W5 Autoimmune Disorders (Roy).pdf

W5 Autoimmune disorders Dr. Alfred Roy, MD Associate Professor Learning Objectives 1. List the important autoimmune disorders. 2. Discuss the etiopathogenesis of Systemic Lupus Erythematosus (SLE). Generate a diagnostic panel for SLE, and mention the the most confirmative tests for this disease. 3....

W5 Autoimmune disorders Dr. Alfred Roy, MD Associate Professor Learning Objectives 1. List the important autoimmune disorders. 2. Discuss the etiopathogenesis of Systemic Lupus Erythematosus (SLE). Generate a diagnostic panel for SLE, and mention the the most confirmative tests for this disease. 3. Describe the morphologic features noted in kidney and skin in a case of SLE 4. Overview of the clinical features and complications in SLE. What is DLE?. 5. Explain the etiopathogenesis of rheumatoid arthritis (RA). 6. Discuss the morphologic findings noted in synovial biopsy seen in RA. 7. Interpret the investigations that help in the diagnosis of RA. 8. List all the important clinical findings seen in RA, and explain the pathogenesis that underlie. 9. Summarize the findings seen in Felty syndrome. Learning Objectives (cont’d) 10. Discuss the immunologic basis of Sjorgen syndrome. 11. Describe the findings noted in the eye and salivary glands in a case of Sjorgen syndrome. 12. List and interpret the investigations that are required for the diagnosis of Sjorgen syndrome. 13. Overview of the clinical findings and complications of Sjorgen syndrome. 14. Explain the etiopathogenesis of Systemic sclerosis. 15. Describe the findings noted in skin and other organ sites in Systemic sclerosis. 16. Make a summary of the clinical findings in Systemic sclerosis and mention its importance. Write a short note on Raynaud’s phenomenon. Learning Objectives (cont’d) 17. Discuss the etiopathogenesis of Dermatomyositis. 18. List out the important diagnostic investigations in Dermatomyositis. 19. Describe the muscle biopsy findings in Dermatomyositis. 20. Explain the clinical features noted in Dermatomyositis. Autoimmune Disorders 5 Systemic Lupus Erythematosus (SLE) Introduction: - multisystem disease of autoimmune origin - presence of numerous ‘autoantibodies’ (anti nuclear antibodies: ANA) - injury mostly due to deposition of immune complexes - acute in onset, thereafter it becomes a chronic, remitting and relapsing disease - targets: skin, joints, kidney, and serosal membranes Incidence: - predominantly women (9:1; female to male) - 2 to 3-fold higher in Hispanics, and African-Americans 6 SLE: Etiology - fundamental defect in SLE is a failure of mechanism that maintain self-tolerance - factors that play: 1. Genetic Factors: - evidences to support a genetic association a) higher incidence among family members b) higher incidence among monozygotic twins c) HLA association: HLA-DQ locus associated with production of - anti-double stranded DNA (ds) - anti- Smith (Sm) - antiphospholipid antibodies d) in some cases, inherited deficiencies of early complement factors (C2, C4, or C1q). Lack of complement impair removal of circulating immune complexes 7 SLE: Etiology 2. Immunological Factors: - this leads to persistence and uncontrolled activation of self-reactive lymphocytes Failure of self-tolerance of B-cells - due to defective elimination of self-reactive B-cells in the bone marrow or defects in peripheral tolerance mechanisms Failure of CD4+ helper T-cells - specific for nucleosomal antigens also escape tolerance and contribute to the production of high-affinity pathogenic autoantibodies - these autoantibodies in SLE show characteristics of T cell-dependent antibodies produced in germinal centers, and increased numbers of follicular helper T cells have been detected in the blood of SLE patients 8 SLE: Etiology 2. Immunological Factors (cont’d) TLR engagement by nuclear DNA and RNA - these contained in immune complexes may activate B-lymphocytes - TLRs function normally to sense microbial products, including nucleic acids - therefore, B-cells specific for