lect 35 - musculoskeletal diseases I_SM.pdf

Recall: Autoimmune Disease Basics • Diseases caused by the immune system reacting against self Ags • Can be organ-specific or systemic ‒ Depends on where the self antigen resides ‒ One organ or many • Autoimmune diseases are chronic, progressive, self-perpetuating • Several effector mechanisms can...

Recall: Autoimmune Disease Basics • Diseases caused by the immune system reacting against self Ags • Can be organ-specific or systemic ‒ Depends on where the self antigen resides ‒ One organ or many • Autoimmune diseases are chronic, progressive, self-perpetuating • Several effector mechanisms can cause disease/organ damage: ‒ Immune-complex deposition causing vasculitis ‒ Auto-antibodies that target cells/tissues for destruction ‒ Autoreactive T cells that kill cells by perforin/granzyme Recall: General Predisposing Factors • Genetic susceptibility – May alter self-tolerance mechanisms • Environmental triggers – Infection o Bystander activation of lymphocytes o Molecular mimicry (also drugs) – Tissue injury and hormones • Gender – more common in females • Age – more common in middle age Figure 28-chapter abstract figure – Immunology for Medical Students, 3rd ed., 2017 Autoimmune Musculoskeletal Diseases Systemic Lupus Erythematosus (SLE), Sjögren’s, and Scleroderma/Sclerosis Systemic Lupus Erythematosus (Lupus or SLE) Systemic Lupus Erythematosus: Epidemiology • Lupus is a chronic multisystemic inflammatory autoimmune disease • Auto-antibodies cause formation of immune complexes (a type III hypersensitivity disease) which results in… • Vasculitis (neutrophils) in small vessels of skin, lungs, kidneys, heart, joints, nervous system. • The disease takes a chronic, fluctuating course • Most commonly seen in middle-aged, non-European women • Hispanic and African-American women typically present with a more severe disease. Why are women more susceptible? Part of the X chromosome encodes TLR7, which may be a vital link between DNA-Ab immune complex activation of innate immunity and development of lupus. FYI, XXY males (Kleinfelters) are also highly susceptible to development of lupus. Celebrities with lupus: Selena Gomez Lady Gaga Nick Cannon Seal Trick Daddy (rapper) Shannon Boxx (soccer) Michael Jackson? Tony Braxton (singer) Snoop Dogg’s daughter Risk Factors for SLE: Genetics • Decreased clearance of Ag-Ab immune complexes – Polymorphism in Fc receptor gene – ↓ binding/phagocytosis of ICs – So, ICs remain in small blood vessels and cause tissue damage • Decreased clearance of apoptotic bodies – Ab can then bind RNA, DNA, histones, and proteins from tissues – Can be caused by complement deficiency (C1q, C2, C4) – Or low expression of CD44 phagocytic receptor – impairs mac phagocytosis – Or rare mutations that reduce DNA degradation after granzymemediated apoptosis (e.g., TREX1, a DNAse) • Increased inflammation – Immune complexes increase IFN-γ production → Ab production • Polymorphisms in HLA (MHC class II genes HLA-DR2 and -DR3) • Polymorphisms in C’ proteins (C2 and C4 MHC class III genes) Figure 28-15 – Immunology for Medical Students, 3rd ed., 2017 Risk Factors for SLE: Environment • Triggers for initial onset or for flares • UV light: tissue damage causing increased self-Ags • Microbial: viral and bacterial infections; via molecular mimicry or bystander cell damage (see notes) • Drug exposure: tissue damage or molecular mimicry Figure 28-16 – Immunology for Medical Students, 3rd ed., 2017 Pathophysiology of Lupus • It’s all about antibodies! • Autoreactive Ab formed to multiple self Ag (next slide) • Ag-Ab complexes form in circulation and are deposited in small blood vessels of highly vascularized tissues (kidneys, joints, skin, etc.) – see next slide • Triggers C’ activation and PMN chemotaxis and activation • Results in release of ROS and degradative enzymes that cause vasculitis, tissue necrosis, thrombosis, ischemia, etc. (see notes) • Ag-Ab complexes also induce production of IFN-γ and other inflammatory cytokines that further stimulate autoantibody production Figure 19-10 – Cellular and Molecular Immunology, 10th ed., 2022 The Autoantibodies of SLE • Auto-Abs + self-Ag cause C’ activation, inflammation, ADCC → tissue damage • Auto-Abs