Systemic Lupus & Connective Tissue Disease
The antibody that tracks the flare, the clot that prolongs the PTT, and the crisis ACE inhibitors reverse
SLE: clinical picture and serology
Who. Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease driven by autoantibodies and immune-complex deposition. It mostly affects women of childbearing age and is more severe in Black and Hispanic patients.
- Skin and mucosa: malar (butterfly) rash sparing the nasolabial folds, scarring discoid rash, photosensitivity, oral ulcers.
- Joints and serosa: nonerosive arthritis; pleuritis and pericarditis.
- Blood: cytopenias, including autoimmune hemolytic anemia, leukopenia and thrombocytopenia.
- Organs: nephritis, Libman-Sacks endocarditis, premature atherosclerosis, seizures and psychosis.
The lupus malar rash spares the nasolabial folds; rosacea and dermatomyositis do not.
| Antibody | Disease | Meaning |
|---|---|---|
| ANA | SLE and other CTDs | Over 95% sensitive: a good screen with poor specificity |
| Anti-dsDNA | SLE | Specific; tracks disease activity and nephritis |
| Anti-Smith | SLE | MOST specific for SLE |
| Anti-histone | Drug-induced lupus | Procainamide, hydralazine, isoniazid, minocycline |
| Anti-Ro/SSA, anti-La/SSB | Sjögren syndrome, SLE | Cross the placenta: neonatal lupus, congenital heart block |
| Anti-U1 RNP | Mixed connective tissue disease | High titer with overlap features |
| Anti-centromere | Limited scleroderma (CREST) | Pulmonary arterial hypertension |
| Anti-Scl-70, anti-RNA polymerase III | Diffuse scleroderma | ILD; renal crisis (highest with RNA polymerase III) |
Flares, lupus nephritis and treatment
Flare markers. Active SLE consumes complement through immune-complex deposition, so a flare shows LOW C3 and C4 with RISING anti-dsDNA titers. Following these labs helps monitor disease and anticipate nephritis flares.
Lupus nephritis. Nephritis is a leading cause of morbidity, so every patient needs periodic urinalysis and urine protein measurement. Diffuse proliferative (class IV) nephritis is the most common and most severe form, with an active sediment (RBC casts), hypertension and falling GFR; membranous (class V) disease presents as nephrotic syndrome. Renal biopsy classifies the lesion and guides therapy, and proliferative disease requires immunosuppression.
Treatment. Hydroxychloroquine is given to ALL SLE patients: it reduces flares, organ damage and mortality (monitor for retinopathy). Flares are treated with NSAIDs and glucocorticoids. Severe organ disease needs mycophenolate mofetil or cyclophosphamide. Active lupus nephritis gets combination therapy with glucocorticoids (KDIGO 2024, ACR 2025): mycophenolate or low-dose cyclophosphamide plus belimumab (anti-BAFF), or mycophenolate plus a calcineurin inhibitor such as voclosporin. Belimumab or anifrolumab (anti-type I interferon receptor) is added for persistent nonrenal activity, and glucocorticoids are tapered to 5 mg/day or less. Sun protection and cardiovascular risk control complete care.
Hydroxychloroquine is continued through pregnancy, because stopping it triggers flares; pregnancy is best planned after the disease has been quiet for about 6 months.
Antiphospholipid syndrome
Definition. Antiphospholipid syndrome (APS) is recurrent arterial or venous thrombosis and/or pregnancy loss with persistent antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, anti-β2-glycoprotein I) confirmed at least 12 weeks apart. It is primary or secondary to SLE.
The lab paradox. Lupus anticoagulant prolongs the aPTT in vitro, and the aPTT does NOT correct on mixing because the problem is an inhibitor, not a missing factor. APS can also cause thrombocytopenia, livedo reticularis and a false-positive VDRL/RPR.
Lupus anticoagulant is a misnomer: it causes clotting in vivo, not bleeding.
Treatment. After a thrombosis, anticoagulate lifelong with warfarin. Direct oral anticoagulants are inferior to warfarin, especially in triple-positive patients (all three antibodies). In pregnancy, warfarin is teratogenic, so use LMWH plus low-dose aspirin.
Anti-Ro, Sjögren syndrome and overlap
Neonatal lupus. Maternal anti-Ro/SSA (and anti-La/SSB), from SLE or Sjögren syndrome, crosses the placenta and causes a photosensitive neonatal rash and, most importantly, permanent congenital complete heart block. Anti-Ro-positive pregnancies are followed with serial fetal echocardiography.
Sjögren syndrome. Lymphocytic destruction of exocrine glands produces keratoconjunctivitis sicca (dry eyes), xerostomia (dry mouth with dental caries) and parotid enlargement; it may be primary or accompany RA or SLE. Anti-Ro/SSA and anti-La/SSB are typical, and the Schirmer test and a lip (minor salivary gland) biopsy confirm. Treatment is symptomatic: artificial tears and muscarinic agonists such as pilocarpine. The long-term risk is MALT lymphoma.
New, persistent unilateral parotid swelling in Sjögren syndrome suggests MALT lymphoma.
Mixed connective tissue disease. High-titer anti-U1 RNP with overlapping features of SLE, scleroderma and myositis, plus Raynaud phenomenon.
Drug-induced lupus. Anti-histone-positive lupus from procainamide, hydralazine, isoniazid or minocycline causes arthralgia, serositis and rash but spares the kidney and CNS, and it resolves after the drug is stopped.
Systemic sclerosis
Overview. Systemic sclerosis (scleroderma) is skin fibrosis with vasculopathy; Raynaud phenomenon is usually the first sign. The extent of skin involvement defines two subtypes.
| Feature | Limited (CREST) | Diffuse |
|---|---|---|
| Antibody | Anti-centromere | Anti-Scl-70 (topoisomerase I) or anti-RNA polymerase III |
| Skin | Distal to elbows and knees, plus face | Widespread, proximal and truncal, rapidly progressive |
| Hallmarks | Calcinosis, Raynaud, Esophageal dysmotility, Sclerodactyly, Telangiectasia | Early internal organ involvement |
| Main organ threat | Pulmonary arterial hypertension | Interstitial lung disease, renal crisis |
Organ care. Calcium channel blockers treat Raynaud phenomenon and PPIs treat reflux from esophageal dysmotility. Screen regularly with PFTs (including DLCO) and echocardiography for ILD and pulmonary hypertension.
Scleroderma renal crisis. Abrupt severe hypertension with acute kidney injury and microangiopathic hemolysis (schistocytes), with the highest risk in early diffuse disease and anti-RNA polymerase III. Treatment is an ACE inhibitor (captopril), which is lifesaving and continued even if dialysis is needed.
AVOID glucocorticoids in scleroderma: moderate-to-high doses can precipitate renal crisis.