UCD Connective Tissue Diseases II (2024): PDF

PATH30190 – Oncology/Immunopathology PATH30260 – Oncology & Rheumatology Connective Tissue Diseases II. (SLE, Scleroderma, Sjӧgren’s syndrome) Dr Melinda Halasz, MD, PhD Email: [email protected] 26 Mar & 3 Apr 2024 Learning Objectives At the end of this lecture, you should be able to Describe th...

PATH30190 – Oncology/Immunopathology PATH30260 – Oncology & Rheumatology Connective Tissue Diseases II. (SLE, Scleroderma, Sjӧgren’s syndrome) Dr Melinda Halasz, MD, PhD Email: [email protected] 26 Mar & 3 Apr 2024 Learning Objectives At the end of this lecture, you should be able to Describe the aetiology and pathogenesis (the role of antinuclear antibodies and immune complexes) of SLE; Discuss common manifestations and long-term prognosis of SLE; Outline the criteria for the diagnosis of SLE; Define chronic discoid LE, subacute cutaneous LE, and drug-induced LE. Know five ANA patterns including the significance of nucleolar and centromere patterns, the importance of DNA and Sm antibodies in SLE, the importance of low serum complement levels in SLE Describe the aetiology, pathogenesis and clinical manifestations of systemic sclerosis; contrast limited cutaneous and diffuse cutaneous systemic sclerosis. Discuss the aetiology, pathogenesis and clinical manifestation of Sjӧgren’s syndrome. PATH30190 CTII 2 Systemic Lupus Erythematosus (SLE) Chronic systemic autoimmune disease characterised by a vast array of autoantibodies resulting primarily in injury to the skin, joints, kidney and serosal surfaces. Follows a relapsing and remitting course 90% of patients are women of child-bearing age In the reproductive age group, F : M = 9:1 In childhood or older adults, F : M = 2:1 1 in 700 among women of child-bearing age Prevalence: 20-150/100,000 Butterfly rash PATH30190 & PATH30260 CTII 3 SLE – Pathogenesis Aetiology: Genetic and environmental factors Environment → Cell injury → Cell death → Release of nuclear antigens → Failure to adequately clear apoptotic cells exposes nuclear antigens + Failure of self tolerance in genetically susceptible individuals Abnormal immune responses Generation of pathogenic autoantibodies and immune complexes Deposit in tissue, activate complement, cause inflammation, and over time lead to irreversible organ damage , Smoking Mechanism of injury is a mix of type II and III hypersensitivity reactions. PATH30190 & PATH30260 Drugs (hydralazine, procainamide, isoniazid) → Hormones CTII 4 SLE – Pathogenesis PATH30190 & PATH30260 CTII 5 Type II hypersensitivity (Ag bound to cell surface) e.g., anti-RBC Ab Type III hypersensitivity: Immune complexes (soluble Ag + antibody complex) form in the circulatory system and deposited in tissues (e.g., basement membranes in glomeruli, blood vessels, joints etc.) Complements rapidly used in large amounts (C3, C4) Anaphylatoxins: Increased vascular permeability → Oedema C3a, C4a, C5a Tissue injury and damage Unsuccessful phagocytosis → Degranulation: Lysosomal enzymes, ROS → Vasculitis PATH30190 CTII Video: https://en.wikipedia.org/wiki/File:Type_III_hypersensivity.webm6 SLE – Autoantibodies Not specific Antinuclear antibody (ANA) (>95%) Anti-dsDNA (40–60%) (Anti-Smith) Anti-Sm (20–30%) Antihistone antibodies Nonhistone nuclear RNA proteins; and blood cells. Hydralazine, procainamide, isoniazid PATH30190 CTII 7 Indirect Immunofluorescence Antinuclear antibodies (ANAs): ❑ antibodies to DNA, ❑ antibodies to histones, ❑ antibodies to non-histone proteins bound to RNA (RNPs), and ❑ antibodies to nucleolar antigens. For detecting ANAs → INDIRECT IMMUNOFLUORESCENCE The pattern of nuclear fluorescence suggests the type of antibody present in the patient’s serum. Four basic ANA patterns in SLE: o Homogeneous (chromatin, histones) o Rim (DNA) o Speckled (non-specific) o Nucleolar PATH30190 & PATH30260 CTII 8 SLE – Skin (80%) o Photosensitivity (70%) o Malar rash or butterfly rash (50%) in acute cutaneous lupus Slightly raised erythema on the face, ears, chin, V region of neck and chest, upper back and extensor surfaces of arms Worsening when flares of SLE o Discoid rash (20%) in chronic cutaneous lupus Slightly raised, scaly hyperpigmented erythematous rims; depigmented atrophic centres o Subacute cutaneous lupus: widespread non-scarring, on sun-exposed areas, scaly red patches similar to psoriasis o Oral and nasal ulcers (40%) o Alopecia (40%) o Vasculitis rash (20%) o Recurring urticaria; bullae o Panniculitis: inflammation of fat tissue (“lupus profundus”) o Livedo reticularis o Raynaud’s Type III hypersensitivity PATH30190 & PATH30260 CTII 9 Chronic cutaneous (discoid) lupus Acute cutaneous lupus – malar rash SLE – Skin Deposits of IgG at the dermo epidermal junction PATH30190 & PATH30260 CTII 11 SLE – Kidney (30-50%) LUPUS NEPHRITIS → The most serious manifestation of SLE! Classification: → Based on light & immunofluorescence (or electron) microscopy of kidney biopsy specimens o o o o o o Class I: Minimal mesangial lupus nephritis Class II: Mesangial proliferative lupus nephritis Class III: Focal (< 50%) lupus nephritis Class IV: Diffuse (> 50%) lupus nephritis Class V: Membranous lupus nephritis Class VI: Advanced sclerotic lupus nephritis PATH30190 & PATH30260 CTII Diagnosis of lupus nephritis: ❑ Blood test - serum creatinine ❑ Urine analysis – proteinuria, haematuria ❑ Histological analysis of kidney biopsy specimens - % of glomeruli affected; - type of kidney injury (intra-, extraglomerular and/or tubulointerstitial). ❑ Renal pathology scoring system is used to assess disease activity and chronic tissue damage, resulting in activity and chronicity indices → prognostic value and guide treatment decisions. 12 SLE – Lupus nephritis Type III hypersensitivity Nature Reviews Nephrology 11, 46–61 (2015) doi:10.1038/nrneph.2014.215 PATH30190 & PATH30260 CTII Deposition of immune complexes (ICs) in glomeruli leads to complement activation and immune cell recruitment, persistent activation and increased pro-inflammatory cytokine production. Intrarenal inflammation can damage podocytes and glomerular capillaries, leading to increased proliferation of parietal epithelial cells to form crescents and increased mesangial cell proliferation and production of extracellular matrix. 13 Proliferation of extracapillary epithelial cells and infiltration of inflammatory cells → formation of cellular crescents. Podocyte injury and foot process effacement. Proliferation of mesangial cells, matrix expansion and mesangial deposition of immune complexes. Class IV-S: segmental fibrinoid necrosis with segmental endocapillary hypercellularity. Class IV-G: global endocapillary and mesangial hypercellularity with infiltration of inflammatory cells. ICDs in the tubular basement membrane, interstitial inflammation with severe interstitial infiltration of mononuclear inflammatory cells, and tubulitis with infiltration of lymphocytes between tubular epithelial cells. Immune complex deposits (ICDs) in the vasculature, arteriosclerosis characterized by arterial