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COLLAGEN DISEASES I. Professor DR. Shahenaz M. Hussien. OBJECTIVES. By the end of this lecture the student will be able to understand the followings: Etiology, pathogenesis, clinical manifestation, investigations and treatment of rheumatoid arthritis.
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COLLAGEN DISEASES I Professor DR. Shahenaz M. Hussien
OBJECTIVES By the end of this lecture the student will be able to understand the followings: • Etiology, pathogenesis, clinical manifestation, investigations and treatment of rheumatoid arthritis. • Etiology, clinical manifestation, investigations, diagnosis and treatment of systemic lupus erymatosis.
Juvenile rheumatoid Arthritis ( JRA ) - Most common of rheumatic diseases and leads to chronic disability. - Idiopathic synovitis of the peripheral joints with soft tissue swelling and effusion. Age at onset < 16yr: -Arthritis (swelling or effusion) or presence of two or more of the following signs : • limitation of range of motion, • tenderness or pain on motion, • and increased heat in one or more joints. - Duration of the disease ; 6wk or longer. Polyarthritis5 or more inflamed joints. Oligoarthritis< 5 inflamed joints. Systemic: arthritis with fever, and exclusion of other forms of juvenile arthritis.
Etiology –Unknown immunologic susceptibility -Environmental trigger: as viruses parvovirus B19, rubella, Ebstein-Barr. - Host hypersensitivity to specific self-antigens (type II collagen) and enhanced T-cell reactivity to bacterial or mycobacterial heat shock proteins. Pathogenesis: Synovitis: Villous hypertrophy and hyperplasia with hyperemia and edema of subsynovial tissues. Vascular endothelial hyperplasia. Pannusformation results in progressive erosion of particular cartilage and contiguous bone. - Preceding infection or trauma. - HLA: DR8, DR5 in pauciarticular type, and DR4 in polyarticular JRA. - Leads to greater amounts of cytokines resulting in more severe disease.
Clinical manifestations: - Morning stiffness and gelling, easy fatigability, joint pain later in the day and joint swelling. Oligoarticular disease (pauciarticular 50%) • Arthritis of big joints less than 5. • Asymmetrical or spotty. • Knees, ankles, hips never involved early, later indicates sign of a deteriorating functional course. - Two types.
Polyarticular disease (35%): - More among girls. - No systemic manifestations. - Large and small joints five or more. - Rheumatoid nodules over extensor surfaces of elbows and over Achilles tendon associated with a more severe course. - Micrognathia due to temporomandibular joint involvement. - Cervical spine with risk of atlantoaxial sublaxation. -Hoarse voice due to cricoarytenoid joint involvement. -Two types.
Systemic-onset disease (15%): - Arthritis, prominent visceral involvement: • Hepatosplenomegaly,lymphadenopathy, and serositis • Fever for a minimum 2wk with daily temperature spikes to at least 39.5c often associated with salmon- colored lesions over the trunk and proximal extremities. -koebner phenomenon: cutaneous hypersensitivity to superficial trauma.
Diagnosis: -No pathognomonic finding. - Clinical subtypes. - Exclusion of other articular diseases. -Elevated ESR, CRP, leukocytosis, thrombocytosis, anemia. Differential diagnosis: • Other rheumatic diseases : SLE, juvenile dermatomyositis, scleroderma -Autoimmune hepatitis, • chronic Mycobacterial or other infections. • Single joint: bacterial infection, psoriatic arthritis. • Hip joint can be due suppurative arthritis, osteomyelitis, slipped capital femoral epiphysis, chondrolysis of the hip. - Persistent arthralgia: juvenile episodic arthritis, inflammatory bowel disease. - Less commonly: leukemia.
Causes of mono arthritis: 1. Trauma. 2. Septic arthritis 3. Mycobacterial infection 4. Chronic active hepatitis 5. Toxic synovitis of the hip. 6. Osteomyelitis with sympathetic effusion. 7. Leukemia (in 5% of causes). 8. Familial Mediterranean fever. 9. Slipped capital femoral epiphysis. 10. Sarcoidosis. Causes of pauci articular arthritis 1. Reactive arthritis. 2. Viral 3. Pauciarticular juvenile rheumatoid arthritis. 4. Acute leukemia. Causes poly articualr arthritis 1. Poly articular rheumatoid arthritis. 2. SLE. 3. TB. 4. Malignancies. 5. Dermatomyositis. 6. Inflammatory bowel disease: Crohn's disease, ulcerative colitis.
