Approach to Diagnosis and Treatment of Inflammatory Arthritis Dr. L. Perlin St. Michale’s Hospital Division of Rheumatology

The Case Ms. M.J. 61 year old woman - early Sept. 2007: left foot MTP pain (fell in Dec. 2007) X ray: no fracture - resolved 3 weeks - Oct. 2007: left shoulder pain - resolved 1 week - Nov. 2007: right wrist pain and swelling - resolved 48 hr - Dec. 2007- Feb. 2008 episodic monoarticular flares wrists, MTP’s knees and shoulders

The Case Ms. M.J. continued - Dx: Palindromic Rheumatism - Tests normal except: RF 28IU CRP 10 - Treated: NSAIDS - Feb. 2008 - June 2008: additive arthritis in 13 joints 4 with effusions

The Case What is the diagnosis? What is the treatment? Ms. M.J. – Summary 61 year old woman with new onset inflammatory, large and small joint, somewhat asymmetric polyarthritis What is the diagnosis? What is the treatment?

DIAGNOSIS OF INFLAMMATORY POLYARTHRITIS History and Physical exam - most important diagnostic tools. Epidemiology, family history, pattern of joint involvement, presence of inflammatory back disease & EAF may be helpful in diagnosis. Synovial fluid analysis (Cell count, Culture, Crystal analysis) Basic laboratory tests are non-diagnostic. Always do a urinalysis & creatinine. RF, ANA & x-rays should be done only if the clinical picture warrants.

Inflammatory Polyarthritis Rheumatoid Arthritis is common ~1% Damage occurs very early Mortality rates increased in poorly controlled disease DMARDS improve clinical outcome if used in early RA – delay is detrimental Identify, refer, treat EARLY

Difficulties Encountered in Assessing Early Inflammatory Arthritis Initial diagnosis may be unclear – RA clinical features are non-specific ie: RA is distinguished by chronicity In patients eventually diagnosed with RA at onset: - 60% normal acute phase reactants - 70% have normal X rays - 60% are RF negative Early NSAID response may suggest cure

Who to Treat? Who to Refer? Patients with features of an early inflammatory arthritis: - joint swelling - MCP and MTP involvement - a good anti-inflammatory response - symmetric distribution of symptoms - family history - significant early morning stiffness

Who to Treat? Consider DMARD therapy for all patients with early inflammatory polyarthritis where persistent disease is likely Most important determinant of chronicity is disease duration > 12 weeks.

Management of Early Inflammatory Arthritis no yes Symptomatic treatment Duration > 12 weeks no yes Recurrence after shot of CS yes ACR classification criteria + no no yes Self-limiting disease undifferentiated confirmed arthritis RA LEAP alogarithm

Management of Rheumatoid Disease NSAIDS and analgesics and corticosteroid DMARDS - methotrexate - sulfasalazine - hydroxychloroquine - leflunomide Biologics - TNF inhibition: infliximab, etanercept, adalimumab - Inhibitor T cell activation: abatacept - B cell inhibition: rituximab - IL 1 inhibition: anakinra

Disease Modifying Anti-Rheumatic Drugs Must change course of RA over 1 year evidenced by sustained improvement in physical function decreased inflammation slowing or prevention of structural joint damage ACR 20 50 70

ACR Improvement Criteria Disease Activity Score Statistically derived index validated Tender Joint count Swollen joint count ESR General health index DAS 28 - modified to be used with 28 joint count ACR 20 denotes 20% improvement in: Tender joint count (TJC) Swollen joint count (SJC) and 3 of the following 5 areas: Patient pain assessment Patient global assessment Physician global assessment Patient self-assessed disability Acute phase reactant (ESR or CRP) ACR 50 denotes 50% improvement ACR 70 denotes 70% improvement

Definition of active RA disease > 6 tender and >3 swollen joints & ESR> 30mm/hr or at least 45 min am stiffness DAS > 5.1 (scale 0 -10)

DMARDS Early mild disease Anti-malarials eg hydroxychloroquine mechanism - decrease protease function - inhibit Ag processing - decrease cytokine release dose - < 6.5 mg/ kg/ day toxicity - ocular, neuromyopathy, rash Sulfasalazine mechanism - unknown; scavenge O2 radicals dose - 2 - 3 gm/day toxicity - hypersensitivity, granulocytopenia, headache, G-I

