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CONNECTIVE TISSUE DISORDERS: GOLD-MEDALIST CLINICAL NOTES

Part I: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

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1. DEFINITION & OVERVIEW

• Female : Male = 9:1 in reproductive age; narrows to 2:1 in children and elderly
• Peak onset: 15-44 years
• Prevalence (USA): ~72.8 per 100,000; incidence ~5.1 per 100,000/year
• Black women > Hispanic > White > Asian women (prevalence and severity)
• Socioeconomic factors are major contributors to disparity in minority populations

Goldman-Cecil Medicine; Harrison's Principles 22E

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2. PATHOGENESIS

• HLA-DR2, HLA-DR3 most strongly associated
• Deficiencies of complement components C1q, C2, C4 predispose (especially C1q deficiency - ~90% develop SLE-like disease)
• Gene variants in IRF5, STAT4, BLK, PTPN22, TREX1 (DNase III)
• Impaired X-chromosome inactivation partially explains female predominance
• KIR/HLA interactions affect NK cell activity

• UV radiation - induces apoptosis and releases nuclear antigens
• Infections: EBV molecular mimicry (anti-Sm antibody cross-reacts with EBV antigen)
• Drugs: hydralazine, procainamide, isoniazid, methyldopa, quinidine, minocycline
• Estrogens promote disease activity (explains sex bias and flares during pregnancy)
• Silica dust exposure

1. Defective clearance of apoptotic cells → accumulation of nuclear debris
2. Nuclear material (DNA/RNA) activates innate immune sensors: TLR7, TLR9 on plasmacytoid dendritic cells
3. Massively elevated type I interferons (IFN-α/β) - the "interferon signature" seen in ~75% of SLE patients
4. Interferon-stimulated genes activate autoreactive B and T lymphocytes
5. NETosis by neutrophils releases NET-DNA, activating pDCs further
6. Autoreactive B cells: loss of tolerance → anti-dsDNA, anti-Sm, anti-Ro/La, antiphospholipid antibodies
7. Immune complex deposition in glomeruli, skin, choroid plexus → complement activation → tissue injury
8. T helper cell imbalance: reduced Treg, elevated Th17 cells

• Features: anti-histone antibodies characteristic, anti-dsDNA usually absent, renal/CNS involvement rare
• Resolves on drug withdrawal (may take months)
• Drugs: procainamide (50% develop ANA; 20% full SLE), hydralazine, isoniazid, minocycline, anti-TNF agents

Harrison's 22E, Goldman-Cecil, Robbins & Kumar Basic Pathology

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3. CLASSIFICATION CRITERIA

2019 EULAR/ACR Classification Criteria for SLE

Note: Class III/IV nephritis on biopsy alone = 10 points = classification as SLE.

2012 SLICC Criteria

• Requires 4 criteria: at least 1 clinical + 1 immunological, OR biopsy-proven lupus nephritis + ANA or anti-dsDNA

Goldman-Cecil Medicine; Harrison's 22E

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4. CLINICAL MANIFESTATIONS

Constitutional

• Fatigue (most common, often debilitating), fever, weight loss, lymphadenopathy
• Type 2 lupus: fatigue, pain, cognitive dysfunction - less responsive to immunosuppression

Musculoskeletal (>90%)

• Arthralgia/non-erosive arthritis - symmetrical, involving small joints of hands, wrists, knees
• Jaccoud's arthropathy - reducible deformity (unlike RA, no erosions on X-ray)
• Avascular necrosis (especially femoral head) - related to disease and corticosteroid use
• Myalgia; rarely true myositis

Mucocutaneous

Renal (Lupus Nephritis)

• Occurs in ~50% of SLE patients; most common cause of SLE mortality
• Usually develops within 5 years of diagnosis
• Presents as: proteinuria, hematuria, pyuria, casts, hypertension, renal failure

• Class III/IV: Hematuria, RBC casts, nephrotic-nephritic picture, hypocomplementemia
• Class V: Pure nephrotic syndrome, ANA and anti-dsDNA may be low
• Class IV "wire-loop" appearance on EM: immune complex deposits along GBM
• "Full house" immunofluorescence: IgG + IgA + IgM + C3 + C1q (highly specific for SLE)

Neuropsychiatric SLE (NPSLE)

• CNS: Seizures, psychosis, cerebrovascular disease (stroke, TIA), cognitive dysfunction, headache (including migraine), chorea, transverse myelitis, aseptic meningitis, demyelinating syndrome
• PNS: Polyneuropathy, mononeuritis multiplex, autonomic neuropathy
• Antiphospholipid antibodies contribute significantly to cerebrovascular events
• Anti-ribosomal P antibody: associated with lupus psychosis and depression
• MRI may show white matter lesions, infarcts, or be normal

Cardiovascular

• Pericarditis - most common cardiac manifestation; pericardial effusion
• Libman-Sacks endocarditis - sterile verrucous vegetations, usually mitral/aortic valve, on both surfaces; associated with antiphospholipid antibodies
• Premature atherosclerosis - major cause of late mortality in SLE
• Myocarditis - uncommon but serious
• Accelerated coronary artery disease (young women with SLE have 50x increased risk of MI vs. age-matched controls)

Pulmonary

• Pleuritis/pleural effusion - most common pulmonary manifestation; exudative
• Pneumonitis - acute lupus pneumonitis (rare, severe); chronic interstitial pneumonitis
• Diffuse alveolar hemorrhage - rare but life-threatening; hemoptysis + bilateral infiltrates + falling Hb
• Pulmonary hypertension (rare)
• Shrinking lung syndrome - restrictive defect without parenchymal disease; diaphragmatic dysfunction
• Anti-Ro antibodies: risk of neonatal lupus and congenital heart block

Hematologic

• Anemia - most common; anemia of chronic disease (most frequent), autoimmune hemolytic anemia (Coombs+), leukopenia, lymphopenia
• Thrombocytopenia - immune-mediated platelet destruction
• Antiphospholipid syndrome (APS) in 25-40%: thrombosis (arterial/venous), recurrent pregnancy loss, thrombocytopenia, livedo reticularis

Gastrointestinal

• Serositis (peritonitis), mesenteric vasculitis (abdominal pain/ischemia)
• Protein-losing enteropathy, pancreatitis (rare)
• Hepatosplenomegaly; elevated LFTs (lupoid hepatitis)

Ocular

• Keratoconjunctivitis sicca (secondary Sjögren's), retinal vasculitis (cotton-wool spots)
• Hydroxychloroquine toxicity: bull's-eye maculopathy (requires annual screening)

