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2 Treatment of Treatment of Rheumatoid Disease Rheumatoid Disease By: By: Ahad Azami M.D. Ahad Azami M.D. Rheumatologist Rheumatologist

3 DMARDs Are a diverse group of the therapeutic agents that reduce the signs & symptoms of RA as well as retard radiographic progression of joint damage Are a diverse group of the therapeutic agents that reduce the signs & symptoms of RA as well as retard radiographic progression of joint damage This class of drugs is central to the control of RA and is part of nearly every patients treatment regimen This class of drugs is central to the control of RA and is part of nearly every patients treatment regimen

4 DMARDs Should be used in all cases except mild and class IV whom little reversibility of disease is expected Should be used in all cases except mild and class IV whom little reversibility of disease is expected Have slow onset of action and require regular monitoring Have slow onset of action and require regular monitoring These drugs have potential to reduce or prevent joint damage, preserve joint integrity and function These drugs have potential to reduce or prevent joint damage, preserve joint integrity and function – Hydroxychloroquine (HCQ) Sulfasalzine (SSZ) – Methotrexate (MTX) Gold salts – D-penicillamine ( DP) Azathioprine ( AZA)

5 DMARDs Timing is Critical Use should not be delayed beyond 3 months for any pt with established diagnosis who in spite of adequate treatment of NSAIDs has Use should not be delayed beyond 3 months for any pt with established diagnosis who in spite of adequate treatment of NSAIDs has – Ongoing pain – Morning stiffness or fatigue – Active synovitis – Persistent elevation of ESR or CRP

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7 DMARDs Factors which affect choice of DMARD: Conscience of administration Conscience of administration Requirement of monitoring program Requirement of monitoring program Cost Cost Time until expected benefit Time until expected benefit Frequency and seriousness of adverse effects Frequency and seriousness of adverse effects Compliance Compliance Comorbid disease Comorbid disease

8 DMARDs Choice of agent HCQ or SSZ in milder disease HCQ or SSZ in milder disease MTX considered by many as the DMARD of choice MTX considered by many as the DMARD of choice – Because it has best long term outcome and less likely to be D/C due to toxicity

9 Methotrexate Contraindications Chronic liver disease Chronic liver disease Pregnancy and breast feeding Pregnancy and breast feeding Immunodeficiency Immunodeficiency Preexisting blood disorders Preexisting blood disorders CrCL <40 ml/min CrCL <40 ml/min Lung disease Lung diseaseMOA: Folic acid antagonist Folic acid antagonist Rapid onset of action 2-3 wks Rapid onset of action 2-3 wks Duration of therapy may be 5-7 years Duration of therapy may be 5-7 years

10 Methotrexate Administration Orally or SQ or IM Orally or SQ or IM Start 7.5 mg once a week as single dose or over 24 hrs Start 7.5 mg once a week as single dose or over 24 hrs Can be increased gradually to mg once a week Can be increased gradually to mg once a week Doses > 20mg/wk given parentrally due to decreased oral bioavailability Doses > 20mg/wk given parentrally due to decreased oral bioavailability IM or SC may be helpful for pts who have GI adverse effects or lose benefit over time orally IM or SC may be helpful for pts who have GI adverse effects or lose benefit over time orally

11 Methotrexate Toxicities Generally well tolerated at low doses GI: Stomatitis, Diarrhea, N/V GI: Stomatitis, Diarrhea, N/V Hematologic: Bone marrow suppression, Thrombocytopenia, Leukopenia Hematologic: Bone marrow suppression, Thrombocytopenia, Leukopenia Liver: Elevated liver enzyme, Cirrhosis, rare Liver: Elevated liver enzyme, Cirrhosis, rare Guidelines for monitoring : Liver biopsy before beginning therapy only for pts with history of liver disease. biopsy during MTX only for pts who develop consistently abnormal liver function tests Guidelines for monitoring : Liver biopsy before beginning therapy only for pts with history of liver disease. biopsy during MTX only for pts who develop consistently abnormal liver function tests Folic acid deficiency; Supplementation with folic acid may alleviate some adverse effects without compromising efficacy Folic acid deficiency; Supplementation with folic acid may alleviate some adverse effects without compromising efficacy Teratogenic and abortificant Teratogenic and abortificant

