1. Arthritis Approach to the Patient with Rheumatic Disease Lior Ness 5.4.2009 4 th year Medical Student Sackler Medical School, Tel-Aviv University Internal Medicine Department Sheba Medical Center ISRAEL

2. 2 Rheumatic Diseases Encompass a range of musculoskeletal and systemic disorders that share the clinical involvement of joints and periarticular tissues. Encompass a range of musculoskeletal and systemic disorders that share the clinical involvement of joints and periarticular tissues. Causes of arthritis range from local trauma to infection, gout, osteoarthritis, and autoimmune connective tissue diseases (RA, SLE). Causes of arthritis range from local trauma to infection, gout, osteoarthritis, and autoimmune connective tissue diseases (RA, SLE).

3. 3 Medical History – Clinical Features Age, gender, ethnicity, family history Age, gender, ethnicity, family history Pattern of joint involvement: Pattern of joint involvement: Monoarticular, oligoarticular, polyarticular Monoarticular, oligoarticular, polyarticular Large vs. small joints Large vs. small joints Symmetry Symmetry Insidious vs. rapid onset Insidious vs. rapid onset Inflammatory vs. noninflammatory pain (e.g. morning stiffness) Inflammatory vs. noninflammatory pain (e.g. morning stiffness) Presence of constitutional symptoms and signs – fever, fatigue, weight loss. Presence of constitutional symptoms and signs – fever, fatigue, weight loss. Involvement of other organ systems (rash, mucous membrane lesions, nail lesions). Involvement of other organ systems (rash, mucous membrane lesions, nail lesions). Presence of arthritis associated diseases (psoriasis, IBD). Presence of arthritis associated diseases (psoriasis, IBD).

4. 4 Clinical Features

5. 5 Laboratory Testing Synovial fluid analysis Synovial fluid analysis

6. 6 Laboratory Testing Autoantibodies Autoantibodies Almost ~100% of patients with SLE have antinuclear antibodies. Rheumatoid factor is found in 80-90% of patients with RA. However, the proportion of patients with positive tests in other rheumatic diseases is much lower. Almost ~100% of patients with SLE have antinuclear antibodies. Rheumatoid factor is found in 80-90% of patients with RA. However, the proportion of patients with positive tests in other rheumatic diseases is much lower. However, 15-25% of healthy persons have positive antinuclear antibodies when commercial tests kits are used. RF can be found in chronic infection, neoplasia, and hyperglobulinemia. However, 15-25% of healthy persons have positive antinuclear antibodies when commercial tests kits are used. RF can be found in chronic infection, neoplasia, and hyperglobulinemia. Therefore, the results should be interpreted only in clinical context. Therefore, the results should be interpreted only in clinical context. Acute phase – CRP, ESR Acute phase – CRP, ESR Nonspecific, but positive results suggest the presence of inflammatory disease. Nonspecific, but positive results suggest the presence of inflammatory disease. Sometimes can be useful both in diagnosis and in following the course disease and therapy (e.g. giant cel arteritis, polymyalgia rheumatica). Sometimes can be useful both in diagnosis and in following the course disease and therapy (e.g. giant cel arteritis, polymyalgia rheumatica).

7. 7 Radiographic Studies Imaging modalities (MRI, US, CT) are often useful in assessing diseases of bones, joints, muscle and soft tissues. Imaging modalities (MRI, US, CT) are often useful in assessing diseases of bones, joints, muscle and soft tissues. Radiographic evaluation often shows changes characteristic of particular diseases. Radiographic evaluation often shows changes characteristic of particular diseases.