DMARDS Moderate - Severe disease Methotrexate / Leflunomide Mechanism - inhibit purine/pyrimidine biosynthesis Dose - MTX 7.5 - 25 mg/wk oral/sc/IM - Leflunomide 10-20 mg/d Toxicity - hepatic, pulmonary, heme, infection, GI, skin, mm ulcer Caution - teratogenetic

Combination DMARD therapy MTX + SSZ + OH-Chloroquine O’Dell 1995 MTX + CSA Tugwell 1995 MTX + Etanercept MTX + Remicade MTX + Adalimumab MTX + Leflunomide excellent safety & improved efficacy over MTX alone

RESEARCH HAS BRIDGED THE GAP BETWEEN BASIC AND CLINICAL RESEARCH Biologic Drugs RESEARCH HAS BRIDGED THE GAP BETWEEN BASIC AND CLINICAL RESEARCH Over one and a half million patients treated worldwide with biologic agents

ODB Indications for Biologic Drugs RA: Failure of DMARD therapy Failure or Intolerance to MTX 20mg/week sc or po x 3 months Arava 20 mg po x 3 months Any combination DMARD JIA Same PSA Same plus failed SSZ therapy

Biologic Drugs Tumor Necrosis Factor α (TNFα) Inhibitors Infliximab (Remicade) Etanercept (Enbrel) Adalimumab (Humira) Interleukin-1 Receptor antagonist (IL-1Ra) Anakinra (Kineret) Fusion protein blocks T cell activation Abatacept (Orencia) CD 20 (B cell) Chimeric Antibody Rituximab

Biologic Drugs Approved in Canada Robert C Offer, Rheumatoid Arthritis, National Grand Rounds Vol 1 Issue 4 2006

Rationale for TNFα Blockade Cytokines are small molecules whose function is to communicate between cells Tumor necrosis factor α = gatekeeper of inflammatory cascade Cytokines can be either pro-inflammatory or anti-inflammatory

Proinflammatory and anti-inflammatory cytokines in RA Rheumatoid Arthritis by Boulos Haraoui & Edward Keystone 5-5 Mechanisms in Rheumatology ©2001

Matrix metalloproteinases in RA Rheumatoid Arthritis by Boulos Haraoui & Edward Keystone 5-6 Mechanisms in Rheumatology ©2001

Etanercept 1st biologic agent approved for RA Agent approved as monotherapy for RA, JIA PSA and AS. Soluble TNFα Receptor administered sc 25 mg 2x/wk or 50 mg qwk pre-filled syringe >300,000 patients treated to date

TNFα and it’s Receptor

Recombinant TNFα Soluble Receptor

Infliximab Monoclonal chimeric human / mouse antibody administered intravenously at 3- 5 mg/kg at 0, 2, 6 and q8 weekly Increased dose 35 mg/kg and /or at more frequent intervals if fail to respond or maintain response Patients: 9 year experience Approved concomitant with MTX for RA

Chimeric monoclonal antibody against TNFα

Monoclonal antibody against TNFα

Adalimumab 1st fully humanized monoclonal IgG antibody High binding affinity and specificity for TNFα Half life = 14 days Subcutaneous dosing 40 mg q2 weekly Clinical trials show improved efficacy with concomitant MTX

Effectiveness of Biologic Drugs Decrease symptoms/signs of inflammation ACR criteria, Eular criteria, DAS Inhibit radiologic progression Modified Sharp score Improve Functional outcome Health Assessment Questionnaire, SF36S

Efficacy of Biological agents in RA All effective; randomized, DB, placebo controlled studies No head to head clinical trials of 3 TNFα drugs Choice Patient preference/access Remuneration by physician Switch for lack of efficacy / adverse events Benefit seen in 1/3

Adverse Effects of TNF Inhibitors Serious Infections TB Intracellular organisms Skin and soft tissue Malignancy ? Lymphoma ? Solid Tumors

Adverse Effects of TNF Inhibitors Autoantibodies Optic neuritis, demyelination Cytopenias Increase LFT ILD Vasculitis; 39 cases reported Pregnancy: ? no increased risk No live vaccines

