Connective Tissue Diseases III (Inflammatory Myopathies & Systemic Vasculitides) 2024 PDF

PATH30190 – Oncology/Immunopathology PATH30260 – Oncology & Rheumatology Connective Tissue Diseases III. (Inflammatory myopathies and systemic vasculitides) Dr Melinda Halasz, MD, PhD Email: [email protected] 2-3 April 2024 The skin may turn white or a lighter colour as blood flow is restricted...

PATH30190 – Oncology/Immunopathology PATH30260 – Oncology & Rheumatology Connective Tissue Diseases III. (Inflammatory myopathies and systemic vasculitides) Dr Melinda Halasz, MD, PhD Email: [email protected] 2-3 April 2024 The skin may turn white or a lighter colour as blood flow is restricted The skin turns blue as blood vessels react Raynaud’s phenomenon Raynaud's may make your fingertips appear paler if you have dark skin The skin may turn red as blood flow returns Learning Objectives At the end of this lecture, you should be able to  Describe the aetiology, pathogenesis and clinical manifestations of inflammatory myopathies (dermatomyositis, polymyositis);  Classify systemic vasculitides;  Describe the pathology and clinical manifestation of vasculitides. PATH30190 & PATH30260 CTIII 4 Inflammatory Myopathies Always  Polymyositis (PM)  Dermatomyositis (DM) occursin adults I canoccurinchildren  Juvenile dermatomyositis  PM/DM associated with malignancy Cancer may trigger PM/DM, possibly through an immune reaction against cancer that also attacks a component of muscles  Inclusion body myositis  Overlap syndromes (with other systemic autoimmune diseases)  Other (eosinophilic myositis, focal myositis etc.) o Weakness of proximal muscles o Increased creatinine-kinase o EMG, muscle biopsy PATH30190 & PATH30260 CTIII 5 USMLE Inclusion body myositis Age >50 Slowly progressive, asymmetrical, proximal and distal muscle weakness; most apparent in finger flexors and knee extensors Light microscopy: - autophagic vacuoles and - inclusion bodies in addition to - inflammation and necrosis. Mainly CD8+ cytotoxic T cells Refractory to immunosuppressive therapy PATH30190 & PATH30260 CTIII Finger flexor weakness and severe thigh muscle atrophy 6 From: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115580/ Dermatomyositis (DM) Connective tissue disorder involving inflammation of skeletal muscle and skin, causing bilateral proximal skeletal muscle weakness and a characteristic rash. Idiopathic At any age Peak of onset in adults: ~50 years Peak of onset in children: ~5-10 years F : M = 2:1 Heliotrope rash Incidence: 9.6 / year / million Adult patients: Increased risk of malignancy PATH30190 & PATH30260 CTIII 7 DM – Muscle Progressive and symmetric proximal muscle weakness  Increasing difficulty with getting up from a chair, climbing steps, lifting objects, or combing hair. Fine motor movements (buttoning a shirt, sewing, writing) are affected late in the course Pharyngeal and neck-flexor muscles often involved  dysphagia  difficulty in holding up the head (head drop) In advanced cases, respiratory muscles may also be affected Ocular muscles, facial muscles are spared Severe weakness, if untreated, is almost always associated with muscle wasting. Sensation remains normal; tendon reflexes are preserved. Myalgia and muscle tenderness PATH30190 & PATH30260 CTIII 8 DM – Skin Heliotrope (lilac/pink-purple) rash (30-60%) Upper eyelids Periorbital oedema PATH30190 & PATH30260 CTIII 9 DM – Skin Gottron's papules (80%) Discrete erythematous papules above the metacarpal and interphalangeal joints Scaly, erythematous knuckles Symmetric PATH30190 & PATH30260 CTIII 10 DM – Skin Erythematous rash can also occur on the knees, elbows, neck and anterior chest (often in a V sign), or back and shoulders (shawl sign), and may worsen after sun exposure. Pruritic rash on the scalp, chest, and back. PATH30190 & PATH30260 CTIII 11 DM – Skin “Mechanic’s hand” Lateral and palmar areas of the fingers may become rough and cracked Telangiectasia Vasculopathic changes Dilated capillary loops in the nailfolds and gum PATH30190 & PATH30260 CTIII 12 DM – Other Manifestations Systemic symptoms Fever, malaise, weight loss, arthralgia, Raynaud’s phenomenon Arthralgia, synovitis or deforming arthropathy with subluxation in the interphalangeal joints Oesophagus - Dysphagia and gastrointestinal symptoms Dysphonia Lung - Pulmonary dysfunction Due to weakness of the thoracic muscles Subcutaneous calcifications, joint contractures Especially in children Cardiac disturbances Malignancy in adults dermatomyositis maytrigger PATH30190 & PATH30260 CTIII 13 DM – Pathogenesis CD4+ T-cells and B-cells in the perimysial connective tissue and around blood vessels (Perimysium is a sheath of connective tissue that groups muscle fibres into bundles/fascicles.) Deposition