Inflammatory connective tissue disorders Notes

NOTES NOTES INFLAMMATORY CONNECTIVE TISSUE DISORDERS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Chronic autoimmune disorders characterized by inflammation; primarily affect connective tissue ▪ Production of autoantibodies → deposition of immune complexes → complement activation → tissue destruction ▪ Inflammatory cytokines stimulate fibroblasts → increased collagen deposition (fibrosis) ▪ Affects multiple organ systems ▫ Skin, heart, respiratory system, urinary, gastrointestinal (GI) tract CAUSES ▪ Genetic, environmental factors COMPLICATIONS ▪ Skin necrosis; renal, cardiac failure; pulmonary insufficiency; GI reflux/bleeding SIGNS & SYMPTOMS ▪ Constitutional symptoms ▫ Low grade fever, fatigue, weight loss ▪ Specific to disease, organ systems affected ▫ “Butterfly skin rash” specific to systemic lupus erythematosus (SLE) DIAGNOSIS DIAGNOSTIC IMAGING Barium swallow X-ray ▪ GI involvement LAB RESULTS ▪ Blood tests ▫ Hematologic abnormalities, increased inflammatory markers, complications (e.g. increased creatinine reflecting renal failure) ▪ Serological tests ▫ Antibodies, confirm diagnosis OTHER DIAGNOSTICS ▪ Physical examination (e.g. characteristic skin rashes) ▪ Pulmonary function tests ▫ Pulmonary involvement TREATMENT ▪ Usually symptomatic (e.g. analgesics) MEDICATIONS ▪ Steroids/other immunosuppressive agents ▫ Reduce inflammation OSMOSIS.ORG 639

CREST SYNDROME osms.it/CREST-syndrome PATHOLOGY & CAUSES SIGNS & SYMPTOMS ▪ Form of limited systemic sclerosis ▪ Composed of five features; see mnemonic ▫ Calcinosis: deposition of calcium under skin ▫ Raynaud’s syndrome: episodic, dramatic constriction of arteries in hands ▫ Esophageal dysmotility: atrophied muscle in esophagus without significant inflammation/fibrosis ▫ Sclerodactyly: fibrosis of skin of digits ▫ Telangiectasia: dilation of small blood vessels ▪ Caused by chronic autoimmune inflammation triggered mainly by anticentromere antibodies (ACAs) ▪ More benign clinical course than other forms of sclerosis ▪ Calcific nodules under the skin ▪ White-blue-red transitions in skin color in response to triggers (e.g. low temperature, stress) ▪ Dysphagia (due to esophageal dysmotility) ▪ Sclerodactyly ▪ Telangiectasias (esp. hands, face) MNEMONIC: CREST Features of CREST syndrome Calcinosis Raynaud’s syndrome Esophageal dysmotility Sclerodactyly Telangiectasia COMPLICATIONS ▪ Ischemic ulcers, gangrene, predisposition to chronic skin infections (due to sclerosis, severe ischemia of skin) ▪ Upper GI bleeding (due to mucosal telangiectasias) Figure 112.1 Sclerodactyly in an individual with CREST syndrome. DIAGNOSIS LAB RESULTS ▪ Serum blood tests ▫ ↑ ANAs: sensitive for systemic sclerosis ▫ ↑ ACAs: highly specific (limited systemic sclerosis); confirm diagnosis OTHER DIAGNOSTICS ▪ Clinical history, physical examination TREATMENT MEDICATIONS ▪ Steroids ▪ If sclerosis progresses, stronger immunosuppressants (e.g. cyclosporine) 640 OSMOSIS.ORG