Laboratory findings: • Elevated white blood cell, and platelet counts, decreased hemoglobin and mean corpuscular volume. • ESR, CRP. • Elevated serum immunoglobulins, elevated ANA, positive rheumatoid factor in older children with rheumatoid nodules. • Abnormal mineral metabolism with active synovitis. • Increased IL-6. Radiologic changes: • Soft tissue swelling, osteoporosis, periostitis about affected joints. • Regional epiphyseal closure may be accelerated and local bone growth increased or decreased, subchondral erosions, narrowing of cartilage space, • varying degrees of bony destruction and fusion most frequently in the neural arch joints at C2-C3, • MRI evaluates both joint and soft tissues
Treatment: -Oligoarticular JRA responds to NSAIDsalone. -Polyarticular patients and some aggressive disease with oligoarticular JRA . Combination therapy should begin with NSAIDs, sulfalsalazine, methotrexate and possibly other immunosuppressive drugs. -Azathioprine and cyclophosphamide are reserved for the very few patients who do not respond to less aggressive therapy. -Glucocorticoid for overwhelming inflammatory or systemic illness. Therapy in lower doses in addition to another drug as methotrexate are most efficacious for ocular and intraarticular use. Routine slit lamp for asymptomatic uveitis. -Appropriate calcium intake, physical and occupational therapy. -Social workers support to alleviate family stresses
Prognosis: - Unpredictable, variable physical function limitations - Chronic uveitis may result in posterior synechiae and blindness. - Functional limitation risk has been associated with: - Older age at onset, rheumatoid factor positivity, rheumatoid nodules, early cervical spine or hip arthritis. - Anemia non responsive to iron therapy, exaggerated by gastrointestinal bleeding. Due to NSAID. - Rare digital endarteritis threatening auto amputation which may respond to I.V prostaglandin E1. - Development of manifestations of other rheumatic diseases overlapping syndrome. - Orthopedic complications: leg length discrepancy, secondary scoliosis, popliteal cysts, flexion contractures. - Psychological adaptation, continuing chronic pain syndromes.
SYSTEMIC LUPUS ERYTHEMATOSIS - Unknown etiology. - Multi organ disease. - Auto antibodies against self-antigens which result into damage of target organs such as the kidneys, blood-forming cell and CNS. - Unpredictable history and course. - Acute life-threatening disease, spontaneous remission smoldering over years, or rapid death. - Initial presentation may be atypical as parotitis, abdominal pain, transverse myelitis.
Etiology: - Many factors: genetics, hormones and the environment contribute to immune dysregulation. - Auto antibodies against DNA and other antigens: ribosome's, platelets, coagulation factors, immunoglobulins, erythrocytes, leukocytes. - Anti-double stranded DNA antibodies with circulating and tissue- bound immune complexes lead to complement fixation and recruitment of inflammatory cells and then tissue injury. - Polyclonal activation of B lymphocytes results in elevated immunoglobulin levels and elevated autoantibody levels. - Dysregulation of apoptosis leads to the presence of self- reactive lymphocytes.
Etiology: - Defects in macrophage phagocytosis and handling of immune complexes. - Complement abnormalities. - Exposure to ultraviolet rays in sun light can exacerbate SLE manifestations through damage to nuclear material. - Drug-induced lupus: anticonvulsants, sulfonamides, antiarrhythmic drugs, these patients have antihistone antibodies Pathogenesis: - Fibrinoid deposits in blood vessel walls of affected organs. - Parenchyma may contain hematoxylin bodies representing degenerated cell nuclei. Rheumatoid nodules, and granulomas in affected tissues.
Clinical manifestations: - Fever, fatigue, arthralgia, arthritis, rash. - Intermittent or persistent symptoms. Cutaneous: • Malar, butterfly rash: nasal bridge and cheeks, photosevsitive. • Discoid lesions more in adults. • Mucous membranes: vasculitic erythema to ulcers on palate and nasal mucosa. -Vasculitic-appearing erythematous macular eruptions on fingers, palms, soles. -Purpura and livedo reticularis which is lace like bluish, purplish or erythematous discoloration of the skin due to vascular instability. -Raynaud phenomenon, -subacute psoriasiform or annular skin lesions, bullous lesions, and alopecia.
CLINICAL MANIFESTATIONS Musculoskeletal:- Arthralgia, arthritis, tendinitis, myositis, osteonecrosis of bones secondary to vasculopathy or corticosteroid therapy. Serositis: pleural, pericardial, peritoneal. - Hepatosplenomegaly, lymphadenopathy. Gastrointestinal:due to vasculitis: pain, diarrhea, infarction, melena, inflammatory bowel disease and hepatitis. Cardiac: valvular thickening, verrucous endocarditis (Libman Sacks disease), cardiomegaly, myocarditis, conduction abnonmalies, heart failure, coronary artery vasculitis or thrombosis.
Clinical manifestations: Pulmonary: - Acute pulmonary hemorrhage, pulmonary infiltrates (superimposed infection), chronic fibrosis. Neurologic: CNS, peripheral nervous tissue, memory loss, cognitive dysfunction. - Neuro psychiatric manifestations, severe psychosis. Arterial and venous thrombosis: - Antiphospholipid antibody syndrome, in any organ leads to thrombocytopenia and Raynaud phenomenon. Renal disease: Leads to hypertension, peripheral edema, renal vascular changes, electrolyte abnormalities, nephrosis, acute renal failure.