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5. INVESTIGATIONS

Autoantibodies in SLE

Complement

• C3, C4 low in active SLE (especially nephritis) - consumed by classical pathway
• CH50 may be undetectable in active flare
• C3, C4 used to monitor disease activity

Other Lab Findings

• ESR elevated; CRP usually normal (elevated CRP suggests infection)
• CBC: anemia (normochromic normocytic), leukopenia, lymphopenia, thrombocytopenia
• Direct Coombs test positive in hemolytic anemia
• Urinalysis: proteinuria, hematuria, casts (RBC casts = active nephritis)
• 24-hour urine protein or spot urine protein:creatinine ratio
• False-positive VDRL/RPR (antiphospholipid antibodies)

Goldman-Cecil Medicine; Harrison's 22E

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6. DISEASE ACTIVITY INDICES

• SLEDAI (SLE Disease Activity Index) - most widely used; 24 items; score ≥6 = active disease
• BILAG (British Isles Lupus Assessment Group)
• SLICC Damage Index - irreversible end-organ damage

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7. SPECIAL SITUATIONS

Lupus in Pregnancy

• Pre-conception counseling mandatory; avoid pregnancy if disease active
• Neonatal lupus: anti-Ro/anti-La antibodies cross placenta → neonatal skin rash (transient), congenital heart block (3rd degree AV block, permanent, mortality 20%)
• Risks: preeclampsia, preterm birth, fetal growth restriction, recurrent miscarriage (APS)
• Hydroxychloroquine safe and protective during pregnancy
• Safe immunosuppressants: HCQ, azathioprine, cyclosporine, low-dose prednisolone
• Avoid: mycophenolate (teratogenic), cyclophosphamide (1st trimester), methotrexate, belimumab

APS in SLE

• Primary prophylaxis: hydroxychloroquine ± low-dose aspirin
• Secondary prophylaxis (after thrombosis): lifelong anticoagulation (warfarin; INR 2-3 for VTE, 3-4 for arterial)
• Pregnancy with APS: LMWH + low-dose aspirin

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8. TREATMENT

General Measures

• Sun protection (UVB triggers flares)
• Cardiovascular risk factor management (statins, BP control)
• Osteoporosis prophylaxis (calcium + Vit D + bisphosphonate if on steroids)
• Hydroxychloroquine for ALL patients unless contraindicated (reduces flares, damage accrual, mortality)

Step-up Pharmacological Approach

Lupus Nephritis Treatment

• Induction (Class III/IV): Mycophenolate mofetil (2-3 g/day) OR cyclophosphamide (IV monthly - NIH protocol, OR Euro-Lupus low dose) + high-dose corticosteroids
• Maintenance: Mycophenolate (preferred) or azathioprine + low-dose prednisone
• Voclosporin (calcineurin inhibitor) + MMF + steroids: approved 2021 for active LN
• Belimumab (anti-BLyS/BAFF): approved for active SLE and active LN; reduces flare frequency
• Anifrolumab (anti-IFN receptor): approved 2021 for moderate-to-severe SLE (non-renal)
• Target: urine protein:creatinine <0.5 g/g, stable renal function

Biologics Summary

Harrison's 22E, Goldman-Cecil

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Part II: SYSTEMIC SCLEROSIS (SCLERODERMA)

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1. DEFINITION & OVERVIEW

1. Fibrosis - skin and internal organs
2. Obliterative vasculopathy - Raynaud's, digital ulcers, PAH
3. Autoimmunity - multiple autoantibodies

• Female : Male = 4.6:1
• Incidence: 9-46 cases per million/year (USA)
• Peak onset: 30-50 years
• Black patients: higher age-specific incidence + mortality
• No curative treatment; management targets individual organ complications

Harrison's 22E; Robbins & Kumar

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2. CLASSIFICATION

Diffuse Cutaneous SSc (dcSSc)

• Rapid onset of skin thickening
• Skin involvement: fingers, hands, ascends proximal to limbs and trunk
• Early visceral involvement: ILD (most common), renal crisis
• Associated antibodies: anti-Scl-70 (anti-topoisomerase I), anti-RNA polymerase III
• Worse prognosis

Limited Cutaneous SSc (lcSSc) / CREST Syndrome

• Skin involvement confined to fingers, distal limbs, face (spares trunk)
• Raynaud's may precede other features by years
• Late complications: PAH, hypothyroidism, primary biliary cholangitis, Sjögren's, digital ischemia
• Associated antibody: anti-centromere antibody (ACA)
• Better prognosis than dcSSc, but late PAH is life-threatening

SSc Sine Scleroderma

• Raynaud's + internal organ involvement + SSc antibodies, WITHOUT detectable skin thickening

Harrison's 22E

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3. PATHOGENESIS

• CD4+ T cells (Th2-skewed) accumulate in skin, release cytokines
• TGF-β (transforming growth factor beta) - master fibrotic mediator; stimulates collagen synthesis
• IL-13 (from Th2 cells) - activates fibroblasts
• CTGF (connective tissue growth factor) - amplifies fibrosis
• Autoantibodies provide diagnostic/prognostic information but do NOT directly drive fibrosis

• Microvascular injury is the earliest detectable event (even precedes skin thickening)
• Repeated endothelial injury → platelet aggregation → PDGF + TGF-β release → intimal proliferation + perivascular fibrosis
• Endothelin-1 overproduction → vasoconstriction + vascular remodeling
• Loss of vascular NO production → unopposed vasoconstriction
• Result: Raynaud's, digital ulcers, renal crisis, PAH

• Culmination of above processes
• Alternatively activated (M2) macrophages secrete fibrogenic cytokines
• Fibroblast hyperresponsiveness to TGF-β → excessive collagen (Types I and III) production
• Ischemic scarring from vascular lesions adds to fibrosis

Robbins; Harrison's 22E

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4. AUTOANTIBODIES IN SSc

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5. CLINICAL MANIFESTATIONS

Raynaud's Phenomenon

• Universal in SSc (present in ~95%); often the initial manifestation
• Classic triphasic color change: white (ischemia) → blue (cyanosis) → red (reactive hyperemia)
• In SSc: typically severe, progressive; can lead to digital pitting scars → ulcers → gangrene → auto-amputation
• Distinguish from primary Raynaud's: no triphasic change, shorter duration, no digital ulcers, no SSc antibodies