nuclear antigens may get second signals from TLRs and may be activated, resulting in increased production of antinuclear autoantibodies 9 SLE: Etiology 2. Immunological Factors (cont’d) Type-I interferons: - these play a role in lymphocyte activation in SLE - high levels of circulating type I interferons is noted in SLE patients and correlates with disease severity - Type-I interferons are anti-viral cytokines that are normally produced during innate immune responses to viruses - self-nucleic acids mimic their microbial counterparts - molecular mimicry - Type III hypersensitivity (Ag-Ab complexes) - Type IV hypersensitivity (IgG and IgM Ab directed against cell surface Ag) 10 SLE: Etiology 3. Environmental Factors a) Exposure to UV rays: - cells exposed to UV rays undergo apoptosis - during the apoptotic process, these cells become immunogenic - thereby inducing an immune response - UV rays modulate immune responses, by activating keratinocytes to produce IL-1 - IL-1 will then promote inflammation b) Estrogen: - may stimulate B cells to produce antibodies directed against DNA - pregnancy may aggravate SLE - hyperestrogenic states (OC use, endometriosis) 11 SLE: mechanisms of disease process SLE: Autoantibodies 1) Antinuclear antibody (ANA) - Ag-Ab complexes found in circulation - classically produce Type III hypersensitivity reaction - these Ag-Ab complexes also activate complement system ( C3, and C4 levels are decreased) - these are positive in other diseases, and are seen in 5% of normal population - test is sensitive but not specific - if the test is negative, SLE is then unlikely - test is reported in titers (1:160 is considered positive) SLE: Autoantibodies 2) Anti double stranded DNA (anti-dsDNA) - this is specific for SLE, and is associated with disease activity (as in flare up) - associated with renal involvement 3) Anti-Smith antibody - this test is also specific for SLE - antibodies are directed against small nuclear ribonucleoprotein (snRNP) SLE: Autoantibodies 4) Autoantibodies specific for rbc, white cells, and platelets - antibody directed against red blood cells: hemolytic anemia - antibody directed against leukocytes: leukopenia - antibody directed against platelets: thrombocytopenia 5) Antiphospholipid antibody - antibody directed against proteins present in phospholipids - patients would have increased risk for thrombotic events (DVT) - lupus anticoagulant, leads to increased PTT (falsely elevated) - false positive syphilis (RPR, VDRL) 15 Criteria for diagnosis of SLE. 4 out 11 must be present 1) Malar Rash 2) Discoid rash 3) Photosensitivity 4) Oral ulcer 5) Arthritis 6) Serositis 7) Cerebritis 8) Cytopenias (anemia, leukopenia, thrombocytopenia) 9) Renal disease 10) Anti-ds DNA 11) Anti-Sm SLE: Drug Induced SLE - SLE (lupus)-like features associated with drug administration - examples: INH, Hydralazine, Procainamide - more in females, triggered by UV light - patients present with rash classically seen in forearm (discoid), arthritis, cytopenias, positive for ANA - diagnosis: clinical features, drug history, and presence of anti histone antibodies, lupus band on skin histology Antibody Features Anti RNP MCTD, SLE, Systemic sclerosis Anti Smith Specific for SLE Anti SS-B (La) Sjorgen syndrome, SLE, Systemic sclerosis Scl-70 Specific for Systemic sclerosis Anti-Jo1 Dermatomyositis SLE LE cells represent phagocytosis by neutrophils of apoptotic bodies, most likely induced by antinuclear antibodies -damaged cells in tissue expose their nuclei to ANA (anti nuclear antibodies) -LE bodies or hematoxylin bodies: damaged nuclei -LE cell is any phagocytic leukocyte that has engulfed denatured nucleus of an injured cell 19 SLE: Morphology 1) Blood vessels - acute necrotizing vasculitis involving capillaries, small arteries and arterioles - these may be present in any tissue. - characterized by fibrinoid necrosis - during chronic stages, vessels undergo fibrous thickening with luminal narrowing SLE: Morphology 2) Kidney - nearly 50% of SLE patients have renal involvement - these are due to deposition of immune complexes present in the mesangium or along the entire basement membrane - both: in situ formation, and deposition of preformed circulating immune complexes may be noted SLE: Morphology 2) Kidney (cont’d): Morphological classification: Class I to Class VI Class I: minimal measngial lupus nephritis Class II: mesangial proliferative lupus nephritis Class III: focal lupus nephritis Class IV: diffuse lupus nephritis Class V: membranous lupus nephritis Class VI: advanced sclerosing lupus nephritis SLE (Class IV): deposits thickening capillary walls. 