Pathology Systemic Autoimmune Disorders PDF

PATHOLOGY 08/28/2024. MOD 4: SYSTEMIC AUTOIMMUNE DISORDERS...

PATHOLOGY 08/28/2024. MOD 4: SYSTEMIC AUTOIMMUNE DISORDERS Dr. Joanne Marie R. Pascual Trans Group: 6B I. AUTOIMMUNE DISEASES 2 Environmental Factors Normally, the immune system can tell the difference between foreign cells and your own cells. A variety of environmental insults may alter the display of Conditions where the immune system mistakes the tissue antigens: body’s cells as foreign, releasing proteins called autoantibodies that attack healthy cells a Infections Infections that promote lymphocyte Result from tissue injury caused by T cells or entry into tissues, activation of antibodies that react against self-antigens self-reactive lymphocytes, inflammation, and tissue damage A. IMMUNE CONTROL MECHANISMS UV b Ultraviolet radiation causes cell death Normally, several mechanisms silence potentially Radiations and may lead to exposure of nuclear autoreactive T and B cells in peripheral tissues antigens which elicit pathological This function is best defined for T cells. immune responses such as in the case of systemic lupus erythematosus (SLE) MECHANISMS THAT SILENCE POTENTIALLY This is the proposed mechanism for AUTOREACTIVE T AND B CELLS the association of lupus flares with exposure to sunlight 1 Anergy c Local Local tissue injury for any reason may 2 Suppression by Regulatory T Cells Tissue also lead to the release of self-antigens Injury and autoimmune responses 3 Deletion by Apoptosis 1. ANERGY C. GENERAL FEATURES OF AUTOIMMUNE DISEASES Lymphocytes that recognize self-antigens are rendered functionally unresponsive GENERAL FEATURES OF AUTOIMMUNE DISEASES Immature lymphocytes that recognize self-antigens in the central lymphoid organs like the thymus are killed 1 Tend to be chronic by apoptosis 2 Sometimes with relapses, remissions, Also affects mature B-cells in the peripheral tissues exacerbations, If B-cells encounter self-antigens in the peripheral tissues, especially in the absence of specific helper 3 Often with progressive damage T-cells, the B-cells become unable to respond to subsequent antigenic stimulations and may be excluded Female predilection: strong gender bias, with many from lymphoid follicles, resulting in their death diseases being more common in women than in men Underlying mechanisms are not well-understood 2. SUPPRESSION BY REGULATORY T CELLS but may involve the effect of hormones and Regulatory T-cells: function to prevent immune currently unknown genes in the X chromosome responses against self-antigens, fetus, and commensal microbes 4 Familial prevalence of the same or other types of autoimmune diseases 3. DELETION BY APOPTOSIS 5 Overlaps in terms of clinical presentation and T-cells that recognize self-antigens may receive serological laboratory findings signals that promote their death by apoptosis B. FAILURE OF SELF-TOLERANCE AUTOIMMUNE DISORDERS The basic underlying cause of autoimmune diseases is the failure of tolerance Organ-Specific Systemic This allows immune responses to develop against self-antigens Mediated by Autoimmune Systemic Antibodies hemolytic anemia lupus Autoimmune erythematosu PREDISPOSING FACTORS OF AUTOIMMUNITY thrombocytopenia s 1 Susceptibility Genes Autoimmune atrophic gastritis Inheritance of susceptibility genes that may interfere with of pernicious self-tolerance. anemia Myasthenia gravis Pathology - Mod 4 Systemic Autoimmune Disorders 1 of 11 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Graves disease directed against Goodpasture blood cells syndrome Antiphospholipid 3 Phospholipid Mediated by Type 1 Diabetes Rheumatoid Antibodies T Cells Mellitus arthritis Multiple sclerosis Systemic 1. ANTINUCLEAR ANTIBODIES (ANAs) sclerosis (scleroderma Directed against nuclear antigens ) Sjögren FOUR CATEGORIES BASED ON SPECIFICITY syndrome Postulated to Inflammatory Polyarteritis 1 Antibodies against DNA (which includes anti-[Sm]) be bowel diseases nodosa autoimmune (Crohn disease, Inflammatory 2 Antibodies to histones ulcerative colitis) myopathies Primary biliary 3 Antibodies to nonhistone proteins bound to RNA cirrhosis Autoimmune 4 Antibodies to nucleolar antigens (chronic active) hepatitis TWO ANTIBODIES AGAINST DNA Detection of these antibodies are virtually diagnostic of SLE. Anti-dsDNA Antibodies to double stranded DNA Anti-[Sm] Antibodies to Smith antigen Type III Hypersensitivity: these antibodies generally form immune complexes that deposit in tissues and cause tissue damage. Spectrum of Autoimmune Diseases. LOCATION AND RESULTING DISORDERS II. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) ANA complexes may deposit in specific tissues and cause: An autoimmune disease involving multiple organs Characterized by a vast array of autoantibodies (i.e., Joints Arthritis antinuclear antibodies (ANAs)) Caused mainly by: Blood Vessels Vasculitis ○ Deposition of immune complexes ○ Antibody binding to cells and tissues Kidneys Glomerulonephritis May be acute or insidious in its onset Typically a chronic, remitting, relapsing, often febrile 2. ANTIBODIES DIRECTED AGAINST BLOOD CELLS illness Virtually any organ in the body may be affected ○ However, most prominent injury are observed in: CELLS TARGETED AND RESULTING DISORDERS Skin Joints These autoantibodies promote phagocytosis and Kidneys destruction of blood cells resulting in: Serosal membranes RBC Anemia A. MECHANISMS OF TISSUE DAMAGE Hallmark: production of autoantibodies WBC Leukopenia ○ These autoantibodies are pathogenic either by: Platelets Thrombocytopenia Forming immune complexes; or Attacking their target cells Type IIa Hypersensitivity: these antibodies against blood cells destroy blood cells through an antibody-mediated B. TYPES OF AUTOANTIBODIES process AUTOANTIBODY GROUPS IN SLE The most common disorder caused by this type of autoantibody is immune thrombocytopenic purpura Hyper- which occurs in up to 10% of patients with SLE. Groups Directed Against sensitivity 3. ANTIPHOSPHOLIPID ANTIBODIES Antinuclear 1 Antibodies Type III Nuclear antigens Present in 30 to 40% of lupus patients (ANAs) Sometimes referred to as “lupus anticoagulant” Patients may develop venous and arterial thrombosis 2 Antibodies Type IIa Blood cells associated with: Pathology - Mod 4 🏠 Systemic Autoimmune Disorders 2 of 11 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  ○ Recurrent spontaneous miscarriages; and SIX PATTERNS OF GLOMERULAR DISEASE IN SLE ○ Focal cerebral or ocular ischemia This constellation of clinical features associated with Class I Minimal mesangial lupus nephritis lupus is referred to as the secondary antiphospholipid antibody syndrome (APAS). Class II Mesangial proliferative lupus nephritis Class III Focal lupus nephritis COMPARISON OF APAS Class IV Diffuse lupus nephritis Primary APAS Secondary APAS Class V Membranous lupus nephritis Association No Yes with SLE Class VI Advanced sclerosing lupus nephritis Arterial and venous thrombosis, Clinical Over time, lesions may also develop from one class to recurrent spontaneous miscarriages, Manifestation another. focal cerebral or ocular ischemia ○ Class I: least common ○ Class IV: most common and most serious Neuropsychiatric manifestations of SLE: ○ Due to antibodies that cross the blood-brain 2.2 Tubulointerstitial Nephritis barrier ○ Antibodies react with neurons or receptors for Changes in the interstitium in tubules are frequently various neurotransmitters present in lupus nephritis. ○ Cytokine production Rarely, tubulointerstitial lesions may be the dominant abnormality. Immune complexes similar to those in the glomeruli are C. MORPHOLOGY present in the tubular or peritubular capillary Morphologic changes in SLE are extremely variable basement membranes in many lupus nephritis The most characteristic lesions result from immune patients. complex deposition in blood vessels, kidneys, Occasionally, there are well-organized B cell follicles connective tissue, and skin following a type III immune in the interstitium with plasma cells that may be complex hypersensitivity mechanism sources of antibodies. 