8. 8 Summary - Evaluation of Arthritis Careful assessment of the location and pattern of joint involvement. Careful assessment of the location and pattern of joint involvement. Differentiation of inflammatory arthritis from mechanical, infectious and other causes. Differentiation of inflammatory arthritis from mechanical, infectious and other causes. Consideration of nonarticular systemic features. Consideration of nonarticular systemic features. Patient ’ s age, gender, family history and medication history are also important and often key features. Patient ’ s age, gender, family history and medication history are also important and often key features. Laboratory and radiographic studies (in particular synovial fluid analysis) provide confirmatory, and sometimes diagnostic information. Laboratory and radiographic studies (in particular synovial fluid analysis) provide confirmatory, and sometimes diagnostic information.

9. 9 Rheumatoid Arthritis Epidemiology/Demographics Epidemiology/Demographics Prevalence 1% among general population. Prevalence 1% among general population. Female-to-male ratio of 3:1. Female-to-male ratio of 3:1. Onset is most common in the third through fifth decades of life. Onset is most common in the third through fifth decades of life. HLA DR4 is a genetic risk factor, and also associated with a more severe disease. HLA DR4 is a genetic risk factor, and also associated with a more severe disease. Pathology Pathology The hallmark of joint involvement is the synovial pannus, a proliferative synovium infiltrated with mononuclear cells. The hallmark of joint involvement is the synovial pannus, a proliferative synovium infiltrated with mononuclear cells. In other tissues, as well as in the synovium, rheumatoid nodules may be seen. These are large granulomas with areas of central necrosis, surrounding mononuclear cells, and an outer layer of palisading histiocytes. In other tissues, as well as in the synovium, rheumatoid nodules may be seen. These are large granulomas with areas of central necrosis, surrounding mononuclear cells, and an outer layer of palisading histiocytes. B cells and plasma cells in the synovium synthesize rheumatoid factor (IgM directed to FC receptor of IgG), associated with vasculitis. B cells and plasma cells in the synovium synthesize rheumatoid factor (IgM directed to FC receptor of IgG), associated with vasculitis.

10. 10 Rheumatoid Arthritis Clinical features Clinical features RA is a symmetrical polyarthritis involving typically the small joints of the hands and feet, the wrists, and the ankles. Any other synovial joint may be involved. RA is a symmetrical polyarthritis involving typically the small joints of the hands and feet, the wrists, and the ankles. Any other synovial joint may be involved. Involved joints are swollen, warm, and tender. The synovium becomes palpable on examination (synovitis). Involved joints are swollen, warm, and tender. The synovium becomes palpable on examination (synovitis). Prolonged morning stiffness, usually lasting more than 1 hour and often many hours, is a classic feature in RA (as well as in other inflammatory arthropathies). Symptoms are generally improved with moderate activity. Prolonged morning stiffness, usually lasting more than 1 hour and often many hours, is a classic feature in RA (as well as in other inflammatory arthropathies). Symptoms are generally improved with moderate activity. Over time, RA progresses to joint destruction and deformity (e.g. swan- neck, boutonniere, ulnar deviation at MCP). Over time, RA progresses to joint destruction and deformity (e.g. swan- neck, boutonniere, ulnar deviation at MCP). Cervical spine disease may lead to C1-C2 subluxation and spinal cord compression. Cervical spine disease may lead to C1-C2 subluxation and spinal cord compression. The clinical course and severity of the arthritis are variable. The clinical course and severity of the arthritis are variable.

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12. 12 Rheumatoid Arthritis Systemic clinical features Systemic clinical features Constitutional symptoms: fatigue, low-grade fever, weight loss, myalgia, and anemia. Constitutional symptoms: fatigue, low-grade fever, weight loss, myalgia, and anemia. Grossly palpable subcutaneous rheumatoid nodules are often seen at the elbow, and less commonly in the lungs, pleura, pericardium, sclerae and other sites. Grossly palpable subcutaneous rheumatoid nodules are often seen at the elbow, and less commonly in the lungs, pleura, pericardium, sclerae and other sites. Pleuritis, pericarditis, and interstitial lung fibrosis occur in a few patients. Pleuritis, pericarditis, and interstitial lung fibrosis occur in a few patients. Vasculitis, associated with circulating complexes of IgG and rheumatoid factor, leads to cutaneous lesions, mononeuritis multiplex, and intestinal infarction. Vasculitis, associated with circulating complexes of IgG and rheumatoid factor, leads to cutaneous lesions, mononeuritis multiplex, and intestinal infarction.

