Pathophysiology of Rheumatoid Arthritis

Etio-pathogenesis, Sign and Symptoms, Criteria for Diagnosis of rheumatoid arthritis

1. Pathophysiology Rheumatoid Arthritis Nem Kumar Jain MS (Pharm.) Pharmacology & Toxicology Assistant Professor, School of Pharmacy ITM University Gwalior

2. Rheumatoid arthritis (RA) Chronic inflammatory disorder of autoimmune origin principally attacks the joints, producing a nonsuppurative proliferative and inflammatory synovitis Articular lesions: destruction of the articular cartilage and, in some cases ankylosis (adhesion) of the joints. Extraarticular lesions: may occur in the skin, heart, blood vessels, and lungs Causes Symmetrical Polyarthritis: affects several joints in pairs on both sides of your body Epidemiology it is three times more common in women than in men The peak incidence between the ages of 30 and 50 years There is an increased incidence in those with a family history of RA

3. Etio -pathogenesis Etiology: Genetic predisposition: Human leucocyte antigen (HLA)-DR4 and HLA-DRB1* 0404/0401 alleles confer susceptibility to RA Insults such as infection (including periodontitis) and smoking Hormonal: Sex hormones In premenopausal women Pathogenesis: as autoimmune diseases, genetic predisposition and environmental factors contribute to the development, progression, and chronicity of the disease The pathologic changes are mediated by antibodies against self-antigens ( arthritogens : chemical or microbial modified self antigen) and inflammation caused by cytokines, predominantly secreted by CD4+ T cells The T cells produce cytokines that stimulate other inflammatory cells to effect tissue injury:

4. Pathogenesis continued IFN-γ from TH1 cells activates macrophages and synovial cells. IL-17 from TH17 cells recruits neutrophils and monocytes. RANKL expressed on activated T cells stimulates osteoclasts and bone resorption TNF and IL-1 from macrophages stimulate resident synovial cells to secrete proteases that destroy hyaline cartilage. Plasma cells produces Seum antibodies against Citrullinated peptides in which arginine residues are posttranslationally converted to citrulline Ex. citrullinated fibrinogen, type II collagen, α-enolase, and vimentin deposit in the joints. Serum antibodies are k/n as anti-citrullinated protein antibodies (ACPA) Another antibodies About 80% of patients have serum IgM or IgA autoantibodies that bind to the Fc portions of their own IgG. These autoantibodies are called Rheumatoid factor and may also deposit in joints as immune complexes

5. Pathogenesis continued The inflammation localizes to the joint, recruiting macrophages and triggering activation and/or proliferation of synovial cells, chondrocytes, and fibroblasts. The production of proteolytic enzymes and cytokines contributes to the destruction of cartilage and, through increased osteoclast activity, bone

6. Morphology the synovium  becomes edematous, thickened, and hyperplastic, transforming its smooth contour to one covered by delicate and bulbous villi  The characteristic histologic features include:   (1) Synovial cell hyperplasia and proliferation;  (2) dense inflammatory  infiltrates  of CD4+ helper T cells, B cells, plasma cells, dendritic cells, and macrophages (3) increased vascularity resulting from angiogenesis;  (4) neutrophils and aggregates of organizing fibrin on the synovial and joint surfaces;  (5) Osteoclastic activity in underlying bone, allowing the synovium to penetrate into the bone, causing periarticular erosions and subchondral cysts.  Pannus Formation : a mass of edematous synovium, inflammatory cells, granulation tissue, and fibroblasts that grows over the articular cartilage and causes its erosion Pannus can lead to fibrous ankylosios and bony ankylosis

7. Clinical Diagnosis: ACPA and RF in blood and Radiographic findings (x-rays) Sign and symptoms Early symptoms: malaise, fatigue, and generalized musculoskeletal pain. After several weeks to months the joint become involved generally Symmetrical Commonly joints of the hands and feet, wrists, ankles, elbows, and knees joints are swollen, warm, and painful Stiffness of the joints when patient rises in the morning or following inactivity joint enlargement and decreased range of motion Inflammation in the tendons, ligaments, and occasionally the adjacent skeletal muscle produces the characteristic ulnar deviation of the fingers and flexion-hyperextension of the fingers (swan-neck deformity, boutonnière deformity). Radiographic hallmarks are joint effusions and juxtaarticular osteopenia with erosions and narrowing of the joint space and loss of articular cartilage Joint effusion

8. Extra-articular RA Systemic – Fever, Fatigue, Weight loss Eyes - Scleritis, Scleromalacia perforans (perforation of the eye) Neurological - Carpal tunnel syndrome, Atlanto -axial subluxation, Cord compression Haematological - Felty’s syndrome (rheumatoid arthritis, splenomegaly, neutropenia), Anaemia (chronic disease, NSAID-induced, gastrointestinal blood loss, haemolysis , hypersplenism), Thrombocytosis Pulmonary - Pleural effusion, Lung fibrosis, Rheumatoid nodules, Rheumatoid pneumoconiosis Heart and peripheral vessels – Pericarditis, Pericardial effusion, Raynaud’s syndrome Vasculitis - Leg ulcers, Nail fold infarcts, Gangrene of fingers and toes Kidneys - Amyloidosis causes the nephrotic syndrome and renal failure

9. Rheumatoid nodules An infrequent manifestation of RA and  typically occur in subcutaneous tissue including the forearm, elbows, occiput, and lumbosacral area. Microscopically, they resemble necrotizing granulomas