Rheumatoid Arthritis. Update in Rheumatoid Arthritis Diagnosis and Therapy. RA: Chronic Joint Destruction and Disability What We Try to Prevent

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1 Rheumatoid Arthritis Update in Rheumatoid Arthritis Diagnosis and Therapy Jonathan Graf, M.D. Associate Professor of Medicine, UCSF Division of Rheumatology, SFGH Director, UCSF Rheumatoid Arthritis Clinic Chronic, inflammatory, predominantly small joint arthritis Affects up to 1% of the US population Female:Male predominance of 3:1 Disability costs are high, both in terms of direct and indirect medical costs 35% of patients with 10 years disease duration are work-disabled Decline from 50% rate reported in 1987 Arthritis Rheum Mar 27;59(4): RA: Chronic Joint Destruction and Disability What We Try to Prevent Improving Outcomes in RA: Three Pillars Improvement in timely and accurate diagnosis Development of better tools to predict disease severity Improvement in therapy 1

2 Improving Outcomes in RA: Three Pillars Improvement in timely and accurate diagnosis Early RA: The Window of Opportunity to Intervene Development of better tools to predict disease severity Improvement in therapy The Window of Opportunity Eventually Closes for Many. Chronic disease progression leads to permanent joint deformity, destruction, and disability Empirically, RA is a different disease the longer disease activity progresses without effective control More difficult to suppress activity and treat More extra-articular disease? ACR Criteria for the Classification of Rheumatoid Arthritis 1987 (>4 criteria required; 1-4 must be present > 6 wks) Morning stiffness > 1 hr Arthritis of 3 or more joint areas Arthritis of wrists, MCPs, and/or PIPs Symmetric arthritis Rheumatoid nodules Serum rheumatoid factor Radiographic changes 2

3 Limitations of ACR Classification Criteria for the diagnosis of early RA Developed for the classification of patients with longstanding disease (for clinical studies, not diagnosis) Classification criteria revised in 2010 to allow for the study of patients with earlier disease, but not as descriptive For early RA, 1987 classification criteria: Specificity: 90% Limited sensitivity: 40-65% Relying on criteria to make a diagnosis of RA can lead to delayed or inappropriate diagnosis Diagnosis of early RA by ACR criteria van Gaalen et al Arth Rheum 50: 709, patients with early inflammatory arthritis Initial evaluation After 3 years 205 RA by ACR criteria undifferentiated 127 RA arthritis 413 other diagnoses Factors predictive of progression from undifferentiated arthritis to RA van Gaalen et al Arth Rheum 50: 709, 2004 At initial evaluation OR (95% CI) Positive rheumatoid factor 1.7 ( ) Positive anti-ccp antibody 38.6 ( ) Posttranslational modification of proteins: PADI converts arginine to citrulline 3

4 RA-associated autoantibodies that recognize peptides containing citrulline Girbal-Neuhauser et al J Immunol 162: 585, 1999 Peptide sequence Antibody recognition Antibodies to citrullinated peptides in RA Detected by ELISAs using synthetic cyclic citrullinated peptides (CCP) ESSRDGSRHPRSHD PADI ESSRDGScitHPRSHD No Yes Sensitivity for very early RA: 50% Sensitivity for early-later RA: 70-80% Specificity for RA: 95-98% Actual citrullinated antigen is not known RF and anti-ccp testing in a cohort of 182 early RA patients Quinn et al Rheumatology (Oxford) 45:478, 2006 Preclinical autoimmunity in RA: appearance of anti-ccp abs and RF prior to onset of arthritis RF+CCP- RF-CCP- RF-CCP+ RF+CCP+ Nielen et al Arth Rheum 50: 380,