22 SLE Diffuse Lupus Nephritis (Class IV) compared to Normal Normal 23 SLE: Morphology 3) Skin: - erythema: butterfly rash (malar) in 50% - exposure to sunlight accentuates the erythema Histology: - vacuolar degeneration of basal cells in epidermis - dermis show edema, perivascular inflammation - vasculitis with fibrinoid necrosis SLE: skin biopsy SLE: Fibrinoid necrosis SLE Skin biopsy- immunofluorescence. Lupus band SLE: Morphology 4) Joints: - produces a non-erosive synovitis with little deformity, this is different from rheumatoid arthritis 5) CNS: - neuropsychiatric symptoms are noted in patients with SLE - may be associated with acute vasculitis (cerebritis) SLE: Morphology 6) Cardiovascular system: Pericarditis- acute, subacute, or chronic forms are seen. During the acute phases, the mesothelial surfaces are sometimes covered with fibrinous exudate Heart- any layer may be involved valvular (Libman-Sacks) endocarditis: - characterized by non-bacterial verrucous endocarditis - single or multiple 1- to 3-mm warty deposits on any heart valve, distinctively on both surfaces of the leaflets - increased risk for Thromboembolism - also, increased risk noted in patient with secondary Antiphospholipid antibody syndrome RHD: Rheumatic Heart Disease (small warty vegetations, along the lines of closure of valve leaflets) IE: Infectious Endocarditis (large irregular masses on the valve cusps that can extend into the chordae) NBTE: Non Bacterial Thrombotic Endocarditis (small bland vegetations usually attached to the lines of closure LSE: Libman Sacks Endocarditis (small or medium-sized vegetations on either or both sides of the valve leaflets) SLE: Diagnosis Labs: 1) Serum ANA: high titers are generally more specific for SLE (>1 : 80) than other autoimmune diseases. (sensitivity 98%) 2) Anti-dsDNA antibodies: most often used to confirm the diagnosis of SLE. (95% specificity, and sensitivity 70%–98%) 3) Anti-Smith antibodies: used to confirm the diagnosis of SLE (99% specificity; rare false positives) 4) Anti-Ro (SS-A) antibodies and anti-La (SS-B) antibodies: these have a low sensitivity (26%–50% and 5%–15%, respectively) 5) APL antibodies (sensitivity 30%–40%) SLE: Diagnosis Labs: 6) Anti-histone antibodies: especially for Procainamide (anti-histone antibodies shows 96% sensitivity) 7) Serum complement: usually decreased because of activation of the complement system by immune complexes 8) Erythrocyte sedimentation rate (ESR) is increased in active SLE 9) Immunofluorescence testing: skin, and renal biopsy SLE: malar rash (butterfly) SLE: Class IV changes: narrowing of glomerular capillaries by mesangial and endocapillary proliferation. Wire-loop deposits and hyaline thrombi are segmentally distributed 31 SLE: Lupus erythematosus (L-E) cell. Pleural fluid. A neutrophil with an ingested large nucleus (nucleophagocytosis) (arrow) compressing the nucleus of the neutrophil (asterisk). This appearance is characteristic of the L-E cell found in the blood, marrow, or serous effusions in patients with lupus erythematosus. Search for such cells as diagnostic clues has been replaced by other immunological tests (e.g. antinuclear antibody). 