1. BLOOD VESSELS 3. SKIN A characteristic erythema affecting the face along the 1.1 Acute Necrotizing Vasculitis bridge of the nose and cheeks called “butterfly”/ malar The deposition of immune complexes in blood vessels rash. result in an acute necrotizing vasculitis involving Seen in approximately 50% of patients. capillaries, small arteries, and arterioles of any tissue. A similar rash may also be seen on the extremities and The arteritis is characterized by fibrinoid necrosis of trunk. the vessel walls. Urticaria, bullae formations, maculopapular lesions, In chronic stages, the vessels undergo fibrous and ulcerations may also occur. thickening with luminal narrowing. Exposure to sunlight excites or accentuates the erythema. Acute Necrotizing Vasculitis. “Butterfly” / Malar Rash. 2. KIDNEYS Up to 50% of SLE patients have clinically significant HISTOLOGIC FINDINGS renal involvement mainly in the form of glomerulonephritis and tubulointerstitial nephritis. The involved areas of the skin show: 2.1 Glomerulonephritis LIGHT MICROSCOPY The glomerular lesions are the result of deposition of immune complexes on the glomerular basement Epidermis Vacuolar degeneration of the basal layer membrane—in the mesangium and sometimes throughout the glomerulus. Dermis Variable edema Pathology - Mod 4 🏠 Systemic Autoimmune Disorders 3 of 11 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Perivascular inflammation (with lymphocytic infiltrates) Vasculitis with fibrinoid necrosis (may also be prominent) IMMUNOFLUORESCENCE MICROSCOPY Dermo- Deposition of immunoglobulin and epidermal complement (may also be present in junction uninvolved skin) This finding is not specific for SLE Sometimes seen in other autoimmune diseases like scleroderma or dermatomyositis Libman-Sacks Endocarditis. 5. OTHER ORGANS OTHER ORGANS Organ Morphology Joints Non-erosive synovitis with little deformity CNS No clear morphologic abnormalities account for the neuropsychiatric symptoms of SLE Non-inflammatory occlusion of small blood vessels by intimal proliferation is sometimes noted which may be due to endothelial damage by autoantibodies or immune complexes Vacuolar degeneration of the basal layer of the epidermis (red circle); Deposition of immunoglobulin and complement along the dermo-epidermal junction (yellow arrows). Other Aside from pericarditis, inflammation of Serosal serosal lining membranes may also occur. 4. CARDIOVASCULAR SYSTEM Activities The inflammation may be: Involvement of the cardiovascular system may manifest Acute as damage to any layer of the heart ○ During this phase, the mesothelial surfaces are sometimes covered 4.1 Pericarditis with fibrinous exudate Symptomatic or asymptomatic pericardial involvement is ○ Later they become thickened, present in up to 50% of patients opaque and coated with a shaggy fibrous tissue that may lead to 4.2 Myocarditis partial or total obliteration of the Inflammation of the myocardium is uncommon serosal cavity When present, it causes: ○ Pleural and pericardial effusions ○ Resting tachycardia may also be present ○ Electrocardiogram changes Subacute Inflammation Chronic Inflammation 4.3 Valvular Abnormalities Primarily affects the mitral and aortic valves D. CLINICAL FEATURES Manifests as diffuse leaflet thickening that may be SLE is a multi-system disease that is highly variable in associated with stenosis and/or regurgitation its clinical presentation. Female > male (10:1 - 20:1) 4.4 Libman-Sacks (or Murantic or Verrucous) 20 to 30 years old: acute Endocarditis Older patients: less acute and better prognosis Before widespread use of steroid therapy, this type of The disease may be acute or insidious in its onset. valvular endocarditis was more common ○ Often, the patient is a young woman with some but A type of sterile nonbacterial thrombotic not necessarily all of the following features: endocarditis (NBTE) secondary to inflammation Nonbacterial verrucous endocarditis takes the form of single or multiple 1-3 mm warty deposits on any 1 A butterfly rash all over the face heart valves distinctively on either surface of the leaflets 2 Fever 3 Joint pain but with NO deformity in one or more peripheral joints (e.g. feet, ankles, knees, hips, Pathology - Mod 4 🏠 Systemic Autoimmune Disorders 4 of 11 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  3. PROGNOSIS fingers, elbows, wrists, or shoulders) The outcome for SLE patients has improved significantly 4 Pleuritic chest pain with approximately 90% 5-year and 80% 10-year survival rates. 