Skin

• Puffy/edematous hands - earliest skin change in dcSSc
• Sclerodactyly - skin tightening of fingers → sausage-like digits initially, then tapering
• Skin induration progresses proximally in dcSSc
• Skin score (modified Rodnan skin score - mRSS): sum of skin thickness at 17 body sites; max 51
• Facial features: small mouth (microstomia), perioral furrowing (purse-string lips), beaked nose, tight skin limiting mouth opening
• Telangiectasias - mat-like, on face, lips, hands, mucosa
• Calcinosis cutis - calcium deposits in subcutaneous tissue (fingers, pressure areas); can ulcerate through skin
• Hypopigmentation/hyperpigmentation - "salt and pepper" pattern

Musculoskeletal

• Arthralgia/arthritis - early, prominent feature
• Tendon friction rubs - coarse leathery crepitation on movement; pathognomonic of dcSSc, indicates rapidly progressive disease
• Flexion contractures - late complication
• Myopathy: inflammatory (overlap with myositis) or non-inflammatory atrophy

Gastrointestinal (most common visceral involvement in SSc)

• Esophagus (>80%): lower 2/3 smooth muscle atrophy → dysmotility → GERD, dysphagia for solids and liquids; Barrett's esophagus risk; stricture
• Gastric antral vascular ectasia (GAVE) / "Watermelon stomach" - GI bleeding
• Small intestine: hypomotility → bloating, malabsorption, bacterial overgrowth, pseudo-obstruction; "hidebound" small bowel on barium (closely packed valvulae conniventes = accordion sign)
• Colon: wide-mouthed sacculations (haustra disappear), constipation, fecal incontinence
• Anorectal dysfunction: internal anal sphincter fibrosis → fecal incontinence (major quality-of-life issue)

Pulmonary

• Interstitial Lung Disease (ILD) - most common cause of death in SSc
  • More common in dcSSc and anti-Scl-70 positive patients
  • Pattern: NSIP (more common in SSc-ILD, better prognosis) > UIP
  • HRCT: ground-glass opacities + subpleural reticulations (basal-predominant) → traction bronchiectasis → honeycombing
  • PFT: restrictive pattern (↓FVC, ↓TLC, ↓DLCO)
  • Annual PFT + HRCT monitoring; DLCO disproportionate ↓ → suspect PAH
• Pulmonary Arterial Hypertension (PAH)
  • 8-12% of SSc patients; late complication; more common in lcSSc/anti-centromere
  • Defined: mPAP >20 mmHg + PCWP ≤15 mmHg + PVR >2 Wood units
  • Symptoms: exertional dyspnea, syncope
  • Echocardiography: screening; right heart catheterization: gold standard diagnosis
  • Annual echocardiographic screening recommended in all SSc patients

Renal

• Scleroderma Renal Crisis (SRC)
  • Occurs in 10-15% of dcSSc patients, usually within first 4 years of diffuse disease onset
  • Associated with anti-RNA polymerase III antibody
  • Triggered by: corticosteroid use (>15 mg/day prednisone), cold exposure, hypovolemia
  • Triad: sudden-onset hypertension (often malignant) + acute renal failure + thrombotic microangiopathy (MAHA + thrombocytopenia)
  • Pathology: onion-skin intimal hyperplasia ("fibrinoid necrosis") of renal vessels, resembling malignant hypertension
  • Treatment: ACE inhibitors (captopril) - first-line, life-saving; use even if renal function worsens; continue even if dialysis required (may recover function in months)
  • Avoid corticosteroids >15 mg/day in high-risk patients

Cardiac

• Fibrosis of conduction system → arrhythmias, heart block
• Myocardial fibrosis → diastolic dysfunction, cardiomyopathy
• Pericardial involvement (10-15%)
• Cardiac manifestations are associated with worse prognosis

Other

• Hypothyroidism (due to thyroid fibrosis) - common
• Sjögren's overlap (secondary)
• Erectile dysfunction in men (vascular)
• Depression, reduced quality of life

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6. INVESTIGATIONS

• ANA (centromere pattern in lcSSc; nucleolar/speckled in dcSSc)
• Specific antibodies: anti-Scl-70, anti-centromere, anti-RNA pol III
• Nailfold capillaroscopy - hallmark investigation for early SSc; shows giant capillaries, avascular areas, hemorrhages ("scleroderma pattern") - crucial for differentiating primary from secondary Raynaud's
• PFT (annual), HRCT chest (baseline + as needed)
• Echocardiography (annual - PAH screening)
• Right heart catheterization (PAH confirmation)
• 24-hour pH monitoring / manometry (GI evaluation)
• U&E, creatinine (renal monitoring)
• ESR usually normal (unlike other CTDs - characteristic of SSc)

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7. CLASSIFICATION CRITERIA FOR SSc (2013 ACR/EULAR)

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8. TREATMENT OF SSc

Raynaud's Phenomenon

• Trigger avoidance (cold, stress, smoking cessation)
• Calcium channel blockers (nifedipine, amlodipine) - first-line
• Phosphodiesterase-5 inhibitors (sildenafil, tadalafil) - for severe/refractory
• IV iloprost (prostacyclin) - for critical digital ischemia
• Endothelin receptor antagonists (bosentan) - PAH, reduces new digital ulcers (not healing)
• Sympathectomy (digital or lumbar) - refractory cases

ILD

• Mycophenolate mofetil (MMF) - first-line (Scleroderma Lung Study II)
• Nintedanib (anti-fibrotic, tyrosine kinase inhibitor) - approved for SSc-ILD; slows FVC decline
• Cyclophosphamide - alternative induction; more toxic
• Tocilizumab (anti-IL-6R): approved for SSc-ILD
• Lung transplant for end-stage disease

PAH

• Endothelin receptor antagonists: bosentan, ambrisentan, macitentan
• PDE-5 inhibitors: sildenafil, tadalafil
• Prostacyclin pathway: epoprostenol (IV), iloprost (inhaled), selexipag (oral)
• Combination therapy typically required
• Riociguat (soluble guanylate cyclase stimulator)

Scleroderma Renal Crisis

• ACE inhibitor (captopril) - continue even with rising creatinine and even on dialysis
• Target: normalize BP aggressively
• May recover renal function over months on ACE inhibitor

Skin Fibrosis

• Methotrexate - for early dcSSc skin disease
• Mycophenolate mofetil
• Autologous HSCT (hematopoietic stem cell transplant) - for rapidly progressive dcSSc with poor prognosis (ASTIS and SCOT trials); significant improvement in EFS compared to cyclophosphamide

GI

• PPI + prokinetics (domperidone, erythromycin) for GERD/dysmotility
• Antibiotics for bacterial overgrowth (rotating antibiotics: rifaximin, metronidazole)
• Nutritional support if malabsorption severe

Harrison's 22E; Robbins & Kumar

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Part III: MIXED CONNECTIVE TISSUE DISEASE (MCTD)

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1. DEFINITION

• Overlap syndrome - two co-existing CTDs each meeting diagnostic criteria
• Undifferentiated CTD (UCTD) - features of CTD not yet meeting criteria for any disease (~4% progress to MCTD)

Whether MCTD is a truly distinct entity or an early form/transition state remains debated. Long-term follow-up: ~60% remain MCTD, 17% evolve to SSc, 9% to SLE.

