Treatment of Rheumatoid Arthritis: The Past, the Present and the Future

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1 Treatment of Rheumatoid Arthritis: The Past, the Present and the Future Lai-Ling Winchow FCP(SA) Cert Rheum(SA) Chris Hani Baragwanath Academic Hospital University of the Witwatersrand

2 Outline of presentation Milestones in the treatment of RA Current treatment strategy:- Early diagnosis Early initiation of DMARDs Synthetic, biological and targeted synthetic DMARDs Corticosteroids Treat to target Remission and Drug-free remission Co-morbidities Take home messages

3 Introduction Rheumatoid arthritis (RA) chronic progressive multi-system autoimmune disorder with a predilection for synovial joints Prevalence of RA: ~1% of the population Joint damage and subsequent deformity leads to considerable functional disability Black South Africans with established RA have significantly worse functional disability compared to SLE patients AlamanosY et al. Autoimmun Rev 2005 Paco MJ et al. Arthritis Rheum 2001 Benitha R et al. Clin Rheumatol 2007

4 Milestones in the treatment of RA Year 1980s 1990s 2000s 2010s RA Management Salicylates + Steroids Gold Salts D-penicillimine Chloroquine (CHQ) Sulphasalazine (SZP) Cyclophosphamide Azathioprine (plasmaphoresis) (Lymphoid irradiation) NSAIDs + Steroids Methotrexate (MTX) MTX plus CHQ SZP Leflunomide MTX/Triple therapy + Steroids MTX/Leflunomide + Anti-TNF Switch Anti-TNF MTX + Biologic Continue or switch biologic Tofacitinib Reduce DMARDs Treatment Target Clinical improvement Poorly defined Treat to Target Remission? Drug-free remission AnastassiadesTP. Can Med Assoc J 1980 Saag K et al. Arthritis Rheum 2008 Singh j et al. Athritis Care Res 2012 Smolen J et al. Ann Rheum Dis 2014

5 Early Diagnosis inflammation Inflammation deformity Deformity Time Quinn MA et al. Clin Exp Rheumatol 2003

6 Early DMARD initiation on radiographic progression Van Aken J et al. Ann Rheum Dis 2004

7 2010 ACR/EULAR Classification Criteria for RA Two requirements: (1) Patient with at least one joint with definite clinical synovitis (swelling) (2) Synovitis is not better explained by another disease 6 = definite RA JOINT DISTRIBUTION (0-5) 1 large joint large joints small joints (large joints not counted) small joints (large joints not counted) 3 >10 joints (at least one small joint) 5 SEROLOGY (0-3) Negative RF AND negative ACPA 0 Low positive RF OR low positive ACPA 2 High positive RF OR high positive ACPA 3 SYMPTOM DURATION (0-1) <6 weeks 0 6 weeks 1 ACUTE PHASE REACTANTS (0-1) Normal CRP AND normal ESR 0 Abnormal CRP OR abnormal ESR 1 Aletaha D et al. Ann Rheum Dis 2010

8 Disease-modifying anti-rheumatic drugs (DMARDs) Conventional synthetic DMARDs Methotrexate Leflunomide Sulfasalazine Anti-malarials Hydroxychloroquine Chloroquine Biological DMARDs Anti-TNFs Etanercept Adalimumab Infliximab Golimumab Certolisumab pegol Rituximab Abatacept Tocilizumab Targeted synthetic DMARDs Tofacitinib

9 Synthetic DMARDs - Methotrexate Anchor drug Folate antagonist 2/3 of patients have adequate response to MTX as monotherapy or combination therapy (non-biological DMARDs) Good retention rates Dose: 10-25mg weekly Folate supplementation: 5-10mg weekly Adverse effects: Gastro-intestinal intolerance and headaches are common; bone marrow suppression, lung and liver toxicities are very uncommon PincusT et al. Bull Hosp Jt Dis 2013 Weinblatt ME. Trans Am Clin Climatol Assoc 2013

10 Biological DMARDs

11 Biological DMARDs anti-tnfs First line biological treatment Subcutaneous or intravenous administration Administration with MTX is superior to monotherapy Safety concerns: increase risk of infection esp. tuberculosis and herpes zoster; slight increase risk of melanoma Cost issues Vivar N et al. F1000Prime Rep 2014

