Treatment of Severe Rheumatoid Arthritis

Treatment of Severe Rheumatoid Arthritis Zhanguo Li Department of Rheumatology and Immunology, People s Hospital Beijing University Medical School, China

Contents Background Challenges Treatment strategies Recommendations

Contents Background Challenges Treatment strategies Recommendations

Background RA is a chronic, systemic autoimmune disease that affects 0.28%-1% of the population Polyarticular synovial inflammation causes swelling, tenderness and stiffness Leads to cartilage damage and bone erosion causing long-term disability Increased comorbidities

Background

Prevalence of RA in the world Prevalence (/1000) 12 10 8 6 4 2 10.7 8.5 7 5.1 4.1 3.3 3.3 3.1 3.1 2.8 2 0 USA UK Greece Sweden China Italy France Agentina Rheumatology (Oxford). 2002;41:793-800. Rheumatology (Oxford). 2002;41:88-95. Ann Rheum Dis. 1998;57:315-8.

Prevalence of RA in China Rheumatology (Oxford). 2012 Apr;51(4):721-9.

Composition of Disabled Diseases 2nd Nationwide Survey on the Disabled (China, 2006) 30 25 Cerebrovascular diseases RA 79.4% M 男 % 20 15 F 女 10 5 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1. Cerebral palsy,2. Dysplasia,3. Dwarfism,4. Congenital disorders,5. Poliomyelitis,6. Cerebrovascular diseases,7. Peripheral angiopathy,8. Neoplasia,9. Arthritis,10.Endemic diseases,11. Spinal cord diseases, 12. Industrial injury,13. Traffic accidents,14. Spinal cord injury,15. Cerebral trauma, 16. other trauma, 17. Tuberculosis,18. Purulent infection,19. Poisoning,20. Others,21. Unknown cause 16 provinces, 734 nationwide counties (cities) 2.6 million people, 2 of the national population

Economic Burden Associated with RA is Higher than Hypertension and Diabetes Yuan / Year 8000 7000 6000 5000 4000 3000 2000 1000 0 7810 3500 631 Hypertension Diabetes RA State Development and Reform Commission (SDRC) (2003) Yang XH, et al. Chin Journal of Generalist. 2005; 4(9): 528.

Contents Background Challenges Treatment strategies Recommendations

Challenges Arthr Res Ther 2012,14:R68

Challenges Arthr Res Ther 2012,14:R68

Challenges Arthritis Rheum. 2008 Sep;58(9):2642-51.

Challenges The overall remission rate is low! Arthritis Rheum. 2008 Sep;58(9):2642-51.

Challenges Rheumatology. 2007 Jun;46(6):975-9.

Challenges Journal of Peking University. 2013 45(2):260-3.

Challenges Journal of Peking University. 2013 45(2):260-3.

However

Contents Background Challenges Treatment strategies Recommendations

Treatment strategies Remission CR improvement of QOL RA traditional DMARDs biological DMARDs Approaches others: NSAIDs GC herbs immunoabsorption Strategies early individualized intensive recommendations & suggestions

Early treatment & prognosis Natural course Delayed treatment Early treatment Bone erosion and joint deformity 3m Ideal course Synovial destruction Onset

Combination therapy Study N Duration Treatments Outcomes Haagsma et al 105 <1yr SSZ or MTX SSZ+MTX Boers et al (COBRA) 155 <2yrs SSZ SSZ+Pred+MTX Mottonen et al 199 <2yrs SSZ±pred MTX+SSZ+HCQ+pred Calguneri et al 180 2.36 yrs HCQ, SSZ or MTX Goekoop- Ruiterman et al 508 <2yrs MTX+HCQ or MTX+SSZ MTX+SSZ+HCQ Hetland et al 160 <6m MTX MTX+CsA St Clair et al ( ASPIRE) 104 9 <3yrs MTX MTX, add SSZ, add HCQ MTX+SSZ+pred MTX+inf MTX MTX+infliximab Breedveld et al 799 <3yrs Adalimumab MTX MTX+adalimumab 52w DAS change: P<0.001 1 yr vdh-s: P<0.0001 2 yrs ACR remission:p=0.003 2 yrs modified Paulus criteria: P<0.001 Median increse in vdh- S: P=0.003 p<0.04 54w % ACR-N: P<0.001 2 yr ACR50: p<0.001 Semin Arthritis Rheum. 2011 Apr; 40(5): 371-88

Combination therapy N=143 articles Including: RCTs: 42 others:101 Conclusion: 1. DMARDs combination therapy is superior 2. biologics+mtx > single drugs Ann Intern Med. 2008; 148(2):124-34.