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2. EPIDEMIOLOGY

• Predominantly women (F:M ~16:1)
• HLA-DR4 and DR2 associations
• Peak age: 15-35 years

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3. DIAGNOSTIC (KASUKAWA) CRITERIA

1. Anti-U1RNP antibody positive (at high titer)
2. Common symptoms: Raynaud's phenomenon, swollen fingers/hands
3. SLE-like features: malar rash, arthritis, serositis, leukopenia/thrombocytopenia
4. SSc-like features: sclerodactyly, pulmonary fibrosis, restrictive lung disease, esophageal hypomotility
5. PM-like features: muscle weakness, elevated CPK, myopathic EMG

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4. KEY SEROLOGICAL FEATURES

• Anti-U1RNP antibody - essential; high titer; speckled ANA pattern on IIF
• Anti-dsDNA, anti-Sm: usually absent or low titer (if present, suggests evolution to SLE)
• Rheumatoid factor: positive in ~70%
• Anti-TS1-RNA antibodies: define a subgroup with lupus-like features
• Complement: may be normal or mildly reduced (unlike SLE where C3/C4 often very low)

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5. CLINICAL FEATURES

• CNS involvement (psychosis, seizures) - uncommon unlike SLE
• Severe proliferative glomerulonephritis - rare unlike SLE
• Scleroderma renal crisis - rare unlike SSc

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6. PROGNOSIS

• Generally better than SSc, worse than SLE
• Major causes of death: PAH (most common), pulmonary fibrosis, cardiovascular events, CNS disease, TTP, infection
• Younger age of onset + PAH + livedo reticularis = higher mortality

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7. TREATMENT

• Corticosteroids (prednisone 1 mg/kg/day) - effective for arthritis, myositis, serositis (SLE-like features)
• SLE features respond best; SSc features least responsive
• Bisphosphonate + steroid-sparing agent early (azathioprine, hydroxychloroquine)
• PAH: treat as per SSc-PAH protocols (ERA + PDE5i)
• Rituximab - refractory disease (thrombocytopenia response rate 80%); life-threatening complications
• Treat Raynaud's as per SSc protocol

Brenner's Kidney; Andrews' Dermatology; Goldman-Cecil

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Part IV: OTHER CONNECTIVE TISSUE DISORDERS

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SJÖGREN'S SYNDROME

Definition

Classification

• Primary: occurs alone
• Secondary: with RA, SLE, SSc, MCTD

Epidemiology

• F:M = 9:1; peak age 4th-5th decade
• Most common autoimmune rheumatic disease

Clinical Features

• Sicca symptoms: Keratoconjunctivitis sicca (xerophthalmia, "gritty eyes"), xerostomia, dry nose/trachea/vagina
• Extraglandular: Arthritis, Raynaud's, vasculitis (palpable purpura), peripheral neuropathy, interstitial nephritis (tubular > glomerular), primary biliary cholangitis
• Lymphoma risk - 40x increased risk of non-Hodgkin's B-cell lymphoma (MALT lymphoma of salivary glands); most important long-term complication

Investigations

• Anti-Ro (SS-A) - 70-75%; most important antibody
• Anti-La (SS-B) - 50%
• ANA positive (60%)
• RF positive (70%)
• Schirmer's test < 5 mm wetting in 5 minutes (dry eyes)
• Rose Bengal staining / fluorescein staining - corneal damage
• Minor salivary gland biopsy (lip biopsy) - gold standard: lymphocytic foci (>50 lymphocytes/4 mm²); "focus score" ≥ 1

Treatment

• Eye: artificial tears, cyclosporine eye drops, punctal occlusion
• Dry mouth: saliva substitutes, pilocarpine/cevimeline (muscarinic agonists)
• Arthritis/systemic: hydroxychloroquine, methotrexate, rituximab
• Watch for lymphoma development

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INFLAMMATORY MYOPATHIES

Classification

1. Polymyositis (PM) - CD8+ T cell mediated muscle damage (endomysial)
2. Dermatomyositis (DM) - complement-mediated microangiopathy (perifascicular atrophy); CD4+ perivascular
3. Inclusion Body Myositis (IBM) - most common in >50 years; distal + proximal weakness; rimmed vacuoles
4. Necrotizing Autoimmune Myopathy (NAM) - anti-SRP, anti-HMGCR antibodies; statin-associated

Clinical Features

• Proximal muscle weakness - symmetric; difficulty rising from chair, climbing stairs, combing hair
• Heliotrope rash - lilac/violaceous discoloration of periorbital skin (DM)
• Gottron's papules - erythematous papules over MCPs, PIPs, DIPs (DM) - pathognomonic
• Gottron's sign - macular erythema over extensor surfaces
• V-sign (anterior chest), shawl sign (posterior neck/shoulders), mechanic's hands (cracked palmar skin)
• Calcinosis - more in juvenile DM
• Dysphagia (pharyngeal + esophageal involvement)
• ILD - associated with anti-synthetase antibodies (anti-Jo-1, anti-PL7, anti-PL12)
• Anti-synthetase syndrome: PM/DM + ILD + arthritis + mechanic's hands + Raynaud's + fever

Malignancy Association

• Dermatomyositis has strong malignancy association (especially in >50 years): ovarian, lung, GI, lymphoma
• PM has weaker association
• IBM: no malignancy association
• Screen all DM patients for occult malignancy

Investigations

• CK (most sensitive muscle enzyme): elevated in PM/DM; may be normal in IBM
• Aldolase, LDH, AST, ALT elevated
• Anti-Jo-1 (anti-histidyl tRNA synthetase): most common myositis-specific antibody; associated with antisynthetase syndrome
• Anti-Mi-2 (DM): good prognosis
• Anti-MDA5 (DM): rapidly progressive ILD, amyopathic DM
• Anti-SRP (NAM): severe, treatment-resistant
• EMG: myopathic pattern (short, low-amplitude polyphasic MUPs; fibrillations; positive sharp waves)
• MRI muscle: edema, inflammation; guides biopsy site
• Muscle biopsy - gold standard