32 Rheumatoid arthritis Introduction: - chronic inflammatory disease, characterized by symmetric, peripheral polyarthritis - inflammatory synovitis resulting in destruction of articular cartilage and ankylosis (fusion) of joints - increases between 25 and 55 years, more in females - small joints of hands and feet (peripheral joints) hands: symmetric involvement of proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints remember: distal interphalangeal joint (DIP) is usually spared (unlike osteoarthritis) extra articular lesions may involve skin, heart, blood vessels, lungs 33 Rheumatoid arthritis 34 Rheumatoid Arthritis: Pathogenesis Rheumatoid arthritis: Pathogenesis 1. Immune factors - CD4+ T helper (TH) cells may initiate autoimmune response by reacting with an ‘arthritogenic’ agent - arthritogenic agent: ?microbial, ?self-antigen - T cells then produce cytokines - these stimulate other inflammatory cells to effect tissue injury 36 Rheumatoid arthritis: Pathogenesis 1. Immune factors (cont’d) most important ones are: IFN-ɣ: from TH1 cells activate macrophages and resident synovial cells IL-17: from TH17 cells recruit neutrophils and macrophages TNF and IL-1: from macrophages stimulate resident synovial cells to secrete proteases that destroy hyaline cartilage RANKL: expressed on activated T cells stimulate bone absorption 37 Rheumatoid arthritis: Pathogenesis Autoantibodies - directed against citrullinated peptides (CCPs) - antibodies directed against CCPs are diagnostic - 80% of RA patients have serum IgM, or IgA autoantibodies (rheumatoid factor) - citrullinated peptides are the most important for diagnosis What are CCPs? - certain interstitial tissue proteins (eg: intracellular filament protein) - undergoes post-translational modification that involves the conversion of arginine to citrulline (citrullination) - CCPs are recognized as foreign by Ag presenting cells, and presented to CD4+ cells 38 Rheumatoid arthritis: Pathogenesis 2. Genetic - 50% of the risk for RA, is genetic - HLA-DRB1 alleles are linked to RA - PTPN22 (encodes for a protein tyrosine phosphatase that inhibit T-cell activation) 3. Environmental - smoking may promote citrullination of self-antigens Rheumatoid arthritis: Pathogenesis - the pathologic hallmarks of RA are synovial inflammation (typically symmetric) and proliferation, focal bone erosions, and thinning of articular cartilage - chronic inflammation leads to synovial lining hyperplasia and the formation of pannus RA: synovial thickening, & chronic inflammation Rheumatoid arthritis: Pathogenesis Pannus: is a thickened cellular membrane of granulation–reactive fibrovascular tissue that grows over the articular cartilage and causes erosion - once articular cartilage is destroyed, Pannus bridges opposing bones to form ‘fibrous ankylosis’ Bone damage: 1. structural damage to the mineralized cartilage and subchondral bone is mediated by the osteoclast 2. another form of bone loss is peri-articular osteopenia that occurs in joints with active inflammation Rheumatoid arthritis: Morphology Joints Gross: edematous synovium, which becomes thickened, and hyperplastic Histology: - synovial cell hyperplasia and proliferation - dense inflammatory infiltrates (with lymphoid follicles) - increased vascularity due to angiogenesis - fibrinopurulent exudate on the synovial and joint surfaces - osteoclastic activity in underlying bone (this allows synovium to penetrate into the bone and cause peri-articular erosions and subchondral cysts) 42 RA: joint findings 43 Rheumatoid arthritis 44 Rheumatoid arthritis Morphology: Skin: Rheumatoid nodules: sites of pressure- ulnar aspect of the forearm, elbows, occiput, lumbosacral area - firm, non-tender round to oval skin lesions Histology: central zone of fibrinoid necrosis, surrounded by epithelioid cells & numerous lymphocytes and plasma cells Blood vessels: Rheumatoid vasculitis: - affects medium to small sized blood vessels (kidney not involved) 45 Rheumatoid nodule: note fibrinoid necrosis, surrounded by epithelioid cells. Rheumatoid arthritis Clinical features: - small joints of hands and feet - early morning stiffness (more than 1 hour after arising) Wrist: - metacarpophalangeal (MCP), and proximal interphalangeal (PIP) joints stand out as the most