are made against nucleic acids and self proteins – Anti-nuclear Ab (ANA) – best screening test for lupus – Anti-double-stranded DNA Ab – more specific than ANA for lupus – Extractable nuclear Ag (ENA; see notes) o Anti-Smith Ab – very specific for lupus, especially in chronic lupus o Anti-Ro/anti-La Ab – associated with lupus nephritis (and Sjögrens) o Anti-erythrocyte Ab – causes anemia o Anti-platelet Ab – causes thrombocytopenia o Anti-lymphocyte Ab – causes lymphopenia o Anti-neuronal Ab- causes neurological clinical signs o Anti-phospholipid (cardiolipin) Ab – thrombosis, thrombocytopenia, abortion o Anti-ribosomal Ab – associated with symptoms of psychosis o Anti-Jo1 – associated with polymyositis, diabetes, mixed connective tissue disease, lupus o Anti-U1RNP – more closely associated with mixed connective tissue disease o Anti-SCL70 or topoisomerase – more closely associated with scleroderma, systemic sclerosis Figure 19-3 – Cellular and Molecular Immunology, 10th ed., 2022 NETosis and Lupus NETs = Neutrophil Extracellular Traps • Dying neutrophils extrude DNA fibers and lysosomal granule contents, forming a matrix • NETs bind pathogens which are then destroyed by innate immune system • DNA extrusion + pathogen trapping + cell death = NETosis (vs. apoptosis or necrosis) • Relevance to SLE – chronic inflammation causes increased NETosis. Results: A note: this is an emerging story with the first description published in data from a mouse model in 2016. Since 2019 several papers of NETosis in human SLE, esp. with demonstration of NETs in kidneys of SLE patients https://www.embopress.org/doi/full/10.1002/emmm.201100167 ‒ Increases exposure of nuclear Ag, esp. PMN DNA ‒ Increases generation and production of autoAb ‒ Increases formation of Ag-Ab immune complexes Clinical Manifestations of SLE • • • • • • • • General – fever, malaise, fatigue, Raynaud’s phenomenon Skin – malar rash, mucosal ulcers, alopecia MSK – joint pain, myalgia (less severe than RA, no deformities) Cardiovascular – pericarditis, myocarditis, endocarditis, atherosclerosis, thrombosis Pulmonary – pleuritis, pleural effusion, pneumonitis, interstitial disease, and pulmonary hypertension, emboli, hemorrhage Renal – membranous glomerulonephritis Blood – anemia, thrombocytopenia, lymphopenia Nervous – seizures, psychosis • Survival: 95% @5y, 90% @10y, 78% @20y ‒ Rarely fatal unless renal involvement Common SLE Symptoms Malar or butterfly rash, often triggered by sun exposure Lupus nephritis Discoid skin lesions (erythematous plaques with central scarring) Raynaud’s phenomenon (reduced blood flow to extremities – cold, discolored digits) Musculoskeletal Manifestations of SLE • Arthralgia, non-erosive arthritis (less severe than RA) – Most common presenting feature of SLE – Symmetric, somewhat inflammatory, involves PIP and MCP joints – Note: generally stated that this is not disfiguring, but I found 1 description of “Lupus Swan’s neck deformity” • Osteonecrosis – Seen in hip and shoulder joints – Related to previous arthritis or treatment with steroids or cytotoxic drugs • Myositis – Mild inflammation – proximal muscle weakness – Rare and often associated with steroid treatment – Clinically, increase in serum creatine kinase (CK) activity https://img.medscapestatic.com/pi/meds/ckb/24/39224tn.jpg blood vascular skin The 2012 SLICC Diagnostic Criteria { { { https://www2.nau.edu/~fpm/immunology/lectures/Chapter03.pdf ria, e t i cr d 1 e r o an l m a r o nic r i l u c f o st 1 e v a ea point. l h t t a s Mu uding ic end g incl unolo im m Immunologic Criteria in SLE • Antinuclear antibodies (ANAs) – Sensitive for SLE (95%), but non-specific – Also seen in o Normal individuals o Rheumatoid arthritis o Scleroderma • Anti-double-stranded DNA antibodies ‒ Highly specific 98%, semi-sensitive 70% • Extractable nuclear antigen Abs (ENAs) ‒ A group of 100+ cytoplasmic and nuclear antigens ‒ Autoantibodies against ENAs are associated with autoimmune connective tissue disorders ‒ Presence of autoantibodies against certain ENAs can confirm SLE after positive ANA test ‒ Anti-Smith antibodies o Most specific antibody for SLE – 100%, seen in severe lupus, but only 30-40% sensitive Note: Some autoAbs show up before clinical signs of