Learning Objectives Degenerative joint disease (Osteoarthritis) Rheumatoid Arthritis Gout Infectious arthritis Ganglion and Synovial Cysts Pigmented Villonodular Tenosynovitis and Giant-Cell Tumor of Tendon Sheath

Normal synovium

Rheumatoid Arthritis Systemic, Auto-immune disease affecting many tissues Nonsuppurative proliferative synovitis destroys articular cartilage and the underlying bone Prevalence – about 1%, 3 to 5 times more in women Peak incidence: 40-70 yrs

Morphology Symmetric arthritis, principally affecting small joints of the hands and feet, ankles, knees, wrists, elbows, and shoulders Proximal interphalangeal and metacarpophalangeal joints are affected, but distal interphalangeal joints are spared

Morphology (1) Synovial cell hyperplasia and proliferation (2) Dense inflammation ( CD4+ T cells, plasma cells, and macrophages ) (3) Increased vascularity (4) Neutrophils and fibrin on the synovial surface, joint space (5) Increased osteoclast activity - bone erosion Plasma cells with some lymphocytes and occasional neutrophils

Synovial cell hyperplasia and proliferation with underlying inflammation

Morphology Pannus: proliferating synovial epithelial cells + granulation tissue The synovial membrane forms frond-like (villous) projections Left: synovial membrane showing many villous folds (gross)

Morphology Articular cartilage and subarticular bone beneath the pannus are eroded and destroyed Pannus fills the joint space, subsequent fibrosis and calcification causes permanent ankylosis Above: Synovial pannus invading bone and cartilage - fibrovascular tissue protrudes from the inflamed synovium into the articular cartilage Below: A sagittal section through a proximal interphalangeal joint demonstrates fibrous ankylosis with obliteration of the joint cavity

Bony Ankylosis X-ray: Soft-tissue swelling around 3 and 4th proximal interphalangeal joints with ankylosis of 2nd metacarpophalangeal joint

Morphology Destruction of tendons, ligaments, and joint capsules produces characteristic deformities - radial deviation of the wrist, ulnar deviation of the fingers, and flexion-hyperextension abnormalities of the fingers (swan-neck deformity, boutonnière deformity)

Swan-neck deformity, Boutonnière deformity Swan neck deformity - Flexion of DIP joint and Extension of PIP joint Boutonnière deformity - Extension of DIP joint and Flexion of PIP joint The tear in the tendon sheet looks like a buttonhole ("boutonniere" in French), and the end of the finger bone actually begins to stick through the hole. As a result, the tendons can't straighten the middle joint (which stays bent) and all of the force of the tendons bypasses the middle joint and goes to the end joint (which flips backward).

Rheumatoid subcutaneous nodules These nodules are seen in about one fourth of the cases of rheumatoid arthritis, correlates with very high titers of RF Firm, non-tender, oval/rounded masses up to 2 cm diameter. along extensor surface of forearm/areas subject to mechanical stress

Rheumatoid subcutaneous nodules Microscopic - central focus of fibrinoid necrosis surrounded by a palisade of macrophages, which in turn is rimmed by granulation tissue

Extra-articular manifestations Vasculitic syndromes - acute necrotizing vasculitis involving small/large arteries, Raynaud phenomenon and chronic leg ulcers Lung disease: interstitial fibrosis, chronic pleuritis with effusions, CAPLAN SYNDROME: rheumatoid nodules in lung with pneumoconiosis Hematologic: Anemia of chronic disease (ACD), Auto Immune Hemolytic Anemia (AIHA), FELTY'S SYNDROME (autoimmune neutropenia, splenomegaly) Carpal tunnel syndrome - Entrapment of median nerve under transverse carpal ligament

Extra-articular manifestations Cervical spine – subluxation of atlantoaxial joint; cord/vertebral artery compression Cardiovascular disease - pericarditis, aortitis, vasculitis POPLITEAL (BAKER'S) CYST: behind the knee joint, out-pouching of posterior joint space in knee Ocular changes - uveitis and keratoconjunctivitis Baker's cyst: sometimes ruptures and dissects into the calf and is frequently misdiagnosed as deep venous thrombosis (DVT), sometimes confused with popliteal artery aneurysm but ultrasound can help in diagnosis.

PATHOGENESIS Genetic factors: 50% risk Susceptibility linked to the HLA-DRB1 locus Non-HLA polymorphisms Polymorphism in PTPN22 Environmental factors: Smoking/infection may induce citrullination of self proteins triggering autoimmune reactions Some initial inciting agents are believed to include Epstein-Barr virus, parvovirus, human herpesvirus 6, Mycoplasma

TNF PATHOGENESIS One of the cytokines definitely implicated in the pathogenesis : TNF In a genetically predisposed person - activation of CD4+ helper T cells in response to a microbe or self-antigen (CCP ) IL-1, IL-8, TNF, IL-6, IL-17, and interferon-γ in the synovial fluid recruit leukocytes such as macrophages, whose products cause tissue injury and activate synovial cells to produce proteolytic enzymes causing destruction of cartilage, ligaments, and tendons of the joints Increased osteoclast activity - bone destruction (production of the TNF family cytokine RANK ligand by activated T cells)

Clinical Course Constitutional symptoms Patient with rheumatoid arthritis showing bilateral ulnar deviation of the hands and prominent swelling of the second and third meta-carpophalangeal joints Constitutional symptoms Arthritis: starts as MORNING STIFFNESS, later - joints become enlarged, motion is limited, and eventually complete ankylosis Chronic, remitting-relapsing course with progressive joint destruction leading to disability after 10-15 years Reactive amyloidosis in 5 to 10% of patients