intimal fibrosis, and thrombotic microangiopathy (TMA) with arteriolar thrombi and swelling of endothelial cells. Normal, H&E SLE – Lupus nephritis Class I: Minimal mesangial lupus nephritis Normal glomeruli by light microscopy (LM) Mesangial immune deposits by immunofluorescence (IF). Class II: Mesangial proliferative lupus nephritis Purely mesangial hypercellularity of any degree or mesangial matrix expansion by LM, with mesangial immune deposits. Class II Normal PATH30190 Class I CTII Class II 15 SLE – Lupus nephritis Class III: Focal (< 50%) lupus nephritis Focal, segmental (affecting only a portion of the glomerulus) or global (involving the entire glomerulus) endo- or extracapillary glomerulonephritis involving ≤50% of all glomeruli, typically with focal subendothelial immune deposits, +/- mesangial alterations. Active or inactive chronic lesions with glomerular scars (Focal proliferative/proliferative & sclerosing/sclerosing lupus nephritis) Class IV: Diffuse (> 50%) lupus nephritis Diffuse, segmental or global endo- or extracapillary glomerulonephritis involving ≥50% of all glomeruli, with diffuse subendothelial immune deposits (→ circumferential thickening of the capillary wall; “wire loop” lesion), +/- mesangial alterations. Diffuse segmental (IV-S) : when ≥50% of the involved glomeruli have segmental lesions Diffuse global (IV-G): when ≥50% of the involved glomeruli have global lesions. Active or inactive proliferative Diffuse segmental proliferative and sclerosing lupus nephritis global sclerosing PATH30190 & PATH30260 CTII 16 SLE – Lupus nephritis Segmental (Affecting less than half of the glomerular tuft) PATH30190 & PATH30260 Global CTII 17 SLE – Lupus nephritis Class V: Membranous lupus nephritis Subepithelial immune deposits by LM and by IF or EM, May occur in combination with class III or IV. Class V lupus nephritis may show advanced sclerosis. Class VI: Advanced sclerosing lupus nephritis ≥90% of glomeruli globally sclerosed without residual activity Small granular immune deposits in the thickened and sclerotic GBMs, in the fibrotic tubulointerstitial compartment or in vessel walls. End-stage kidney disease PATH30190 & PATH30260 CTII 18 Minimal mesangial LN Mesangial proliferative LN Focal (< 50%) LN Diffuse (> 50%) LN Membranous LN SLE – Other Manifestations Systemic (95%): Fatigue, low-grade fever, anorexia, weight loss Musculoskeletal (95%) (type III hypersensitivity reaction): Arthralgia, myalgia (95%), polyarthritis (60%) Synovitis without joint deformity Haematological (85%) (type II hypersensitivity): Anaemia of chronic disease (70%); haemolytic anaemia (10%) Leukopaenia; thrombocytopaenia Lymphadenopathy, splenomegaly Neurological (60%) (type III hypersensitivity): Focal neurologic symptoms, seizures and psychosis Cardiopulmonary (60%) (type III hypersensitivity): Pleuritis or pleural effusions, pericarditis Accelerated atherosclerosis → Cardiovascular diseases Libman-Sacks endocarditis (nonbacterial fibrous inflamm.) Interstitial fibrosis; intraalveolar haemorrhage Shrinking lung syndrome (giant emphysematous bullae) Gastrointestinal: pain, nausea; abnormal liver enzymes Ocular: Sjogren’s Pregnancy: recurrent miscarriage PATH30190 & PATH30260 CTII 22 SLE – Diagnostic Criteria It can be challenging to diagnose SLE. It can mimic other diseases and its initial presentation varies from patient to patient. It is not unusual to have minor symptoms for years prior to a lupus diagnosis. American College of Rheumatology (1982): 4 or more (out