Inflammatory Joint Diseases

1. Inflammatory Joint Diseases Prof. Dr. Ece AYDOĞ PhysicalMedicineandRehabilitation

2. Learning objectives: be able to describe epidemiology and etiopathogenesis of rheumatoid arthritis be able to describe clinical forms of rheumatoid arthritis according to initial patterns (insidious, acute, intermediate) be able to enumerate the old and new diagnostic criteria formed the League of American College of Rheumatism.

3. be able to describe the laboratory findings, radiographic findings of early and late stage, articular (disease-specific deformities), and extra-articular signs of rheumatoid arthritis be able to enumerate pharmacological and non pharmacological treatment and poor prognostic criteria of rheumatoid arthritis. be able to describe the clinical signs of polimyalgiarheumatica and Sjögren's syndrome

4. RHEUMATOID ARTHRITIS (RA)

5. DEFINITION Systemic autoimmune inflammatory disorder of unknown etiology that primarily affects the synovial lining of the diarthrodial joints. This chronic, symmetric erosive synovitis develops in the joints and leads to destruction. These erosions are pathognomonic of RA.

6. EPIDEMIOLOGY • Female to male ratio is 3:1 • Prevalence: approximately 1% of the population • Age range from 20 to 60 years, prevalence rises with age, peak incidence between 4th and 5th decade

7. ETIOLOGY • Multiple and multifactorial • Genetic • Sex and sex hormones • İnfectious agents • Diet, trauma, stress, cigarette

8. ETIOLOGY Genetic factors • Twin studies • Major Histocompatability Complex (MHC) on chromosome 6 • Class II MHC allele HLA-DR4 (HLA-DR4 haplotype) and DR1

9. ETIOLOGY Two major theories: • 1. Infectious agents • 2. Immunogenetic→ Class II surface antigens-presenting cells

10. Immun response in RA Antigen presenting cells +CD4+ T cells (sinovial)--- macrophage activation, cytokine release (IL-1)--- T cell infiltration of sinovia, cytokine release (IL-2,IL-4)---- B lenfosit proliferation and activation--- Ig production and immuncomplexes Fagositosis of IC by PNL and monosits--- Tissue injury

11. Numerous Cellular Interactions Drive the RA Process Immune complexes Bacterial products IL-1, TNF-, etc Rheumatoid factors B cell IL-1 Soluble factors and direct cell–cell contact T cell HLA -DR Antigen- presenting cells Macrophage B cell or macrophage IL-1 and TNF- Synoviocytes Chondrocytes Pannus Articular cartilage Production of collagenase and otherneutral proteases Arend W. Semin Arthritis Rheum. 2001;30(suppl 2):1-6.

12. Cytokines • synovial lining proliferation, pannus• endothelial activation, angiogenesis• fibroblast activation, fibrosis

13. Results of Joint Destruction in RA • Injury to synovial microvasculature • Synoviocytes are activated via class III HLA Ag (cellular process): Synovial cells proliferate • Leads to congestion, edema, and fibrin exudation • T Lymphocytes infiltrate • Synovium is hypertrophied (cartilage is destroyed) • Pannus formation

14. Pannus Formation is the Most Important Destructive Element in RA • Pannus: • Membrane of granulation tissue that covers the articular cartilage at joint margins • Fibroblast-like cells invade and destroy the periarticular bone and cartilage at joint margins • Vascular granulation tissue is composed of: • Proliferating fibroblasts • Numerous small blood vessels • Various number of inflammatory cells mainly T lymphocytes (Polymorphic Neutrophil PMN are in fluid) • Occasionally collagen fibers are seen within phagolysosomes of cells at the leading edge of pannus • Joint ankylosis may occur in later stages

15. RA Is Characterised by Synovitis and Joint Destruction NORMAL RA Inflamed synovial membrane Synovial membrane • Major cell types • T lymphocytes • macrophages Pannus Cartilage • Minor cell types • fibroblasts • plasma cells • endothelium • dendritic cells Synovial fluid • Major cell type • neutrophils Capsule Cartilage thinning Adapted from Feldmann M, et al. Annu Rev Immunol. 1996;14:397-440.

