Very detailed note for a gold medalist about SLE, and other connective tissue disorders including scleroderma, mctd covering all the clinical aspects

Reading File

Finding Sources

Reading File

Here is your complete, gold-medalist level note on connective tissue disorders. The content is sourced from Harrison's 22E, Goldman-Cecil Medicine, Robbins & Kumar Pathology, Andrews' Dermatology, and Brenner's Kidney.

CONNECTIVE TISSUE DISORDERS: GOLD-MEDALIST CLINICAL NOTES

PART I: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

1. DEFINITION & OVERVIEW

SLE is a chronic, multisystem autoimmune disease characterized by immune complex-mediated tissue injury, production of autoantibodies to nuclear antigens (especially nucleic acids and nucleic acid-binding proteins), and complement activation. It follows a relapsing-remitting course in most patients, though some show chronic persistent activity.

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

2. PATHOGENESIS

The "multiple hit" model - cumulative genetic susceptibility + environmental triggers + immune dysregulation

a) Genetic Factors

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

b) Environmental Triggers

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

c) Immunological Mechanisms - Type I Interferon Pathway (Central)

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

d) Drug-Induced Lupus (DIL)

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

3. CLASSIFICATION CRITERIA

2019 EULAR/ACR Classification Criteria

Entry criterion: ANA titer ≥ 1:80 (if absent, do NOT classify as SLE)

Domain	Criterion	Points
Constitutional	Fever	2
Neuropsychiatric	Delirium	2
	Psychosis	3
	Seizure	5
Mucocutaneous	Non-scarring alopecia	2
	Oral ulcers	2
	Subacute cutaneous or discoid lupus	4
	Acute cutaneous lupus (malar rash)	6
Musculoskeletal	Joint involvement	6
Serosal	Pleural or pericardial effusion	5
	Acute pericarditis	6
Hematologic	Leukopenia	3
	Thrombocytopenia	4
	Autoimmune hemolysis	4
Renal	Proteinuria >0.5 g/24h	4
	Biopsy: Class II or V nephritis	8
	Biopsy: Class III or IV nephritis	10
Antiphospholipid Ab	aCL or anti-β2GPI or lupus anticoagulant	2
Complement	Low C3 OR low C4	3
	Low C3 AND low C4	4
SLE-specific Ab	Anti-dsDNA	6
	Anti-Sm	6

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.

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

Feature	Key Points
Malar (butterfly) rash	Fixed erythema over malar eminences; spares nasolabial folds; acute cutaneous lupus
Discoid lupus	Scarring, hyper/hypopigmented plaques; ear canals, scalp
Subacute cutaneous LE	Photosensitive, annular/papulosquamous; anti-Ro associated
Oral ulcers	Usually painless; hard palate
Non-scarring alopecia	Diffuse thinning; "lupus hair" at frontal hairline
Livedo reticularis	Associated with antiphospholipid syndrome
Raynaud's phenomenon	~30% of SLE patients

Renal (Lupus Nephritis)

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

ISN/RPS Classification of Lupus Nephritis:

Class	Description	Key Features
I	Minimal mesangial	Light microscopy normal
II	Mesangial proliferative	Mesangial deposits
III	Focal proliferative	<50% glomeruli; sub-endothelial deposits
IV	Diffuse proliferative	≥50% glomeruli; most common, most severe
V	Membranous	Nephrotic syndrome; sub-epithelial deposits
VI	Advanced sclerosing	>90% globally sclerosed

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

5. KEY AUTOANTIBODIES IN SLE

Antibody	Prevalence	Clinical Significance
ANA	95-99%	Screening; high sensitivity, low specificity
Anti-dsDNA	60-70%	Highly specific; correlates with disease activity and nephritis
Anti-Sm (Smith)	25-30%	Most specific (>99%) for SLE; does not correlate with activity
Anti-Ro (SS-A)	30-40%	Neonatal lupus, congenital heart block, subacute cutaneous LE, Sjögren's
Anti-La (SS-B)	10-15%	Always with anti-Ro; neonatal lupus
Anti-histone	60-70%	Drug-induced lupus (>95%)
Anti-C1q	~40%	Lupus nephritis activity marker
Anti-ribosomal P	10-20%	Neuropsychiatric lupus (psychosis, depression)
Antiphospholipid	25-40%	Thrombosis, recurrent fetal loss, thrombocytopenia

Complement:

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)

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

7. TREATMENT

Principle: Prevent flares, minimize organ damage, lowest effective immunosuppression.

