Rheumatoid Arthritis


    Rheumatoid Arthritis

    • Introduction:
      • Symmetric inflammatory polyarthritis affecting small joints and is associated with prolonged morning stiffness and extra-articular manifestations
      • Leads to joint damage and disability
      • Joint damage occurs rapidly early in disease + correlates to exposure to inflammation
        • Early recognition and treatment is ESSENTIAL
        • Life expectancy is reduced. 
      • Risk Factors: Genetic, Environmental, autoantibodies, infection, hormones. 
    • Epidemiology
      • 30 in 100,000 worldwide
      • 1% of Caucasians
      • 2:3 (men:women)
      • Age 30-55
      • High risk of CAD (contributes to poor RA life expectancy?)
      • Hormonal Factors (estrogen? lack of testosterone is risk factor?)
      • Genetic Factors (50-65% of RA has familial link) (HLA is important)
      • Environmental Factors:Smoking (risk lowers if stop smoking), miners, construction workers (toxic inhalation?), asbestos, silica, low SES status. 


    Clinical Features

    • Classically symmetric polyarthritis (small, med, large joints)
      • Can present as oligoarthritis with asymmetric distribution
    • Joints: Pain & Swelling in multiple (>3) small joints of hands/feet
      • Morning stiffness > 1hr.
      • Characteristic Joints: MCP, PIPs, Wrist
      • "Symmetry" refers to same rank of joints (i.e. MCPs), not same joints on both sides
      • Must be present >6 weeks (viral etiologies can cause this)
    • Constitutional
      • Fatigue, malaise
      • Weight Loss
      • Depression
      • Myalgias
    • Functional Status (declining?)
    • NOTES:
      • DIP involvement is RARE!
      • 1 joint possible initially 



    Diagnostic Criteria


    • 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for RA:
    • Total score of ≥6 = Definite RAjoints RA.png       
      + MUST have at least 1 joint with definite clinical swelling not better described by another disease.
    • Feature Score
      A) - Joint Involvement (Swollen or tender)  
          - 1 large joint (shoulders, elbows, hips, knees, ankles) 0
          - 2-10 large joints 1
          - 1-3 small joints (+/- involvement of large joints) 2
          - 4-10 small joints (+/- involvement of large joints) 3
          - >10 joints (at least 1 small joint) 5
      B) - Serology (at least 1 test result needed)  
          - Negative RF, Negative Anti-CCP 0
          - Low-Positive RF or low positive Anti-CCP (>ULN ≤ 3x ULN) 2
          - High-Positive RF or High Positive Anti-CCP (>3x ULN) 3
      C) - Acute Phase Reactants (at least 1 test result needed)  
           - Normal CRP, Normal ESR 0
           - Abnormal CRP or Abnormal ESR 1
      D) - Duration of Joint Symptoms (by patient self-report)  
          - < 6 weeks 0
          - ≥ 6 weeks 1
      NOTE: "Small joints" are MCP, PIP, 2nd to 5th MTP, thumb IP joint, wrists

    Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010 Sep;62(9):2569-81. 


    Disease Activity

    • Disease Activity Score (DAS)
      • Composite (includes swollen + tender joints) - visual analog scale, ESR, CRP, 
      • Calculator tool gives DAS score
    • DAS28 
      • Shorter version (only 28 joints)
      • More commonly used
    • ACR20 ACR50, ACR 70
      • Stands for "American College of Rheumatology"
      • Outcome measures in clinical trials 
      • I.e. ACR20 is 20% improvement in tender/swollen joints, 20% improvement in 3 of 5 other criteria (i.e. ESR/CRP, patient global assessment, physician global assessment, pain, disability and function).
      • More recent trials with better drugs --> expect a better than 20% outcome
      • Not used clinically
    • HAQ - Health Assessment Questionaire 
      • Purely functional, patients fill out. (walking, grooming, etc..)
      • Measure of disease activity AND damage
      • Prognostic
      • Short Version of HAQ: multidimensional HAQ, Rapid 3, etc...  (many useful + practical)


    Extra-Articular Manifestations

    • System Vasculitic Lymphocytic Infiltrate

      MSK & Periarticular


      Subluxation, malalignment, tenosynovitis, ligamentous laxity, loss of ROM (joints & soft tissues)

      Muscular weakness (disuse, drug-induced through steroids)


      Osteoporosis (risk is usually higher than DEXA scan determines), lower threshold to treat via FRAX calculator.