of C5b-9 (MAC) in capillary vessels Autoantibodies PATH30190 & PATH30260 CTIII 14 DM – Autoantibodies 40-60% ANA + Anti-Mi2 antibodies (25% of patients) Anti-helicase (implicated in nucleosome remodelling) Specific for DM With Gottron’s papules and heliotrope rash Anti-Jo1 antibodies Anti-histidyl-tRNA-synthetase With interstitial lung disease, arthritis and “mechanic’s hands” Highly associated with inflammatory myopathies (DM & PM) Anti-P155/P140 antibodies Against several transcriptional regulators With paraneoplastic and juvenile cases of dermatomyositis PATH30190 & PATH30260 CTIII 15 Polymyositis – PM Bilateral proximal muscle weakness, like dermatomyositis but NO RASH! In adults The cause of polymyositis is unknown. May involve viruses and autoimmune factors. Different pathogenesis: CD8+ cytotoxic T cells probably directly injuring myocytes In endomysium Anti-Jo1 in 20% of patients Poor prognosis with interstitial lung disease PATH30190 & PATH30260 CTIII 16 DM & PM – Pathogenesis CD8+ T cells In endomysium CD4+ T cells In perimysium Perivascular localization Nature Reviews Rheumatology 7, 297-306 (2011) doi:10.1038/nrrheum.2011.39 PATH30190 & PATH30260 CTIII 17 DM & PM – Diagnosis Patients delay seeking medical advice for weeks or months PATH30190 & PATH30260 CTIII Rash facilitates early recognition 18 Systemic Vasculitides Group of systemic disorders with vessel inflammation and various clinical presentations. Classification based on the size of the vessels involved. S M S L PATH30190 & PATH30260 CTIII 19 Systemic Vasculitides for Direct damage prediction General symptoms from inflammatory response: fever, fatigue, weight loss + Specific symptoms Endothelial cells are attacked immunecellsaccidentally by because Bacteria of antigenmimicity (e.g., MPO, PR3) Immune cell Exposed collagen and tissue factor  Coagulation + Weakened vessel walls (aneurysm may develop) + Stiffer vessel walls from vesselis fibrin deposits (healing) Dependingon which  Reduced lumen  affected wewillseedifferent Reduced blood flow  Organ symptoms https://en.wikipedia.org/wiki/File:Vasculitis_video.webm ischaemia PATH30190 & PATH30260 CTIII 20 L Giant Cell Arteritis Former name: Temporal arteritis Granulomatous arteritis of large to small-sized arteries, mainly arteries in the head (extracranial branches of carotids) Commonest primary systemic vasculitis >50 years F>M symptom whendamaged Elevated ESR (adjusted for age), CRP Symptoms: Fever, fatigue, weight loss Headaches Visual disturbances Facial pain Scalp tenderness Complication: 25% untreated go blind Therapy: steroids PATH30190 & PATH30260 branch CTIII 21 Giant Cell Arteritis Multinucleated giant cells in elastic lamina (75%) = granuloma = group of monocytes + Mononuclear infiltrates (CD4+ > CD8+) Disrupted internal elastic lamina Healing  medial attenuation and scarring with intimal thickening, with residual elastic tissue fragmentation and adventitial fibrosis. Segmental Patchy inflammation with thickening and stenosis vs skip lesions  long section for biopsy free PATH30190 & PATH30260 I partsappearnormal Becausesome CTIII 22 USMLE Polymyalgia Rheumatica An inflammatory disorder that causes sudden bilateral neck, shoulder and low back muscle pain and stiffness; worse in the morning May be associated with malaise, tiredness, weight loss, depression and fever Elevated ESR & CRP Marked improvement with steroids Prevalence for over 50s is 1:133 F>M Often seen with giant cell arteritis Forme fruste of giant cell arteritis Similar demographics Similar response to steroids Some evidence of minimal aortitis 50% of patients with giant cell arteritis have symptoms of PMR and up to 20% of PMR patients have biopsy findings of GCA Minimal histopathology (CD4+ T-cell infiltrate) Temporal relationship to parainfluenza, parvovirus B19, Mycoplasma and Chlamydia outbreaks PATH30190 & PATH30260 CTIII 23 L Takayasu Arteritis subclavian Hisapected “Pulseless syndrome”/ ”Aortic arch syndrome” Upper extremities: weak or no pulse Granulomatous vasculitis Mainly affects the aorta and its branches Head: visual and neurologic symptoms ifare id appec Ocular disturbances & marked weakening of the pulses in the upper extremities Segmental and patchy granulomatous inflammation Asian women F) Symptoms vague, varied and perplexing Low grade fever Ischemia and infarction of affected tissues and organs GI (mesenteric a.): Abdominal pain and GI bleeding  melena (50%) Renal disease is significant (25%)  rapidly accelerating hypertension Skin: Rash (50%) lower limb punched out ulcers Muscular aches and peripheral neuritis Acute, subacute, chronic, relapsing and remitting Untreated: usually fatal Treatment: steroids Association with HBV (30%) (Immune complex deposits containing