1. 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

3. Normal synovium

4. 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: yrs

5. 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

6. 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

7. Synovial cell hyperplasia and proliferation with underlying inflammation

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

9. 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

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

11. 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)

12. 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).

13. 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

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

15. 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

16. 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.

17. 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

18. 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)

19. 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 years
Reactive amyloidosis in 5 to 10% of patients

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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.

27. 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)

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

29. 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

30. 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

32. 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