Histology

• PM: endomysial CD8+ T cell infiltrate around non-necrotic fibers (direct cytotoxicity)
• DM: perimysial/perivascular CD4+ infiltrate; perifascicular atrophy (pathognomonic) - caused by complement-mediated microangiopathy
• IBM: rimmed vacuoles + endomysial CD8+ cells + congophilic inclusions

Treatment

• High-dose corticosteroids (prednisone 1-2 mg/kg/day) - first-line
• Steroid-sparing: methotrexate, azathioprine
• IVIg - for refractory DM; approved for DM
• Rituximab - refractory cases
• Anti-synthetase ILD: mycophenolate, rituximab

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ANTIPHOSPHOLIPID SYNDROME (APS)

Definition

Classification (Revised Sapporo Criteria 2006)

1. Vascular thrombosis (arterial, venous, or small vessel)
2. Pregnancy morbidity: ≥3 consecutive unexplained fetal losses <10 wk OR ≥1 fetal death ≥10 wk OR ≥1 premature birth <34 wk due to eclampsia/placental insufficiency

1. Lupus anticoagulant (most strongly associated with thrombosis)
2. Anticardiolipin antibody (IgG or IgM, medium-high titer ≥40 GPL/MPL)
3. Anti-β2-glycoprotein I antibody (IgG or IgM)

Clinical Features

• Venous thrombosis: DVT, PE (most common)
• Arterial thrombosis: stroke (most common arterial), TIA, MI
• Pregnancy loss, IUGR, preeclampsia
• Thrombocytopenia (usually mild, 100-150k)
• Livedo reticularis (and livedo racemosa)
• Sneddon's syndrome: livedo reticularis + recurrent strokes
• Libman-Sacks endocarditis (associated, especially in SLE-APS)
• Catastrophic APS (CAPS): thrombosis in ≥3 organs simultaneously, within 1 week; high mortality (50%); triggers: surgery, infection, withdrawal of anticoagulation; treatment: anticoagulation + steroids + IVIG + plasma exchange

"Triple positivity" = Highest thrombotic risk (all 3 antibodies positive)

Laboratory Notes

• Lupus anticoagulant (LA): paradoxically prolongs clotting tests (aPTT) in vitro but causes thrombosis in vivo; confirmed by: prolonged aPTT not corrected by mixing study + positive dilute Russell's viper venom time (dRVVT)
• False-positive VDRL (RPR) - classic association

Treatment

• Primary thromboprophylaxis: hydroxychloroquine ± aspirin
• Secondary (after thrombosis): Warfarin INR 2-3 (VTE) or 3-4 (arterial/recurrent)
• DOACs (rivaroxaban, apixaban): RAPS and TRAPS trials show higher recurrent thrombosis risk vs. warfarin in LA-positive patients - avoid DOACs if LA positive
• Pregnancy APS: LMWH + low-dose aspirin throughout pregnancy + postpartum anticoagulation
• CAPS: anticoagulation + high-dose steroids + IVIG + plasma exchange ± rituximab/eculizumab

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COMPARISON TABLE: SLE vs SSc vs MCTD vs SJÖGREN'S

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HIGH-YIELD MNEMONICS & PEARLS

• SAND: Sm (specific), ANA (sensitive), Anti-dsDNA (activity/nephritis), Anti-histone (drug-induced)
• Anti-Ro → neonatal lupus, congenital heart block (permanent 3rd degree AV block)
• Anti-ribosomal P → lupus Psychosis

• Wire-loop lesion = Class IV (diffuse proliferative)
• Full-house IF = IgG + IgA + IgM + C3 + C1q (pathognomonic for LN)
• Class V = pure nephrotic; normal complements often

• Tendon friction rubs = dcSSc = rapidly progressive disease
• Anti-centromere = lcSSc/CREST = PAH risk (late)
• Anti-RNA pol III = dcSSc = Renal crisis risk
• ACE inhibitor even if creatinine rises in SRC
• ESR usually NORMAL in SSc (unlike other CTDs)
• NSIP pattern on lung biopsy = better prognosis than UIP in SSc-ILD

• Anti-U1RNP + no anti-Sm = MCTD; anti-Sm = SLE
• CNS disease and severe nephritis are rare in MCTD
• SSc features least responsive to treatment; LE features most responsive

• Heliotrope rash + Gottron's = DM (always)
• Perifascicular atrophy = DM (pathognomonic)
• Malignancy: DM >> PM (IBM = none)
• Anti-Jo-1 = antisynthetase syndrome = ILD + arthritis + mechanic's hands

• LA = longest aPTT, most thrombotic = paradox!
• DOACs UNSAFE in LA-positive APS (use warfarin)
• Triple-positive = highest thrombotic risk
• CAPS = 3+ organs + 1 week + 50% mortality

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SOURCES

• Harrison's Principles of Internal Medicine, 22nd Edition (2025)
• Goldman-Cecil Medicine, International Edition
• Robbins & Kumar Basic Pathology / Robbins Cotran Pathologic Basis of Disease
• Andrews' Diseases of the Skin, Clinical Dermatology
• Brenner and Rector's The Kidney

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CONNECTIVE TISSUE DISORDERS: GOLD-MEDALIST CLINICAL NOTES

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PART I: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

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1. DEFINITION & OVERVIEW

• Female : Male = 9:1 in reproductive age; narrows to 2:1 in children and elderly
• Peak onset: 15-44 years
• Prevalence (USA): ~72.8 per 100,000; incidence ~5.1 per 100,000/year
• Black women > Hispanic > White > Asian (prevalence and severity)
• Socioeconomic factors are major contributors to racial/ethnic disparity

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2. PATHOGENESIS

• HLA-DR2, HLA-DR3 most strongly associated
• Deficiencies of complement components C1q, C2, C4 predispose (C1q deficiency: ~90% develop SLE-like disease)
• Gene variants in IRF5, STAT4, BLK, PTPN22, TREX1 (DNase III)
• Impaired X-chromosome inactivation partially explains female predominance

• UV radiation - induces apoptosis, releases nuclear antigens
• Infections: EBV molecular mimicry (anti-Sm cross-reacts with EBV antigen)
• Drugs: hydralazine, procainamide, isoniazid, methyldopa, quinidine, minocycline, anti-TNF agents
• Estrogens promote disease activity
• Silica dust exposure