16. IL-1 and TNF- Have a Number of Overlapping Proinflammatory Effects Proinflammatory effects of IL-1 Proinflammatory effects of TNF- COX-2PGE2NOAdhesion moleculesChemokinesCollagenasesIL-6 TNF-Osteoclast activation Angiogenic factors IL-1 cell death COX-2 = cyclo-oxygenase type 2; PGE2 = prostaglandin-E2; NO = nitric oxide

17. IL-1 Plays a Pivotal Role in the Inflammatory and Destructive Processes of RA IL-1 Activates monocytes/macrophages Induces fibroblast proliferation Activates chondrocytes Activates osteoclasts Inflammation Synovial pannus formation Cartilage breakdown Bone resorption

18. PATTERN OF ONSET • Insidious → 50%–70% • Initial symptoms can be systemic or articular • Slow onset from weeks to months • Constitutional symptoms: fatigue, malaise • Diffuse musculoskeletal pain may be the first nonspecific complaint with joint involvement later • Most commonly symmetric involvement although asymmetric involvement may be seen early • Morning stiffness in the involved joints lasting one hour or more • Swelling, erythema • Muscle atrophy around the affected joints • Low grade fever without chills

19. Acute Onset→ 10%–20% • Onset over several days • Less symmetric in presentation • Severe muscle pain • Intermediate Onset→ 20%–30% • Onset over several days to weeks • Systemic complaints more noticeable

20. DIAGNOSIS OF RA 1988 American Rheumatologic Association (ARA) Criteria • Must satisfy 4–7 criteria • Criteria 1 through 4 must be present for at least six weeks ARA Criteria: • 1. Morning Stiffness • In and around the joint • Must last at least one hour before maximal improvement • 2. Arthritis of Three or More Joints • Three or more joint areas simultaneously affected with soft tissue swelling or fluid • Observed by a physician • 14 possible joint areas are bilateral proximal interphalangeal (PIP), metacarpal phalangeal (MCP), wrist, elbow, knee, ankle and metatarsal phalangeal (MTP)

21. ARA Criteria • 3. Arthritis of the Hand Joints • At least one joint area swollen in the wrist, MCP and/or PIP • 4. Symmetric Arthritis • Simultaneous involvement at the same joint area on both sides of the body • Absolute symmetry is not needed • 5. Rheumatoid Nodules • Subcutaneous nodules over extensor surfaces, bony prominence or in juxta-articular regions • Observed by a physician • 6. Serum Rheumatoid Factor (RF [+]) • 7. Radiographic Changes (Hand and Wrist) • Erosions, bony decalcification, and symmetric joint-space narrowing

22. The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis Patients who: 1) have at least 1 joint with definite clinical synovitis (swelling) 2) with the synovitis not better explained by another disease Classification criteria for RA (score-based algorithm: add score of categories A–D;a score of ≥6/10 is needed for classification of a patient as having definite RA) A. Joint involvement: Score: 1 large joint0 2-10 large joints1 1-3 small joints (with or without involvement of large joints) 2 4-10 small joints (with or without involvement of large joints) 3 >10 joints (at least 1 small joint)5

23. B. Serology (at least 1 test result is needed for classification)Score Negative RF and negative ACPA0 Low-positive RF or low-positive ACPA 2 High-positive RF or high-positive ACPA 3 C. Acute-phase reactants (at least 1 test result is needed for classification) Normal CRP and normal ESR0 Abnormal CRP or abnormal ESR 1 D. Duration of symptoms <6 weeks 0 ≥6 weeks 1

24. Rheumatoid factor ESR and C-reactive protein Thrombocytosis, Hypochromic normocytic anemia, Eosinophilia Hypergammaglobulinemia Hypocomplementemia Synovial fluid analysis Low viscosity WBC → 1,000–75,000 mm3 > 70% PMNs Transparent - cloudy LABORATORY

25. Rheumatoid Factor • 85% of the patients with RA have a (+) Rheumatoid Factor (RF [+]) • Associated with severe active disease with increased systemic manifestations (nodules) • Serial titers are of no value • Can still be RF (−) and have RA because (+) diagnosis needs four to seven diagnostic criteria • + RF can be seen in other diseases: Rheumatic (SLE, scleroderma, Sjögren’s), viral, parasitic, bacterial, neoplasms, hyperglobulinemic purpura

26. RADIOGRAPHIC FINDINGS • (+) Juxta-articular osteopenia (bone wash-out)(early RA)

27. Marginal bone erosions (near attachment of joint capsule)

28. Erosion of the ulnar styloid

29. Ulnar deviation and volar subluxation seen at the MCP joint of the phalanges

30. Radial deviation of the radiocarpal joint

31. Hallux valgus

32. Erosion of the metatarsal head of the MTP joint

33. Atlantoaxial subluxation (> 2.5–3 mm)

34. RADIOGRAPHIC FINDINGS • Early findings • Soft tissue swelling • ↑ joint space

35. RADIOGRAPHIC FINDINGS • Late findings • Uniform joint space narrowing due to loss of articular cartilage (hips, knees, etc.) • Axial migration of the hip (Protrusio Acetabulum) • Malalignment and fusion of joints