Chapter 112 Inflammatory Connective Tissue Disorders FIBROMYALGIA osms.it/fibromyalgia PATHOLOGY & CAUSES ▪ Chronic condition of central sensitization; hypersensitivity to pain, sleep disturbances ▫ ↓ serotonin (inhibits pain signals) ▫ ↑ substance P, ↑ nerve growth factor (involved in propagating pain signals) ▫ Predominance in individuals who are biologically female CAUSES ▪ Genetic factors ▪ Environmental factors (child abuse) ▪ Negative emotions (depression, anxiety, negative beliefs) can amplify pain SIGNS & SYMPTOMS ▪ Low threshold to pain ▪ Widespread muscle pain ▪ Extreme tenderness in various parts of body ▪ Sleep disturbances → fatigue, headache ▪ Difficulty concentrating, remembering things; AKA “fibro fog” DIAGNOSIS OTHER DIAGNOSTICS Diagnostic Criteria ▪ Pain in ≥ seven areas of body with symptom severity (SS) of ≥ 5 (of 12)/pain in ≥ five areas of body with SS of ≥ 9 (of 12) ▪ Final score between 0–12 ▪ Symptoms present ≥ three months ▪ Pain not due to another disorder Symptom severity (SS) measures ▪ Fatigue; waking unrefreshed; cognitive symptoms; somatic symptoms ▫ 0: no problem ▫ 1: slight/mild/intermittent ▫ 2: moderate/considerable/often present ▫ 3: severe, continuous, life disturbing TREATMENT MEDICATIONS ▪ If non-pharmacologic measures fail, drug therapy ▪ Antidepressants ▫ Inhibit pain by elevating levels of serotonin, norepinephrine ▫ Tricyclic antidepressants (TCAs): amitriptyline first line treatment ▫ Serotonin-norepinephrine reuptake inhibitors (SNRIs): milnacipran ▪ Anticonvulsants ▫ Slow nerve impulses, relieve sleep disturbances PSYCHOTHERAPY ▪ Cognitive behavioral therapy (CBT) ▫ Manage pain, change negative feelings OTHER INTERVENTIONS ▪ Physical therapy, relaxation techniques, sleep hygiene to reduce pain, fatigue OSMOSIS.ORG 641

MIXED CONNECTIVE TISSUE DISEASE (MCTD) osms.it/mixed-connective-tissue-disease PATHOLOGY & CAUSES DIAGNOSIS ▪ Overlap autoimmune syndrome; constellation of SLE, systemic sclerosis, polymyositis; may not occur simultaneously ▪ Can evolve into classic SLE/systemic sclerosis ▪ Confirmation requires characteristic clinical presentation COMPLICATIONS ▪ Pulmonary hypertension; interstitial lung disease; renal disease SIGNS & SYMPTOMS ▪ Arthralgias (due to polyarthritis) ▪ Myalgias (due to mild myositis) ▪ Swollen hands with puffy fingers (due to synovitis) ▪ Sclerodactyly ▪ Early development of Raynaud phenomenon ▪ Fatigue ▪ Low-grade fevers 642 OSMOSIS.ORG LAB RESULTS ▪ High serum levels of anti-U1 ribonucleoprotein (anti-U1-RNP) antibodies ▪ High ANAs, RF, anti dsDNA, anti Sm, anti Ro TREATMENT ▪ Depends on predominant autoimmune disease MEDICATIONS ▪ Corticosteroids ▫ Suppress immune system

Chapter 112 Inflammatory Connective Tissue Disorders POLYMYALGIA RHEUMATICA (PMR) osms.it/polymyalgia-rheumatica PATHOLOGY & CAUSES ▪ Immune-mediated rheumatic condition affecting joints, sparing muscles ▪ Most commonly affects shoulder, hip joints ▪ Usually occurs in individuals who are biologically female > 50; mean age 70 ▪ Strongly associated with giant-cell arteritis, AKA temporal arteritis ▪ Can regress without treatment after 1–2 years/remain chronic CAUSES ▪ Genetic defects: specific allele of human leukocyte antigen (HLA)-DR4 ▪ Environmental factors: exposure to adenovirus/human parvovirus B19 SIGNS & SYMPTOMS ▪ Joint pain, stiffness (shoulder, hip joints) ▫ Often starts unilaterally, progresses to bilateral within few weeks ▫ More severe after prolonged inactivity (e.g. morning) ▫ Typically lasts > one hour ▫ Affects nearby nerves in muscle → muscle pain (referred pain) ▪ Constitutional symptoms ▫ Low grade fever (interleukins act as pyrogens) ▫ Fatigue ▫ Loss of appetite → weight loss ▪ If severe headache, jaw pain, vision problems ▫ Temporal arteritis DIAGNOSIS LAB RESULTS ▪ Increased serum inflammatory markers ▫ Erythrocyte sedimentation rate (ESR) ▫ C-reactive protein (CRP) ▪ Biopsy ▫ Inflammation in joints OTHER DIAGNOSTICS ▪ Physical examination ▫ Decreased passive range of motion of affected joints TREATMENT MEDICATIONS ▪ Low dose of corticosteroids ▫ Suppress immune response OSMOSIS.ORG 643