lupus, whereas others become detectable after onset of clinical signs Diagnosing and Treating Lupus • Diagnosis ‒ Lab tests o CBC and erythrocyte sedimentation rate (ESR) o Urinalysis – looking for proteinuria which indicates nephritis o ANA, anti-dsDNA, and other ENAs as indicated ‒ Imaging – chest X-ray and/or echocardiogram if indicated ‒ Biopsy – skin and/or kidney if indicated • Treatment ‒ Current standard of care = treat symptomatically, but associated with toxicity (see suppl. slide) o Anti-inflammatory agents, corticosteroids (high dose) o Immunosuppressants (IV cyclophosphamide) o Symptomatic treatment or replacement therapy if there is a deficit (e.g., insulin for diabetes, thyroid hormone for hypothyroidism) ‒ New therapies are being developed to manage/treat lupus Immunomodulatory Therapies RECENTLY APPROVED IMMUNOTHERAPIES • Benlysta or belimumab – monoclonal Ab that recognizes and blocks B cell activating factor, to reduce auto-antibody production • Rituximab – monoclonal Ab against the B cell surface protein CD20 that depletes B cells – used with methotrexate in RA patients resistant to anti-TNF therapy ON THE HORIZON • B cell inhibitors (epratuzumab – anti-CD22 monoclonal Ab) • Biological therapies (anti-TNFα, anti-IFNα, or anti-IL6 therapies) • Intravenous immunoglobulin (IVIG) • Synthetic tolerogens (4 strands of dsDNA covalently linked to clear anti-dsDNA Abs) • Autologous hematopoietic stem cell transplant Scleroderma and Systemic Sclerosis Pathophysiology of Scleroderma • A chronic immune-mediated fibrosis / vasculopathy of skin • Cause is unknown. Potential triggers include: – Infection – cytomegalovirus and parvovirus B19 – Exposure to organic substances and solvents, e.g., rapeseed oil, xylene, toluene – Microchimerism (fetal antigens circulating in maternal blood) • Hypothesized pathophysiology (see next slide) ‒ Triggers activate T cells, NK cells, macs, and Ab against endothelial cells o Immune targeting of endothelium causes edema ‒ Perivascular T cells release IL-2 and TGF-β which activate fibroblasts ‒ Fibroblasts deposit collagen and extracellular matrix proteins in skin • Females > males (4:1), usually not fatal (poor prognosis if multiple organs involved) A Picture of Scleroderma Pathogenesis https://www.dovepress.com/current-perspectives-on-the-immunopathogenesis-of-systemic-sclerosis-peer-reviewed-fulltext-article-ITT Systemic Sclerosis • Multisystem scleroderma = systemic autoimmune fibrosis • Organ systems affected, other than skin: ‒ Musculoskeletal, pulmonary, gastrointestinal, renal • Edema à sclerosis à atrophy • Major criteria ‒ Proximal diffuse sclerosis (skin tightness, thickening, induration) ‒ Altered pigmentation, telangiectasia, ulceration • Minor criteria → patient should have 2 (of 3) ‒ Sclerodactyly (hardening of skin on fingers/toes) ‒ Digital pitting scars or loss of “pulp” in finger pads (atrophy, a chronic sign) ‒ Pulmonary fibrosis https://www.nature.com/articles/nrdp20152 Scleroderma and CREST • CREST syndrome – an acronym for clinical features of patient with scleroderma https://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/19507.jpg Skin Symptoms of Scleroderma • First symptom is swollen fingers and hands +/- ulceration. • Then skin becomes hard, thickened, and scarred. • Skin appears tight, red, and scaly. • Fingers often develop flexion contractures. • Usually affects hands, face but can affect limbs, trunk. • Blood vessels appear prominently (mottled color). • Late stage – telangiectasia, calcinosis, digital ischemia. • Raynaud’s phenomenon – see next slide Patient with calcinosis or calcium deposition in the tissues. https://rheumatology.uw.edu/patient-care/scleroderma Raynaud’s Phenomenon • Raynaud’s phenomenon – present in >95% of scleroderma pts https://domf5oio6qrcr.cloudfront.net/medialib rary/6775/conversions/205878-thumb.jpg – Vasospasm that constricts blood flow to fingers and/or toes – Mild symptoms – numbness, tingling, blanching of skin due to loss of blood flow https://www.nejm.org/doi/full/ 10.1056/nejmicm1304702 – More severe symptoms and progression – blue phase with extend loss of blood flow (cyanosis) and then red phase as blood flow is restored – Repeated, severe episodes leads to potential