 46: 1164 \200\22370. Mot tonen 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 gr oup. Lancet. 353(9164): 1568 \200\22373. Triple com- bination treatment with MTX, hydroxych loroquine, and sulfasalazine (the COBRA regime, or MTX and hydroxy- chloroquine) is better than MTX and sulfasalazine in com- bination. Induction of apoptosis of activated T cells This effect may be linked to the NFkB inhibitio n, since NFkB inhibits the action of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). Activity of this ligand results in apoptosis of T cells, which is enhanced following in vitro treatment with sulfasalazine. Cytokine Inhibition (IL-1 and TNF A) Sulf asalazine has been shown to inhibit TNF expression in monocytes in vitro and to reduce IL-1 and TNF A levels in vivo, which may clearly be an important mechanism of action in in \202 ammatory arthritis. Inhibition of folate uptake Although probably not important as a mechanism of action, this action interferes with the uptake of MTX and predisposes patients on sulfasalazine to folat e de \201 ciency. SSZ, methotrexate, and prednisolone Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. (2005) Clinical and radiographic outcomes of four different treatment strategies in patients with early rheu- matoid arthritis (the BeSt study): a randomized controlled trial . Arthritis Rheum 52: 3381 \200\22390. The BeSt study showed that early combination treatme nt with methotrexate and anti-TNF, or methotrexate, sulfasalazine, and prednisolone, result ed in more rapid improvement clinically and joint damage suppression than sequential monoth erapy or step-up combination therapy. Prescribing considerations What do I need to do befor e starting the treatment? \200 Patient education: dosing, side effects, monitoring. \200 Ensure your patient has a monitoring booklet. Evidence base: the main clinical trials with SSZ and what they showed Summary \200 SSZ is effective as monotherapy in psoriatic arthritis and appear more ef \201 cacious tha n methotrexate in this condition. SSZ is less effective in rheumatoid arthritis than meth- otrexate, but is nonetheless ef \201 cacious as monotherapy. It is more bene \201 cial wh en combined with methotrexate, alongside hydroxychloroquine or prednisolone. Psoriatic arthritis Farr M, Kitas GD, Waterhouse L, et al. (1990) Sulphasala- zine in psori atic arthritis: a double-blind placebo-controlled study. Br J Rheumatol 29: 46 \200\2239. CHAPTER 19 DMARDs and immunosuppressive drugs 539 Dermatological toxicity As well as causing photosensitization, SSZ can rarely cause hyperse nsitivity reactions, including acute Stevens Johnson syndrome, and the treatment should be discontinued immediately if these reactions occur. Record at baseline FBC LFTs ESR or CRP Renal function Allows monitoring of changes Allows monitoring of changes Monitor disease activity Adjust d ose if impaire Orange body \202 uids SSZ may cause body secretions to become an orange color \200\223 u rine, tears, sweat. This can cause staining of clothes and contact lenses, but is otherwise not clinically signi \201 cant. Patients should be warned of this possibility. What dose should I prescribe? The usual treatment dose in both rheumatoid arthritis and pso riatic arthritis in 1 g bd. The dosage is built up over the \201 rst 4 weeks of treatment : Week 1 500 mg od. Week 2 500 mg bd. Week 3 1 g mane, 500 mg nocte. Week 4 1 g bd. Sperm counts SSZ can cause a reversible oligospermia/azospermia. Male patients should be advised of decr eased fertility. Sulfasala- zine should be discontinued 3 months prior to planned conceptio n in males. FAQs How long does it take to work? A clinical response is usually seen after 3 months of t reat- ment with sulfasalazine. The dose can be increased to 3 g if an inadequate re- sponse is achieved at the 1 g bd dose . In the author \200\231s expe- rience this is more likely to be bene \201 cial in patient s with psoriatic arthritis. Folic acid prescription? Folic acid supplementation has not been shown to be ben- e \201 c ial in reducing the side effects of sulfasalazine (unlike methotrexate). However, sulfasala zine can cause elevation of homocysteine levels and a macrocytosis. In these in- stances, f olic acid supplementation (as is used with metho- trexate) can be considered. What do I do if I want to get pregnant? No major teratogenic effects have been seen with su l- fasalazine and it is generally considered reasonably safe in pregnancy. However, adequat e folic acid supplementation prior to conception and during pregnancy should be as- sured g iven the anti-folate effects of sulfasalazine. As in all cases, the risk versus the bene \201 ts of continuing treatment should be discussed in an individual case Important drug interactions Digoxin: sulfasalazine may reduce digoxin levels by inter- feri ng with absorption. What about breastfeeding? Sulfasalazine appears to be safe to use during lactation. However , the available data only relate to healthy non-ker- nicteric term infants. It is unclear w hether this is applicable to premature infants or those with haemolysis. Monitoring of SSZ FBC & LFTs Can I drink alcohol? \200 Example monitoring regime (local guidelines may vary) \200 \200 \200 There is no evidence that alcohol interferes with sul- fasalazine. Fortnightly for the \201 rst 2 weeks. Monthly, thereafter, for the \201 rst 3 months. T hereafter, 3 monthly. What to do if side effects occur Common side effects These frequently resolve if the patient can continue with treatment for 2 \200\2233 weeks. If they fail to resolve and the patient cannot tolerate, reduce the dose of SSZ and try to increase a few weeks later. \200 \200 \200 Renal function 6-monthly (the bene \201 ts of monitoring renal function with sulfasalazine are questionable). WBC <3.5 \227 109/l: stop sulfasalazine and review. Platelets <150 \227 109/l: stop sulfa salazine and review. ALT >twice upper limit: stop sulfasalazine and review. ESR Useful for monitoring response to treatment. Macrocytosis Side effects and what to discuss with your patients Common Nausea, abdominal discomfort, di arrhea, skin rashes, mal- aise, headache, anorexia, oral ulceration, orange discolou- ratio n of body secretions. Check B12 and folate and consider folic acid supplementa- tion. 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. LEFLUNOMIDE 540 Le \202 unomide Trade name Arava. Rheumatoid arthritis Le \202 unomide monotherapy Smolen JS, Scott DL, Rozman B, et al. (19 99)Ef \201 cacy and safety of le \202 unomide compared with placebo and sul- phasalazine in active rheumatoid arthritis: a double-blind, randomized, multicentre trial. European Le \202 unomide Study Group. Lancet 353(9149): 259 \200\22366. MN301 study \200\223 (358 pat ients) le \202 unomide is signi \201 cantly better than placebo and similar in ef \201 c acy to sulfasalazine (up to 2 g/day). Strand V, Cohen S, Schiff M, et al. (1999) Treatment of ac- tive rheumatoid arthritis with le \202 unomide compared with placebo and methotrexa te. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med 159: 2542 \200 \223 50. US301 study (482 patients) showing that le \202 unomide is signi \201 cantly bet ter than placebo and similar in ef \201 cacy to methotrexate (up to 15 mg/week). History \200 1992: le \202 unomide (HWA 486 \200\223 5-methyl-N-(4-tri \202 uor- omethylphenyl)-4-iso xazole carboximide), an immuno- suppressant with an unknown mechanism of action, is demonst rated in-vivo to have bene \201 t in a murine arthri- tis model. 1995: le \202 unomide \200\231s mechanism of action in vitro is eluci- dated \200\223 inhibition of de novo pyri midine synthesis by competitive inhibition of dihydro-orotate dehydroge- nase resulting in inhibited uridine synthesis and reduced lymphocyte proliferation (particularly T cells). 19 95: le \202 unomide is shown in Phase II clinical studies to be ef \201 cacious in rheuma toid arthritis. 1999: le \202 unomide is shown in 2 large Phase III clinical studies to ha ve similar ef \201 cacy to methotrexate and sul- fasalazine in rheumatoid arthritis. 2000: le \202 unomide is licensed in the UK for patients with active rheumatoid arthritis. Le \202 unomide combination therapy Le \202 unomide and methotrexate Kremer JM, Genovese MC, Cannon GW, et al. (2002) Concomitant le \202 unomide therapy in patients with active r heumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, place bo-controlled trial. Ann Intern Med 137(9): 726 \200\22333. Good ef \201 cacy for the comb ination treatment, but problems with elevated liver transaminases Mechanism of action Le \202 unomide is rapidly metabolized following absorption to an acti ve substrate A77 1726. This active compound causes inhibition of dihydro-orotate dehydrogen ase, re- sulting in inhibited uridine nucleotide synthesis and impair- ment of cellular pro gression through the cell cycle from G1 to S phase. \200 Le \202 unomide and sulfasalazine Dougados M, Emery P, Lemmel EM, et al. (2005) When a DMA RD fails, should patients switch to sulfasalazine or add sulfasalazine to continuing le \202 unomide? Ann Rheum Dis 64: 44 \200\22351. No signi \201 cant bene \201 t in adding s ulfasalazine to le \202 unomide (in le \202 unomide partial-responders) in this pla- cebo controlled study (106 patients). T cells: there is good evidence that the uridine synthesis pathway is particularly importan t in T cell proliferation, and this may be the major mechanism of action in rheu- matoid ar thritis. Dendritic cells: A77 1726 also interferes with dendritic cell