36. Hand and Wrist Deformities Boutonnière Deformity Mechanism • Weakness or rupture of the terminal portion of the extensor hood (tendon or central slip), which holds the lateral bands in place • The lateral bands slip downward (or sublux) to the axis of the PIP joint turning them into flexors • The PIP then protrudes through the split tendon as if it were a button hole (boutonnière = button hole) • The distal phalanx hyperextends

37. Result • Hyperextension of the MCP • Flexion of the PIP • Hyperextension of the DIP Note:Positioning of the finger as if you were buttoning a button Orthotic • Tripoint finger splint

38. Swan Neck Deformity Mechanism • Contracture of the intrinsic and deep flexor muscles and tendons of the fingers Result • Flexion contracture of the MCP • Hyperextension of the PIP • Flexion of the DIP Orthotic • Swan neck ring splint

39. Ulnar Deviation of the Fingers Mechanism • Weakening of the extensor carpi ulnaris (ECU), ulnar and radial collateral ligament • Wrist deviates radially • Increases the torque of the stronger ulnar finger flexors • Flexor/extensor mismatch deviates the fingers in the ulnar direction as the patient tries to extend the joint Result • Ulnar deviation is due to the pull of the long finger flexors Orthotic • Ulnar deviation splint

40. Tenosynovitis of the Flexor Tendon Sheath • One of the most common manifestation of the hands in RA • Can be a major cause of hand weakness Result • Diffuse swelling of the volar surfaces of the phalanges between the joints with palpable grating of the flexor tendon sheath • May be confused with de Quervain’s disease

41. Carpal Bones Rotate in Zig-Zag Pattern Mechanism • Ligament laxity • Radial deviation of the wrist • Ulnar styloid rotates dorsally • Carpal bones rotate • Proximal row: volarly • Distal row: dorsally Result • Zig-zag pattern

42. Cervical Spine • Atlantoaxial Joint Subluxations→ Most Common are Anterior Subluxation • Instability • Odontoid or Atlas can erode • With flexion, the Atlantoaxial (AA) space should not increase significantly: any space larger than 2.5 or 3 mm is considered abnormal • Tenosynovitis of the transverse ligament of C1 • Cervical myelopathy → erosion of the odontoid process, ligament laxity or rupture

43. Foot • Hammer Toe Deformities • Hyperextension of the MTP and DIP with flexion of the PIP • Claw Toe Deformities • Hyperextension at the MTP joint and flexion of the PIP and DIP joints • Pain on the metatarsal heads on weight bearing • Hallux Valgus Deformity • Lateral Deviation of the Toes

45. Ankle • Ligament weakness leading to pronation of the hindfoot • Tarsal tunnel syndrome • Synovial inflammation leads to compression of the posterior tibial nerve Hip Deformities • Symmetric involvement • Protrusio acetabulum: Inward bulging of the acetabulum into the pelvic cavity • Accompanied by arthritis of the hip joint, usually due to RA

46. Shoulders • Glenohumeral arthritis • Effusions can occur; decreased range of motion (ROM) may lead to frozen shoulder • Rotator cuff injuries Elbow • Subcutaneous nodules • Olecranon bursitis • Loss of full elbow extension is an early problem and may lead to flexion deformities • Ulnar Neuropathies

47. Knee Deformities • Common symmetric joint involvement • Loss of full knee extension which may lead to flexion contractures • Quadriceps atrophy leading to increased amount of force though the patella • Force leads to increased intra-articular pressure in the knee joint causing the synovial fluid to drip into the popliteal space called a popliteal (Baker’s) cyst

48. EXTRA-ARTICULAR MANIFESTATIONS • More common in patients that are: • RF (+) • With rheumatoid nodules • Severe articular disease • MHC class HLA DRB1 Alleles • General • Malaise or fatigue

49. Skin • Subcutaneous Nodules • Present in 50% of RA patients • Form subcutaneously, in bursae, and along tendon sheaths • Typically located over pressure points • Extensor surface of the forearm • Can occur singly or aggregate in clusters • Methotrexate may enhance the development or accelerate the development of rheumatoid nodules • Vasculitic Lesions • Leukocytoclastic vasculitis and palpable purpura

50. Ocular • Keratoconjunctivitis sicca (dry-eye syndrome) • Episcleritis → benign, self-limited • Scleritis • Pulmonary • Interstitial lung disease • Interstitial fibrosis • Rheumatoid nodules • Pulmonary fibrosis • Pleurisy • Inflammation of the cricoarytenoid joint → dysphagia, dysphonia • Bronchiolitis obliterans