RAYNAUD'S DISEASE osms.it/raynauds-disease PATHOLOGY & CAUSES SIGNS & SYMPTOMS ▪ Vasospasm of skin arteries in response to triggers, resulting in skin color transitions ▪ Exposure to trigger → stimulation of sympathetic nerves in arteriole walls → vasospasm of arterioles → decrease in blood flow ▪ Usually affects hands, fingers, toes; can affect nose, ears, lips ▪ Common triggers ▫ Emotional stress; low temperatures; nicotine; caffeine; medications that affect sympathetic nervous system (e.g. pseudoephedrine) ▪ Vasospasm → changes in skin color of hands, fingers, toes ▫ White: ischemia ▫ Blue: hypoxia after prolonged ischemia ▫ Red: reactive hyperemia (vasospasm ends, oxygenated blood rushes into tissue) ▪ Raynaud phenomenon ▫ Affects hand fingers, toes symmetrically; severity remains constant ▪ Raynaud syndrome ▫ Asymmetrical; progressive severity ▪ Swelling, numbness, tingling, pain (due to reactive hyperemia) TYPES Primary: Raynaud phenomenon/disease ▪ Common in pregnant individuals, people who work in jobs involving vibration (e.g. jackhammer) Secondary: Raynaud syndrome ▪ Connective tissue disorders ▫ Systemic lupus erythematosus (SLE), scleroderma, mixed connective tissue disease ▪ Disorders affecting blood vessels ▫ Buerger’s disease, Takayasu’s arteritis, thromboangiitis obliterans ▪ Medications ▫ Beta blockers, nicotine COMPLICATIONS ▪ Ulceration, infarction, tissue necrosis, gangrene (if severe) DIAGNOSIS ▪ Based upon description of episodes DIAGNOSTIC IMAGING ▪ Nailfold capillary microscopy to examine finger capillaries ▫ Normal appearance: Raynaud phenomenon ▫ Damaged appearance: Raynaud syndrome TREATMENT MEDICATIONS ▪ Vasodilators (e.g. calcium channel blockers) SURGERY ▪ If severe, surgery to cut sympathetic nerve fibers supplying affected areas OTHER INTERVENTIONS ▪ Avoid triggers 644 OSMOSIS.ORG

Chapter 112 Inflammatory Connective Tissue Disorders Figure 112.2 A hand with pale fingers caused by Raynaud’s disease. SCLERODERMA osms.it/scleroderma PATHOLOGY & CAUSES ▪ AKA systemic sclerosis ▪ Chronic inflammatory autoimmune disease, can result in widespread damage to small blood vessels, excessive fibrosis ▫ T helper cells activated by unknown antigen → release cytokines → stimulate inflammatory cells, fibroblasts → chronic inflammation, excessive collagen deposition ▫ Mediators released by inflammatory cells → damage microvasculature → ischemic injuries, scarring ▪ Primarily affects skin, can involve visceral organs ▫ GI tract, kidneys, heart, muscles, lungs TYPES Limited (80%) ▪ Skin involvement limited to fingers, forearms, face ▪ Late visceral involvement ▪ Some individuals develop CREST syndrome ▫ Calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia ▪ Associated with anticentromere antibodies ▪ Relatively benign Diffuse (20%) ▪ Widespread skin involvement ▪ Early visceral involvement ▪ Rapid progression ▪ Associated with anti-DNA topoisomerase I antibodies ▪ Poor prognosis RISK FACTORS ▪ More common in individuals who are biologically female (3:1 ratio) ▪ Average age of onset: 35–50 ▪ Genetic factors ▪ Environmental factors (e.g. viruses, toxins, drugs) OSMOSIS.ORG 645

COMPLICATIONS ▪ Excessive skin fibrosis → painful ulcers, disfigurement, disability ▪ Severe internal organ involvement → renal, cardiac failure; pulmonary insufficiency; intestinal malabsorption SIGNS & SYMPTOMS ▪ Raynaud phenomenon ▫ Precedes other symptoms, present in almost all individuals ▪ Cutaneous changes of face, extremities ▫ Skin thickening, tightening, sclerosis (most common); edema, erythema (precede sclerosis) ▪ GI involvement ▫ Esophageal fibrosis → dysphagia, GI reflux ▫ Small intestine involvement → abdominal pain, obstructions, constipation, diarrhea, malabsorption syndrome (weight loss, anemia) ▪ Pulmonary involvement with interstitial fibrosis ▫ Right-sided cardiac dysfunction/ pulmonary hypertension ▪ Cardiac involvement ▫ Pericardial effusions, myocardial fibrosis → congestive heart failure, arrhythmias ▪ Renal involvement (diffuse disease) → fatal hypertensive crisis (rare) Figure 112.3 The finger of an individual with systemic sclerosis showing sclerosis, erythema and ulcer formation. DIAGNOSIS DIAGNOSTIC IMAGING ▪ Upper endoscopy ▫ Esophageal fibrosis/reflux esophagitis LAB RESULTS ▪ Serologic tests ▫ ↑ ANAs in almost all individuals with systemic sclerosis; low specificity ▫ ↑ ACAs highly specific (limited) ▫ Anti-topoisomerase I antibodies (antiScl-70) highly specific (diffuse) ▪ Complete blood count (CBC) ▫ Anemia due to malabsorption, increased serum creatinine due to renal dysfunction OTHER DIAGNOSTICS ▪ Clinical presentation ▫ Skin thickening, swollen fingers, Raynaud’s phenomenon, GI reflux ▪ Pulmonary function tests ▫ Restrictive ventilatory defect due to pulmonary interstitial fibrosis Figure 112.4 A rash on the back of an individual with a form of localised scleroderma known as morphea. 646 OSMOSIS.ORG

