Rheumatoid Arthritis- Have we made any progress

Rheumatoid Arthritis: Have we made any progress? Elizabeth Araujo, M.D. Assistant Professor of Medicine Loyola University Attending Rheumatologist Edward Hines, Jr. VA Hospital Overview • Impact of the disease • Clinical manifestations • “New” diagnostic tools • Insights into pathogenesis • Treatment modalities RHEUMATOLOGY THIRD EDITION; Painting by Jacob Jordaens (1593-1678), entitled The Painter's Family Overview • Impact of the disease • Clinical manifestations • “New” diagnostic tools • Insights into pathogenesis • Treatment modalities RA: a benign condition? RA is associated with: • Shorter life expectancy, matched for age and gender – Mortality rates are increased at least 2 fold in RA, and are linked to clinical severity of disease • Increased risk for infection • Increased risk of lymphoma • Increased risk of cardiovascular and cerebrovascular disease morbidity due to MI, CHF, and probably CVA RA: a benign condition? RA: a benign condition? RA: a benign condition? RA: a benign condition? Overview • Impact of the disease • Clinical manifestations • “New” diagnostic tools • Insights into pathogenesis • Treatment modalities RHEUMATOID ARTHRITIS Hand deformities C1-C2 subluxation Extra-articular manifestations • Constitutional symptoms • Rheumatoid nodules • Vasculitis • Ocular manifestations – Keratoconjunctivitis sicca, episcleritis, scleritis • Pulmonary manifestations – Cricoarytenoid involvement, interstitial lung disease, pleural involvement Extra-articular manifestations (2) • Cardiac involvement – Constrictive pericarditis • Renal involvement – Secondary amyloidosis • Neurologic manifestations – Mononeuritis multiplex, entrapment neuropathies • Hematological – Anemia Risk factors for more severe disease • Positive rheumatoid factor • Presence of rheumatoid nodules • Presence of shared epitope (MHC class II HLA-DRB1* 0401 allele) • Positive anti-CCP antibodies ABIM “Classics” • RA + splenomegaly + leukopenia+ leg ulcers = FELTY’S SYNDROME • RA + pulmonary nodules + coal miners = CAPLAN’S SYNDROME Overview • Impact of the disease • Clinical manifestations • “New” diagnostic tools • Insights into pathogenesis • Treatment modalities ACR Classification Criteria of RA 1. 2. 3. 4. 5. 6. 7. Morning stiffness Arthritis of three or more joint areas Arthritis of hand joints Symmetric arthritis Rheumatoid nodules Serum rheumatoid factor Radiographic changes * For classification purposes, a patient shall be said to have RA if he/she has satisfied at least 4 of these 7 criteria. Criteria 1 through 4 must have been present for 6 weeks. The problem of early diagnosis… Early arthritis- case scenario • 42 y/o Caucasian woman with bilateral hand and wrist pain x 3 months • ROS: + morning stiffness x 45-60 minutes, + fatigue • Family History: + RA (mother and maternal aunt) • Social Hx: + tobacco • PE: synovitis over right 2nd and 3rd MCPs and right wrist • Labs: CBC with mild normo/normo anemia; RF and ANA negative x 2; CRP 2.3 • Hand XRAY-s: no abnormalities • A/P: Pt was given small dose Prednisone with mild improvement and referred to Rheumatology Does she have RA? ACR Classification Criteria of RA 1. 2. 3. 4. 5. 6. 7. Morning stiffness Arthritis of three or more joint areas Arthritis of hand joints Symmetric arthritis Rheumatoid nodules Serum rheumatoid factor Radiographic changes * For classification purposes, a patient shall be said to have RA if he/she has satisfied at least 4 of these 7 criteria. Criteria 1-4 must have been present for at least 6 weeks. How can we improve our diagnostic sensitivity in early RA? • The role of anti-CCP antibodies • The role of MRI and US The role of anti-CCP antibodies • Anti-cyclic-citrullinated peptide antibodies • Peptides are post-translationally modified: arginine -> citrulline (requires enzyme peptidylarginine deaminase) • Studies done in early arthritis showed 98% specificity and 50% sensitivity The role of anti-CCP antibodies • They can appear years before the development of disease • They correlate with more aggressive disease • In RA patients shared epitopes alleles are strongly associated