      Inflammation lowers BMD, steroid use, etc..


      Small Vessel Vasculitis (purpura)

      Ocular Episcleritis/Scleritis Keratoconjunctivitis sicca
      Pulmonary   Pulmonary fibrosis, Pleural Effusion, pleuritis
      pulmonary nodules

      Coronary Artery Disease

      (risk reduced w trtmt)

      Peri/-myocarditis, valvular disease, conduction defects

      Felty Syndrome - rare hematologic complication or RA

               --> can cause increased infections

      • Features:
        • Pancytopenia (Neutropenia < 2.0)
        • Splenomegaly
        • Leg Ulcers
      • May require GCSF (does not respond to anti-rheum drugs)

      Amyloidosis (if chronic, poorly controlled), rare nowadays

      Neurologic Peripheral Neuropathy, sensory
      stocking-glove, mononeuritis multiplex

      Cutaneous ulcers, palpable purpura

      Rheumatoid Nodules


    • Poor prognosis criteria (Important for Guidelines) ≥1 of following:
      • Functional Limitation (use questionnaire)
      • Extra-articular Disease (Rheumatoid Nodules, RA vasculitis, Felty's Syndrome, etc..)
      • Positive RF (80% of RA) or Anti-CCP
      • Bony Lesions on X-Ray



    • LaboratoryXraysRA.png
      • RF (non-specific [50%], somewhat sensitive [70%])
        • 20% of RA pts lack RF
        • 10% of healthy people have RF+ (higher if hospitalized)
        • RF not specific to RA (also seen in Sjogren's, SLE, poly/dermatomyositis, cryo, PBC, SBE, sarcoid etc.)
        • Defines "seropositive" or "seronegative"
      • Anti-CCP (same sensitivity, but very specific [95%]) --> Higher risk of erosive disease and progression
      • ESR and CRP --> elevated in active disease (do not rule out)
      • Albumin Low (chronic inflammation)
      • CBC  (normocytic normochromic anemia, thrombocytosis)
    • Imaging Studies
      • 50% untreated patients develop erosions
      • XRay Findings: (hands, wrists, feet)
        • 1. Periarticular osteopenia
        • 2. Marginal Bony erosions (near joint edges)
        • 3. Symmetric joint space narrowing
        • MCPs, PIPs and Wrists usually
        • Subluxation if advanced  
      • Hand Xrays required at diagnosis (most rheumatologists follow yearly Xrays)
      • NOTE: Image takenfrom: WebMD on Pinterest (https://www.pinterest.com/pin/291537775850308333/)