13. 13 Rheumatoid Arthritis Diagnosis Diagnosis Early diagnosis is important, as all current treatment paradigms stress early and aggressive use of DMARDs. However, no physical or laboratory finding is pathognomonic, and diagnosis requires a collection of historical and physical features. Once disease has been present for a number of years, deformities are obvious but unfortunately not amenable for medical treatment. Early diagnosis is important, as all current treatment paradigms stress early and aggressive use of DMARDs. However, no physical or laboratory finding is pathognomonic, and diagnosis requires a collection of historical and physical features. Once disease has been present for a number of years, deformities are obvious but unfortunately not amenable for medical treatment. Classical presentation consists of symmetrical synovitis of small joints (warm, swollen with synovial hypertrophy), morning stiffness, fatigue. Classical presentation consists of symmetrical synovitis of small joints (warm, swollen with synovial hypertrophy), morning stiffness, fatigue. About 20-30% of patients present with monoarticular disease, usually in the knee. About 20-30% of patients present with monoarticular disease, usually in the knee. SLE can have a similar clinical presentation and may be difficult to differentiate unless other features are present. SLE can have a similar clinical presentation and may be difficult to differentiate unless other features are present. Examination of joint fluid: inflammatory, with more than 10,000 WBC (PMN predominance, >80%). Examination of joint fluid: inflammatory, with more than 10,000 WBC (PMN predominance, >80%). Rheumatoid factor is found in 80-90% of patients with RA. Presence of RF is neither necessary nor sufficient for diagnosis. SLE is also may be associated with a positive RF. Rheumatoid factor is found in 80-90% of patients with RA. Presence of RF is neither necessary nor sufficient for diagnosis. SLE is also may be associated with a positive RF.

14. 14 Rheumatoid Arthritis Treatment Treatment The goals of treatment are to control pain, preserve maximal function, and prevent deformity. The goals of treatment are to control pain, preserve maximal function, and prevent deformity. NSAIDs are useful in controlling pain and inflammation and thus improve daily function, however they do not affect the underlying disease process. NSAIDs are useful in controlling pain and inflammation and thus improve daily function, however they do not affect the underlying disease process. DMARDs, also known as “ slow-acting antirheumatic drugs ” inhibit the progression of erosive disease. DMARDs, also known as “ slow-acting antirheumatic drugs ” inhibit the progression of erosive disease. Biologic agents- anti TNF, anti IL-1 Biologic agents- anti TNF, anti IL-1

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16. 16 Seronegative Spondyloarthropathies Ankylosing spondylitis Ankylosing spondylitis Reactive arthritis (Reiter ’ s disease) Reactive arthritis (Reiter ’ s disease) Enteropathic arthritis (IBD) Enteropathic arthritis (IBD) Psoriatic arthritis Psoriatic arthritis Not always associated with spondylitis.

17. 17 Seronegative Spondyloarthropathies Epidemiology/Demographics Epidemiology/Demographics Ankylosing spondylitis is much more common among adolescent boys and young men (may reflect underdiagnosis in women, in whom disease manifestations may be milder). Ankylosing spondylitis is much more common among adolescent boys and young men (may reflect underdiagnosis in women, in whom disease manifestations may be milder). Reactive arthritis is more common among men. Can be induced by genitourinary infection with Chlamydia trachomatis, Neisseria gonorrhoeae. Reactive arthritis is more common among men. Can be induced by genitourinary infection with Chlamydia trachomatis, Neisseria gonorrhoeae. Inflammatory arthritis including spondylitis affects approximately 5-8% of patients with psoriasis and 10-25% of patients with UC/Crohn ’ s disease. Patients usually young or middle adulthood. Inflammatory arthritis including spondylitis affects approximately 5-8% of patients with psoriasis and 10-25% of patients with UC/Crohn ’ s disease. Patients usually young or middle adulthood. Prevalence of spondyloarthropathy also increases in association with HIV. Prevalence of spondyloarthropathy also increases in association with HIV. Strong association with HLA-B27. Strong association with HLA-B27.

