RA

• Rheumatoid Arthritis (RA)


  An autoimmune condition leading to inappropriate immune system activity causing synovial and connective tissue inflammation
• Chronic inflammation in RA

  Growth of tissue (pannus) leading to loss of bone and cartilage
• Trigger for RA

  Genetics and a "stochastic" event
• Inflammation consequences in RA

  • Loss of cartilage
  • Formation of scar tissue
  • Ligament laxity
  • Tendon contractures
• Epidemiology of RA

  • Affects 1-2% of adult population
  • More common in women (3:1)
  • Earlier onset in women
  • No difference with ethnicity
  • Occurs at any age
• Clinical Presentation of RA

  • Symmetrical joint pain and stiffness >6 weeks
  • Muscle pain
  • Fatigue, weakness, low-grade fever, appetite decrease
  • Joint tenderness with warmth and swelling over affected joints
  • Rheumatoid nodules may develop
  • Rapid onset starting in peripheral joints
• Joint Damage in RA

  • Occurs early in the course of RA
  • 30% of patients have bone erosion at time of diagnosis
  • Damage is irreversible
  • Functional loss follows if left untreated
• Extraarticular sequalae of RA

  • Blood vessels
  • Lungs
  • Eyes
  • Heart
  • Muscle
  • Bone
  • Skin
  • Hematologic abnormalities
• Extraarticular sequalae - Blood vessels


  • Rheumatoid vasculitis occurs with severe, long-standing RA
  • Leads to substantial morbidity
  • Can affect any blood vessel
  • Symptoms depend on affected vessels
  • Treatment: Aggressive treatment of RA itself
• Extraarticular sequalae - Lungs

  • Pleuritis, pleural effusion, fibrosis, pulmonary nodules
  • Drugs used to treat RA may impact lung function
• Extraarticular sequalae - Eyes

  • Episcleritis, scleritis, uveitis, and iritis
  • Painful, visual acuity loss
• Extraarticular sequalae - Heart

  • Pericarditis, myocarditis
  • Increased risk of CAD, heart failure, and atrial fibrillation
• Extraarticular sequalae - Muscle


  Generalized weakness and pain from synovial inflammation, myosit
• Overview – Clinical Presentation

  1. Extraarticular sequalae

  2. Eyes: Episcleritis, scleritis, uveitis and iritis, Painful, visual acuity loss

  3. Heart: Pericarditis, myocarditis, Increase risk of CAD, heart failure and atrial fibrillation

  4. Muscle: Generalized weakness and pain from synovial inflammation, myositis, vasculitis, Steroid-induced

  5. Bone – from disease and corticosteroid overuse: Osteopenia common, Local bone loss around affected joints

  6. Skin: Rheumatoid nodules, Ulcers, Steroid-induced changes

  7. Hematologic abnormalities: Anemia with chronic disease, Iron incorporation into RBCs, Treat inflammatory pathway of RA
• Overview - Diagnosis


  Cannot be established by a single lab test or procedure, Established diagnostic criteria/scoring system, Joint involvement, Lab test findings: Rheumatoid factor in 60-70% of patients, Elevated ESR and CRP, Anti-cyclic citrullinated peptide antibody (anti-CCP), Duration of symptoms
• Lecture Outline

  Part 1 – Overview: Pathophysiology, Epidemiology, Clinical Presentation, Diagnosis, Part 2 – Treatment, Part 3 – Special Populations
• Treatment

  Goals of RA treatment: Prevent and control joint damage, Prevent loss of function, Maintain QoL, Decrease pain, Achieve remission or low disease activity, Tender/swollen joint count < 1, HAQ score < 1, CRP score < 1, Physician global assessment < 2, Patient assessment of global disease activity < 2
• Treatment

  General principles of management: Early recognition and diagnosis, Significant damage occurs in first two years of disease, Early use of DMARDs, Start within 3m of diagnosis, Treat aggressively, Start low, go slow
• Treatment


  General principles of management: Concept of “tight control”, Treat until remission or low disease activity, Quickly treat exacerbations, Aggressively add DMARDs or early switch, Adjunct NSAID/steroids, Frequent reassessment, Responsible NSAID and glucocorticoid use: Reduce/discontinue as disease enters remission
• Treatment

  Non-pharmacologic therapy: Patient education, Rest important but balance with activity, Reduce joint stress with RA friendly tools, Occupational and physical therapy, Diet/weight loss, Surgery depending on joint condition
• Treatment

  Main classes of treatment: Traditional Disease Modifying Anti-Rheumatic Drugs (tDMARDs), Biologic DMARDs, Synthetic DMARDs, Corticosteroids, NSAIDs/Analgesia, Combinations, Maintenance, Flares
• Treatment

  Traditional Disease Modifying Anti-Rheumatic Drugs (DMARDs): Slow onset of action, Controls symptoms, May delay or stop progression of disease, Requires regular monitoring, Includes: Hydroxychloroquine, Sulfasalazine, Methotrexate, Leflunomide, Others
• Treatment

  Traditional Disease Modifying Anti-Rheumatic Drugs (DMARDs) Mechanisms of action: Hydroxychloroquine inhibits neutrophils and chemotaxis, impairs complement system, Sulfasalazine modulates mediators of inflammatory response, may inhibit
• Traditional Disease Modifying Anti-Rheumatic Drugs (DMARDs)

  • Hydroxychloroquine
  • Sulfasalazine
  • Methotrexate
  • Leflunomide
• Hydroxychloroquine