Combination therapy 48 weeks, double-blind trial 353 active RA patients MTX+HCQ+SASP (triple therapy) MTX+etanercept primary outcome: DAS28 NEJM. Jul 25;369(4):307-18.

Combination therapy NEJM. Jul 25;369(4):307-18.

NEJM. Jul 25;369(4):307-18.

Intensive treatment Intensive treatment vs. routine care (18-month assessment) 100% 82% 95% 91% 84% Remission rate(%) 80% 60% 40% 20% 44% 14% 64% 40% 71% 18% intensive routine 0% EULAR response EULAR remission ACR 20 ACR 50 ACR 70 Lancet 2004;364:263-69

High remission and low relapse of RA with prolonged intensive DMARD therapy (a prospective multicenter study) DAS>5.1 RA patients(n=400) LEF 10mg qd HCQ0.2 bid + MTX 7.5mg/w Dr. Ru Li and colleagues MTX +2.5-5mg/w 7.5-20mg/w, LEF 20mg qd Adjustment by physicians Unpublished data

High remission and low relapse of RA with prolonged intensive DMARD therapy (a prospective multicenter study) Unpublished data

High remission and low relapse of RA with prolonged intensive DMARD therapy (a prospective multicenter study) Unpublished data

High remission and low relapse of RA with prolonged intensive DMARD therapy (a prospective multicenter study) Unpublished data

High remission and low relapse of RA with prolonged intensive DMARD therapy (a prospective multicenter study) Unpublished data

Comprehensive therapy Intraarticular GC injection Physical exercise Comprehensive/ NSAIDs Topical medication individualized Immunoabsorption surgery

Contents Background Challenges Treatment strategies Recommendations

Recommendations-ACR 2012 Figure 1. 2012 ACR recommendations update for the treatment of early RA, defined as a disease duration <6 months.

Recommendations-ACR 2012 Figure 2. 2012 ACR recommendations update for the treatment of established RA, defined as a disease duration >6 months or meeting the 1987 ACR classification criteria. Depending on a patient s current medication regimen

1. Treatment with DMARDs should be initiated as soon as diagnosis is made, with the aim of reaching a target of remission or LDA. 2. As first-line treatment, MTX or combination therapy of MTX with other conventional synthetic DMARDs should be suggested. 3. Low-dose GCs should be considered in combination with DMARDs for up to 6 months and be tapered as soon as clinically feasible. 4. In patients failing to respond within 6 months and when poor prognostic factors are present, biological DMARDs (TNFinhibitors, abatacept or tocilizumab or under certain circumstances rituximab) should be administered in combination with MTX.

5. Patients failed to respond to an initial biologic DMARD should receive another biologic DMARD. 6. Patients failed to respond to an initial TNFi may receive another TNFi, or an alternative biologic. If biologic treatment has failed, tofacitinib may be considered. 7. In patients achieving persistent remission and after having tapered GCs, clinicians should consider tapering the biological DMARD, particularly if the treatment is in combination with a conventional synthetic DMARD. In cases of sustained longterm remission, cautious dose-reduction of conventional synthetic DMARDs should be considered.

Conclusions 1 2 Remission is not as common in daily practice as in clinical trials, drug-free remission can be achieved in RA patients. Early, combined, intensive, and individualized strategies should be adopted in the treatment of RA. 3 RA management recommendation should be followed in daily practice.

Future of RA patients 43

Challenges Most stringent Least stringent Journal of Peking University. 2013 45(2):260-3.

Early diagnosis 1. stiffness 30min E-RA criteria 2. polyarthritis: 3 in 14 areas 3. Arthritis of hand joints: 1 area in wrist, MCP, or PIP joint 4. Positive RF 5 抗 CCP 抗 体 阳 性 * 14 areas:bilateral PIP, MCP, wrist, elbow, knee, ankle, and MTP joints * 3 points RA diagnosis Sensitivity 84% Specificity 87%

Sensitivity (%) Specificity (%) E-RA criteria 84 87 2010 ACR/Eular criteria 79.5 73.3 1987 ACR criteria 58 93.6