Diagnosis Differentials: SLE, scleroderma, polymyositis, dermatomyositis, Lyme disease Diagnosis based on characteristic clinical/radiographic findings Synovial fluid: sterile, turbid with decreased viscosity, poor mucin clot formation, and neutrophils Anti-CCP and RF (80% of patients) Mucin clot: Acid added to synovial clots hyaluronic acid, so poor clot formation reflects decreased hyaluronic acid indicating joint inflammation

RF and CCP 80% of patients have serum IgM autoantibodies that bind to Fc portions of their own (self) IgG - RHEUMATOID FACTOR RF + IgG immune complex (Type III hypersensitivity) activates complement system to produce C5a (chemotactic for leukocytes) leading to chronic synovitis and pannus formation Antibodies against CYCLIC CITRULLINATED PEPTIDES (CCP) or Anti-cyclic Citrullinated Peptide Antibodies (ACPA) CCP- relatively specific for rheumatoid arthritis, raised levels of anti-CCP antibodies + T-cell response to citrullinated proteins contribute to chronicity

Diagnosis requires presence of at least 4 of the following criteria: Morning Stiffness (lasting > 30 min) Arthritis in > 3 joints Arthritis of hand joints Symmetric Arthritis Rheumatoid Nodules Serum RF (Rheumatoid Factor) / (?CCP) Typical Radiographic changes

Treatment Physical therapy emphasizing movement of joints, swimming pool exercises are very useful b. Initial treatment with NSAIDS c. Early treatment with disease-modifying drugs (1) Minimizes long-term joint damage (2) Methotrexate (most commonly used agent) (3) Cyclosporine; corticosteroids; hydroxychloroquine; gold compounds (4) Tumor necrosis factor (TNF)-α blockers (if disease-modifying drugs ineffective) Anti-TNF agents can prevent or slow joint destruction but are not curative Also, patients treated with anti-TNF agents are susceptible to certain infections, particularly M. tuberculosis

Juvenile Rheumatoid Arthritis CHRONIC IDIOPATHIC ARTHRITIS in children < 16 years, persists > 6 weeks Oligoarthritis (40%) Polyarthritis (40%) Systemic - Still disease (20%) RF and rheumatoid nodules are absent Uveitis may be present More common in girls In pauciarticular JRA (40% of cases), the arthritis limited to a few joints and the associated uveitis may lead to blindness Polyarthritis and muscle atrophy in chronic juvenile rheumatoid arthritis Still disease: Fever with neutrophilic leukocytosis (WBC 15-25,000/μL), hepatosplenomegaly, generalised lymphadenopathy, and rash

Seronegative Spondyloarthropathies Pathologic changes begin in ligamentous attachments Involvement of the sacroiliac joints Absence of RF ("seronegative“) Association with HLA-B27 Ankylosing spondylitis Reiter syndrome Psoriatic arthritis Spondylitis associated with inflammatory bowel diseases Reactive after infections (Yersinia, Shigella, Salmonella, Campylobacter) Sacroiliitis is a common manifestation in all of these disorders, pathogenesis remains obscure

Ankylosing spondylitis Initially blateral sacroiliitis in young men with morning stiffness Later involves vertebral column - fusion of vertebrae ("bamboo spine") with forward curvature (kyphosis) Aortitis with aortic regurgitation Anterior uveitis (20%) may cause blindness Schober test evaluates degree of restriction to forward bending: Patient stands erect, mark midline at 5 cm below and 10 cm above iliac spine, when patient bends at waist to full forward flexion distance between 2 lines should normally increase to >20 cm. If not then it indicates decreased lumbar spine range of motion, may suggest ankylosing spondylitis.

Bamboo spine in ankylosing arthritis BONY BRIDGE Radiographs of lumbar spine show bony bridging of adjacent vertebrae as a result of ossification in the peripheral portions of the intervertebral discs (annulus fibrosus)

Treatment NSAIDs (2) Disease modifying agents Methotrexate Cyclosporine Corticosteroids (3) TNF-α inhibitors

Reiter's syndrome Urethritis + Arthritis + Conjunctivitis Urethritis/cervicitis due to Chlamydia trachomatis Arthritis and Achilles tendon periostitis (confirmatory radiologic sign) Conjunctivitis (non-infectious) This arthritis is probably caused by an autoimmune reaction initiated by prior infection of the gastrointestinal tract (Shigella, Salmonella, Yersinia, Campylobacter) and the genitourinary system (Chlamydia), it is also seen in HIV patients can’t pee, can’t see, can’t climb a tree

Psoriatic arthritis Characteristic skin lesions Sausage-shaped DIP joints Radiographs show erosive joint disease “pencil-in-cup" deformity Extensive nail pitting Histologically, psoriatic arthritis is similar to rheumatoid arthritis Distal interphalangeal joint of the middle finger shows the classic "pencil-in-cup" deformity (arrows). Metallic foreign body was an incidental finding

Summary Rheumatoid arthritis (RA) - chronic autoimmune inflammatory disease affecting mainly small joints, but can affect multiple tissues Autoimmune response against self-antigen(s) such as citrullinated proteins leading to T cells and cytokines causing synovitis The cytokine TNF plays a central role, and antagonists against TNF are of great clinical benefit