of 11) must be present to diagnose SLE Arthritis Renal disease (proteinuria, cellular casts) ANA (positive antinuclear antibody) Serositis (pleuritis or pericarditis) Haematological disorders (haemolytic anaemia, leukopaenia, lymphopaenia, thrombocytopaenia) Photosensitivity Oral ulcers Immunological disorder (e.g., anti-dsDNA, anti-Sm, anti-phospholipid antibodies) Neurological disorders (seizures or psychosis, in the absence of other causes) Malar rash Discoid rash Mnemonic: “A RASH POINts MD.” PATH30190 & PATH30260 CTII 23 SLE – Diagnostic Criteria PATH30190 & PATH30260 CTII 24 SLE – Clinical Course and Prognosis Variable and unpredictable; acute or insidious onset. Often characterized by flare-ups and remissions Rare acute cases → Death within weeks to months. Lab tests to follow the course of disease (flares or organ damage) (+ identify adverse effects of therapy) Survival in patients with SLE is improving: Activity indices o ESR o Decreased complement levels o High anti-DNA o Anti-C1q antibodies 5-year survival: 95% 10-year survival: 90% 20-year survival: 78% Poor prognosis (~50% mortality in 10 years), if at diagnosis: High serum creatinine levels, hypertension, nephrotic syndrome, anaemia, hypoalbuminemia, hypocomplementemia, antiphospholipid antibodies + Male gender, ethnicity, low socioeconomic status Cause of death: Renal failure, intercurrent infections, coronary artery disease, thromboembolic events, CNS Increased risk for malignancy PATH30190 CTII Damage indices Renal monitoring o Serum creatinine levels o Proteinuria o Haematuria o Cylindruria 25 SLE – Pathogenesis Nature Reviews Rheumatology 10, 181–186 (2014) doi:10.1038/nrrheum.2013.184 PATH30190 & PATH30260 CTII 26 SLE – Treatment Goal: To induce remissions of acute flares and then maintain it and prevent organ damage. Disease manifestations are life threatening or likely cause organ damage? → Aggressive therapy: high-dose corticosteroid + second immunosuppressive agent Manifestations reversible? NSAIDs for arthritis and fever Topical steroid creams for skin rashes Hydroxychloroquine (anti-malaria drug) for rash, joint pain Immunosuppressive agents: Steroids (Prednisone) Cyclophosphamide (cytostatic drug) for serious kidney, CNS involvement Mycophenolate mofetil for serious kidney disease Azathioprine Belimumab - inhibits B-cell activation Rituximab PATH30190 & PATH30260 CTII 27 USMLE SLE Variants SLE limited to the skin - Chronic discoid lupus erythematosus (DLE) o Negative for anti-dsDNA o Confined to skin: Circular with slightly raised, scaly hyperpigmented erythematous rims; depigmented atrophic centres (all dermal appendages are permanently destroyed) o 5% of people with DLE have SLE o 20% of people with SLE has DLE Drug-induced lupus o Fever, malaise, arthritis/arthralgia, myalgia, serositis, and/or rash o No kidney or CNS involvement o ANA +, anti-histone Abs o E.g., anti-hypertensive hydralazine, antiarrhythmic drug procainamide, antibiotic isoniazid etc. Neonatal lupus o Anti-SSA/Ro and/or anti-SSB/La antibodies from the mother affect the foetus o At birth: skin rash, liver problems, low blood cell counts → disappear completely after six months o Most serious symptom: congenital heart block, which causes a slow heartbeat → does not disappear, and affected infants will eventually need a pacemaker. Antiphospholipid syndrome (secondary type) PATH30190 & PATH30260 CTII 28 USMLE Antiphospholipid Syndrome An autoantibody-mediated acquired thrombophilia (i.e., hypercoagulable state) characterized