5 Photosensitivity (appearance of disease flare-ups The most common causes of death are renal failure upon exposure to UV light) followed by intercurrent infections. Coronary artery disease is also becoming an important cause of death. In many patients, however, the presentation of SLE is subtle and puzzling, taking the form of: F. KEY CONCEPTS SLE is a systemic autoimmune disease caused by the 1 A febrile illness of unknown origin production of autoantibodies against numerous self-antigens. 2 Abnormal urinary findings including hematuria, red cell casts, proteinuria, and classic nephrotic syndrome 3 MAJOR GROUPS OF AUTOANTIBODIES IN SLE 3 Joint disease masquerading as rheumatoid arthritis Antinuclear Directed against nuclear or rheumatic fever Antibodies antigen (ANAs) (Type III) (Type III) Responsible for the formation 4 Laboratory evidence of some hematologic of circulating immune derangement (normally seen in every patient with complexes SLE but in some cases, anemia or thrombocytopenia may be the presenting Antibodies React with red blood cells, white manifestation and the dominant clinical problem) Directed Against blood cells, and platelets (Type II) Blood Cells 5 Mental aberrations including psychosis or (Type II) convulsions Antiphospholipid Composed of various complexes of 6 Coronary artery disease Antibodies phospholipids and proteins (lupus (Antiphospholipid), “lupus anticoagulant) anticoagulant” MOST COMMON SIGNS AND SYMPTOMS Hematologic 100% DISEASE MANIFESTATIONS IN SLE Musculo-skeletal (Arthritis) 90% Type III All caused by the deposition of Nephritis immune complexes following a Skin (Butterfly rash) 85% Vasculitis Type III hypersensitivity disorder (skin lesions) Fever 83% Arthritis Renal, Pulmonary, Cardiac 30 to 50% Type II Mediated by Type II hypersensitivity Hematologic Others abnormalities Neurologic abnormalities ANAs detected by immunofluorescence assays are found in virtually 100% of patients with anti-dsDNA and anti-Sm being virtually diagnostic. SLE is more common in females. The course of the disease is variable and unpredictable. E. CLINICAL COURSE SLE follows a relapsing and remitting course The course of SLE is variable and unpredictable. spanning a period of years, or even decades. Rarely, death ensues within weeks to months. The most common cause of death in SLE patients is More often, with appropriate therapy, the disease follows renal failure followed by intercurrent infections. a relapsing and remitting course, spanning a period of years or even decades. III. SJOGREN SYNDROME 1. ACUTE A chronic autoimmune disease Characterized by dry eyes (keratoconjunctivitis sicca) During acute flare-ups, increased formation of immune and dry mouth (xerostomia). complexes result in complement activation, often leading ○ These symptoms result from an immunologically to hypocomplementemia like decreased C3 levels. mediated destruction of lacrimal and salivary Disease flares are usually treated with corticosteroids glands. or other immunosuppressive drugs. Discovered by a Swedish ophthalmologist named Henrik Sjogren in 1930 through observing a patient with low 2. INDOLENT secretions from the lacrimal and salivary glands Even without therapy in some patients, the disease runs an indolent course with relatively mild manifestations A. FORMS such as skin changes and mild hematuria for years. Pathology - Mod 4 🏠 Systemic Autoimmune Disorders 5 of 11 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. 