5 Improving Outcomes in RA: Three Pillars Improvement in timely and accurate diagnosis Development of better tools to predict disease severity Possible to predict which patients require more aggressive therapy up front? Improvement in therapy Classic Predictors of Disease Severity More difficult to treat, destructive, extraarticular disease: Rheumatoid factor positive Erosive disease Genetic factors HLA class II DR4 molecule (HLA DRB1*04 ) Not practical to genotype all patients HLA DR and rheumatoid arthritis HLA DRB1 alleles and rheumatoid arthritis: shared epitope hypothesis Serologic designation DR4 DR4 Nomenclature by DNA sequence DRB1*0401 DRB1*0404 HLA DR4 allele confers RR 6:1 for developing RA More copies of DR4, more severe disease Not every DR4 allele confers the same risk Some non DR4 alleles do confer risk of RA HLA DR (MHC class II): Antigen presentation by APC s to T-cells amino acid position on the DRβ chain DRB1 allele Q R R A A 0401 Q K R A A 0404 Q R R A A 0405 Q R R A A 0408 Q R R A A 1402 Q R R A A 1001 R R R A A CONSENSUS Q/R R/K R A A 5

6 The shared epitope (DRB1*0401) Relationship between shared epitope and CCP antibodies in RA Van Gaalen et al. Arthritis and Rheumatism 2004:50;7: A74 Q70 A73 R72 Effect of SE on presence of CCP antibodies in RA Presence of CCP antibodies, not SE, confers risk for more aggressive RA Huizinga, Criswell et al. Arthritis and Rheumatism 2005:52;11: Van Gaalen et al. Arthritis and Rheumatism 2004:50;7: Huizinga, Criswell et al. Arthritis and Rheumatism 2005:52;11: At least one copy of SE 42% 80% 49% 6

7 Progression of joint damage in subgroups of early RA Huizinga et al Arthritis Research& Therapy 7: 949, 2005 radiographic joint damage score anti-ccp + anti-ccp - Anti-CCP status Anti-CCP positive RA patients are unique compared to anti-ccp negative patients Shared epitope positive compared to controls No additional contribution to risk of developing RA from SE independent of CCP status (data not shown) More erosive disease More progressive course of disease (radiographically) Is rheumatoid arthritis a single disease? RA #1 SE + - CCP + - Erosive dz + - RA#2 Summary: Clinical utility of the anti- CCP antibody test Diagnosis: Clinical suspicion of rheumatoid arthritis Early, undifferentiated inflammatory arthritis Distinguish RA from other RF + polyarthritis Not useful to monitor disease activity Best single predictor for destructive disease in patients with early onset RA 7

8 Improving Outcomes in RA: Three Pillars Improvement in timely and accurate diagnosis RA: Chronic Joint Destruction and Disability What We Try to Prevent Development of better tools to predict disease severity Improvement in therapy Joint damage in RA: progressive narrowing and erosion of a MCP joint Irreversible damage can develop within months of onset of RA At presentation: 1 year 5 years normal 1 year prior to 6 months after 3 years after onset onset of RA onset of symptoms of symptoms Radiographic changes in the same joint over time 8

9 Treatment of early RA Effective treatment should be started when the diagnosis is made Effective treatment = therapies shown to slow joint destruction Goal is to induce and then maintain remission Combination of drugs more effective than monotherapy RA: Traditional Treatment Paradigm Pyramid of therapy Start conservatively Gradually ascend the pyramid in order of potency and toxicity of therapy Only the most severely affected patients receive immunosupressive, DMARDs DMARD therapy begun only after period of significant delay Re-Thinking the RA Treatment Pyramid Emphasizes earlier diagnosis and initiation of therapy with disease modifying anti-rheumatic drugs ACR RA Practice Guidelines 2002 Most patients with Rheumatoid Arthritis should be evaluated expeditiously Treatment with DMARD instituted within 3 months of diagnosis Goals are to prevent or control joint damage, prevent loss of function, and decrease pain 9

10 ACR Treatment Guidelines 2008 Encourages more formal assessments of disease activity Similar to hemoglobin A1C for diabetes Several formal disease scores available: DAS28 CDAI, SDAI, etc Vectra-DA biomarker assay Treat to target of mild disease activity or better DAS: Treating to target DAS 28 disease activity cutoffs: DAS28 <2.6 Remission DAS Mild Activity DAS Moderate Activity DAS28 >5.1 High Disease Actiivty DMARD Therapies Methotrexate Leflunomide (Arava) Sulfasalazine Azathioprine Mycophenolate Mofetil Corticosteroids Hydroxychloroquine Minocycline Combination DMARD Therapies: Some Step Up, Others Step Down Methotrexate +SSZ +Plaquenil +/- Prednisone Arava + SSZ + Plaquenil +/- Prednisone More and more, combination therapies of DMARDs and Biologic medications being used earlier in the course of treatment 10