1. Defective clearance of apoptotic cells → accumulation of nuclear debris
2. Nuclear material (DNA/RNA) activates innate immune sensors: TLR7, TLR9 on plasmacytoid dendritic cells
3. Massively elevated type I interferons (IFN-α/β) - the "interferon signature" seen in ~75% of SLE patients
4. Interferon-stimulated genes activate autoreactive B and T lymphocytes
5. NETosis by neutrophils releases NET-DNA, activating pDCs further
6. Autoreactive B cells → loss of tolerance → anti-dsDNA, anti-Sm, anti-Ro/La, antiphospholipid antibodies
7. Immune complex deposition in glomeruli, skin, choroid plexus → complement activation → tissue injury
8. T helper imbalance: reduced Treg, elevated Th17

• Anti-histone antibodies characteristic; anti-dsDNA usually absent
• Renal and CNS involvement rare
• Resolves on drug withdrawal
• Procainamide: 50% develop ANA, 20% full DIL

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3. CLASSIFICATION CRITERIA

2019 EULAR/ACR Classification Criteria

Classify as SLE if score ≥ 10 points. Class III/IV nephritis on biopsy alone = 10 points. Within each domain, only the highest-weighted criterion is counted.

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4. CLINICAL MANIFESTATIONS

Constitutional

• Fatigue (most common, often debilitating), fever, weight loss, lymphadenopathy
• Type 1 vs. Type 2 lupus: Type 1 = inflammatory (nephritis, vasculitis, arthritis) - responds to IS; Type 2 = fatigue, pain, cognitive dysfunction - poor IS response

Musculoskeletal (>90%)

• Symmetric, non-erosive arthritis of small joints of hands, wrists, knees
• Jaccoud's arthropathy - reducible deformity (no erosions on X-ray)
• Avascular necrosis (femoral head) - disease and/or corticosteroid-related
• Myalgia; rarely true myositis

Mucocutaneous

Renal (Lupus Nephritis)

• Occurs in ~50%; major cause of SLE mortality; usually within 5 years of diagnosis

• Class IV "wire-loop" lesion - massive sub-endothelial immune deposits on EM
• "Full-house" immunofluorescence - IgG + IgA + IgM + C3 + C1q - pathognomonic for LN
• Class V: normal or mildly reduced complements; anti-dsDNA may be low

Neuropsychiatric SLE (19 ACR-defined syndromes)

• CNS: Seizures, psychosis, cerebrovascular disease (stroke, TIA), cognitive dysfunction, chorea, transverse myelitis, aseptic meningitis
• PNS: Polyneuropathy, mononeuritis multiplex, autonomic neuropathy
• Antiphospholipid Ab → cerebrovascular events
• Anti-ribosomal P Ab → lupus psychosis and depression

Cardiovascular

• Pericarditis - most common cardiac manifestation
• Libman-Sacks endocarditis - sterile verrucous vegetations on BOTH surfaces of mitral/aortic valve; associated with antiphospholipid antibodies
• Premature atherosclerosis - major cause of late mortality (young women: 50x increased MI risk)
• Myocarditis - uncommon

Pulmonary

• Pleuritis/effusion - most common pulmonary manifestation (exudative)
• Diffuse alveolar hemorrhage - rare but life-threatening; hemoptysis + bilateral infiltrates + falling Hb
• Shrinking lung syndrome - restrictive defect; diaphragmatic dysfunction without parenchymal disease
• Pneumonitis (acute lupus pneumonitis)

Hematologic

• Anemia of chronic disease (most common), autoimmune hemolytic anemia (Coombs+)
• Leukopenia, lymphopenia, thrombocytopenia (immune)
• APS in 25-40%: thrombosis, recurrent pregnancy loss, livedo reticularis

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5. KEY AUTOANTIBODIES IN SLE

• C3, C4 low in active SLE (classical pathway consumption) - used to monitor activity
• CH50 may be undetectable in active flare
• CRP usually normal in active SLE (elevated CRP suggests superimposed infection)

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6. LUPUS IN PREGNANCY

• Neonatal lupus: anti-Ro/anti-La antibodies cross placenta → transient neonatal rash + permanent 3rd-degree AV block (20% mortality; pacemaker needed)
• Active disease at conception = worse outcomes (preeclampsia, IUGR, preterm birth)
• Safe drugs: hydroxychloroquine (protect against flares), azathioprine, cyclosporine, low-dose prednisolone
• Avoid: mycophenolate (teratogenic), cyclophosphamide (1st trimester), methotrexate, belimumab, warfarin

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7. TREATMENT

Lupus Nephritis (Class III/IV)

• Induction: MMF (2-3 g/day) preferred OR IV cyclophosphamide + high-dose steroids
• Maintenance: MMF (preferred) or azathioprine + low-dose prednisone
• Voclosporin (calcineurin inhibitor) + MMF + steroids - FDA approved 2021 for active LN
• Target: urine protein:creatinine <0.5 g/g

Biologics

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PART II: SYSTEMIC SCLEROSIS (SCLERODERMA)

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1. DEFINITION

1. Fibrosis - skin and visceral organs
2. Obliterative vasculopathy - Raynaud's, digital ulcers, PAH
3. Autoimmunity - specific autoantibodies

• F:M = 4.6:1; incidence 9-46 per million/year
• Early stages: inflammatory/edematous; later: fibrotic, atrophic
• ESR usually normal - characteristic distinguishing feature from other CTDs

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2. CLASSIFICATION

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3. PATHOGENESIS (Three Interrelated Processes)

• Repeated endothelial injury → platelet aggregation → PDGF + TGF-β → intimal proliferation + perivascular fibrosis
• Endothelin-1 overproduction → vasoconstriction
• Loss of NO production → unopposed vasoconstriction
• Results in: Raynaud's, digital ulcers, renal crisis, PAH

• CD4+ T cells (Th2-skewed) accumulate in skin
• TGF-β (master fibrotic mediator) + IL-13 stimulate collagen synthesis in fibroblasts
• CTGF amplifies fibrosis
• Autoantibodies: diagnostic/prognostic but do NOT directly drive fibrosis

• M2 macrophage accumulation + fibrogenic cytokines
• Fibroblast hyperresponsiveness to TGF-β → excess collagen Types I and III
• Ischemic scarring from vascular lesions

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4. AUTOANTIBODIES IN SSc

These antibodies are largely mutually exclusive in any individual patient.