by recurrent arterial or venous thrombosis and/or pregnancy morbidity. Anti-phospholipid autoantibodies against: o Cardiolipin o β2-glycoprotein I o Phosphatidylserine o Phosphatidylinositol o Phosphatidylethanolamine o Lupus anticoagulant: Binds to prothrombin Hepatic vein thrombosis F>M PATH30190 & PATH30260 CTII 29 Sjogren’s Syndrome Chronic systemic autoimmune disease characterized by immune-mediated destruction of exocrine glands (primarily salivary and lacrimal glands) → No saliva, no tears. Prevalence: 0.5-1% Middle-aged women Onset: 30-50 years F : M = 9:1 Genetic predisposition: o HLA-DR52 o HLA-DR3, HLA-DQ2, HLA-B8 (in Caucasians) o IRF-5 (interferon-regulatory factor) o STAT4 Enlarged parotid glands (Mikulicz syndrome: enlargement of the salivary and lacrimal glands) Smooth, firm, rarely painful (unless obstruction or infection) PATH30190 & PATH30260 CTII 30 Sjogren’s Syndrome - Pathogenesis Viral infection of the salivary glands Cell death and release of autoantigens In genetically susceptible individuals, CD4+ T cells and B cells specific for these self antigens may have escaped tolerance and are able to react. Inflammation, tissue damage, fibrosis Lymphocytic infiltration (Activated T & B cells) Ductal epithelial cell hyperplasia → Obstruction Atrophy Fibrosis Hyalinization PATH30190 & PATH30260 Nature Reviews Rheumatology 9, 544-556 (2013) doi:10.1038/nrrheum.2013.110 CTII 31 Sjogren’s Syndrome – Clinical manifestations ✓ Lacrimal glands → Keratoconjunctivitis sicca → Dry eyes EXTRAGLANDULAR SYMPTOMS ✓ Salivary glands → Chronic sialoadenitis → Xerostomia (dry mouth) → Difficulty swallowing, tasting, chewing; tooth decay, stones in salivary glands etc. o Polyarthritis o Raynaud’s phenomenon o Lymphadenopathy (enlargement of axillary or cervical lymph nodes) o Systemic vasculitis → Purpura on skin o Kidney: interstitial nephritis, kidney stones, renal tubular acidosis, concentrating problems etc. Kidney failure o Chronic hepatobiliary disease o Splenomegaly o Myositis 1/3 of patients with systemic manifestations Involvement of OTHER EXOCRINE GLANDS o Skin → Xeroderma (Dry skin) o Nose → Dryness in airways o Respiratory tract → Pneumonitis → Pulmonary infection o GI tract → Esophageal dismotility Gastric mucosal atrophy, Decreased pancreas exocrine function + Increased risk of developing non-Hodgkin lymphoma o Vagina → Vulvovaginitis sicca PATH30190 & PATH30260 CTII 32 Sjogren’s Syndrome – Diagnosis CLASSIFICATION ❑ PRIMARY Sjogren’s – “sicca syndrome” ❑ SECONDARY Sjogren’s – in association with other connective tissue disease (RA, SLE, systemic sclerosis, MCTD, polymyositis), or autoimmune disorder (e.g., autoimmune hepatitis, primary biliary cirrhosis, autoimmune thyroiditis) LABORATORY FINDINGS o Elevated ESR o Normal CRP o Anaemia o Thrombocytopenia o Leukopenia SEROLOGY o Polyclonal hypergammaglobulinaemia SS-B/La and SS-A/Ro: o Autoantibodies: Anti-SS-A/Ro (in 75% of patients) Extractable nuclear antigens (ENA) Composed of RNA and protein Anti-SS-B/La (in ~50% of patients) ANA (Anti-nuclear antibody) (in 70% of patients) RF (Rheumatoid factor) (Primary: ~50% +, 2ndary: 98% +) PATH30190 & PATH30260 CTII 33 Sjogren’s Syndrome – Diagnosis Schirmer’s test EYE TESTS o Schirmer’s test o Tear breakup time test o Etc, Sialometry (test for saliva secretion rate), Salivary scintigraphy LIP BIOPSY (if diagnosis is uncertain) Focal lymphoid infiltration in the minor salivary gland PATH30190 & PATH30260 CTII 34 Systemic Sclerosis (Scleroderma = thickened