11 Why Move Towards Combination Regimens with Biologics?? The Current Pyramid Paradigm Early initiation and titration of DMARD If incomplete response to DMARD alone, after reasonable titration, addition of biologic recommended Families of Biologic Therapies Anti-Tnf medications (5 total) Etanercept (TNF decoy receptor fusion protein) Infliximab, Adalimumab, certolizumab, golimumab (variations of anti-tnf antibodies or Fab ) B-cell depleting agents Rituximab T-cell costimulation inhibitors (receptor-ligand ) Abatacept Inhibitors of Il-6 signaling Tocilizumab (anti Il-6 receptor antibody) Il-1 Inhibitors (Il-1 cytokine receptor decoy) Anakinra Families of Biologic Therapies Anti-Tnf medications (5 total) Etanercept (TNF decoy receptor fusion protein) Infliximab, Adalimumab, certolizumab, golimumab (variations of anti-tnf antibodies or Fab ) B-cell depleting agents Rituximab T-cell costimulation inhibitors (receptor-ligand ) Abatacept Inhibitors of Il-6 signaling Tocilizumab (anti Il-6 receptor antibody) Il-1 Inhibitors (Il-1 cytokine receptor decoy) Anakinra 11

12 Biology of TNF : Good and the Bad Good: TNF-alpha regulates biological functions necessary for normal inflammatory, immune, and tumor surveillance responses. TNF-alpha absolutely essential for granulomatous host defenses against intracellular bacteria MTb, fungal infections, listeria Bad: TNF-a binds membrane-bound TNF receptors and mediates pro-inflammatory processes implicated in inflammatory arthritis. Anti-TNF: A Family whose members are subtly different Anti-Tnf medications Etanercept (TNF receptor fusion protein) Infliximab (anti-tnf antibody) Adalimumab (anti-tnf antibody) Certolizumab pegol (anti-tnf Fab-PEG) Golimumab (anti-tnf antibody) Anti-TNF therapies: Regulating a TNF thermostat Give just enough TNF blocking therapy to reduce inflammation But not too much so as to affect immunosuppression and tumor surveillance A word about pharmacokinetics... Remember these medications have long half lives This is important for duration of the biologic effect Also important in case someone develops a side effect or infection while on one of these medicines Etanercept 4.25 days Infliximab 8-12 days Adalimumab 14 days Many patients, especially those on IV therapy, (infliximab, rituxan, etc ) may not mention to their MD that they are on therapy Contraindications History of latent tuberculosis unless/until they have completed an adequate courses of prophylactic therapy (Duration up for debate) Active acute or chronic infections (HCV exception) Active or suspected malignancies. Anti-TNFs are generally contraindicated in patients with moderate or severe congestive heart failure (some have black box warning) History of demyelinating disease 12

13 Initiating Anti-TNF Therapy Asses Latent TB status at baseline PPD Follow up CXR if necessary Consider Coccidiomycosis and Histoplasmosis in endemic regions before prescribing (should weigh into decision of risks/benefits) Age appropriate cancer screening - good idea Monitoring Recommended NOT to receive live vaccines within two weeks of initiating therapy CDC does recommend zoster vaccine prior to starting therapy Screening for active infections by history in all patients on active therapy Use contraindicated in active infections Hepatitis B carriers (HepB core Ab+/Sag-) Follow Lfts carefully for re-activation Anti-TNFs: Adverse Events Increased risk of infections! (OR of 2.0 for serious infection in large meta analysis published in JAMA 2006) Increased malignancy risk: Always thought of as a theoretical risk, now controversial evidence that RA patients may be at increased risk of lymphoma and/or solid tumors May worsen symptoms of congestive heart failure. Specifics: Anti-TNF and TB Reviews of the FDA Adverse Events Reporting System (First of which published by Keane et al., NEJM 2001) Incidence of TB 4X background rate in US general and RA populations (24.4 cases/100,000 pts/year) 56% Extra Pulmonary TB 24% Disseminated disease Average onset 12 weeks after initiation (3-4 th dose) Wolfe published separate study with rate as high as 60/100,000 pts/year) 13

