DMARDS IN RHEUmatoid Arthritis

DISEASE MODIFYING ANTIRHEUMATOID DRUGS IN RHEUMATOID ARTHRITIS.

1. DMARDS IN RHEUMATOID ARTHRITIS AYAN GHOSAL PGT DEPT OF PMR

2. EFFICACY OF DMARDS IN RA High Chances of remission. Control of Extra-articular disease To some extent. Prevention of Radiographic damage To some extent. Control of associated Co-morbidities Only to limited extent.

3. DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS

4. csDMARDs FIRST LINE: Methotrexate (MTX) Sulfasalazine (SSZ) Hydroxichloroquine (HCQ) Leflunomide (LEF)

5. DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS: 2 nd LINE

6. METHOTREXATE: DMARD OF CHOICE . In 50-60% of patients remission or low disese activity seen with monotherapy. The initial DMARD for majority of patients. The main component of combination DMARDs. With Biologics , increase efficacy , reduce antibody formation. Successful in treating RA associated conditions: Felty’s syndrome, large granular lymphocyte syndrome, Adult onset still disease, Cutaneous vasculitis of RA .

7. METHOTREXATE: MECHANISM OF ACTION : Inhibition of ATIC→↑Adenosine BOTH intra and extracellular. ADENOSINE HAS POTENT ANTI INFLAMMATORY EFFECT . Inhibition of TYMS→↓pyrimidine synthesis Inhibition of DHFR→ ↓Transmethylation reactions, ESSENTIAL FOR CELLULAR FUNCTIONING

8. SAFETY MONITORING: Baseline < 3 month 3-6 months > 6 months CBC, LFT, Cr, HBV, HCV; Vaccinate: Influenza, Pneumococcus, HBV Every 2-4 wk Every 8-12 wk Every 8-12 wk HALF LIFE: 6 Hours . Elimination by kidney. Active Form : MTX PG, Elimination half life 3.1 weeks. DOSE: 7.5 – 25mg/ wk , escalated at 2.5mg/ wk basis in 8wks Oral dose, when > 15 mg , split or give SC . METHOTREXATE:

9. SIDE EFFECTS: Dyspepsia, Nausea, Anorexia: 20-70% in 1 st Year. Mucocutaneous: 33% ,Dose dependent, respond to folic acid. Hepatotoxicity: AST/ALT elevation. Severe myelosuppression: 1-2%, Dose dependent, respond to folic acid. Pulmonary : Interstitial pneumonitis, interstitial fibrosis, noncardiogenic pulmonary oedema(rare), pleuritis and effusion, pulmonary nodule. MTX Flu: after the weekly dose. Nodulosis : 8% Leucocytoclastic vasculitis.

10. SPECIAL CASE Fertility: F: no effect M: reversible sterility Stop 3 mo before conception Pregnancy: Contra-indicated (X) Aminopterin syndrome. Abortifacient Lactation Contraindicated Elderly Lower initial dose (5-7.5mg/ wk ) based on CrCl , NOT >2Omg/ wk Pediatrics Based on wt .0.3-1 mg/kg/wk.

11. CONTRAINDICATION OF METHOTREXATE Active infection, Symptomatic pulmonary disease, WBC <3000/mm 3 , Platelet <50,000/ml 3 , CrCl <30 ml/min, History of myelodysplasia or recent lymphoproliferative disorder, LFT >2 x Upper Limit of Normal, Acute or chronic HBV or HCV, Pregnancy, lactation

12. LEFLUNOMIDE : MECHANISM OF ACTION:

13. LEFLUNOMIDE: HALF LIFE : 2 WEEKS. Elimination: Kidney 50% Gut 50% DOSE : 10-20 MG/DAY,100mg loading dose for 3 days. No dose adjustment in elderly. Pediatrics : Based on wt., SAFETY MONITORING: Baseline < 3 month 3-6 months > 6 months CBC, LFT, Cr, HBV, HCV; vaccinate: influenza, Pneumococcus HBV Every 2-4 wk Every 8-12 wk Every 8-12 wk <20kg, 20-40 kg >40kg 10mg other day 10mg daily 20mg daily