Disease Activity	Treatment
Mild (constitutional, joint, skin)	NSAIDs, hydroxychloroquine (200-400 mg/day), low-dose prednisone
Moderate	HCQ + methotrexate or azathioprine + medium-dose prednisone
Severe (nephritis, CNS, hematologic, vasculitis)	High-dose corticosteroids + cyclophosphamide or mycophenolate
Refractory	Rituximab, belimumab, voclosporin

Hydroxychloroquine for ALL SLE patients: reduces flares, damage accrual, cardiovascular events, mortality; annual ophthalmologic screening (bull's-eye maculopathy toxicity)

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

Drug	Mechanism	Indication
Belimumab	Anti-BLyS/BAFF	Active SLE, active LN
Anifrolumab	Anti-IFNAR1 (blocks type I IFN)	Moderate-severe non-renal SLE
Voclosporin	Calcineurin inhibitor	Active lupus nephritis
Rituximab	Anti-CD20	Refractory SLE, thrombocytopenia

PART II: SYSTEMIC SCLEROSIS (SCLERODERMA)

1. DEFINITION

SSc is a systemic autoimmune disease with three hallmarks:

Fibrosis - skin and visceral organs
Obliterative vasculopathy - Raynaud's, digital ulcers, PAH
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

2. CLASSIFICATION

Feature	dcSSc (Diffuse Cutaneous)	lcSSc (Limited Cutaneous) / CREST
Skin	Fingers + proximal limbs + trunk	Fingers, distal limbs, face; trunk spared
Onset	Rapid skin thickening early	Raynaud's precedes by years
ILD	Common, early	Late, less severe
PAH	Less common	More common (late)
SRC	More common (10-15%)	Rare
Antibody	Anti-Scl-70	Anti-centromere
Prognosis	Worse	Better (but late PAH fatal)

CREST = Calcinosis, Raynaud's, Esophageal dysmotility, Sclerodactyly, Telangiectasia

SSc sine scleroderma = Raynaud's + internal organ involvement + SSc antibodies, WITHOUT skin thickening

3. PATHOGENESIS (Three Interrelated Processes)

a) Vascular Damage (earliest event)

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

b) Autoimmunity

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

c) Fibrosis (culmination)

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

4. AUTOANTIBODIES IN SSc

Antibody	Subtype	Key Association
Anti-centromere (ACA)	lcSSc (60-80%)	CREST, PAH (late), better prognosis
Anti-Scl-70 (anti-topoisomerase I)	dcSSc (40%)	ILD, diffuse disease, worse prognosis
Anti-RNA polymerase III	dcSSc (20%)	Scleroderma renal crisis, cancer association
Anti-U3-RNP (anti-fibrillarin)	dcSSc	Pulmonary, cardiac, muscle
Anti-PM/Scl	SSc-myositis overlap	ILD, myositis

These antibodies are largely mutually exclusive in any individual patient.

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

Interstitial Lung Disease (ILD) - most common cause of SSc death

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

Pulmonary Arterial Hypertension (PAH)

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

6. 2013 ACR/EULAR CLASSIFICATION CRITERIA FOR SSc

Criterion	Weight
Skin thickening of fingers extending proximal to MCPJs (sufficient alone)	9
Fingertip digital ulcers	2
Fingertip pitting scars	3
Telangiectasias	2
Abnormal nailfold capillaries	2
PAH or ILD	2 each
Raynaud's phenomenon	3
SSc-related antibodies (centromere, Scl-70, RNA pol III)	3

Score ≥ 9 = classified as SSc (sensitivity 91%, specificity 92%)

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)

PART III: MIXED CONNECTIVE TISSUE DISEASE (MCTD)

1. DEFINITION (Sharp Syndrome)

Overlap of SLE + SSc + polymyositis/DM features with high-titer anti-U1RNP antibodies, in the absence of anti-Sm.