    • 2016: Recommended:
      • Early DMARD therapy
      • Treat to target:
        • Zero swollen joints (can be a reasonable target early on)
        • Composite Disease activity scores:
          • DAS, CDAI, etc.
          • Remission: Various Definitions!
    • Non-Pharmacologic
      • Education
        • The Arthritis Society
      • Exercise (but avoid load on inflamed joint)
      • Occupational Aids (Splinting, gait aids, joint protection strategies)
      • Physical and/or occupational therapy improves QOL.
      • Risk Factor Modification
        • Smoking Cessation (reduces disease activity)
        • Nutritional advice (keep ideal BMI, less joint stress)
      • Avoid Complications
        • CAD risk factor modification
        • Vaccines (influenza+pneumococcal)
          • Avoid live vaccine if ≥20mg prednisone or ≥15mg MTX or biologic DMARD
    • Pharmacologic therapy
      • Symptomatic Therapy
        • NSAIDs, COX-2 inhibitors.
        • Corticosteroids
      • Non-Biologic DMARDs (Disease Modifying Therapy)
        • Start with methotrexate and then add other combo agents (sulfasalazine, Hydroxychloroquine)
        • Methotrexate (First line) -> start, titrate to maximum dose, disease response in 3 months.
          • Most effective with least adverse events, low cost. 
          • Folic acid supplementation (weekly or daily) decreases the GI and hepatic toxicity of MTX.
          • Add hydroxychloroquine, sulfasalazine, or leflunomide
        • Other agents can be added with limited benefit:
          • Sulfasalazine (less effective than MTX)
            • bone marrow suppression, sulfa allergy
          • Hydroxychloroquine (very very mild)
            • retinal toxicity, skin discoloration
        • Leflunomide
          • Quite effective
          • Use if fails methotrexate
          • Came out at same time as TNF inhibitors, so lost spotlight
      • Biologic DMARDs
        • Indication: Inadequate response to Non-Biologic DMARDs.
          • Biologics not used first due to high price.
        • Available 1st line biologics:
          • Infliximab [Remicade] (chimeric monoclonal)
          • Etanercept  [Embrel] (TNF receptor)
          • Adalimumab [Humira] (Human monoclonal)
          • Golimumab  [Simponi] (Human monoclonal) - once/month benefit
          • Certolizumab pegol [Cimzia] (Humanized monoclonal)
        • Available 2nd line (if no response to 1st line)
          • Abatacept [Orencia] (mod-high disease activity, poor prognostic features, no response to TNF)
          • Rituximab (problem with infusion reactions, usually give steroids pre-infusion)
        • All biologics have similar efficacy (different people respond to different ones)
        • See section on "anti-rheumatic drugs" for details
        • Biologic + methotrexate = BETTER efficacy than each alone, less radiologic disease progression. (Note biologic and MTX each have equal efficacy in monotherapy)
        • Monitor disease activity:
          • Disease activity score (DAS28) - Low DAS is ≥2.6 - < 3.2,   high DAS is >5.1
        • Guidelines come from ACR 2008 and EULAR 2010 (European counterpart)
        • RATreatmentGuidelines.png
    • Surgery
      • Last Line once medical therapy is exhausted. 
      • Can fuse/replace joint. 


    • Key points:
      • Treatment with DMARD should begin as soon as Dx of RA is made
      • Intensify q3-6mo with DMARDs, with methotrexate as part of regimen unless contraindicated.
      • Most treatments include leflunomide and MTX (Improve symptoms and reduce radiologic progression).



    • Follow: Fatigue, weight loss, joint symptoms, functional status, radiographic monitoring, inflammatory markers


    Other Considerations

    • Yearly cardiovascular risk screening (high risk patients) (EULAR guidelines: CV risk score, statins, ACEi, ARBS etc.)
      • Caution prescribing NSAIDs and COX-2i
      • Smoking Cessation
    • Perioperative Management:
      • Get C-spine Xrays (flexion+extension views) before surgery that may require GA
        • High risk of cervical subluxation (atlantoaxial joint) when RA patients undergo ET intubation + cord compression
        • Risk is high in severe deforming RA
      • For Surgery  (weigh risks of flare vs. risk of infection)
        • HOLD NSAIDS
        • Continue MTX generally
        • HOLD Anti-TNF inhibitors
    • Reference:
      • Visser K, Katchamart W, Loza E, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis. 2009;68(7):1086-1093. PMID: 19033291
      • ACP MKSAP16 Audio Companion 


    • Generally disease less active in pregnancy
    • Methotrexate and Leflunomide are very teratogenic
    • Must consel on pregnancy - must plan 3 cycles prior.
    • TNFi
      • Unsure if safe.
      • Typically try to hold, but may be continuged in pregnancy if disease state requires
      • (few studies - appears safe, but poor evidence - 2016)
      • Fc Receptor of antibody concentrates in placenta (so thought to use non-Fc biologics
    • Steroids - can do during pregnancy, but lowest effective dose for shortest period of time.
      • Steroids <13w increases risk of cleft palate
      • Avoid in last trimester --> can close ductus arteriosus early
    • NSAIDs - ok in later pregnancy (3rd trimester)
    • Sulfasalazine and hydroxychloroquine considered relatively safe in pregnancy
    • Lactation
      • Likely ok NSAIDs and low-dose steroids.
      • Avoid MTX and Leflunomide


    • Announ N, Guerne PA. Treating difficult crystal pyrophosphate dihydrate deposition disease. Curr Rheumatol Rep. 2008;10(3):228-234. PMID: 18638432
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