Diagnosis: - Clinical, laboratory manifestations revealing multisystem disease. - Presence of 4 of 11 criteria serially or simultaneously 1- Malar rash: fixed erythema, flat, raised over malar eminences. 2- Discoid rash: erythematous raised patches with adherent keratotic scaling and follicular plugging. 3- Photosensitivity: rash as a result of unusual reaction to sunlight. 4- Oral ulcers: oral or nasopharyngeal painless ulceration. 5- Arthritis: nonerosive arthritis of two or more peripheral joints, tender, swollen, effusion. 6- Serositis: pleurisy or pericarditis or peritonitis or all. 7- Renal disorder: persistent proteinuria, cellular casts, (RBC, Hb, granular, tubular, or mixed).
8- Neurologic disorder: seizures, psychosis. 9- Hemolytic disorder: - With reticulocytosis or - Leukopenia on two or more occasions or - Lymphopenia on two or more occasions or -Thrombocytopenia. 10- Immunologic disorder: - Positive LE cell. or - Anti-DNA antibody or - Anti-smooth muscle nuclear antibodies. -Presence of antiphospholipid antibodies. -Antinuclear antibody: abnormal titer in absence of drugs inducing lupus syndrome. 11- Renal biopsy.
Laboratory findings: - Elevated ANA titers: screening tool. - Anti-double-stranded DNA are more specific and measures degree of disease activity. - Total hemolytic complement (CH50), C3, C4, are decreased in active disease. • Anti- Smith antibody. - Hypergammaglobulinemia. Antibodies found in SLE: - Coombs antibodies cause hemolytic anemia. - Antiphospholipid antibodies cause antiphospholipid syndrome. - Lupus anticoagulant causes coagulopathy. - Antithyroid antibodies cause hypothyroidism. • Antiribosomal antibodies cause lupus cerebritis.
Treatment: - Regimen depends on affected target organs and disease activity and severity. - Frequent reevaluation of patients and monitoring indefinitely. NSADs: for arthralgia and arthritis. Watch for hepatotoxicity. Hydroxychloroquine: for mild manifestations, skin lesions, fatigue, arthritis, arthralgia. Corticosteroids: control symptoms and autoantibodies production, improves kidney disease, but exclude tuberculosis before treatment. 1- 1-2 mg/kg/day Prednisone oral in divided doses until complement level increases to within normal range,dose is tapered over 2-3 years to lowest effective dose.
Treatment: 2- Alternate-day dose of csorticosteroid. 3- Pulse intravenous corticosteroid 30mg/kg/day, maximum1gm over 30min daily for 3days in severe cases. 4- Intermittent steroid pulse therapy in combination with oral low-dose daily. 5- Cytotoxic therapy in severe disease: intravenous. - Cyclophosphamide: maintains renal function and prevents progression particularly with diffuse proliferative glomerulonephritis. - Treatment of vasculitis, pulmonary hemorrhage, CNS disease refractory to corticosteroids.
Treatment - Azathioprine:Can prevent renal disease progression, causes secondary infections, gonadel dysfunction, risk of malignancies. - Methotrexate, cyclosporine and mycophenolate mofetil. - Bone marrow stem cell transplantation. Staging by renal biopsy: - Class 1: no abnormalities on light and electron microscopy and immunofluorescence studies. - Class 2a: minimal immunoglobulin and complement deposition in mesangium, good prognosis for renal function. - Class 2b: mesangial glomerulonephritis: increased lymphocyte infiltration of the mesangium with variable prognosis.
Staging by renal biopsy: - Class 3: focal and segmental proliferative glomerulonephritis near capillaries, necrosis and lymphocyte infiltration, chronic renal disease. - Class 4: diffuse proliferative glomerulonephritis: majority of glomeruli with cellular infiltration, mesangeal cellular proliferation, crescent formation and scarring leads to end-stage renal disease. - Class 5: membranous glomerulonephritis: thickened capillary walls, subepithelial deposits along basement membrane associated with proteinuria, chronic renal disease, poor response to treatment.
* Neonatal lupus: Lupus in newborns results from maternal transfer of IgG autoantobodies in the 12-16 weeks gestation. - Manifests as congenital heart block, cutaneous lesions, hepatitis, thromocytopenia, neutropenia, pulmonary and neurologic disease. - At 6w of age skin lesion develops on the face and scalp lasts for 3-4 months. 25% develops scar. Treatment:supportive - Congenital heart block is permanent requires cardiac pacing even antenatally. - Slightly prolonged P-R intervals, cardiomyopathy is rare. Differential diagnosis: Infantile multisystem inflammatory disease: -Rare, fever rash, arthropathy, chronic meningitis, seizures, uveitis, and lymphadenopathy -Requires long-term immunosuppression.