1. PRIMARY SJOGREN FORM When this autoimmune disorder occurs on its own (an isolated disorder) Also known as “Sicca syndrome” 2. SECONDARY SJOGREN FORM If it occurs in association with another autoimmune disease such as: ○ Rheumatoid arthritis (most common) ○ SLE ○ Polymyositis ○ Scleroderma ○ Vasculitis ○ Mixed Connective Tissue Disease (MCTD) B. PATHOGENESIS Lymphocytic infiltrates around salivary ducts and blood AUTOANTIBODIES IN SJOGREN SYNDROME vessels. Rheumatoid Autoantibody seen in rheumatoid Earliest histologic findings in involved salivary glands is Factor arthritis the aggregation of lymphocytes around salivary ducts An antibody reactive with self IgG and blood vessels. (antibodies against antibodies) The inflammatory infiltrate contains: Present in about 75% of patients ○ Activated CD4 Helper T-cells (predominantly) with Sjogren syndrome, whether or ○ B-cells including plasma cells (some) not coexisting rheumatoid arthritis is Eventually, the lymphocytic infiltrate becomes present extensive and lymphoid follicles with germinal centers may appear. Antinuclear 50-80% of patients have antinuclear Antibody antibodies that are detectable by immunofluorescence assays A host of other organ specific and non-organ specific antibodies have also been identified Most important are antibodies directed against two ribonucleoprotein antigens: ○ Anti-SS-A (Ro) ○ Anti-SS-B (La) These two antibodies can be detected in as many as 90% of patients and are considered as serological markers of the disease ○ Take note: These autoantibodies are also present in a smaller percentage of Obliterated salivary duct lumen due to hyperplasia of ductal patients with SLE, hence, it is lining epithelial cells. not entirely specific for Sjogren syndrome Ductal lining epithelial cells may show hyperplasia that lead to the obstruction of the ducts. Later there is atrophy of the acini, fibrosis, C. MORPHOLOGY hyalinization, and replacement of parenchyma with Lacrimal and salivary glands are the major targets of fatty tissue. this autoimmune disease. Grossly, salivary glands enlarge secondary to the Other exocrine glands (those lining the respiratory, inflammatory reaction. gastrointestinal tracts, and vagina) may also be involved. D. CLINICAL FEATURES Most commonly occurs in women, 50 to 60 years of 1. SALIVARY GLANDS age Symptoms results from inflammatory destruction of the exocrine glands producing: ○ Keratoconjunctivitis (drying of the eyes) ○ Xerostomia (drying of the mouth) 1. KERATOCONJUNCTIVITIS Results in: ○ Blurring of vision ○ Burning and itching Pathology - Mod 4 🏠 Systemic Autoimmune Disorders 6 of 11 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  ○ Thick secretions that accumulate in the The skin is the most commonly affected but organs conjunctival sac such as the GI tract, kidneys, heart, muscles, and the ○ Drying of the corneal epithelium due to lack of lungs are also frequently involved tears which becomes inflamed, eroded and ulcerated B. MAJOR CATEGORIES 2. XEROSTOMIA TWO MAJOR CATEGORIES Results in: ○ Difficulty in swallowing solid food DIFFUSE LIMITED ○ Decrease in the ability to taste Skin involvement is confined to the ○ Cracks and fissures in the mouth Widespread skin fingers, forearms, and face ○ Dryness of the buccal mucosa (i.e. drying of the involvement at the (Hence, its clinical course is mouth) onset of the disease relatively benign as compared to ○ Possible atrophy of oral mucosa with diffuse) inflammatory fissuring and ulceration In some patients: remains 3. OTHER SYMPTOMS confined after many years Majority of patients: Parotid gland enlargement in 50% of cases progresses to a visceral Dryness of the nasal mucosa Rapid progression involvement with death from Epistaxis (nose bleeding) renal failure, cardiac failure, Recurrent bronchitis and pneumonitis pulmonary insufficiency, or Extraglandular disease in ⅓ of patients which includes: intestinal malabsorption ○ Synovitis ○ Diffuse pulmonary fibrosis Early visceral ○ Peripheral neuropathy involvement Late visceral involvement ○ More common in patients with high