18. 18 Seronegative Spondyloarthropathies Clinical features Clinical features The spondyloarthropathies have considerable clinical overlap with one another and are most easily considered as a group of related disorders. The spondyloarthropathies have considerable clinical overlap with one another and are most easily considered as a group of related disorders. Because of the delay in presentation of different clinical manifestations of these chronic diseases, the condition in some patients appears to “ evolve ” from one type of spondyloarthropathy to another. Because of the delay in presentation of different clinical manifestations of these chronic diseases, the condition in some patients appears to “ evolve ” from one type of spondyloarthropathy to another.

19. 19 Seronegative Spondyloarthropathies Sacroiliitis and spondylitis are the hallmarks of the spondyloarthropathies and are not seen in any other rheumatic diseases. Sacroiliitis and spondylitis are the hallmarks of the spondyloarthropathies and are not seen in any other rheumatic diseases. Sacroiliitis may present as low back or gluteal area pain. Patients generally have significant morning stiffness, sometimes of many hours ’ duration. Sacroiliitis may present as low back or gluteal area pain. Patients generally have significant morning stiffness, sometimes of many hours ’ duration. Spondylitis may occur at any area of the spine, but often progresses first in the lumbar spine, and subsequently in the cervical and thoracic regions. Spondylitis may occur at any area of the spine, but often progresses first in the lumbar spine, and subsequently in the cervical and thoracic regions. Peripheral arthritis, when occurs, begins as an episodic, asymmetrical, oligoarticular process often involving the lower extremities. Peripheral arthritis, when occurs, begins as an episodic, asymmetrical, oligoarticular process often involving the lower extremities. Enthesitis may occur in many different anatomic locations. Enthesitis may occur in many different anatomic locations. Uveitis is also a common extra-articular manifestation of the spondyloarthropathies. Uveitis is also a common extra-articular manifestation of the spondyloarthropathies.

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21. 21 Seronegative Spondyloarthropathies Specific clinical features of the spondyloarthropathies: Specific clinical features of the spondyloarthropathies: Reactive (Reiter ’ s) arthritis: urethritis, conjunctivitis. Arthritis may be self limiting, frequently recurring, chronic or progressive. Reactive (Reiter ’ s) arthritis: urethritis, conjunctivitis. Arthritis may be self limiting, frequently recurring, chronic or progressive. Enteropathic arthritis (IBD): frequently associated with both spondyloarthropathy and peripheral arthritis. Enteropathic arthritis (IBD): frequently associated with both spondyloarthropathy and peripheral arthritis. Psoriatic arthritis: 5 identifiable clinical patterns of psoriatic arthritis are recognized. Clinical overlap is significant. Psoriatic arthritis: 5 identifiable clinical patterns of psoriatic arthritis are recognized. Clinical overlap is significant. 1. DIP joint involvement with nail pitting 2. Asymmetrical oligoarthropathy of both large and small joints 3. Arthritis mutilans- a severe, destructive arthritis 4. Symmetrical polyarthritis- identical to RA 5. Spondyloarthropathy (however, spondylitis or sacroiliitis may occur along with any of the other four patterns).