with anti-CCP antibodies (role in pathogenesis?) The role of MRI and US • Both methods have higher sensitivity than XRAY-s to detect erosions • US – Advantage: inexpensive – Disadvantage: operator dependent, not available in all sites • MRI – Advantage: available – Disadvantage: expensive Overview • Impact of the disease • Clinical manifestations • “New” diagnostic tools • Insights into pathogenesis • Treatment modalities The normal synovium The RA synovium Cellular composition of RA Synovium • Abundant cell populations • T lymphocytes • Macrophage –like (type A) synoviocytes • Fibroblastic (type B) synoviocytes • Other cell populations • Dendritic cells • B lymphocytes • Plasma cells • Mast cells • Osteoclasts Adapted from Fox, DA; Arch Int Med 2000, 160:437-444 RA: Mechanisms of Disease Choy EH, Panayi GS. N Engl J Med. 2001;344:907–916 Cytokines in RA Cytokine TNF-a IL-1 IL-6 IL-8 IL-10 IL-12 IL-15 IL-2 IL-17 INF-g TGF-b GM-CSF Source M M M,F Multiple M,T M F,M T T T Multiple M,T Target Multiple Multiple Multiple Neutrophils T T T T F Multiple T Multiple Abundance +++ +++ ++ ++ ++ + + +/+ + ++ ++ Effect on Inflammation or Tissue Damage +++ +++ ++ ++ ++ ++ + ++ ++ ++ Adapted from Fox, DA; Arch Int Med 2000, 160:437-444 The central role of TNF-alpha • Drives events in the proinflammatory cytokine cascade • Triggers production of other proinflammatory cytokines, including IL-1 • Facilitates activation of T lymphocytes by foreign antigens • Causes accumulation of T cells in tissues & neutrophils in synovial fluid • Stimulates fibroblasts & macrophages to release destructive enzymes • Stimulates osteoclastogenesis directly through differentiation of progenitor cells through enhanced expression of RANKL Fox, DA; Arch Int Med 2000, 160:437-444 Overview • Impact of the disease • Clinical manifestations • “New” diagnostic tools • Insights into pathogenesis • Treatment modalities New Treatment Paradigm • Early intensive therapy is CRITICAL • Use of DMARD combinations • Introduction of biological therapies Traditional DMARDS • Hydroxychloroquine • Sulfasalazine • Injectable gold salts • D-Penicillamine • Azathioprine • Methotrexate Drugs approved for RA in 1998 • Leflunomide (Arava) • Anakinra (Kineret) • Infliximab (Remicade) • Etanercept (Enbrel) • Adalimumab (Humira) Cytokine blockade therapy Example:IL-1 receptor antagonist Example: TNF receptor fusion proteins, monoclonal antibody against TNF Adapted from Choy EH, Panayi GS. N Engl J Med. 2001;344:907–916 Tumor necrosis factor-a blockade • TNF-a has a central role in RA • TNF-a exerts its action through receptor binding • There are two TNF-a receptors: P55 and P75 TNF Antagonists: A Molecular Comparison INFLIXIMAB a chimeric monoclonal antibody S S S S SS SS S SS S Human IgG1 S S CH3 S S CH2 Mouse Fc region of Extracellular domain of human IgG1human p75 TNF receptor ETANERCEPT a soluble human IgG1-TNF receptor construct Human IgG1 ADALIMUMAB a fully human monoclonal antibody Tumor necrosis factor-a blockade • Etanercept – Dose: 25 mg SQ twice weekly or 50 mg SQ once weekly • Infliximab – Dose: 3 mg to 10 mg/kg IV every 6-8 weeks • Adalimumab – Dose: 40 mg SQ once every other week Tumor necrosis factor-a blockade: efficacy • Relief joint pain and swelling • Lower ESR and CRP • Slow or prevent radiographic progression • Improve QOL, reduce disability • Prolong life? Potential consequences of anti-TNF therapy • Human anti-chimeric antibodies (HACA) with mouse-human anti-TNF antibody • Shift in cytokine balance that could facilitate expression of new autoimmune phenomenon • Impairment of host defenses – Risk of infections – Risk of malignancies Anti-TNF therapies: risk of infections • Serious infections were not increased in clinical trials • Post-marketing data base reveals reports of tuberculosis and other opportunistic infections in patients treated with TNF inhibitors Experimental Models of TB in animals • TNF expression increases in parallel with formation of granulomas and apoptotic cells • Depletion of TNF: – Prevents granuloma formation in acute infection – Leads to dissolution of granulomas in established infections