14. LEFLUNOMIDE: SIDE EFFECTS : Diarrhea: Most common. Hepatotoxicity: More common with MTX combination. Cardiovascular: HTN, Dyslipidemia Dermatological: Skin rash,2 nd to 5 th month, SJS or TEN,Alopecia Pulmonary: ILD, 3 Month. Hematological: Rare, Pancytopenia, NOT LYMPHOPROLIFERATIVE DISORDER . Weight Loss.

15. SPECIAL CASE: Fertility: No much data, test level, may require washout. Pregnancy: Contra-indicated (X) Measure level in blood , when>0.02mg/L require active washout . Wait for three full menstrual cycle after washout. Lactation: Contraindicated

16. LEFLUNOMIDE: CONTRAINDICATION : Active infection, WBC<3000/µl Platelet<50000/µl , History of myelodysplasia or recent lymphoproliferative disorder, LFT >2 x ULN, Acute OR Chronic HBV/HCV. Pregnancy, Lactation. Severe renal impairment. Severe hypoproteinemia . Hypensensitivity .

17. HYDROXYCHLOROQUINE: Do not retard bone erosion in RA. Slowest acting DMARD. MECHANISM OF ACTION:

18. HYDOXYCHLOROQUINE Half Life : 40-50 days. Elimination: Via urine unchanged. Dose: 200–400mg/day orally. 6.5mg/kg/day of ideal body wt to prevent ocular toxicity. Pediatrics: 3-5mg/kg/day SAFETY MONITORING: Baseline < 3 month 3-6 months > 6 months OPHTHALMOLOGICAL EXAMINATION CBC, LFT, Cr ; Vaccinate: influenza, Complete ophthalogical examination within 1 yr. none none none 2-5 YEARLY SHOULD START <=5 YR

19. HYDOXYCHLOROQUINE SIDE EFFECTS : Ocular toxicity : blurring of vision, accommodation or conversion defect. Retinal toxicity: high dose, prolonged use, CKD stage III, tamoxifen Dermatological: hyperpigmentation, photosensitivity, alopecia, hair depigmentation. Neuromuscular: Headache,insomnia,irritability, Proximal weakness with peripheral neuropathy and cardiac myotoxicity , normal CPK Metabolic: reduce blood glucose HbA1C. Cardiovascular: Rare; Conduction defect, Cardiomyopathy . GI: nausea,vomiting diarrhoea abdominal cramp.

20. SPECIAL CASE : FERTILITY: No effect. PREGNANCY: Relatively safe (C) LACTATION: Relatively safe.

21. CONTRAINDICATION H/O Vision changes attributed to 4-aminoquinolone derivatives Hypersensitivity. Severe liver disease.

22. SULFASALAZINE:

23. SULFASALAZINE:

24. HALF LIFE : SSZ: 6-17HOURS, SULFAPYRIDINE: 8-21 HRS ELIMINATION : Extensively liver metabolization ,excreted by urine(5-ASA), feces( sulfapyridine ) DOSE : START AT 500MG/DAY, INCRESED BY 500MG/ WEEK , MAX DOSE : 2-3 G/DAY Concominant Folate administration . SAFETY MONITORING: SULFASALAZINE: Baseline < 3 month 3-6 months > 6 months CBC, LFT, Cr, ; Vaccinate:influenza , Pneumococcus Every 2-4 wk Every 8-12 wk Every 8-12 wk

25. SIDE EFFECT : Gastrointestinal: Nausea, Upper abd . Discomfort, 8%, with dizziness and headache,diarrhoea Dermatological: 5%, 3 Months ;Mainly rash, Photosensitivity. Hematologic: 3%, 3 months , avoid in G6PD deficiency. Hepatotoxicity: Transient liver enzyme elevation. Pulmonary: Rare, Revesible infiltrate, cough, eosinophilia, fever, wt loss. Minor: irritability, anxiety, hypogammaglobulinemia,aseptic meningitis.