22. 22 Seronegative Spondyloarthropathies No cure has yet been found for any of the spondyloarthropathies, but effective treatment for many of the manifestations is available. No cure has yet been found for any of the spondyloarthropathies, but effective treatment for many of the manifestations is available. Treatment Treatment NSAIDs NSAIDs Intra-articular glucocorticoid injection Intra-articular glucocorticoid injection Physical therapy Physical therapy Orthopedic surgery Orthopedic surgery Anti-TNF agents Anti-TNF agents

23. 23 Gout Epidemiology/Demographics Epidemiology/Demographics Gout is principally a disease of men, and to a lesser extent, postmenopausal women. Gout is principally a disease of men, and to a lesser extent, postmenopausal women. Overall, gout occurs in 2-3% of adult male population. Prevalence is age dependent, and directly related to the degree of hyperuricemia. Overall, gout occurs in 2-3% of adult male population. Prevalence is age dependent, and directly related to the degree of hyperuricemia. In individuals with normal uric acid levels, the risk is less than 1%, rising to 20 to 30% in those with uric acid levels 2 to 3 mg/dL above normal. In individuals with normal uric acid levels, the risk is less than 1%, rising to 20 to 30% in those with uric acid levels 2 to 3 mg/dL above normal. Pathology Pathology When there is an imbalance between uric acid production and excretion, uric acid accumulates at various sites as both microscopic deposits and grossly visible deposits - called tophi. When there is an imbalance between uric acid production and excretion, uric acid accumulates at various sites as both microscopic deposits and grossly visible deposits - called tophi. Attacks of gout are thought to result from either local trauma leading to shedding of crystals from local deposits or de novo precipitation of microcrystals. Attacks of gout are thought to result from either local trauma leading to shedding of crystals from local deposits or de novo precipitation of microcrystals.

24. 24 Gout Hyperuricemia Hyperuricemia More than two thirds of individuals with primary gout, have normal production of uric acid but have a primary and specific defect in uric acid clearance; that is, a higher serum uric acid level is needed to excrete the same amount of uric acid. More than two thirds of individuals with primary gout, have normal production of uric acid but have a primary and specific defect in uric acid clearance; that is, a higher serum uric acid level is needed to excrete the same amount of uric acid. Secondary gout may result from any disorder leading to decreased renal function; from decreased urine flow and acidosis, which favor urate reabsorption; or from drugs that compete for organic acid transport. Secondary gout may result from any disorder leading to decreased renal function; from decreased urine flow and acidosis, which favor urate reabsorption; or from drugs that compete for organic acid transport.

25. 25 Gout Clinical features Clinical features Acute gouty arthritis is characterized by a rapid crescendo onset. Typically, the patient goes to sleep without symptoms and is awakened by severe pain, erythema, and swelling in the affected joint. Acute gouty arthritis is characterized by a rapid crescendo onset. Typically, the patient goes to sleep without symptoms and is awakened by severe pain, erythema, and swelling in the affected joint. The first metatarsophalangeal joint is the most commonly involved, and this involvement is termed podagra. The first metatarsophalangeal joint is the most commonly involved, and this involvement is termed podagra. Pain and inflammation extend to the skin, which is often very erythematous and warm. Pain and inflammation extend to the skin, which is often very erythematous and warm. Occasionally two or more joints are simultaneously involved. Occasionally two or more joints are simultaneously involved. When there is significant uric acid accumulation in the body, visible tophi may be present. These are most commonly seen adjacent to joints near articular surfaces, in bursae, on extensor surfaces of tendons, and, less commonly, on cartilaginous structures such as the pinnae of the ear. When there is significant uric acid accumulation in the body, visible tophi may be present. These are most commonly seen adjacent to joints near articular surfaces, in bursae, on extensor surfaces of tendons, and, less commonly, on cartilaginous structures such as the pinnae of the ear.

