Rheumatoid Arthritis: Musculoskeletal Diseases II Lectures

Rheumatoid Arthritis Pathophysiology of RA • Genetics + environmental stimulus = disease – Genes w/ susceptibility – MHC Class II genes, e.g., HLA-DR4 • Disease onset may be due to prior infection (mycoplasma, EBV, CMV, parvo, rubella) or other environmental stress such as cigarettes • Self-react...

Rheumatoid Arthritis Pathophysiology of RA • Genetics + environmental stimulus = disease – Genes w/ susceptibility – MHC Class II genes, e.g., HLA-DR4 • Disease onset may be due to prior infection (mycoplasma, EBV, CMV, parvo, rubella) or other environmental stress such as cigarettes • Self-reactive CD4 and B cells activated – maybe molecular mimicry? • Auto-Abs secreted • ICs deposited in small blood vessels with slow flow, esp. synovium, kidneys, lungs • Initiates inflammation which persists chronically perpetuated by: ‒ Macrophages and fibroblasts ‒ TNF, IL-1, IL-6, IL-8, IL-15, TGF-β, FGF, PDGF ‒ Fibroblasts secrete IL-6 – causes plasma cells to continue autoAb secretion → a vicious cycle • Result – joint destruction and loss of function Figure 19-11 – Cellular and Molecular Immunology, 10th ed., 2022 RA Pathophysiology in a Snapshot The Synovium in Rheumatoid Arthritis normal RA https://i.ytimg.com/vi/lVo9a851MCg/maxresdefault.jpg Rheumatoid Arthritis vs Osteoarthritis • RA – synovitis/doughy swelling, worst in morning, swelling subsides with movement • OA – erosion of cartilage causing bones to rub together (wear and tear), pain gets worse with movement https://images.medicinenet.com/images /illustrations/arthritic_joints.jpg Rheumatoid Arthritis (RA) • Progressive and persistent symmetric polyarthritis (synovitis) that affects hands and feet • Inflammation à joint destruction/loss of function. • Signs and symptoms: – Weakness and fatigue also common – Insidious onset with small joints generally affected first: MCP, PIP, DIP, MTP – Joint pain (hands, feet, cervical spine), doughy swelling, erosion, deformity (e.g., ulnar deviation) in chronic cases – Positive squeeze test across MCP and MTP – Boutonniere deformity (hyperflexed PIP, hyperextended DIP) – Swan neck deformity (hyperextended PIP, hyperflexed DIP) – Morning stiffness (generally <1 hr) – Extra-articular manifestations: weight loss, depression, fatigue – Rheumatoid nodule (subcutaneous lump by olecranon = vasculitis) Rheumatoid Arthritis in the Hands Boutonniere deformity: • See ring fingers ‒ Hyperflexed PIP ‒ Hyperextended DIP Z deformity (thumb): Hyperextended interphalangeal joint Swan Neck deformity: • Hyperextended PIP • Hyperflexed DIP Rheumatoid Arthritis in the Feet Extra-Articular RA • Occurs ~40% pts. • Associated w/ ↑ disease severity. • Osteopenia • Myositis and muscle weakness • Abnormal body composition – ↑ body fat mass and ↓lean body mass • Eye – scleritis, episcleritis • Lung – interstitial fibrosis, pulmonary nodules • CV – ↑ coronary artery disease, myocarditis, heart failure, vasculitis • Heme – anemia, neutropenia Rheumatoid Nodules • Chronic inflammation ‒ Thought to be triggered by vasculitis ‒ Characterized by central necrosis and granulomatous inflammation (macs, fibroblasts) • Tend to appear on pressure points • Typically, subcutaneous and firm and may be either mobile or adherent to underlying structures • Usually seen in patients with a history of cigarette smoking American College of Rheumatology Diagnostic Criteria for RA https://www.rheumatology.org/Portals/0/Files/2010_revised_criteria_classification_ra.pdf Diagnosis of RA • Labs – Rheumatoid factor (RF) in serum, antibody to IgG Fc region o 80% of RA patients are RF+ – Antibodies to cyclic citrullinated peptides (anti-CCP Ab) – high specificity for RA, equal sensitivity to RF – ESR and CRP – general measures of inflammation, not specific – ANA – may be positive in ~30% of RA • Arthrocentesis – looking for inflammatory synovitis – synovial fluid leukocytosis = WBC count greater than 2,000/mm3 • Imaging – X-rays of hands, wrists, feet, and other affected joints – look for joint destruction/erosions & deviations – also serves as baseline for monitoring disease progression https://arthritis-research.biomedcentral.com/articles/10.1186/ar1027/figures/4 https://www.labpedia.net/wp-content/uploads/-rheumatoidfactor-rf-rheumatoid-arthritis-factor-ra-factor-/RA-factor-1-0.JPG Treatment/Management of RA • Goal – control synovitis and prevent joint injury • DMARDS – Non-biologics – methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, – Biologics – produced by recombinant DNA technology and target cytokines or their receptors or other cell surface molecules. • e.g., anti-TNF therapies including etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira) • Adjuncts – NSAIDS, local corticosteroid injections • Joint replacement surgery, arthrodesis • Non-pharmaceutical – Reduce CV risks – Physical and occupational therapy – Immunizations to decrease risk of infections – since therapies are immunosuppressive (see notes) – Nutrition and diet, (tobacco, lipids) Prognosis and Complications of RA • High degree of economic loss, morbidity and mortality before DMARD use • Currently, ~40% pts become disabled after 10 yrs, but highly variable • Risks for worse disease – HLA-DR4 genotype, high titer autoantibodies, extraarticular manifestations, # lg+ joints, early age of presentation • Overall mortality is reportedly 2.5 times higher than that of the general age-matched population • CORONARY ARTERY DISEASE!!! • Increased risk of cancer and infection due to DMARDs that suppress immune system