Chapter 112 Inflammatory Connective Tissue Disorders TREATMENT ▪ Depends on disease subset, severity of internal organ involvement MEDICATIONS ▪ Usually symptomatic ▫ Analgesics for musculoskeletal pain ▫ Proton pump inhibitors for gastroesophageal reflux ▫ Calcium channel blockers for Raynaud’s phenomenon ▫ Angiotensin converting enzyme (ACE) inhibitors for renal hypertensive crisis ▪ Immunosuppressive therapy initiation: diffuse skin/severe internal organ involvement SJOGREN'S SYNDROME (SS) osms.it/sjogrens-syndrome PATHOLOGY & CAUSES SIGNS & SYMPTOMS ▪ Chronic autoimmune inflammatory disease; lymphocytic infiltration, destruction of exocrine glands of eyes, mouth ▪ Proposed mechanisms ▫ Immune reactions against antigens of viral infection of exocrine glands ▫ Autoimmune T cell reaction against unknown self antigen expressed in salivary, lacrimal glands ▪ Variety of extraglandular manifestations may occur ▪ Usually occurs in individuals who are biologically female, 50–60 years ▪ Dry eyes ▫ Irritation, itching, foreign body sensation, keratoconjunctivitis ▪ Oral dryness reflecting salivary hypofunction ▪ Salivary gland enlargement (parotid, submandibular, etc.) ▪ Extraglandular manifestations ▫ Musculoskeletal symptoms (arthralgias, arthritis); rashes; interstitial nephritis, vasculitis CAUSES ▪ Primary: sicca syndrome ▪ Secondary (to other autoimmune diseases): rheumatoid arthritis (most common) COMPLICATIONS ▪ Periodontal complications; oral infections; mucosal associated lymphoid tissue (MALT) lymphoma DIAGNOSIS ▪ Clinical presentation: persistent dry eyes/ mouth, parotid gland enlargement DIAGNOSTIC IMAGING Parotid gland MRI ▪ Honeycomb pattern Salivary gland ultrasound ▪ Multiple hypoechoic areas LAB RESULTS ▪ CBC ▫ Leukopenia, thrombocytopenia, anemia ▪ ↑ ESR ▪ Urinalysis OSMOSIS.ORG 647

▫ Proteinuria/hematuria reflecting glomerulonephritis ▪ Labial salivary gland biopsy (confirm diagnosis) ▫ Focal lymphocyte foci (collections of tightly aggregated lymphocytes) ▪ Serologic tests (support diagnosis) ▫ ↑ antinuclear antibodies (ANAs) in 95% of individuals ▫ ↑ rheumatoid factor (RF) in 50–75% of individuals with/without rheumatoid arthritis ▫ Anti-Sjögren syndrome A (SSA) (Ro), Anti-Sjögren syndrome B (SSB) (La) specific to SS, found elevated only in 55%, 40% of individuals, respectively OTHER DIAGNOSTICS Tear deficiency tests ▪ Schirmer test ▫ Measures reflex tear production; wetting of test paper < 5mm indicative of tear deficiency ▫ Ocular surface staining with Rose Bengal stain and slit-lamp examination—assess tear break-up time (TBUT); TBUT < 10 seconds indicative of tear deficiency ▪ Salivary gland tests ▫ Salivary gland scintigraphy: low uptake of radionuclide characteristic of SS ▫ Sialometry: low volume of saliva indicative of salivary gland hypofunction 648 OSMOSIS.ORG Figure 112.5 A lymphocytic infiltrate in a minor salivary gland excised from an individual with Sjögren’s syndrome. TREATMENT MEDICATIONS ▪ Mild SS ▫ Secretagogues ▫ Local treatment for ocular, oral dryness (e.g. artificial tears) ▪ Moderate to severe SS ▫ Immunosuppressive treatment