skin) Systemic autoimmune disorder characterised by: chronic inflammation (probably autoimmune) widespread small vessel damage progressive perivascular and interstitial fibrosis in skin and multiple organs F > M (3-6:1) Onset: ~30-50 year Rare 1 new case / year / 100,000 https://www.sruk.co.uk/find-support/personalstories/connors-story-scleroderma-and-raynauds/ PATH30190 & PATH30260 CTII 35 Systemic Sclerosis - Pathogenesis Pro-fibrotic cytokines Skin Lung Heart https://doi.org/10.2147/ITT.S82037 PATH30190 & PATH30260 CTII 36 Systemic sclerosis Extensive deposition of dense collagen in the dermis with virtual absence of appendages (e.g., hair follicles) and foci of inflammation (arrow). Normal skin Systemic Sclerosis – Classification LIMITED CUTANEOUS SYSTEMIC SCLEROSIS o 10-30 years before visceral involvement o CREST syndrome: Calcinosis Raynaud’s Esophageal dysmotility Sclerodactyly Telangiectasia o Skin involvement: face, hands o Anti-centromere Ab DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS o Organ failure < 5 years o Widespread skin involvement o Anti-topoisomerase I Ab (Scl-70) PATH30190 & PATH30260 CTII 38 Systemic Sclerosis – Manifestation Skin (majority): Thickened skin Distal first Claw-like hands Microstomia Subcutaneous calcification Ischaemic ulceration Kidneys (60%): Arteries Hypertension (accelerated) Renal failure Raynaud’s phenomenon Lungs (50%): Main cause of death: Pulmonary hypertension 17% Fibrosis 41% GIT (90%): Rubber hose oesophagus Dysmotility Malabsorption Musculosketal: Early synovitis Non-destructive +/- myositis PATH30190 & PATH30260 CTII 39 Calcinosis Telangiectasia Sclerodactyly & Raynaud’s PATH30190 & PATH30260 CTII Typical claw-like flexion deformity, with ulceration, loss of skin creases 40 PATH30190 & PATH30260 CTII 41 Salt and pepper dyspigmentation Skin hyperpigmentation of the lower legs is surrounded by areas of hypopigmentation. “salt-and-pepper appearance” Radial furrowing around the mouth Raynaud’s Disease vs Raynaud’s Phenomenon PRIMARY Raynaud’s phenomenon = RAYNAUD’S DISEASE o Idiopathic, typically in young women o Episodic small artery vasospasm in the extremities, nose, or ears; o Blanching and cyanosis of the fingers or toes upon exposure to cold or stress o Normal nailfold capillaries o ANA negative Phase 1 Ischaemia Phase 2 Cyanosis Phase 3 Rubor SECONDARY Raynaud’s phenomenon Caused by arterial insufficiency secondary to an underlying disease E.g., systemic autoimmune diseases, obstructive disorders, drugs, etc. PATH30190 & PATH30260 CTII 43 Nailfold capillaroscopy 90% < of patients : Scleroderma pattern on capillaroscopy PATH30190 & PATH30260 CTII 44 Systemic Sclerosis – Autoantibodies ANA+ (~90%) Possible ANA-patterns in systemic sclerosis: o Speckled (Anti-Scl-70) o Centromere o Nucleolar PATH30190 & PATH30260 (Anti-Scl-70) CTII 45 Systemic Sclerosis – Clinical Course Natural course highly variable and difficult to predict Raynaud’s phenomenon typically precedes other disease manifestations by years or even decades. Median survival: 11 years dcSSc 5-year survival: 70% 10-year survival: 55% lcSSc 5-year survival: 90% 10-year survival: 75% To date, no therapy has been shown to significantly alter the natural history of systemic sclerosis. Treatments for alleviating symptoms, slowing the progression of cumulative organ damage. PATH30190 & PATH30260 CTII 46 Nature Reviews Rheumatology 2019 DOI:10.1038/s41584-019-0184-z SUMMARY Connective Tissue Diseases: ANA Patterns PATH30190 & PATH30260 CTII 48