damage/shortening of digit and/or skin ulceration blanching phase (L) and blue and red phases (R) https://rheumatology.uw.edu/patient-care/scleroderma Musculoskeletal Symptoms of Scleroderma Radiographs of patient hands with scleroderma and calcinosis • Scleroderma can affect more than skin. • Musculoskeletal symptoms – Joint pain, arthritis – especially fingers, knees – Reduced joint motility – due to calcinosis – Fibrous thickening of tendons – Myopathy – muscle weakness, due to fat and muscle wasting Recall: several organ systems may be involved including pulmonary (e.g., interstitial fibrosis, pulmonary hypertension); digestive symptoms (e.g., reflux esophagitis); and renal symptoms Muscular atrophy associated with systemic sclerosis Pulmonary Symptoms of Scleroderma 10-15% scleroderma pts have lung symptoms • Dyspnea, nonproductive cough • Lower lobe interstitial pulmonary fibrosis – Bilateral basal crepitations (crackling at base of lungs) – Decreased diffusion capacity (pulmonary function test) – Restrictive lung disease (fibrosis) Normal lung (above) Fibrotic lung (below) • Pulmonary hypertension – Elevated pressure in pulmonary arteries – Leads to right heart failure – Causes lower extremity edema Note: patients may also have GI, renal symptoms: GERD, dysphagia, malabsorption, colitis… Diagnosing Scleroderma and Systemic Sclerosis • Diagnosis – clinical signs + presence of auto-antibodies – Anti-centromere – Anti-topoisomerase – Anti-nuclear • Treatments: – Symptomatic – e.g., NSAIDS, steroids, etc. – Calcium channel blockers for Raynaud’s – Chemotherapy, e.g., bleomycine, taxane, methotrexate, or cyclosporine for autoimmunity Sjӧgren’s Syndrome Epidemiology of Sjӧgren’s Syndrome • Autoimmune disorder of moisture-producing glands • Affects 4 million Americans, 90% women, onset late 40’s • Symptoms – Dry eyes (keratoconjunctivitis sicca) – Dry mouth and throat, sore/cracked tongue, dental decay (xerostomia) – Parotid gland swelling – Debilitating fatigue and joint pain – Also affects other organs – kidney, GI, vessels, lung, liver, CNS • 50% of patients have a second connective tissue disease – Rheumatoid arthritis – Systemic lupus erythematosus – Systemic sclerosis / scleroderma – Polymyositis / dermatomyositis https://www.nejm.org/doi/full/10.1056/nejmcp1702514 FYI… Venus Williams is a Sjögren’s patient. http://info.sjogrens.org/conqueringsjogrens/bid/250226/Venus-Williams-Stands-up-for-Sjogren-s-Awareness Pathophysiology of Sjӧgren’s Syndrome • Damage to epithelium (maybe by viral infection) activates multiple components of resident immunity (e.g., DCs, IFN-α) • Adaptive immunity, esp. CD4+ T cells to make cytokines and B cells to secrete Ab, are activated • CD4 cytokines activate other mediators (e.g., CD8, NK) which target and destroy exocrine glands that produce: – Tears (lacrimal glands) – Saliva (salivary glands) • It is thought that an environmental stimulus such as viral infection may trigger: – CD4+ T cell-mediated apoptosis of glandular epithelial cells, and… – B cell production of auto-antibodies against glandular epithelium https://www.nature.com/articles/nrrheum.2013.143 Ocular Manifestations of Sjӧgren’s Syndrome • Normal components of tears: – Water, electrolytes, proteins (e.g., cytokines, mucin, enzymes, antibodies) • Cause of dry eye (keratoconjunctivitis sicca) ‒ Autoimmune attack of lacrimal gland, decreasing tear production ‒ Manifests as gritty, burning sensation and can lead to corneal damage • Diagnosis – Schirmer test (tear production) and tear stability – Rose Bengal and Lissamine green – detect corneal damage • Treatment – Symptomatic – artificial tears, avoid dust, goggles, warm compresses – Punctal occlusion – block duct that drain tears away – Ophthalmic cyclosporine (Restasis™) or corticosteroids – Hydroxypropyl cellulose ophthalmic insert (dissolves, lubricates) Oral Sjӧgren’s Syndrome • Saliva has >60 components that have the following functions: – Lubricate the mouth to aid in chewing and swallowing – Cleanse mouth and teeth to protect against tooth decay • Cause of dry mouth (xerostomia) – includes dry cracked tongue, dry sore throat – Due to autoimmune destruction of salivary glands – Manifests as changed sense of taste, difficulty chewing and