12 Biological DMARDs - Rituximab Chimeric Anti-CD20 monoclonal antibody Approved for treatment of RA patients in combination with MTX who have had an inadequate response to anti-tnf Increase efficacy in seropositive patients Administered IV 2 doses (500mg or 1g/dose) 2 weeks apart Safety concerns: Infusion reactions (common) ; hypogammaglobulinaemia; reactivation of hepatitis B; progressive multifocal leukoencephalopathy No increase incidence of TB/malignancy Mok CC. Drug Des Devel Ther 2014

13 Targeted synthetic DMARDs - Tofacitinib JAK kinase 1/3 inhibitor Inhibits the JAK-STAT intracellular signalling pathway, hence inhibiting gene transcription of inflammatory cytokines 5mg BD orally as monotherapy or with background DMARDs Shuai K et al. Nat Rev Immunol 2003 Jiang JK et al. J Med Chem 2008

14 Corticosteroids Bridging therapy and NOT monotherapy Oral, intramuscular and intra-articular administration Low dose: Prednisone < 10mg daily Early disease reduces radiographic progression by at least 50% Modified-released prednisone significantly reduces morning stiffness Santiago T et al. Acta Rheumatol Port 2015

15 TIght COntrol in Rheumatoid Arthritis (TICORA) study Grigor C,et al. Lancet 2004

16 In a local setting Tight Control Strategy (n=98) Historical Cohort (n=134) p-value Remission, n (%) 33 (33.7) 13 (10.4) < LDA, n (%) 30 (30.6) 24 (17.9) Patients lost to follow-up, n (%) 2(2.0) 35 (20.5) < Hodkinson B et al. Rheumatology 2015

17 Instruments assessing RA disease activity variables for determining therapy Score Range Remission Low Moderate High DAS < to < to 5.1 >5.1 SDAI >3.3 to 11 >11 to 26 >26 CDAI >2.8 to 10 >10 to 22 >22 DAS28 = Disease Activity Score with 28 joint counts SDAI = Simplified Disease Activity Index CDAI = Clinical Disease Activity Index Anderson J et al. Arthritis Care Res 2012

18 SA Recommendations for the treatment of rheumatoid arthritis Hodkinson B et al. S Afr Med J 2013

19 Drug-free Remission Drug-free remission is only achievable in a small minority of patients Risk of flares are 3x greater in those that have stopped DMARDs Best predictors of flares: IgM-RF and ACPA positivity Strong evidence: step-down DMARD combinations, wean dose or extend dosing intervals Smolen JS et al. Lancet 2013 Scott IC et al. Clin Exp Rheumatol 2013

20 Comorbidities in RA Cardiovascular disease (CVD): ischemic heart disease, subclinical atherosclerosis and heart failure Infections: increase risk of serious infections Mental health conditions: depression and anxiety Malignancies: increased incidence of lymphoproliferative malignancies Osteoporosis: increase fracture risk Michaud K et al. Best Pract Res Clin Rheumatol 2007 Dougados M et al. Ann Rheum Dis 2013

21 Take home messages Inadequately treated RA leads to significant functional disability and morbidity Early diagnosis Prompt initiation of DMARDs and escalation of therapy Tight control strategy (based on measurement of disease activity) Treat to target remission or LDA Drug- free remission still remains elusive Monitor and treat comorbidities

22 Thank you

23 Instruments assessing RA disease activity Disease activity score with 28 joint counts (DAS28) = 0.56 * sqrt(28tjc) * sqrt (28SJC) * ln(esr) * PtGA Simplified disease activity index (SDAI) = 28SJC + 28TJC + PrGA + PtGA + CRP Clinical disease activity index (CDAI) = 28SJC + 28 TJC +PrGA + PtGA TJC=Tender joint count; SJC=Swollen joint count; PrGA=Provider s global assessment of of disease activity; PtGA=Patient s global assessment of disease activity; Anderson J et al. Arthritis Care Res 2012

24 Remission Felson DT et al. Ann Rheum Dis 2011

25 Novel therapeutic targets Koenders MI et al. Trends Pharmacol Sci 2015