26. SPECIAL CASE: FERTILITY: FEMALE: No effect Male: reversible seritity , improves in 2-3 months Pregnancy: category B,C; First choice in women wishing to be pregnant. Breast feeding: Relatively safe.(B, C) Lactation: Relatively safe. Elderly: Not required. Pediatrics: Based on wt. 10-12.5mg/kg/day wkly increase to 50mg/kg/day. SULFASALAZINE:

27. SULFASALAZINE: CONTRAINDICATION : Sulfa allergy, salicylate allergy. Plt <50,000/mL3, LFT >2 X ULN, Acute HBV/HCV, Some classes of chronic HBV/HCV.

28. COMBINATION DMARD THERAPY IN RA Superior efficacy without increased toxicity. Early suppression of bony progression. MTX is the ANCHOR DRUG. Initial or Step up both are superior to monotherapy Triple therapy (MTX,HCQ,SSZ) superior than MTXmonotherapy or double combination(MTX+HCQ or MTX+SSZ) Triple therapy non inferior to MTX+etanercept . Initial combination and step up combination both are similarly effective in sudjective and objective disese control at 1-2 years. INITIAL COMBINATION = MORE EARLY SUPPRESSION OF BONY PROG.

29. AZATHRIOPINE : (DOSE: 50-200MG/DAY) SUBSTITUTE TO METHOTREXATE. Reduce antibody foration when used with biologics.(50% vs 77%) Pregnancy, liver, pulmonary & renal diseases,MTX Flu. RA associated ILD. NEUTROPENIA IS MOST COMMON SIDE EFFECT. CYCLOSPORINE: (DOSE: 2.5-5mg/kg/day) Showed efficacy with MTX. NOT used because of side effect: HTN and Raised Serum Crt . May be used in RA patient with Hepatitis C. USE OF SENOND LINE DMARDS IN RA

30. Tetracyclines: Minocycline(100mg BD) and doxycycline (20-100mg BD) showed efficacy in combination with MTX. Minocycline showed potential in early RF positive patients . Potential side effects: Vertigo,Light headedness , Lupus like syndrome, cutaneous hyperpigmentation. USE OF SENOND LINE DMARDS IN RA

31. NOVEL DRUG :TARGETED SYNTHETIC DMARDS: TARGETED TO JANUS KINASE (JAK) Tofacitinib : Active RA with MTX, with or without biologics. Pan-JAK inhibitor 5mg BD orally S/E: ↑risk of infection, ↑LFT, Dyslipidemia, neutropenia, URTI, Nasopharyngitis, diarrhea Safety precautions : CBC & LFTmonthly for 3 month, then 3 monthly. Screening for latent TB. Lipid profile: 8-12 weekly Vaccination. Contraindication : Active infection Lymphocyte <500/ miL Acute or chronic hepatitis. Baricitinib : JAK1/2 inhibitor, Phase III trial Fibotinib : JAK1 inhibitor, Phase III trial Decernotinib : JAK 1/3 inhibitor Peficitinib : JAK 1/3 inhibitor

32. ACR-EULAR 2019 UPDATE:

33. SPECIAL CASE : Pregnancy and RA : RA Tend to improve in pregnancy. Active RA during pregnancy result in LBW. Methotrexate and Leflunomide must be discontinued. 75% will show improvement and flare after delivery. Flare managed by: Prednisolone, HCQS, SSZ. HIV & RA : HCQ,SSZ, Corticosteroid HEP B & HEP C : Acute/Active & Receiving treatment: continue Not receiving treatment: In Hep C , avoid MTX, LEF, Cylosporine . In Hep B, refer for antiviral management.

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