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

2. EPIDEMIOLOGY

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

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

4. CLINICAL FEATURES

System	Manifestations
Hallmark	Sausage-like swollen fingers (dactylitis) + Raynaud's
Joints	Arthralgias, deforming RA-like arthritis, positive RF
Muscles	Myalgia, myositis, elevated CPK
Skin	Malar rash, discoid lesions, alopecia, sclerodactyly
Pulmonary	Restrictive disease + PAH (major cause of death)
GI	Esophageal dysmotility (SSc-like)
Cardiac	Pericarditis, myocarditis
Renal	Mild (10-26%); glomerular (like SLE) or vascular (like SSc)
Hematologic	Mild anemia, lymphocytopenia, hypergammaglobulinemia

Key distinguishing NEGATIVE features:

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

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

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

PART IV: OTHER CONNECTIVE TISSUE DISORDERS

SJÖGREN'S SYNDROME

Definition: Autoimmune exocrinopathy with lymphocytic infiltration of salivary and lacrimal glands

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

Clinical Features:

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

Investigations:

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)

Treatment:

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

INFLAMMATORY MYOPATHIES

Classification

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

Key Clinical Features

Feature	DM Specific	PM
Rash	Heliotrope (periorbital) + Gottron's papules (MCP/PIP/DIP)	None
Pattern	Proximal symmetrical weakness	Proximal symmetrical weakness
Biopsy	Perifascicular atrophy (pathognomonic) + perimysial CD4+ infiltrate	Endomysial CD8+ infiltrate
Malignancy	Strong association (ovarian, lung, GI, lymphoma)	Weak association

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

ANTIPHOSPHOLIPID SYNDROME (APS)

Definition: Recurrent arterial/venous thrombosis and/or pregnancy morbidity with persistent antiphospholipid antibodies

Revised Sapporo (Sydney) Criteria 2006

≥ 1 clinical + ≥ 1 laboratory criterion (positive on ≥ 2 occasions, ≥ 12 weeks apart)

Clinical:

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

Laboratory:

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

Clinical Features:

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

Triple positivity (all 3 antibodies positive) = highest thrombotic risk

Lupus Anticoagulant paradox: prolongs aPTT in vitro (not corrected by mixing study) → causes thrombosis in vivo; confirmed by prolonged dRVVT

Catastrophic APS (CAPS):

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

Treatment:

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

MASTER COMPARISON TABLE

Feature	SLE	dcSSc	MCTD	Sjögren's
F:M	9:1	4.6:1	16:1	9:1
Raynaud's	30%	95% (universal)	~100%	20%
Skin	Malar rash, discoid	Sclerodactyly, induration, calcinosis	Sausage fingers, sclerodactyly	-
Joints	Non-erosive, Jaccoud's	Contractures (late)	RA-like deforming	Arthritis
Kidneys	Nephritis (Class III/IV)	SRC (onion-skin)	Mild glomerular (10-26%)	Interstitial nephritis
Lungs	Pleuritis, DAH	ILD (NSIP/UIP) + PAH	PAH > fibrosis	Mild ILD
ANA pattern	Homogenous/speckled	Nucleolar/centromere	Speckled	Speckled
Specific Ab	dsDNA, Sm, Ro, La	Scl-70, centromere, RNA pol III	U1-RNP	Ro (SS-A), La (SS-B)
Complement	↓↓ (active)	Usually normal	Normal/mildly ↓	Normal/mildly ↓
ESR	Elevated	Usually normal	Elevated	Elevated
Major mortality	CAD, nephritis, infection	ILD, SRC, PAH	PAH, pulmonary fibrosis	Lymphoma
Biologics	Belimumab, anifrolumab	Nintedanib, tocilizumab	Rituximab	Rituximab

HIGH-YIELD MNEMONICS & PEARLS

SLE antibodies:

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

Lupus nephritis must-knows:

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

SSc must-knows:

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

MCTD pearls:

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

Myositis:

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

APS:

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

Sources: Harrison's Principles of Internal Medicine 22E (2025); Goldman-Cecil Medicine; Robbins & Kumar Basic Pathology; Andrews' Diseases of the Skin; Brenner and Rector's The Kidney

This is a shared conversation. Sign in to Orris to start your own chat.