frequently involved joints - flexor tendon tenosynovitis is a frequent hallmark of RA and leads to decreased range of motion, reduced grip strength, and “trigger” fingers - ulnar deviation results from subluxation of the MCP joints, with subluxation of the proximal phalanx to the volar side of the hand 47 Rheumatoid arthritis Swan neck deformity boutonnière deformity Hyperextension of the PIP joint with flexion of the DIP joint (“swan-neck deformity”) Flexion of the PIP joint with hyperextension of the DIP joint (“boutonnière deformity”) 48 Rheumatoid arthritis Baker cyst: - popliteal (Baker) cyst develops posteriorly and inferiorly to the knee as a distention of a local bursa - diagnosis may be made by aspiration of mucinous fluid - when rupture produces pain (D/D: DVT) Rheumatoid nodule - seen as nodules over the extensor surface of the fingers, forearms, and pressure points (Achilles tendon, olecranon process) and in the lungs - on microscopy show necrobiosis, and fibrinoid necrosis - often associated with patients who are RF positive Hematologic findings: - Anemia of chronic disease (ACD) Carpal tunnel syndrome: - entrapment of median nerve under the transverse carpal ligament Lung: Interstitial Lung Disease 49 Rheumatoid Arthritis: Baker’s cyst Rheumatoid nodule Rheumatoid arthritis Atlantoaxial joint - cervical spine is commonly involved - cervical instability is the most serious and potentially lethal manifestation - the most common problem: subluxation at C1-C2 - muscle wasting, decreased range of motion, and compressive neuropathy Rheumatoid Arthritis: - Subluxation of cervical spine in rheumatoid arthritis. A) Flexion, showing widening of the space (arrow) between the odontoid peg of the axis (behind) and the anterior arch of the atlas (in front) B) Extension, showing reduction in this space Rheumatoid arthritis: Investigations - Rheumatoid Factor (RF): most common is IgM (seen in 60 to 80%) - Normal to increased serum C3 - antibodies to cyclic citrullinated peptides (ACAPA). Remember: CCPs have over 90% specificity - increased C-reactive protein (CRP), and increased ESR - association with HLA-DR4 - Thyroid Function Test: to rule out an autoimmune thyroid disease Synovial fluid analysis: - presence of white cells (tend to be neutrophils) - remember: synovium contains chronic inflammatory cells - also note: C3 levels are low in synovial fluid - RF can be detected in synovial fluid Radiology: Plain X-ray, USG, MRI 53 Rheumatoid arthritis Felty Syndrome Introduction: - triad: splenomegaly, neutropenia, and RA - seen in patients who have severe, prolonged RA Clinical Importance: - repeated infections due to decreased neutrophils Sjögren Syndrome Introduction: - chronic, slowly progressive autoimmune disease - characterized by lymphocytic infiltration of exocrine glands - resulting in dry mouth (xerostomia), and dry eyes (keratoconjunctivitis) Incidence: - middle aged women - Female:Male is 9:1 - Primary Sjogren syndrome: idiopathic - Secondary Sjogren syndrome: RA, SLE, Systemic Sclerosis - increased association with: Rheumatoid arthritis, Systemic lupus erythematosus, Scleroderma, Mixed connective tissue disease, Primary biliary cirrhosis, Vasculitis, Chronic active hepatitis 55 Sjögren Syndrome Pathogenesis: - characteristic feature: decrease in tears and saliva (sicca syndrome) - due to lymphocytic infiltrate and fibrosis of lacrimal and salivary gland - CD4+ helper T-cells predominate the inflammation, along with B cells, and plasma cells - lymphocytic sialadenitis (Type IV Hypersensitivity reaction) - also, antinuclear antibodies such as rheumatoid factor, and other are present - most important are 1) SS-A (Ro) 2) SS-B (La) - these two are seen in over 90% of the patients - HLA association: HLA-B8, HLA-DR3 56 Sjögren Syndrome Morphology: Salivary glands: - periductal and perivascular lymphocytic infiltration - lymphoid follicles with germinal centers may appear - ductal lining cells show hyperplasia, this leads to obstruction - later there is acinar