Anti-TNF therapy and risk of TB • Risk with any of the TNF antagonists • Risk is reduced by screening and close clinical monitoring • Evidence of latent infection (positive PPD or CXR) should prompt initiation of anti-TB therapy prior to anti-TNF therapy Anti-TNF therapies: risk of malignancies • The incidence of lymphomas is increased in patient with RA • Higher incidence of lymphoma has been associated in patients treated with anti-TNF therapy • Is this a effect of the treatment or the severity of the disease? Anti-TNF therapies: safety concerns • Infections • Malignancy • Demyelinating disorders • Congestive Heart Failure Can the available anti-TNF therapies be compared? • Different study design – Inclusion and exclusion criteria – Length of study – Primary endpoint – Rescue arm – Previous therapy – Baseline radiographic damage • Different statistical methods Medication costs ACR Treatment Guidelines; Arth Rheum 2002; 46:328-346 IL-1 receptor antagonist: anakinra • IL-1 is a pro-inflammatory cytokine produced by monocytes, macrophages, and synovial cells • IL-1 has a significant role in RA by stimulating release of MMP and increasing bone resorption IL-1 receptor antagonist: anakinra • Anakinra is a recombinant human IL-1 receptor antagonist • Typical dose: 100 mg SQ daily • Modest effect when compared to TNF blockade therapy • Side effects: injection site reactions, increased risk of infections • Should not be used in combination with TNF-blockade therapy! Other biologic therapies • B cell depletion therapy • T cell costimulatory blockade B cell depletion therapy (Rituximab) • Chimeric monoclonal antibody against human CD20 • CD20 is expressed on mature B cells (not in B cell precursors or plasma cells) • Approved in 1997 for B cell, CD 20 + , non-Hodgkin’s lymphoma • Proposed mechanism of action – Complement mediated and antibody dependent cell mediated –cytotoxicity, induction of apoptosis B cell depletion therapy (Rituximab) • Results in rapid depletion of “short-lived” CD 20 + B cells • B cells are replenished in 3-12 months • Efficacy in RA with benefits persisting after a single course • Alternative in RA patients who failed anti-TNF therapy • Side effects: infusion reactions T cell costimulation Sharpe and Abbas; NEJM 2006; 355: 973-975 T cell costimulatory blockade (Abatacept) • Abatacept is a fusion protein consisting of cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) linked to the Fc region of a human IgG1 • It binds to B7on antigen presenting cells, blocking T cell activation • Effective for the treatment of RA • Should be considered in anti-TNF failures On the horizon… • Anti-interleukin 6 receptor antibody (Tocilizumab) • P38 MAP kinase inhibitor • Inhibition of interleukin 15, 12, and 18 • Inhibition of leukocyte migration • Osteoclast inhibitors • Potential targets: metalloproteinases, cadherin 11 Back to our case… What is the BeSt initial treatment strategy in early RA? BeSt Study • Single-blind, multicenter randomized clinical trial comparing 4 treatment strategies in patients with early RA (< 2 years) • The goal was to obtain low level of disease activity by adjusting therapy as needed every 3 months • If patient had no significant activity for 6 consecutive months, the drugs were tapered BeSt Study 1. Sequential substitution monotherapy 2. Step-up add-on combination therapy 3. Initial combination therapy with Methotrexate, Sulfasalazine and short course of high dose Prednisone 4. Initial combination therapy of Methotrexate and Infliximab BeSt Study • Primary end points were functional ability (HAQ) and evidence of radiographic joint damage • Combination therapy groups (3 & 4) had more rapid clinical improvement in the first year • After 4 years, 51% of patients in group 4 were able to discontinue IFX and, when compared to initial monotherapy, they had significantly less joint damage progression Conclusions • Early diagnosis and early intervention are crucial in the treatment of RA • Better understanding of mechanisms of disease has led to the development of targeted therapies • The use of biologics has had a tremendous impact on the management of RA