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5. CLINICAL MANIFESTATIONS

Raynaud's Phenomenon

• Present in ~95% of SSc; universal; often the first symptom
• Triphasic: white (ischemia) → blue (cyanosis) → red (hyperemia)
• In SSc: severe, progressive → digital pitting scars → ulcers → gangrene → auto-amputation
• Nailfold capillaroscopy: giant capillaries, avascular areas, hemorrhages = "scleroderma pattern" - best test for differentiating primary vs. secondary Raynaud's

Skin

• Puffy/edematous hands (earliest change in dcSSc)
• Sclerodactyly - skin tightening of fingers
• Facial: small mouth (microstomia), perioral furrowing (purse-string lips), beaked nose
• Telangiectasias - mat-like on face, lips, hands
• Calcinosis cutis - calcium deposits, can ulcerate through skin
• "Salt and pepper" pigmentation
• Modified Rodnan Skin Score (mRSS): 17 body sites, max 51; measures extent of thickening

Musculoskeletal

• Arthralgia/arthritis
• Tendon friction rubs - coarse leathery crepitus on movement; pathognomonic of dcSSc; indicates rapidly progressive disease
• Flexion contractures (late)
• Myopathy (inflammatory or non-inflammatory atrophy)

Gastrointestinal (most common visceral involvement)

• Esophagus (>80%): lower 2/3 smooth muscle atrophy → dysmotility → GERD, dysphagia (solids and liquids), Barrett's, stricture
• GAVE ("Watermelon stomach") - gastric antral vascular ectasia; GI bleeding
• Small bowel: bacterial overgrowth, malabsorption, pseudo-obstruction; "hidebound" bowel on barium
• Colon: wide-mouthed sacculations, constipation, fecal incontinence
• Anorectal dysfunction: fecal incontinence (major QOL issue)

Pulmonary

• More common in dcSSc + anti-Scl-70 positive
• Histology: NSIP pattern (most common in SSc-ILD; better prognosis) > UIP
• HRCT: bilateral lower lobe subpleural ground-glass opacities + reticular pattern (basal, apicobasal gradient) → traction bronchiectasis → honeycombing
• PFT: restrictive pattern (↓FVC, ↓TLC, ↓DLCO)
• Annual PFT + HRCT monitoring

• 8-12% of SSc; late complication; more common in lcSSc/anti-centromere
• Definition: mPAP >20 mmHg + PCWP ≤15 mmHg + PVR >2 Wood units
• Symptoms: exertional dyspnea, syncope, RV failure
• Echo: screening; Right heart catheterization: gold standard
• Annual echocardiographic screening for all SSc patients

Renal - Scleroderma Renal Crisis (SRC)

• Occurs in 10-15% of dcSSc; usually within first 4 years of diffuse disease
• Associated with anti-RNA polymerase III antibody
• Triggers: corticosteroids >15 mg/day, cold exposure, hypovolemia
• Triad: sudden-onset malignant hypertension + acute renal failure + thrombotic microangiopathy (MAHA + thrombocytopenia)
• Pathology: onion-skin intimal hyperplasia (fibrinoid necrosis) of renal vessels
• Treatment: ACE inhibitor (captopril) is life-saving - continue even if creatinine rises; continue even on dialysis (may recover renal function over months)
• Avoid corticosteroids >15 mg/day in high-risk dcSSc patients

Cardiac

• Myocardial fibrosis → diastolic dysfunction, arrhythmias, heart block
• Pericardial involvement (10-15%)
• Cardiac involvement = poor prognosis

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6. 2013 ACR/EULAR CLASSIFICATION CRITERIA FOR SSc

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7. TREATMENT OF SSc

Raynaud's Phenomenon

• 1st line: Calcium channel blockers (nifedipine, amlodipine)
• 2nd line: PDE-5 inhibitors (sildenafil, tadalafil)
• Digital ischemic crisis: IV iloprost (prostacyclin analogue)
• New digital ulcer prevention: Bosentan (ERA)

ILD

• 1st line: Mycophenolate mofetil (MMF) - Scleroderma Lung Study II
• Nintedanib (anti-fibrotic tyrosine kinase inhibitor) - approved for SSc-ILD; slows FVC decline
• Tocilizumab (anti-IL-6R) - approved for SSc-ILD
• Cyclophosphamide - alternative induction (more toxic)
• End-stage: lung transplant

PAH

• Endothelin receptor antagonists: bosentan, ambrisentan, macitentan
• PDE-5 inhibitors: sildenafil, tadalafil
• Prostacyclin analogues: epoprostenol (IV), iloprost (inhaled), selexipag (oral)
• Riociguat (sGC stimulator)
• Combination therapy usually required

Scleroderma Renal Crisis

• ACE inhibitor (captopril) - first-line; titrate to BP control; continue even on dialysis

Skin Fibrosis

• Methotrexate - early dcSSc skin disease
• MMF
• Autologous HSCT - for rapidly progressive dcSSc with poor prognosis (ASTIS + SCOT trials: superior to cyclophosphamide for EFS)

GI

• PPI + prokinetics (domperidone, erythromycin)
• Rotating antibiotics for bacterial overgrowth (rifaximin, metronidazole)

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PART III: MIXED CONNECTIVE TISSUE DISEASE (MCTD)

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1. DEFINITION (Sharp Syndrome)

• Whether MCTD is truly distinct vs. transitional remains debated
• Long-term follow-up: 60% remain MCTD; 17% evolve to SSc; 9% to SLE
• Distinct from "overlap syndrome" (each disease meets criteria) and UCTD

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2. EPIDEMIOLOGY

• F:M = ~16:1; HLA-DR4 and DR2 associations; peak age 15-35 years

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3. KEY SEROLOGICAL FEATURES

• Anti-U1RNP - essential; high titer; speckled ANA pattern
• Anti-dsDNA and anti-Sm: usually absent (if present, suggests evolution to SLE)
• RF positive: ~70%
• Complement: normal or mildly reduced
• Anti-TS1-RNA: defines subgroup with predominant lupus features

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4. CLINICAL FEATURES

• CNS disease (psychosis, seizures) - uncommon (unlike SLE)
• Severe proliferative glomerulonephritis - rare (unlike SLE)
• Scleroderma renal crisis - rare (unlike SSc)

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5. PROGNOSIS

• Better than SSc, worse than SLE
• Major causes of death: PAH (most common), pulmonary fibrosis, cardiovascular events, TTP, infection
• Younger age + PAH + livedo reticularis = higher mortality risk

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6. TREATMENT

• Corticosteroids (prednisone 1 mg/kg/day) for inflammatory features (arthritis, myositis, serositis)
• LE features respond best; SSc features respond least
• Early steroid-sparing: azathioprine, hydroxychloroquine
• Bisphosphonate for osteoporosis prophylaxis
• PAH: treat as per SSc-PAH (ERA + PDE5i)
• Rituximab - refractory disease; thrombocytopenia response 80%
• Raynaud's: as per SSc protocol