atrophy, fibrosis, and hyalinization 57 Sjogren syndrome: Salivary gland: lymphocytic infiltrates, interstitial fibrosis, and acinar atrophy 58 Sjogren syndrome: Note the asymmetric swelling of the left parotid gland Note: dense lymphocytic inflammation, fibrosis 59 Salivary gland: normal and in Sjorgen syndrome 60 Sjögren Syndrome Clinical features: - dryness of mouth/eye - Keratoconjunctivitis sicca: dry and redness of eyes - Xerostomia: dry mouth - Nasal dryness: epistaxis - Dental caries - Dysphagia - Vaginal dryness - histological diagnosis: lip biopsy/salivary gland biopsy 61 Sjögren Syndrome Labs: antibodies in serum: - SS-A(Ro), SS-B(La), positive RF, positive ANA (not specific) Schrimer test: - amount of wetting measured in mm over 5 minutes Salivary gland scintigraphy: - low uptake of radionucleotide Whole sialometry: - measures volume and weight of saliva Complication: - risk for low grade B-cell lymphoma (Extra nodal marginal zone lymphoma) Diagnosis of Sjogren Syndrome: 4 out of 6 1) Eye symptoms 2) Ocular symptoms 3) Ocular signs: Schrimer test 4) Salivary testing 5) Biopsy: Lymphocytic sialadenitis 6) Anti-SSa or Anti-SSb Systemic Sclerosis (scleroderma) Introduction: - characterized by 1) chronic inflammation (autoimmune), 2) widespread damage to small blood vessels, and 3) progressive interstitial and perivascular fibrosis in skin and multiple organs 64 Systemic Sclerosis Etiology: Autoimmunity: CD4+ T cells responding to unknown antigen in skin - this activates inflammatory cells and fibroblasts - cytokines from T-cells (TGF-β, IL-13) Vascular damage: - intimal proliferation, endothelial activation, and injury Fibrosis: - activated macrophages, fibrogenic cytokines (PDGF, TGF-β) - fibroblast activation leading to increasing collagen deposition 65 Systemic Sclerosis Morphology: Skin: - diffuse sclerotic atrophy, begins with fingers and distal regions of upper extremities - later involve neck and face - histology: edema, perivascular infiltrates (CD4+ T cells) - swelling and degeneration of collagen (eosinophilic staining) - capillaries and small vessels show thickened basal lamina, endothelial damage, and partial occlusion 66 Systemic Sclerosis Morphology: Skin (cont’d): - increasing fibrosis of dermis, tightly bound to subcutaneous structures - increase in compact collagen, and thinning of epidermis, loss of rete pegs CREST syndrome (limited type of Systemic Sclerosis) C: calcinosis cutis R: Raynaud’s phenomenon E: esophageal dysfuntion S: sclerodactly (tapered fingers, claw-like) T: telangiectasia 67 Systemic sclerosis: Note: stretched parchmentlike skin, claw hand 68 Systemic sclerosis: Note skin induration on the fingers, and fixed flexion contractures at the proximal interphalangeal joints in a patient with progressive systemic sclerosis 69 Systemic sclerosis: 70 Systemic sclerosis: perivascular mononuclear cell infiltrate at the early stages of disease. Perivascular changes are shown at high power in the left panel. Later stage disease show skin sclerosis, a low density of blood vessels, and absence of inflammatory cells. At this stage, there may be associated epidermal changes with thickening and loss of secondary skin structures, including hair follicles and sweat glands. Absence of the rete ridges is also characteristic at the later stages71 Systemic Sclerosis Raynaud's phenomenon - is an episodic vasoconstriction in the fingers and toes that occurs in virtually every patient with scleroderma - vasoconstriction may also affect the tip of the nose and earlobes - attacks are triggered by exposure to cold, a decrease in temperature, emotional stress, and vibration - typical attacks start with pallor, followed by cyanosis of variable duration - eventually erythema develops spontaneously or with rewarming of the digit - progression of the three-color phases reflects the underlying pathogenic mechanisms of vasoconstriction, ischemia, and reperfusion 72 Sharply demarcated necrosis of the fingertip in a patient with systemic sclerosis associated