titers of (fibrosis of visceral (fibrosis of visceral organs) anti-SS-A organs) Glomerular lesions are extremely rare in contrast to SLE CREST syndrome: seen in some Defects of tubular function are often seen and/or patients with this type) associated with tubulointerstitial nephritis Tend to live longer About 60% of patients have an accompanying autoimmune disorder (most common of which is rheumatoid arthritis) CREST SYNDROME 4. MARGINAL ZONE LYMPHOMA Calcinosis Calcium deposits in the skin If the reaction continues unabated, there is a strong Very common manifestation of tendency overtime for the emergence of a dominant Scleroderma B-cell clone, increasing the risk of developing marginal Caused by episodic zone lymphoma. vasoconstriction (spasm) of A specific type of B-cell malignancy that often arises arteries and arterioles in response in the setting of chronic lymphocytic inflammation. to cold or stress In early stages of the disease, involved glands show Raynaud’s Manifests as numbness and intense inflammatory infiltrates which consist of a Phenomenon tingling of the fingers and toes mixture of polyclonal T- and B-lymphocytes. A characteristic white-blue-red color transition of the skin that E. KEY CONCEPTS corresponds to pallor, cyanosis, Sjorgen syndrome is an autoimmune disease and hyperemia resulting from characterized by the production of autoantibodies that spasmodic alteration in blood leads to inflammation primarily affecting salivary and flow lacrimal glands. ○ Causing dryness of the mouth (xerostomia) and Esophageal Acid reflux and decrease in motility of eyes (keratoconjunctivitis sicca) Dysfunction/ esophagus Disease is believed to be caused by the presence of Dysmotility autoantibodies against an unknown self-antigen expressed in these glands or possibly immune reactions Thickening and tightening of the skin Sclerodactyly against antigens of a virus that infects these tissues. on the fingers and hands Dilation of capillaries causing red IV. SYSTEMIC SCLEROSIS (SCLERODERMA) Telangiectasia marks on the skin surface Scleroderma literally translates to “sclerosis of the skin” Better named as systemic sclerosis as it is an autoimmune disorder characterized by excessive fibrosis affecting not only the skin but other parts of the body as well A. PATHOLOGY An autoimmune disorder characterized by abnormal accumulation of fibrous tissue in the skin and multiple organs Pathology - Mod 4 🏠 Systemic Autoimmune Disorders 7 of 11 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  2. ENDOTHELIAL INJURY AND MICROVASCULAR DAMAGE Widespread damage to small blood vessels Microvascular disease is consistently present early in the course of systemic sclerosis and may be the initial pathologic lesion. EVIDENCE OF ENDOTHELIAL ACTIVATION AND INJURY 1 Increased levels of von Willebrand Factor 2 Increased circulating platelet aggregates Raynaud’s Phenomenon: white-blue-red color transition corresponding to pallor, cyanosis, and hyperemia, Causes of vascular injury are not known, it could be the respectively. initiating event or the result of chronic inflammation, with mediators released by inflammatory cells inflicting C. PATHOGENESIS damage on microvascular endothelium. The cause of systemic sclerosis is not known. Ischemic injury and scarring results from repeated But this unknown exogenous trigger may have caused cycles of endothelial injury and platelet aggregation. three interrelated processes that may be responsible for systemic sclerosis: 3. FIBROSIS ○ Chronic inflammation Progressive interstitial and perivascular fibrosis in ○ Widespread damage to small blood vessels the skin and multiple organs ○ Progressive interstitial perivascular fibrosis in Progressive fibrosis, characteristic of systemic the skin and multiple organs sclerosis may be the culmination of the multiple abnormalities: FACTORS LEADING TO PROGRESSIVE FIBROSIS 1 Accumulation of alternatively activated macrophages 2 Actions of fibrogenic cytokines 3 Hyperresponsiveness of fibroblasts to the cytokines 4 Scarring (following ischemic damage) Three processes causing systemic sclerosis. D. MORPHOLOGY Virtually all organs may be involved in systemic sclerosis 1. CHRONIC INFLAMMATION Prominent changes occur in the skin, gastrointestinal Thought to be the result of autoimmunity tract, musculoskeletal system, and kidneys Lesions are often present in the blood vessels, heart, lungs, and peripheral nerves MEDIATORS OF CHRONIC INFLAMMATION 1. SKIN 1 CD4 T Cells responding to Majority of patients have diffuse sclerotic atrophy of unidentified antigens accumulate in the skin CD4 T Cells the skin and release cytokines that Usually begins in the fingers and distal regions of the activate inflammatory cells and upper extremities fibroblasts. Extends proximally to involve the upper arms, 2 Evidence of inappropriate activation shoulders, neck, and the face Auto- of humoral immunity and the antibodies presence of various autoantibodies 3 Present in virtually all scleroderma patients React with a variety of nuclear antigens Antinuclear Anti-Scl 70: a type of ANA Antibodies directed against DNA (ANAs) topoisomerase 1 which is highly specific Role in pathogenesis of disease is still unclear but it is believed that some may stimulate fibrosis Effect of Systemic Sclerosis on the Skin. Pathology - Mod 4 🏠 Systemic Autoimmune Disorders 8 of 11 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. 1.1 Scleroderma Effects of Advanced Stage Scleroderma to the Face and Hands. Normal (A) and Scleroderma (B) Histologic sections of the Loss of blood supply to the phalanges may lead to skin. cutaneous ulcerations and atrophic changes The tips of the fingers may simply fall off and undergo Skin changes include: auto-amputation (in some cases). ○ Infiltrates containing CD4 T-cells (pointed by the black arrow) ○ Edema around blood vessels ○ Degeneration of collagen fibers that eventually become eosinophilic Effects of Advanced Stage Scleroderma to the Fingers. 2. GASTROINTESTINAL TRACT Affected in approximately 90% of patients with systemic sclerosis AFFECTED ORGANS IN GASTROINTESTINAL TRACT Progressive atrophy and fibrosis of the muscularis may develop at any level of the gut Progression of Scleroderma. Esophagus Most severe development of With progression of the disease, it shows increasing progressive atrophy and fibrosis of fibrosis of the dermis that becomes tightly bound to the muscularis the subcutaneous structures Fibrosis causes the lower 2⁄3 of the Marked increase in compact collagen in the dermis esophagus to develop a rubber along with the following: hose-like inflexibility ○ Thinning of the epidermis Results in dysfunction and ○ Atrophy of the dermal appendages dysmotility of the lower esophageal ○ Hyaline thickening of the walls of the dermal blood area vessels Focal and sometimes diffuse subcutaneous Small Loss of villi and microvilli sometimes calcifications may develop especially in patients with Intestine produces malabsorption syndrome the CREST syndrome 1.2 Advanced Stages 3. MUSCULOSKELETAL SYSTEM Synovitis (inflammation of the synovium) is common in The fingers take on a tapered, claw-like appearance the early stages and joint motion is limited Followed later on by fibrosis WITHOUT joint The face also undergoes fibrosis and becomes a drawn destruction mask Synovitis with fibrosis; NO joint deformity 4. KIDNEYS Renal abnormalities occur in 2⁄3 of the patients with systemic sclerosis Most commonly involve the renal blood vessels Manifestations: ○ Thickening of the intimal layer of the blood vessels ○ Concentric proliferation of the intimal cells Pathology - Mod 4 🏠 Systemic Autoimmune Disorders 9 of 11 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  These manifestations may then cause hypertension ○ 20% of cases with hypertension take an ominously AUTOANTIBODIES IN SYSTEMIC SCLEROSIS rapid downhill course termed malignant hypertension eventually followed by renal failure Anti-Scl-70 Present in 10-20% of patients with NO specific glomerular morphologic changes diffuse systemic sclerosis