  Inhibits neutrophils and chemotaxis; impairs complement system
• Sulfasalazine


  Modulates mediators of inflammatory response; may inhibit TNF
• Methotrexate

  Anti-folate → less DNA synthesis, repair, cellular replication and immune response. People need to supplement with folic acid
• Leflunomide


  Inhibits pyrimidine synthesis, leading to anti-inflammatory effects. Modulates many signaling pathways
• Onset of Traditional Disease Modifying Anti-Rheumatic Drugs (DMARDs)

  • Hydroxychloroquine – 2-6 months
  • Sulfasalazine - 2-3 months
  • Methotrexate – 1-2 months
  • Leflunomide – 1-3 months
• Dosing and administration of Traditional Disease Modifying Anti-Rheumatic Drugs (DMARDs)

  • Hydroxychloroquine – initial 200mg daily, increase to 200mg BID
  • Sulfasalazine – initial 500mg BID, increase to 1000mg BID or TID
  • Methotrexate – 7.5 to 25mg PO weekly
  • Leflunomide – 20mg daily
• Common side effects of Traditional Disease Modifying Anti-Rheumatic Drugs (DMARDs)

  • Hydroxychloroquine: NVD, stomach cramps, Skin/allergic lesions, Headaches, dizziness
  • Sulfasalazine: Headache, Photosensitivity, NVD
  • Leflunomide: Nausea/diarrhea, Rash, hypertension, Reversible alopecia
  • Methotrexate: Nausea/vomiting, Fatigue, Stomatitis, Photosensitivity, Hair loss, Skin itch/burning/rash
• Serious side effects of Traditional Disease Modifying Anti-Rheumatic Drugs (DMARDs)

  • Hydroxychloroquine: Myopathy, Ocular toxicity
  • Sulfasalazine: Hematologic abnormalities
  • Methotrexate: Hepatotoxicity, Hematologic abnormalities, Pulmonary toxicity, Reversible sterility in men, Infection increase
  • Leflunomide: Hepatotoxicity, Significant weight loss, Infection increase
• Contraindications of Traditional Disease Modifying Anti-Rheumatic Drugs (DMARDs)

  • Hydroxychloroquine: Pre-existing retinopathy due to optic toxicity
  • Sulfasalazine: Hypersensitivity to salicylates or sulfonamides, Asthma attacks precipitated by ASA or NSAIDs, Severe renal/hepatic impairment, Existing gastric or duodenal ulcer
• Precautions/contraindications of Traditional Disease Modifying Anti-Rheumatic Drugs (DMARDs)

  • Methotrexate: Caution in lung dysfunction, Severe hepatic impairment, Current hematologic abnormalities, Pregnancy/breastfeeding
  • Leflunomide: Moderate-severe renal/hepatic impairment
• DMARDs precautions/contraindications

  Methotrexate: Caution in lung dysfunction, Severe hepatic impairment – CI, Current hematologic abnormalities – CI, Pregnancy/breastfeeding – CI; Leflunomide: Moderate-severe renal (<60ml/min)/hepatic impairment – CI, Current hematologic abnormalities or serious infection – CI, Pregnancy/breastfeeding – CI
• DMARDs drug interactions

  Hydroxychloroquine: No CYP interactions, High risk QT-prolongation – especially with other risk factors + other drugs; Sulfasalazine: Additive nausea if used with MTX, Possible issue with Warfarin (↑ or ↓ INR); Leflunomide: Bile-acid sequestrants cause rapid elimination – cholestyramine can be used as benefit to quickly clear from the body if experiencing toxicity (d/c 2 years prior to pregnancy but if added with bile acid sequestrant then lowered to 6 months), Additive immunosuppression – will flag with other immunosuppressive agents (very common to combine with other immunosuppressive agents), Live vaccines – co-administration with live vaccines is an issue due to immunosuppression
• Methotrexate drug interactions


  Many drug interactions only significant based on cancer doses (e.g. 500 - 2000mg weekly); NSAIDs: Decreases clearance of MTX, increased toxicity potential; Trimethoprim (mono agent or in combination with sulfamethoxazole): Significantly increases risk of pancytopenia at any MTX dose, consider contraindicated; PPIs: Only an issue if MTX >500mg/week; Loop diuretics: Decreases clearance of MTX, may increase nephrotoxicity potential, likely only an issue on high doses; Live vaccines
• Monitoring – efficacy of DMARDs

  Disease activity (ESR, CRP) every 1-3 months initially, Radiographs every 6-12 months, Chronic disease activity index - administered by HCP, Health Assessment Questionnaire (HAQ) – done by patient
• Monitoring - safety of DMARDs

  Hydroxychloroquine: No lab tests required, Ocular toxicity – ophthalmic exam baseline and annually after 5 years; Sulfasalazine: CBCs and LFTs, creatinine; Methotrexate: CBCs and LFTs, creatinine, Chest x-ray (baseline); Leflunomide: CBCs and LFTs, creatinine
• Efficacy data of DMARDs

  Hydroxychloroquine vs. placebo: decreases # affected joints, pain, QoL assessments, vs. other DMARDs: less effective, Does not decrease radiographic damage; Sulfasalazine vs. placebo: Decreases symptoms by half, vs. other DMARDs: typically less effective, Limited monotherapy evidence, Use if other options not tolerated; Methotrexate/Leflunomide: “Healing” of bone may occur