RA FINALS CLIN 2

• Rheumatoid arthritis

  A systemic inflammatory disease which affects not only the joints but a wide range of extra-articular organs

  
• If not treated early, rheumatoid arthritis will lead to progressive joint deformity and increased morbidity and mortality

  
• Etiology and pathophysiology of rheumatoid arthritis

  • Genetic factors contribute 53-65% of the risk
  • Cigarette smoking is a strong risk factor
  • Characterized by infiltration of inflammatory cells into the joint
  • Synovial membrane becomes highly vascularized and hypertrophied
  • Proliferation of synovial fibroblasts and increase in inflammatory cells
  • Inflammatory cells involved include T-cells, B-cells, macrophages and plasma cells
  • Cytokines released cause synovium to release proteolytic enzymes, resulting in destruction of bone and cartilage
• Clinical manifestations of rheumatoid arthritis

  • May present as polyarticular or monoarticular arthritis
  • Predominant symptoms are pain, stiffness and swelling
  • Early stages affect metacarpophalangeal, proximal interphalangeal, wrists, and metatarsophalangeal joints
  • RA-associated deformities include boutonniere, ulnar deviation, and swan-neck
  • Morning stiffness may last 30 minutes to several hours
  • Up to one-third of patients suffer prominent myalgia, fatigue, low-grade fever, weight loss and depression

  
• Diagnosis of rheumatoid arthritis

  Based on patient history, presenting symptoms, clinical findings, family history, blood tests, ultrasound, and X-rays

  
• Treatment goals for rheumatoid arthritis

  • Symptom relief including pain control
  • Slowing or prevention of joint damage
  • Preserving and improving functional ability
  • Achieving and maintaining disease remission

  
• Education is extremely important as patients cope better if they understand their condition and have realistic expectations of the benefits and disadvantages of their treatment strategies
• Drug treatment categories for rheumatoid arthritis

  • NSAIDs
  • Glucocorticoids
  • DMARDs
  • Biological therapies

  
• Simple analgesia

  • Paracetamol, codeine, and paracetamol/opiate combination products
  • Provide symptom relief but do not have anti-inflammatory effect or aid disease modification
• NSAIDs

  • Reduce joint pain and swelling
  • Provide only symptomatic relief to improve joint function, and should always be used with other disease-modifying agents

  
• Rofecoxib, a selective COX-2 inhibitor, was withdrawn from the market in 2004 due to increased risk of serious thrombotic events
• A dose-dependent increase in cardiovascular risk is associated with use of celecoxib, high dose diclofenac, and high-dose ibuprofen
• Naproxen is associated with a lower risk of arterial thrombotic events than COX-2 inhibitors
• Patients should use the lowest effective dose and shortest duration of NSAIDs to minimize the risk of adverse events
• NSAID adverse effects

  • Dyspepsia, nausea, diarrhea
  • Gastric erosion, bleeding, and duodenal/gastric ulceration
  • Gastroprotective agents like H2 antagonists, misoprostol, and PPIs can reduce adverse events
  • Concomitant use of aspirin and non-selective NSAIDs increases GI toxicity
• Disease-modifying antirheumatic drugs (DMARDs)

  Inhibit release or reduce activity of inflammatory cytokines like TNF-α, IL-1, IL-2, and IL-6
• Characteristics of DMARDs

  • Slow onset of action, require at least 8 weeks before clinical effect, months for optimal response
  • Require blood monitoring
  • Patients with new RA should be offered combination DMARD therapy as first-line, ideally within 3 months of onset
• Methotrexate

  • Recognized as the gold standard DMARD
  • Given once weekly orally or parenterally
  • Primarily excreted unchanged by kidneys, so lower doses for elderly/renal impairment
  • Folic acid reduces adverse effects and improves adherence
  • Associated with lung, liver, and bone marrow toxicities
• Sulfasalazine

  • Slows joint erosions and suppresses inflammatory activity
  • Blood dyscrasias usually occur within first 3-6 months
• Hydroxychloroquine

  • Less effective than other DMARDs, but gives symptomatic relief and is least toxic
  • Regular visual assessment for retinopathy is recommended
• Leflunomide

  • Long half-life of approximately 2 weeks
  • Associated with hepato- and hemato-toxicity
• Gold

  • Given IM as sodium aurothiomalate or orally as auranofin
  • IM gold is more effective than oral
  • ADRs include proteinuria, blood disorders, rashes, GI side effects or bleeding
• Glucocorticoids

  • Inhibit cytokine release and give rapid relief of symptoms and decrease inflammation
  • Prednisolone is most commonly used oral steroid
  • Intra-articular injections provide local anti-inflammatory action, pain relief, and reduce deformity
  • Used as bridging therapy when introducing DMARDs
  • Can induce osteoporosis, so prophylactic therapy like calcium, vitamin D, and bisphosphonates should be considered
• Anti-TNF drugs


  • Adalimumab, etanercept, golimumab, infliximab, certolizumab pegol
  • Inhibit TNF-α, an inflammatory cytokine found in high concentrations in RA joint synovium
  • Patients are more susceptible to serious and opportunistic infections
• Osteoarthritis

  • A chronic disease and the most common rheumatological disorder
  • Involves an imbalance in erosive and reparative processes in bone, cartilage, and synovium

  
• Etiology of osteoarthritis

  • Increasing age
  • Gender
  • Genetic predisposition
  • Congenital abnormalities
  • Obesity
  • Previous injury
  • Previous diseases like RA or gout
  • Systemic disorders like acromegaly
  • Neuropathic joint disease

  
• Pathogenesis of osteoarthritis

  1. Initial repair: Proliferation of chondrocytes synthesizing extracellular matrix

  2. Early-stage: Degradation of extracellular matrix as protease activity exceeds chondrocyte activity

  3. Intermediate-stage: Failure of extracellular matrix synthesis and increased protease activity further increasing cartilage loss

  4. Late-stage: Complete loss of cartilage with joint space narrowing
• Clinical manifestations of osteoarthritis

  • Affects hands, feet, hips, knees, spine, less commonly shoulder, temporomandibular, sacroiliac, wrist
  • Pain increased by movement and loading on the joint
  • Stiffness in early morning lasts less than 30 minutes
  • In hands, commonly affects distal interphalangeal, proximal interphalangeal, and first carpometacarpal joints
  • Hip pain felt particularly in the groin

  
• Osteoarthritis treatment

  • Education, advice and access to information
  • Strengthening exercises to improve muscle strength and aerobic fitness
  • Weight loss if overweight or obese
  • Paracetamol as first-line drug treatment
  • Topical NSAIDs, capsaicin, and rubefacients for local pain relief
  • Non-selective NSAIDs or COX-2 inhibitors if paracetamol/topical NSAIDs inadequate, at lowest dose and shortest duration
• explain the mechanism of action of folic acid antagonist in diagram