12 Methotrexate Drug Interactions In elderly, concurrent use with NSAIDs increase serum concentration of MTX In elderly, concurrent use with NSAIDs increase serum concentration of MTX TMP/SMX and trimethoprim → increase bone marrow suppression TMP/SMX and trimethoprim → increase bone marrow suppression

13 GOLD Have been used for many years and can induce complete remission Have been used for many years and can induce complete remission Injectable more effective than oral Injectable more effective than oral Effect may be delayed up to 3-6 months Effect may be delayed up to 3-6 months Dosage and Administration Oral: auranofin 3 mg bid or 6 mg OD Oral: auranofin 3 mg bid or 6 mg OD If disease dose not respond in 3-6 Mths ↑ to 3 mg tid If disease dose not respond in 3-6 Mths ↑ to 3 mg tid If response is still unsatisfactory D/c drug If response is still unsatisfactory D/c drug

14 GOLD IM: aurothioglucose or gold sodium thiomalate IM: aurothioglucose or gold sodium thiomalate Dose: test dose of 10 mg → after once week → 25 mg q week → for 1-2 wks → 50 mg weekly for up to 20 wks or longer if improvement continues → ↑ from q 2 wks → q 3wks to monthly Dose: test dose of 10 mg → after once week → 25 mg q week → for 1-2 wks → 50 mg weekly for up to 20 wks or longer if improvement continues → ↑ from q 2 wks → q 3wks to monthly D/c of gold may result in arthritis recurrence that may not remit when gold is restarted. D/c of gold may result in arthritis recurrence that may not remit when gold is restarted.

15 GOLD Toxicities Dermatologic: Skin rash, stomatitis → require D/c of gold Dermatologic: Skin rash, stomatitis → require D/c of gold Renal: Proteinuria, Hematuria Renal: Proteinuria, Hematuria Hematologic Anemia, Leukopenia, thrombocytopenia, Hematologic Anemia, Leukopenia, thrombocytopenia, Reversible if drug is discontinued Reversible if drug is discontinued GI: stomatitis, N/V, diarrhea, Metallic taste GI: stomatitis, N/V, diarrhea, Metallic taste Resolve with time or dosage reduction Resolve with time or dosage reduction

16 GOLD Toxicities Post injection flare: Patient may experience increase joint symptoms for Patient may experience increase joint symptoms for 1 -2 days after an injection 1 -2 days after an injection If the flare is sever, therapy must be changed If the flare is sever, therapy must be changed Oral gold causes less mucocutaneous, bone marrow, and renal toxicities but more diarrhea and GI reactions Oral gold causes less mucocutaneous, bone marrow, and renal toxicities but more diarrhea and GI reactions

17 Hydroxychloroquine Antimalarial Antimalarial Moderalty effective for mild RA Moderalty effective for mild RA Lacks myelosuppression, hepatic, renal toxicities Lacks myelosuppression, hepatic, renal toxicitiesPharmacology Onset of action may be delayed up to 6 weeks Onset of action may be delayed up to 6 weeks Therapeutic failure when 6 months of therapy without response Therapeutic failure when 6 months of therapy without response Dose: 200 mg bid Dose: 200 mg bid

18 Hydroxychloroquine Toxicities Short term: Short term: – GI: N/V, diarrhea → can be managed by taking drug with food Ocular toxicities: Ocular toxicities: – Accommodation defect/ Scotomas – Night blindness / Blurred vision – Any visual changes must be reported – Vision must be monitored and keep dose < 6.5 mg/kg/d – d/c when signs of retinal toxicity first appear

19 Hydroxychloroquine Toxicities Dermatologic: Dermatologic: – Rash, alopecia, increased skin pigmentation Neurological: Neurological: – Headache, vertigo, insomnia are usually mild – Proximal Muscles weakness(vacuolar myopathy)

20 Sulfasalazine Prodrug cleaved by bacteria in the colon to sulfapyridine – which is responsible for antirheumatic effect- and 5-aminosalicylic acid Prodrug cleaved by bacteria in the colon to sulfapyridine – which is responsible for antirheumatic effect- and 5-aminosalicylic acid Effect should be seen in 1-2 months Effect should be seen in 1-2 months Administration and Dose : 2 g/day 2 g/day Start by 500mg bid and increase to 1g bid Start by 500mg bid and increase to 1g bid

21 Sulfasalazine Toxicities GI(comm drug d/c) N/V- diarrhea- anorexia N/V- diarrhea- anorexia Can be minimized Can be minimized – by initiating therapy with low doses – gradually titrating to higher doses – dividing the dose more evenly throughout the day – using enteric coated preparations

22 Sulfasalazine ToxicitiesDerma – Rash- urticaria- serum sickness – Can be managed with antihistamine and steroids. – If hypersensitivity occurs therapy should be stopped immediate and another DMARD used Other – Leukopenia- alopecia- stomatitis- elevated LFTs- yellow/orange discoloration of urine and skin.