function, reducing t he expression of co-stimulatory molecules on these key antigen presenting cells. This may b e an additional important mechanism of action. Psoriatic arthritis Monotherapy Kaltwasser JP, Nash P, Gladman D, et al. (2004) Ef \201 ca cy and safety of le \202 unomide in the treatment of psoriatic arthritis and psoriasis: a multinational, double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum 50: 1939 \200\223 50. The TOPAS study \200\223 a placebo controlled study showing that in patients with psoriatic arthritis (with skin disease) le \202 unomide was signi \201 can tly better than placebo for both the joints and the skin (190 patients). The active metabolite A77 1726 is cleared extremely slowly (due to high levels of protein b inding) by renal and hepato- biliary clearance. Plasma levels therefore remain detectable f or up to 2 years following discontinuation of treatment. Evidence base: the clinical trials with le \202 unomide and what they showed Summary There is good evidence for ef \201 cacy of le \202 unomide mono- therapy in rheumatoid arthrit is and psoriatic arthritis. Systemic lupus erythematosis Tam LS, Li EK, Wong CK, et al. (2004) Double-blind, ran- domiz ed, placebo-controlled pilot study of le \202 unomide in systemic lupus erythematosus. Lup us.13(8): 601 \200\2234. A small placebo controlled study showing ef \201 cacy in mild to mod- erate SLE. Combination treatment with methotrexate is ef \201 cacious in rheumatoid arthritis, but th ere is a high prevalence of elevated liver transaminases. There is no trial data to support le \202 unomide use in com- bination with other DMARDs or with biologics. Wegener \200\231s granulomatosis Metzler C, Fink C, Lamprecht P, et al. (2004) Maintenance of remission with le \202 unomide in Wegener \200\231s granulomato- sis. Rheumatol (Oxf) 4 3: 315 \200\22320. A small open label study showing ef \201 cacy of 20 \200\22340 mg/day o f le \202 unomide in main- tenance of remission in Wegener \200\231s granulomatosis. There is some limited evidence for le \202 unomide use in SLE and in remission maintenance in vasculitis (Wegener \200\231s granulomatosis). All the trial studies in in \202 ammatory arthritis use a 3-day 100 mg loading dose follow ed by 20 mg/day regular dosing. CHAPTER 19 DMARDs and immunosuppressive drugs 541 Prescribing considerations What do I need to do before starting the treatment? Counseling r egarding conception is particularly important for le \202 unomide given the teratogenic ri sks and the long half-life of the active metabolite. This needs to be discussed before comm encing treatment (in both men and women). Patients should be advised that contraception use is essen- tial and conception should be avoided for 2 years post- treatment in women and 3 months post-treatment in men. \200 Patient education re: dosing, side effects, monitorin g, drug interactions, etc., is needed. Ensure your patient has a patient held monitoring bo oklet Teratogenic risk Patients should be advised that contraception use is essential and concept ion should be avoided for 2 years post-treatment in women and 3 months post-treatment in me n. Hematological toxicity \200 \200 Neutropenia, thrombocytopenia, pancytopenia. Warn patients to report infections/sore throat /bruising. Pulmonary toxicity \200 Acute interstitial pneumonitis (as seen with methotrex- ate) has been reported with le \202 unomide. This is a hypersensitivity reaction to le \202 unomide. Counsel patients re: acute shortness of breath. \200 Record at baseline FBC LFTs Hepatic toxicity \200 Allows monitoring of changes. Allows monitoring of changes. Avoid if elevated baseline tran sami- nases or significantly decreased serum protein levels Monitor disease activity Impair ed renal function increases leflunomide levels. Moderate/se- vere impairment is a relative con- traindication. Either history or serology Allows comparison in pulmonary toxicity. All ows comparison for monitoring. Le \202 unomide can cause an acute (potentially life threat- ening) hepatitis (most common ly in the \201 rst few months of treatment), but there is no evidence to suggest it cause s progressive cirrhosis. Warn patients minimize alcohol intake. ESR or CRP Renal function Hypertension Le \202 unomide can cause hypertension and BP should be monitored regularly. It can usually be managed with a re- duced dose +/ \200\223 appropriate anti-hypertensive t reatment. If signi \201 cant side effects occur or a patient conceives whilst on treatment a washout with colestyramine/acti- vated charcoal or activated charcoal is required. Varicella status CXR Colestyramine/activated charcoal/activated charcoal washout regime Colestyramine 8 g 3 time s a day for 11 days OR activated charcoal 50 g 4 times a day for 11 days. BP