with severe Raynaud's phenomenon 73 Systemic Sclerosis Morphology: GIT: - progressive atrophy and collagenous fibrous replacement of the muscularis may develop - at any level of the gut but are most severe in the esophagus - lower two thirds of the esophagus often develops a rubber-hose like inflexibility - lower esophageal sphincter (LES) hypotonia gives rise to gastro-esophageal reflux and its complications, including Barrett esophagitis (metaplasia) 74 Systemic Sclerosis Morphology: Musculoskeletal system: - synovium show inflammation, hypertrophy & hyperplasia - however, unlike RA, no joint destruction Kidney: - vascular lesions (interlobular arteries show intimal thickening with mucinous or collagenous material) - concentric proliferation of intimal cells, similar to those seen in hypertension - hypertension seen in 30% (in some complicated by malignant hypertension) 75 Systemic Sclerosis Morphology: Lungs: - involved in 50% of cases - pulmonary hypertension, & interstitial fibrosis - pulmonary hypertension may progress to right-sided heart failure Heart: - pericarditis with effusion, myocardial fibrosis - thickening of intra-myocardial arterioles - conduction disturbances (bundle branch blocks) 76 Systemic Sclerosis: Clinical Features - females, peak incidence- 50 to 60 years - cutaneous changes- skin thickening - Raynaud phenomenon - dysphagia - abdominal pain, malabsorption, anemia - respiratory- features of right-sided heart failure, myocardial fibrosis, arrhythmia, - hypertension Lab: - presence of ANA in all patients 1) Anti topoisomerase I (anti-Scl 70) 2) Anticentromere antibody (seen in 20 to 30% of patients who tend to have CREST syndrome) 3) Anti-RNA polymerase III antibody 77 Dermatomyositis Introduction: - heterogeneous group of genetically determined autoimmune disorders that predominately target - the skeletal musculature and/or skin and typically result in - symptomatic skeletal muscle weakness and/or cutaneous inflammatory disease Pathogenesis: - immunologic disease in which there is damage to small blood vessels - contributing to muscle injury - vascular findings are present as telangiectasia (dilated capillary loops) - seen in nail folds, eyelids, and gums - biopsy of muscle/skin show deposits of complement: C5b-9 78 Dermatomyositis Pathogenesis (cont’d): - antibodies associated include: Anti-Mi2 antibodies: associated with Gottron papules Anti-Jo1 antibodies: associated with interstitial lung disease, non-erosive arthritis, skin rash Anti-P155/P140 antibodies: associated with paraneoplastic & juvenile cases of dermatomyositis 79 Dermatomyositis Morphology: Muscle biopsy: - mono-nuclear inflammatory cells, mostly around perimysial connective tissue and around blood vessels - perifasicular atrophy of muscle Immunohistochemistry: inflammatory cells stain positive for CD4+ T-helper cells, and - deposition of C5b-9 in capillary vessels 80 Dermatomyositis Note atrophic changes in muscle bundles in the marked-out area Skeletal muscle: normal and in Dermatomyositis 82 Dermatomyositis Clinical Features: - muscle weakness (proximal musle), slow onset - often accompanied by myalgias - getting up from chair, climbing stairs become difficult - elevated serum creatinine kinase levels - lilac colored discoloration of upper eyelids (heliotrope rash) - scaling erythematous eruption or dusky red patches over knuckles/elbows/knee: Gottron papules. Mechanic’s hands (cracks/fissures on the palm) - dysphagia - interstitial lung disease (10%) - risk of malignancies. 83 Dermatomyositis: heliotrope rash Note the confluent macular violaceous erythema, most pronounced over the metacarpophalangeal/interphalangeal joints, extending in a linear array overlying the extensor tendons of the hand and fingers. These changes, referred to as Gottron sign, are a hallmark cutaneous feature of DM 84 “besides the noble art of getting things done, there is the noble art of leaving things undone. The wisdom of life consists in the elimination of nonessentials” Lin Yutang (1895-1976)