swallowing (dysphagia), and enlarged salivary glands (due to inflammation) – Often leads to dental decay and oral infections (often fungal) • Diagnosis – Parotid salivary flow rate can be measured by scintigraphy (measure radioactive material from salivary glands to mouth) – Sialography – x-ray of salivary duct system – Biopsy salivary glands • Treatment – FYI: pilocarpine, cevimeline increase salivary secretion – Good oral hygiene and regular dental care – Symptomatic – chew gum, use lip balm, humidify air, sip water – not acidic drinks Diagnosing Sjӧgren’s Syndrome • Presence of ocular and oral symptoms for > 3 months – Schirmer’s tear test – Sialmetry for flow of saliva, duct obstruction • Extractable anti-nuclear antibodies (ENAs) – About 70% Sjögren’s patients are ANA positive. – About 50% Sjögren’s patients are Anti-Ro and anti-La positive • Rheumatoid factor (RF) – 90% Sjögren’s patients are RF+ • Other tests can be done to diagnose the ocular and oral forms of the disease (outlined in previous slides) Summary • Lupus – Pathophysiology: T3H, inflammation following IC deposition, multisystem disease, environmental triggers, NETosis – Diagnosis: SLICC, gender/ethnic predisposition, HLA-DR and complement links, ANA nonspecific – Treatments: NSAIDS, CCS, cyclophosphamide, other therapies for refractive patients • Scleroderma/systemic sclerosis – Pathophysiology: vasculitis/thrombosis/fibrosis, endothelial cell targeting, T cell production of IL-2 and TGF-β which recruit and activate fibroblasts that cause fibrosis – Raynaud’s phenomenon: vasospasm that causes digital discoloration – CREST syndrome: calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly, telangiectasia (systemic sclerosis) – Diagnosis: Ab against centromere, topoisomerase, ANA – Treatments: NSAIDS, CCS, calcium channel blockers (vasodilation), chemotherapy in severe cases • Sjögren’s syndrome – Pathophysiology: T4H-mediated attack on exocrine glands (tears, salivary glands); Th1, IFN-α, and autoantibodies against epithelium; probably viral/infectious trigger – Diagnosis: symptoms of dry eye (by Schirmer’s, fluorescein) and mouth (by sialometry), ANA, RF – Treatments: symptomatic, mechanical, CCS, chemotherapy Top 10 Takeaways 1. Genetic polymorphisms (ex: MHC class II or CD44 phagocytic receptor or TREX-1 DNAse mutations) + environmental triggers (infection, hormones, chemicals for example) increase susceptibility to autoimmune disease. 2. Lupus: multisystemic autoimmune disease triggered by autoantibody formation and IC formation leading to neutrophil vasculitis. Also type III hypersensitivity. 3. Autoantibodies in lupus are mainly against nucleic acids and self-proteins (ANA, dsDNA, Smith, Ro/La – ENAs or extractable nuclear antigens). Smith is specific for chronic lupus. 4. Dying neutrophils in lupus extrude DNA fibers (NETS) to bind pathogens; this increases autoantibody exposure to DNA and makes things worse. This is called NETosis. 5. MSK effects of lupus: joint pain, osteonecrosis, myalgia, Raynaud’s phenomenon. 6. SLICC criteria requires presence of 4 criteria (1+ clinical, 1+ immunologic) for diagnosis of lupus. 7. Scleroderma pathophysiology: T cell, NK cell and phagocyte targeting of endothelial cells which causes IL-2 and TNF-alpha inflammation, vascular damage, edema, then fibrosis/sclerosis, then muscle atrophy/wasting. Hands and face involved: telangiectasia, calcinosis, digital ischemia, Raynaud’s, flexion contractures. Systemic sclerosis is same pathophysiology (endothelial cell targeting) but causes edema and fibrosis in esophagus, skin and lungs – CREST syndrome. 8. Ocular Sjogren’s syndrome: T cell and autoantibody attack of moisture producing lacrimal glands that produce tears. This causes keratoconjunctivitis sicca (dry eye), and can be multisystemic, or present with second autoimmune disease. 9. Oral Sjogren’s syndrome: T cell and autoantibody attack of moisture producing salivary glands that produce saliva. This causes dry mouth and throat, dental decay, salivary gland swelling. 10. Treatments for autoimmune diseases are often symptomatic or immune suppressing (corticosteroids, DMARDS, chemotherapeutics, or specific biologics like Humira – anti-TNF). More treatments are coming on the horizon.