What dose should I prescribe and should I use a loading dose? FAQs What if I want to get pregnant? Leflunomide is teratogenic in women and should be avoi ded before and during pregnancy. Women should gen- erally be advised to have a 2-year washo ut period prior to conception to allow full elimination of le \202 unomide. An al- ternati ve is a colestyramine/activated charcoal washout 3 months prior to conception. In either ca se, the serum con- centration of the active metabolite should be measured prior to concepti on and should be less than 0.02 mg/l. The clinical trials all use a 3-day loading regime of 100 mg/day followed by 20 mg/day. Regular dosing at 20 mg/day (without the 3-day loading dose) is associated with less side e ffects (particularly gas- trointestinal), but a delay in the onset of action. Important drug interactions \200 \200 \200 Phenytoin: increases plasma concentration. Warfarin: enhances effects of warfarin. Tolbutam ide: enhances hypoglycaemic effect. It is unclear whether le \202 unomide has effects on the sperm, but men should be advised to have a similar wash- out regime to women 3 months prior to conception. Monitoring FBC & LFTs The British National Formulary advises: \200 \200 Breast feeding on le \202 unomide is also contraindicated. What about fertility? There is no evidence that le \202 unomide effects fertility in eithe r men or women Fortnightly for the \201 rst 6 months of treatment. Thereafter, 2 monthly. ESR Useful for monitoring response to treatment How long does it take to work? With a loading dose clinical response is usually seen in 4 \200\2236 weeks. Without a loading dose clinical response usually takes longer ( 12 weeks). BP Should be checked every 3 months. What about injections? \200 Side effects and what to discuss with your patients Common Nausea, abdominal discomfort, di arrhea, mouth ulcers, weight loss, allergic reactions (including skin rashes and rarely ana phylaxis), taste disturbance, headache, and hair loss. The gastrointestinal side-effects ar e by far the com- monest and are more frequent when the loading regime is used. Live attenuated vaccines need to be avoided by patients taking le \202 unomide: yellow fev er, MMR and rubella, BCG, oral polio, oral typhoid. Other vaccines will not be a problem. P atients should be advised to have an annual in \202 uenza immunization since they are at a n increased risk of in \202 uenza. \200 LEFLUNOMIDE 542 Can I drink alcohol? Although there is no evidence for an interaction, it is advis- able fo r patients to minimize alcohol consumption given the hepatotoxic potential of the treatment . Unplanned pregnancy Immediate colestyramine/activated charcoal washout. Surgical considerations There is inadequate data on the safety of continuing le \202 u- no mide in the perioperative period. However, the long half-life of the active metabolite mean s that stopping the treatment would be impractical and may be associated with worse post-op erative outcomes due to impaired re- habilitation. What if I miss a dose? Take the missed dose as soon as the patient remembers. If it is clos e to the next due dose omit the missed dose and take the normal daily dose (do not double d oses). What to do if side effects occur Common side effects Reduce the dose of le \202 unomide (the lowest evidence based dose for treatment is 10mg/day) ASYMPTOMATIC PATIENT SYMPTOMATIC PATIENT Persistent Neutropenia (<1.5x109/L) or Thrombocytopenia (<150x109/L) Neutropenia (<1.5x109/L) or Thrombocytopenia (<150x109/L) Stop leflunomide Give appropriate antibiotics for neutropenic sepsis Give colestyramine or activated charcoal washout Monitor response Consider G-CSF if recalcitrant Stop leflunomide and monitor response Resolved Persists Patient improves Colestyramine or activated charcoal Washout regime Consider Retreatment at Lower dose Consider Retreatment at Lower dose Assessment with Hematologist Persists Assessment with Hematologist Figure 19.4 Hematological toxicity. CHAPTER 19 DMARDs and immunosuppressive drugs 543 Acute Respiratory Illness (Dry Cough +/- dyspnoea and fever) Stop leflunomide CXR (look for diffuse interstitial shadowing) \200\223 lesmpale with base line CXR FBC (looking for eosinophilia) ABGs (looking for hypoxia) Blood and sputum culture s Pulmonary Function Test (decrease TLCO and VC suggestive) Suspicious of pneumonitis No evidence of pneumonitis Colestyramine/activated charcoal washout Consider HRCT and BAL (need to exclude pneumocysti s pneumonia) Liaise with respiratory physicians Restart leflunomide Assess for other causes Treatment High dose oral prednisolone or IV Methylprednisolone Oxygen +/- Ventilatory suppo rt Consider IV cyclophosphamide AVOID RETREATMENT IN FUTURE 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.