Chapter 112 Inflammatory Connective Tissue Disorders SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) osms.it/systemic-lupus-erythematosus PATHOLOGY & CAUSES ▪ Chronic systemic autoimmune disorder; wide range of clinical, serological features ▪ Periods of flare-ups, remittance ▪ Environmental triggers damage DNA → apoptosis → release of nuclear bodies ▪ Clearance of apoptotic bodies ineffective due to genetic defects → increased amount of nuclear antigens in bloodstream → initiates immune response → production of antinuclear antibodies → bind to antigens, form immune complexes ▪ Complexes deposit in tissues (e.g. kidneys, skin, joints, heart) → Type III hypersensitivity reaction ▪ Individuals may develop antibodies targeting molecules (e.g., phospholipids) of red, white blood cells → marking them for phagocytosis → Type II hypersensitivity reaction ▪ Antiphospholipid syndrome ▫ Hypercoagulable state; individuals prone to develop clots (e.g. deep vein thrombosis, hepatic vein thrombosis, stroke) SIGNS & SYMPTOMS ▪ Fever, joint pain, rash in sun-exposed areas ▪ Typical rashes ▫ Malar rash (butterfly rash): over cheeks ▫ Discoid rash: plaque-like/patchy redness, can scar ▫ General photosensitivity: typically lasts few days RISK FACTORS Genetic defects associated with SLE UV radiation Smoking Viral, bacterial infections Medications (e.g. procainamide, hydralazine, isoniazid, estrogens) ▪ More common in individuals who are biologically female, of reproductive age ▪ ▪ ▪ ▪ ▪ COMPLICATIONS ▪ Cardiovascular disease ▫ Libman–Sacks endocarditis, myocardial infarction (MI) ▪ Serious infections; renal failure; hypertension Figure 112.6 A butterfly rash on the face of an individual with systemic lupus erythematosus. OSMOSIS.ORG 649

▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ Weight loss Ulcers in oral/nasal mucosa Serositis (e.g. pleuritis/pericarditis) Libman–Sacks endocarditis: formation of nonbacterial vegetations on ventricular, atrial valve surfaces; mitral, aortic valves (most common) Myocarditis Renal disorders ▫ Abnormal levels of urine protein, diffuse proliferative glomerulonephritis Neurologic disorders ▫ Seizures, psychosis Hematologic disorders ▫ Anemia, thrombocytopenia, leukopenia DIAGNOSIS OTHER DIAGNOSTICS Diagnostic criteria (4 of 11) ▪ Malar rash ▪ Discoid rash ▪ General photosensitivity ▪ Oral/nasal ulcers ▪ Serositis ▪ Arthritis in ≥ two joints ▪ Renal disorders ▪ Neurologic disorders ▪ Hematologic disorders ▪ Antinuclear antibodies ▫ Very sensitive, not specific ▪ Other antibodies ▫ SLE specific: anti-Smith, anti-dsDNA ▫ Anti-phospholipid: anticardiolipin (false-positive test for syphilis); lupus anticoagulant (lupus antibody); anti-beta 2 glycoprotein I TREATMENT ▪ Goal: prevent relapses, limit severity MEDICATIONS Figure 112.7 An MRI scan of the head of an individual with SLE who presented with altered mental status and seizures. There a numerous small infarcts suggestive of cerebral vasculitis. The individual improved after treatment with steroids. 650 OSMOSIS.ORG ▪ Long term therapy ▫ Antimalarial agents ▪ Mild to moderate manifestations ▫ Non-steroidal anti-inflammatory drugs (NSAIDs), low doses of corticosteroids ▪ Severe/life-threatening manifestations ▫ High doses of corticosteroids, intensive immunosuppressive drugs OTHER INTERVENTIONS ▪ ▪ ▪ ▪ ▪ Avoid sun exposure Physical exercise Balanced diet Smoking cessation Immunizations

Chapter 112 Inflammatory Connective Tissue Disorders Figure 112.8 A histological section of a lymph node from an individual with lupus lymphadenopathy. There is necrosis, with an absence of neutrophils, and large numbers of hematoxylin bodies. Figure 112.9 Histological appearance of the glomerulus in a case of lupus nephritis. There is global mesangial cell proliferation and abundant mesangial matrix. OSMOSIS.ORG 651