Autoantibodies Infliximab + DSDNA 17% vs. 4% placebo Etanercept + ANA 11% vs. 5% placebo + DSDNA 17% vs. 4% placebo 16 Lupus- like syndrome cases Infliximab +ANA 26-49%; +DSDNA 13% vs. 0% placebo; 4 new cases SLE Antichimeric antibodies 17% may decrease drug effectiveness of infliximab

TNF inhibitors and TB Mycobacterium tuberculosis currently infects approximately one third of the world's population (close to 2 billion people). Approximately 2 million people die of TB each year and there are 8 million new cases reported annually. TNF is essential for formation and sustainment of granuloma, which sequester mycobacteria and prevent their dissemination. The calculated risk ratio of TB in infliximab-treated patients with RA versus patients with RA not exposed to this agent was 19.9 (95% confidence interval [CI], 16.2–24.8) in the year 2000 and 11.7 (95% CI, 9.5–14.6) in the year 2001. Screening has almost eliminated this increased risk in Spain and Germany

Safety data for 5 years Injection Site Reactions: frequent, mild Infusion reactions Congestive Heart Failure: increased risk Malignancy & Lymphoma: Conflicting data

Robert C Offer, Rheumatoid Arthritis, National Grand Rounds, Vol 1 Issue 4 2006

Management of TNF Drugs Pre Surgery No randomized clinical trials Half life variable Hold Rx 4x half life pre surgery Infliximab 4-5 weeks Etanercept 2 weeks Adalimumab 8 weeks Resume post surgery

TNF Drugs Rheumatoid Arthritis 70% response; 30% non response Best clinical & radiological outcome in RA patients failed Methotrexate - early in course of disease Improved symptom control does not equate to reduction in disease progression or disability Different mechanism responsible for symptoms and structural damage in TNFα IL-1ra drugs

Recombinant Human Interleukin-1 Receptor Antagonist (IL-1Ra) Competitive inhibitor of Il-1. Therefore must have adequate amounts of IL-1Ra produced to counteract effect of IL-1 41% vs. placebo reduction radiological joint damage suppresses MMP production Modest effects on clinical improvement measures MTX + IL-1Ra >> MTX alone¹ Safety Profile: Injection site reactions Infection rarely observed ¹Cohen, A&R, Vol 46, No 3 Mar 2002

Abatacept = Orencia Recombinant fusion protein that blocks co-stimulatory CD 28 molecule and inhibits T cell activation Approved for RA refractory to TNF-Canada Admin IV at 10 mg/kg at 0,2,4 and q 4 weekly Efficacy (with MTX) and decreased structural damage demonstrated No increased risk of malignancy but post marketing surveillance pending

Rituximab = Rituxan Theraputic B-lymphocyte depletion; “remission induction” Approved for RA patients who failed TNF and are receiving MTX 43% acheived ACR 50 at 24 weeks c/w 13% on MTX alone Admin 1000 mg IV day 1 and 15 q 6-16 months (?# of treatments for RA) Higher incidence of infection; TB screening not required but Hepatitis B is 1st infusion reaction common (treat with steroid) No live vaccines Post-marketing data pending

Drugs & Pregnancy NSAIDS: safe until week 34 (patent ductus) OH-chloroquine: safe, ?cleft palate Sulfasalzine: continue if on it; safe Imuran: continue if on it; safe Methotexate: teratogen ??? ok in small doses; stop 3 months before conception Arava: teratogen may be present for 2 yrs Cyclophosphamide:? teratogen ? Safe > 2nd trimester Biologic agents: unknown; stop 3 months before conception Steroids: non-fluorinated do NOT cross placenta

Summary Biologic Agents are: Effective in decreasing inflammation Effective in decreasing structural change in RA TNFα inhibitors are effective in RA plus PS, PSA, AS Effective in improving health outcomes No head to head trials; limited comparison to combination Rx ? change paradigm; treat in very early disease; step down Clarify malignancy/infection risk with post market surveillance 30% of patients have no clinical response; Need to identify those patients with rapidly progressive disease that will respond to biologic therapy

Quality of Life in Rheumatoid Arthritis