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PART IV: OTHER CONNECTIVE TISSUE DISORDERS

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SJÖGREN'S SYNDROME

• Primary (alone) vs. Secondary (with RA, SLE, SSc, MCTD)
• F:M = 9:1; most common autoimmune rheumatic disease; peak 4th-5th decade

• Sicca complex: Keratoconjunctivitis sicca ("gritty eyes," xerophthalmia), xerostomia, dry nose, vaginal dryness
• Extraglandular: arthritis, Raynaud's, peripheral neuropathy, interstitial nephritis (tubular > glomerular), primary biliary cholangitis, vasculitis (palpable purpura)
• Lymphoma risk: 40x increased risk of B-cell NHL (MALT lymphoma of salivary glands) - most important long-term complication

• Anti-Ro (SS-A) - 70-75% - most important antibody
• Anti-La (SS-B) - 50%
• Schirmer's test <5 mm in 5 min = dry eyes
• Rose Bengal/fluorescein staining - corneal damage
• Minor salivary gland biopsy (lip biopsy) - gold standard: lymphocytic foci (focus score ≥ 1 = >50 lymphocytes per 4 mm²)

• Artificial tears, cyclosporine drops, punctal occlusion (eye)
• Pilocarpine/cevimeline (muscarinic agonists) for dry mouth
• Hydroxychloroquine, methotrexate, rituximab (systemic)
• Monitor for lymphoma development

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INFLAMMATORY MYOPATHIES

Classification

1. Polymyositis (PM) - CD8+ T cell-mediated endomysial inflammation
2. Dermatomyositis (DM) - complement-mediated microangiopathy; perifascicular atrophy
3. Inclusion Body Myositis (IBM) - most common >50 years; distal + proximal; rimmed vacuoles; no malignancy
4. Necrotizing Autoimmune Myopathy (NAM) - anti-SRP, anti-HMGCR; statin-associated

Key Clinical Features

• Anti-synthetase syndrome: PM/DM + ILD + arthritis + mechanic's hands + Raynaud's + fever; anti-Jo-1 (most common)
• Anti-MDA5 (DM): rapidly progressive ILD, amyopathic DM
• Anti-Mi-2 (DM): good prognosis
• IBM: rimmed vacuoles + congophilic inclusions; poor response to IS

Investigations

• CK markedly elevated (PM, DM); may be normal (IBM)
• EMG: myopathic (short, low-amplitude polyphasic MUPs + fibrillations)
• MRI muscle: guides biopsy site
• Muscle biopsy: gold standard

Treatment

• High-dose prednisone (1-2 mg/kg/day) - first-line
• Steroid-sparing: methotrexate, azathioprine
• IVIg - refractory DM
• Rituximab - refractory cases; anti-synthetase ILD
• Screen ALL DM patients for occult malignancy

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ANTIPHOSPHOLIPID SYNDROME (APS)

Revised Sapporo (Sydney) Criteria 2006

1. Vascular thrombosis (arterial, venous, small vessel)
2. Pregnancy morbidity: ≥3 unexplained losses <10 wk, OR ≥1 fetal death ≥10 wk, OR ≥1 premature birth <34 wk (eclampsia/placental insufficiency)

1. Lupus anticoagulant - most strongly associated with thrombosis
2. Anticardiolipin IgG/IgM (medium-high titer ≥40 GPL/MPL)
3. Anti-β2-glycoprotein I IgG/IgM

• Venous: DVT, PE (most common)
• Arterial: stroke (most common arterial event), TIA, MI
• Livedo reticularis, livedo racemosa
• Thrombocytopenia (mild, 100-150k)
• Sneddon's syndrome: livedo reticularis + recurrent strokes
• Libman-Sacks endocarditis

• Thrombosis in ≥3 organs simultaneously within 1 week
• Mortality ~50%; triggers: surgery, infection, anticoagulation withdrawal
• Treatment: anticoagulation + high-dose steroids + IVIG + plasma exchange ± rituximab/eculizumab

• Primary prophylaxis: HCQ ± low-dose aspirin
• Secondary (after thrombosis): warfarin (INR 2-3 for VTE; 3-4 for arterial/recurrent)
• DOACs are UNSAFE in LA-positive APS (RAPS + TRAPS trials: higher recurrence vs. warfarin)
• Pregnancy: LMWH + low-dose aspirin throughout + postpartum anticoagulation

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MASTER COMPARISON TABLE

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HIGH-YIELD MNEMONICS & PEARLS

• ANA = sensitive (95-99%), not specific
• Anti-dsDNA = activity + nephritis (monitor with C3/C4)
• Anti-Sm = most specific, no correlation with activity
• Anti-Ro = neonatal lupus + congenital 3rd-degree AV block (permanent; anti-La co-positive)
• Anti-histone = drug-induced lupus (>95%)
• Anti-ribosomal P = lupus Psychosis
• Antiphospholipid = thrombosis + APS

• Wire-loop = Class IV; Full-house IF = pathognomonic
• Class V = nephrotic; complements may be normal
• Only Class III/IV alone gives 10 points on EULAR/ACR criteria

• Tendon friction rubs = dcSSc = rapidly progressive disease
• Anti-centromere = lcSSc = late PAH
• Anti-RNA pol III = dcSSc = renal crisis risk (+ malignancy)
• ACE inhibitor saves lives in SRC - do NOT stop even if creatinine rises
• ESR usually NORMAL in SSc
• NSIP on biopsy = better prognosis than UIP in SSc-ILD
• Skin proximal to MCPJs alone = 9 points = classified as SSc

• Anti-U1RNP positive + anti-Sm ABSENT = MCTD (anti-Sm = SLE)
• CNS disease and severe nephritis are RARE (key negative features)
• LE features respond best to treatment; SSc features worst
• PAH = most common cause of death

• Heliotrope + Gottron's = DM (always)
• Perifascicular atrophy = DM (pathognomonic)
• Malignancy: DM >> PM (IBM = none)
• Anti-Jo-1 = antisynthetase syndrome = ILD + arthritis + mechanic's hands
• IBM: rimmed vacuoles + no malignancy + no IS response

• LA = longest aPTT, most thrombotic (paradox!)
• DOACs UNSAFE in LA-positive APS - use warfarin
• Triple-positive = highest thrombotic risk
• CAPS = ≥3 organs + ≤1 week + 50% mortality

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