14 Infliximab and TB Keane et al. N Engl J Med Oct 11;345(15): Best Practice & Research Clinical Rheumatology 2006 Counsel Risks of TB Screen with PPD +/- CXR (we do both) Treatment of latent disease for 6-9 months with INH. Duration of time before using anti-tnf not established (1 wk-6 mo.) Be alert to atypical presentations of TB Specifics: Hepatitis B TNF-A may play role in clearing and/or containing HBV infection As of 2006, 11 reported cases of chronic HBV treated with infliximab (not just with RA) 1 pt with adult stills Fulminate hepatitis 2 cases with MTX Reactivation (increase in transaminases and/or HBV DNA) 3 cases without MTX Reactivation 4 cases with 3TC Stable without HBV reactivation 1 pt reverted from HBV DNA+ to negative Hepatitis B Recommendations: We screen all patients for HBV serologies Follow LFTs in carriers who are Hep B Core Ab+, even if also SAb+ Avoid anti-tnf therapy in patients who have chronic active infection (Hep B Sag+) unless: If use anti-tnfs in Hep B Sag+ patients: we initiate anti-hep B therapy (RT inhibitors) Follow Hep B DNA PCR for log changes in viral copies 14

15 Specifics: Hepatitis C TNF appears to be implicated in chronic liver injury rather than having protective anti-viral effects Some clinical evidence to support benefit in HCV cirrhosis Interval monitoring of LFTs and (? HCV viral load recommended) Specifics: Endemic Fungal Infections No clear guidelines Incidence of fungal infections/listeria appears to be lower than for TB Counsel about risk Avoid high risk behavior where possible (cave exploring, cleaning bird cages, farming in the central valley, etc.) Consider drawing Cocci titers. If positive, some recommend empiric prophylaxis with fluconazole Follow carefully for first few months after initation of therapy and consider fungal infecton if ill. Specifics: Anti-TNFs and Malignancy Elevated risk of lymphoma in patients with RA with some likely relation to disease activity and duration Large meta-analysis suggested an OR 3.3 for all malignancies in patients using anti-tnf, especially high doses). Only studied anti-tnf antibodies (Bongartz et al., JAMA 2006) Longitudinal analysis of 20,000 patients from the National Databank of Rheumatic Diseases found no increased risk of lymphoma compared to general population or those with RA (Wolfe et al., A&R 2007) ACR 2006 Recommendations No need to be overly alarmed, although safety of patients on immunosupressive therapy always of paramount concern Counsel patients about risks JAMA: number needed to harm 154 ACR published information sheet on website No study has established new or incr. risk of TNF-inhibitor solid tumors No guidance on safety of use in patients with prior malignancies 15

16 Specifics: CHF Guidelines Furst et al. Best Practice & Research Clinical Rheumatology 2006 Patients without history of CHF do not need baseline Echo Patients with mild compensated CHF (NYHA class I&II) should receive ECHO prior to starting Rx. Normal EF, counsel about risks Abnormal EF, would avoid use Contraindicated in NYHA class III&IV Discontinue if new onset CHF develops unexplained by other events When patients fail anti-tnf therapy Up to 30% of patients fail to respond or lose response to anti-tnf therapy Additional patients are intolerant or have contraindication to anti-tnf therapy There are now many other biologic therapies available When Patients fail anti-tnf therapy: B-cell depleting agents Rituximab T-cell costimulation inhibitors (receptor-ligand ) Abatacept Inhibitors of Il-6 signaling Tocilizumab (anti Il-6 receptor antibody) Il-1 Inhibitors (Il-1 cytokine receptor decoy) Anakinra Future directions in RA therapy Oral small molecule biologic inhibitors are coming to a rheumatologist s office near you sooner than you think. Interfere with signaling that occurs between the time a cytokine binds its receptor and when that binding exerts its biologic effect on DNA transcription Kinases are enzymes that mediate this signaling between the cell surface and the nucleus 16

17 Cytokine Signaling through Kinases Cytokine Signaling through Kinases Current Biologic Therapies Cytokine: eg. TNF Current Biologic Therapies Cytokine: eg. TNF Kinases Kinases Future Therapies Transcription Biologic Effect Kremer et al. A&R July

18 Brighter Future for Patients with RA 18