23 Sulfasalazine Sulfasalazine Drug Interactions Absorption is decreased with concomitant Antibiotics because they destroy colonic bacteria Absorption is decreased with concomitant Antibiotics because they destroy colonic bacteria Iron binds to it causing decreased absorption Iron binds to it causing decreased absorption Can potentate warfarin effect by displacing it from protein-binding sites. Monitor INR closely Can potentate warfarin effect by displacing it from protein-binding sites. Monitor INR closely

24 AZATHIOPRINE An antimetabolite, immunosuppressive drug An antimetabolite, immunosuppressive drug Effect can be seen within 3-4 weeks Effect can be seen within 3-4 weeks If no response after 12 weeks at maximal dosage, should be D/C If no response after 12 weeks at maximal dosage, should be D/CMOA A purine analog that is converted to 6- mercaptopurine and interferes with DNA and RNA synthesis A purine analog that is converted to 6- mercaptopurine and interferes with DNA and RNA synthesis Administration and dose mg daily mg daily

25 AZATHIOPRINE Toxicities Reversible bone marrow suppression Reversible bone marrow suppression Dose related Dose related When it occurs stop drug temporarily until marrow recovers When it occurs stop drug temporarily until marrow recovers They reinstitute at 25% dose reduction They reinstitute at 25% dose reduction GI intolerance GI intolerance Oncogenic potential Oncogenic potential Stomatitis Stomatitis Drug fever Drug fever Hepatotoxicity Hepatotoxicity

26 AZATHIOPRINE Drug Interactions Allopurinal Allopurinal – Inhibits xanthenes oxidize which ↓ metabolism of 6-mercaptopurine and ↑ myelosuppression – If the two agents are to be used together reduce azathiprine dose to 30% of usual dose.

27 D-Penicillamine A heavy metal chelating agent A heavy metal chelating agent Effect seen after 1-3 months up to 6 months Effect seen after 1-3 months up to 6 months Dose : Dose : – mg daily Drug Interaction – Food, antacids, and iron will decrease absorption

28 Newer Agents-leflunomide A DMARD that inhibites pyrimidine synthesis A DMARD that inhibites pyrimidine synthesis It reduces the progression of erosion It reduces the progression of erosionDose LD of 100 daily for 3 days → 20 mg daily LD of 100 daily for 3 days → 20 mg daily 10 mg OD for those experiencing SE 10 mg OD for those experiencing SE With LD response time is 1 month With LD response time is 1 month Toxicities : Liver function abnormalities Liver function abnormalities ALT should be monitored monthly initially then periodically ALT should be monitored monthly initially then periodically Teratogenic Teratogenic

29 Combination Therapy More effective than individual drugs More effective than individual drugs MTX+HCQ+ sulfasalazine MTX+HCQ+ sulfasalazine MTX+ Sulfasalzine+ prednisone MTX+ Sulfasalzine+ prednisone

30 Combination Therapy Using DMARDS Patients receiving single DMARDS respond only partially. Patients receiving single DMARDS respond only partially. Many discontinue therapy due to adverse effects or lack of efficacy Many discontinue therapy due to adverse effects or lack of efficacyGoal: Control of inflammation as completely and quickly as possible before permanent joint damage occurs

31 Combination Therapy Using DMARDS Advantages Combining agents with complementary MOA greater efficacy might be achieved. Combining agents with complementary MOA greater efficacy might be achieved. Lower doses of drugs may be used potentially reducing toxicity. Lower doses of drugs may be used potentially reducing toxicity. Combination therapy produced more sustained benefits over time. Combination therapy produced more sustained benefits over time. Combination more effective in early RA (disease duration < 2 yrs) Combination more effective in early RA (disease duration < 2 yrs) Efficacy also confirmed in established RA but less substantial than early RA. Efficacy also confirmed in established RA but less substantial than early RA.

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