HBsAg-HBsAb complexes in affected vessels) PATH30190 & PATH30260 CTIII 26 Polyarteritis Nodosa Hathtion Segmental transmural necrotizing inflammation of small- to medium sized arteries. wallisapected Everylayeroftheartery Transmural inflammation of the arterial wall with a mixed infiltrate of neutrophils, eosinophils, and mononuclear cells + fibrinoid necrosis Later, fibrous (occasionally nodular) thickening of the vessel wall that can extend into the adventitia. All stages represented Fibrinoid necrosis and thrombotic occlusion of the lumen PATH30190 & PATH30260 CTIII 27 Kawasaki Disease M “Mucocutaneous lymph node syndrome” Acute febrile, usually self-limited illness (6-8 weeks) of infants and children (< 4 years, boys) Mucocutaneous symptoms and cervical lymph node enlargement E Large, medium and even small arteries; mostly coronary arteries murmur Without treatment: ~25% risk for heart complications, i.e., aneurysm, MI (cardiac symptoms appear later  Monitoring for late-onset coronary artery changes is necessary Classic symptoms: Conjunctivitis (spares limbus) Rash Adenopathy – enlarged lymph nodes (cervical) Strawberry tongue + red mouth & throat Hands and feet: swollen and rash + Fever Anti-endothelial and smooth muscle antibodies Treatment: IVIG PATH30190 & PATH30260 CTIII 28 Buerger’s Disease / Thromboangiitis Obliterans M Affects medium & small vessels Epidemiology: Heavy smokers Males, 20-40 years Pathogenesis: Clots in vessels supplying fingers and toes Patients develop ulcers on fingers and toes Often co-exists with Raynaud’s phenomenon Intermittent claudication may lead to Gangrene Digit auto-amputation Superficial nodular phlebitis Histology: Segmental thrombosing vasculitis Treatment: Smoking cessation PATH30190 & PATH30260 Auto CTIII amputf opfingers 30 Small Vessel Vasculitides S ANCA (anti-neutrophil cytoplasmic antibody)-associated  Microscopic polyangiitis  Granulomatosis with polyangiitis / Wegener’s granulomatosis  Eosinophilic granulomatosis with polyangiitis / Churg-Strauss syndrome Mediated by immune complexes  IgA vasculitis / Henoch-Schonlein purpura PATH30190 & PATH30260 CTIII 31 Microscopic Poliangiitis Leukocytoclastic or hypersensitivity vasculitis S Transmural, necrotizing vasculitis Small vessels: arterioles, capillaries, venules All lesions of the same age in any given patient Organs involved: Skin - 40%; palpable purpura Mucous membranes Lungs - 20%; pulmonary capillaritis GI - 20%; bleeding & mucosal ulceration Kidneys - 90%; necrotizing glomerulonephritis Heart - 20% Brain name older Muscle Is (MPO-ANCA) perinuclear ANCA / anti-myeloperoxidase p-ANCA newername Treatment: glucocorticoids, cyclophosphamide PATH30190 & PATH30260 CTIII 32 S Granulomatosis with polyangiitis / Wegener’s Granulomatosis In middle aged men Classical clinical triad: Kidney: Focal necrotizing glomerulonephritis; +/-haematuria, red cell casts, present in ~15% initially, ultimately affects 50%. 2 Nasopharynx: Chronic pain from sinusitis, bloody mucus from ulcers (combined with possible perforation of nasal septum, otitis media, mastoiditis) Saddle-nose deformity 3 Lungs: Pneumonitis, +/- haemoptysis, cough, dyspnea; Chest x-ray: large nodular densities D Biopsy: Focal necrotising vasculitis, granulomatous change & PR3-ANCA (anti-proteinase 3/c-ANCA) positive Rapidly fatal if left untreated Treatment: glucocorticoids, cyclophosphamide PATH30190 & PATH30260 CTIII 33 Granulomatosis with polyangiitis / Wegener’s Granulomatosis PATH30190 CTIII S 34 Eosinophilic granulomatosis with polyangiitis Churg-Strauss Syndrome S Small vessel necrotizing vasculitis Typically affects vessels of respiratory tract Strongly associated with asthma, eosinophilia and pulmonary infiltrates. May also have GI (e.g., colitis, bleeding), skin, cardiac symptoms and/or peripheral neuropathy Microscopic pathology: Granulomatous vasculitis; p-ANCA (MPO-ANCA)+ (~ 50%) & elevated IgE Supportive therapy and glucocorticoids PATH30190 & PATH30260 CTIII 35 Henoch-Schonlein Purpura S ANCA negative IgA antibodies (directly target endothelial cells) Small vessel IgA & immune complex mediated vasculitis often following upper respiratory tract infection in young children Presentation: Skin lesions on buttocks & leg, progressing from blanching macules to petechiae to palpable purpura Oedema, polyarthritis, colicky abdominal pain, haematuria May have associated IgA nephropathy Diagnosis: Clinical as lab results often normal Usually resolves on its own Supportive therapy +/- corticosteroids for GI symtopms PATH30190 & PATH30260 CTIII 36 Vasculitides p-ANCA c-ANCA (MPO-ANCA) (PR3-ANCA) PATH30190 & PATH30260 CTIII p-ANCA (MPO-ANCA) 37 Vasculitides PATH30190 & PATH30260 CTIII 38 Vasculitides PATH30190 & PATH30260 CTIII 39