26. 26 Gout Treatment Treatment Acute arthritis Acute arthritis Colchicine Colchicine Methylprednisone/prednisone Methylprednisone/prednisone NSAIDs NSAIDs Intercritical gout Intercritical gout Colchicine Colchicine Probenecid (uricosuric) Probenecid (uricosuric) Allopurinol Allopurinol

27. 27 Chronic Polyarticular Gout Gout may manifest as chronic polyarthritis with or without acute attacks of arthritis. Gout may manifest as chronic polyarthritis with or without acute attacks of arthritis. Patients often have multiple juxta-articular tophi and develop destructive, erosive joint disease. Patients often have multiple juxta-articular tophi and develop destructive, erosive joint disease. Occasionally, polyarticular gout may look like rheumatoid arthritis, and tophi may be mistaken for rheumatoid nodules. Radiographs in gout typically show sclerotic changes at erosive borders, in contrast to the nonreactive margins in rheumatoid arthritis. Occasionally, polyarticular gout may look like rheumatoid arthritis, and tophi may be mistaken for rheumatoid nodules. Radiographs in gout typically show sclerotic changes at erosive borders, in contrast to the nonreactive margins in rheumatoid arthritis. Examination of synovial fluid is diagnostic, and every rheumatoid arthritis patient should have synovial fluid examined for crystals at least once. Examination of synovial fluid is diagnostic, and every rheumatoid arthritis patient should have synovial fluid examined for crystals at least once.

28. 28 Pseudogout (Calclium Phyrophosphate Deposition Disease) Pseudogout (CPPD) is due to deposition of crystals of calcium pyrophosphate in articular cartilage and fibrocartilage. Such deposits are common and increase in incidence with advancing age, affecting over 30% of individuals older than the age of 80. In most individuals, these are an asymptomatic radiographic finding termed chondrocalcinosis. Acute gout-like attacks of arthritis may result when crystals are shed from such deposits. CPPD arthropathy may be asymptomatic, acute, subacute, or chronic. The knee is the joint most frequently affected in CPPD arthropathy. Other sites include the wrist, shoulder, ankle, elbow, and hands.

29. 29 Osteoarthritis Epidemiology/Demographics The most common joint disorder. Occurs radiographically in 60%-90% of individuals older than 65, and symptomatically in up to 20%. Pathology Whole joint failure with deterioration in most joint structures, including cartilage, bone, muscle, synovium, and joint capsule. Progressive loss of articular cartilage with associated remodeling of subchondral bone. A complex disorder with various risk factors, which range from biomechanical, metabolic, and inflammatory processes to age, gender, and genetic factors. OA may result from a variety of biomechanical insults, including repetitive or isolated joint trauma.

30. 30 Osteoarthritis OA is classified into two basic forms: primary and secondary. Primary OA is the idiopathic variety, which may be localized or generalized, and its causes are multifactorial. Secondary OA occurs when a particular cause of OA overwhelms all others and serves as a sole cause of disease.

31. 31 Osteoarthritis Clinical features Pain – deep aching discomfort, slow in onset, initially aggravated with activity, improved with rest. Occasionally, pain is referred to a distant site. Stiffness, particularly after prolonged inactivity, is characteristic but not as prolonged as that associated with RA, usually lasting for 20-30 minute. Exacerbation of symptoms with weather change is a common feature. Examination- joint line tenderness, bony enlargement of the joint with or without effusion. Crepitation on motion and limitation of joint motion. Characteristic radiographic features.

32. 32 Infectious Arthritis In adults, almost all cases of infective arthritis of natural joints occur through hematogenous seeding. Underlying joint disease, particularly RA, predisposes to septic arthritis. Many patients with septic arthritis give a history of joint trauma antedating symptoms of infection. Polyarticular infectious arthritis Acute rheumatic fever- migratory, asymmetrical arthritis of the knees, ankles, elbows, and wrists. Viral infections- hep. B, rubella, parvovirus, and mumps. In mumps and rubella, arthritis results from direct infection of articular tissue; with hep.B virus joint inflammation is a secondary result of the host immune response (immune complex deposition). Disseminated gonococcal infection may manifest with arthritis involving several joints.

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