Patients who have this antibody are more likely to have pulmonary Blood vessels are affected: (1) thickening of the blood fibrosis and peripheral vascular vessel intima; (2) concentric proliferation of intimal disease. cells → hypertension → malignant hypertension → renal failure Anti- Found in 20-30% of cases who tend to Centromere have the CREST syndrome (thus, limited type) 5. LUNGS ○ Patients with this syndrome have May manifest as interstitial fibrosis and pulmonary relatively limited involvement of hypertension in more than 50% of individuals the skin often confined to the Can lead to right-sided heart failure fingers, forearms, and face, and exhibit calcification of the Pulmonary and interstitial fibrosis → pulmonary subcutaneous tissue. hypertension → right sided heart failure ○ Involvement of the viscera may not occur at all or may occur late. Patients with anti-centromere 6. HEART antibodies tend to live longer than 1⁄3 of patients present with: those with diffuse visceral involvement ○ Pericarditis with effusion; at the onset of the disease. ○ Myocardial fibrosis ○ Thickening of intramyocardial arterioles F. KEY CONCEPTS Systemic sclerosis commonly called as scleroderma Myocardial fibrosis → arrhythmias, cardiac failure An autoimmune disorder characterized by progressive fibrosis involving the skin, gastrointestinal tract, and E. CLINICAL FEATURES other tissues. Female predilection: Female > Male (3:1) Fibrosis may be the result of fibroblast activation by Peak incidence: 50-60 year age group cytokines produced by T lymphocytes but what triggers the T cell response is unknown. Endothelial injury and microvascular disease of CLINICAL FEATURES OF SYSTEMIC SCLEROSIS unknown pathogenesis which are commonly present in (fibrosis of organs and its result) the lesions of systemic sclerosis, perhaps causing chronic ischemia and scar formation. Organ Features Skin Distinctive features are striking cutaneous changes, notably, skin fibrosis Blood Virtually, all patients present with vessels Raynaud’s Phenomenon Also precedes other symptoms in 70% of cases of the disease (presenting symptom in most cases) Systemic Lupus Erythematosus (left), Sjogren's Syndrome Esophagus Dysphagia (difficulty of swallowing) is (middle), and Systemic Sclerosis (right). attributable to esophageal fibrosis and resultant hypomotility present in more than 50% of patients. Small Intestinal obstruction or malabsorption intestines syndrome with weight loss and anemia (due to nutritional deficiency) reflect involvement of small intestines. Lungs Respiratory difficulties caused by pulmonary fibrosis may result in right-sided cardiac dysfunction. Heart Myocardial fibrosis may cause either arrhythmias or cardiac failure. Kidneys Proteinuria may occur in some patients but the most ominous renal manifestation is malignant hypertension with subsequent development of renal failure. Pathology - Mod 4 🏠 Systemic Autoimmune Disorders 10 of 11 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  ANNEX A: 1977 Revised Criteria for Classification of Systemic Lupus Erythematosus Because SLE is very heterogeneous in its disease presentation and any patient may present with any number of clinical features, its diagnosis relies on a constellation of clinical, serologic, and morphologic changes In this regard, the American College of Rheumatology has established a complex set of criteria for this disorder which is helpful for clinicians and for the assessment of patients in clinical trials. In this revised criteria, a patient is classified as having SLE if four of the clinical and immunologic criteria are present at any time (not necessarily concurrently), including at least one clinical and one immunologic criterion. ○ Reiteration: 4 of those criteria in Annex A should be present and of those 4, at least 1 should be clinical and and the other should be immunologic before a patient can be diagnosed as having SLE Pathology - Mod 4 🏠 Systemic Autoimmune Disorders 11 of 11 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.