Crystal Arthropathies & Autoimmune Connective Tissue

Crystal arthropathies: gout and pseudogout

Gout. Deposition of monosodium urate (MSU) crystals from hyperuricemia. Neutrophils engulf the crystals and release IL-1 and other mediators, producing an exquisitely painful monoarthritis, classically of the first MTP joint (podagra). Urate precipitates most readily in cool peripheral joints. Chronic disease forms tophi (chalky urate deposits ringed by foreign-body giant cells) in the ear helix, olecranon bursa, and Achilles tendon, punched-out erosions with overhanging edges on X-ray, and radiolucent uric acid kidney stones.

Crystal identification. Aspirated fluid shows needle-shaped crystals that are negatively birefringent: yellow when parallel to the red compensator. Needle and Negative both start with N.

Underexcretion beats overproduction. Most hyperuricemia reflects reduced renal urate excretion: thiazide and loop diuretics, low-dose aspirin, renal failure, and alcohol (its lactate competes with urate for tubular secretion). Overproduction causes are tumor lysis and myeloproliferative disease (high cell turnover), Lesch-Nyhan syndrome (HGPRT deficiency, a purine salvage defect), and von Gierke disease (glucose-6-phosphatase deficiency). Attacks are triggered by alcohol and purine-rich red meat and seafood.

Treatment principles. Acute flares respond to NSAIDs (e.g., indomethacin), colchicine (blocks microtubule assembly and neutrophil migration), or glucocorticoids. Long-term urate lowering uses the xanthine oxidase inhibitors allopurinol and febuxostat, the uricosuric probenecid, or recombinant uricase (pegloticase).

Pseudogout. Deposition of calcium pyrophosphate dihydrate (CPPD): rhomboid crystals that are positively birefringent (blue when parallel to the compensator). X-ray shows chondrocalcinosis (calcified cartilage), usually of the knee. It is associated with older age, hemochromatosis, and hyperparathyroidism (also hypomagnesemia and hypophosphatasia), and acute attacks are treated like gout flares, without urate-lowering therapy.

Systemic lupus erythematosus

Mechanism and epidemiology. SLE is a type III hypersensitivity (immune complex) disease of reproductive-age women, more common and more severe in Black patients. Loss of tolerance to nuclear antigens yields autoantibodies whose immune complexes deposit in skin, joints, serosa, and glomeruli and activate complement, so C3 and C4 fall during flares. Inherited deficiency of early complement components (C1q, C2, C4) predisposes by impairing clearance of immune complexes and apoptotic debris.

Classic features. Malar (butterfly) rash, discoid rash, photosensitivity, oral ulcers, nonerosive arthritis, serositis (pleuritis, pericarditis), nephritis, and cytopenias. Diffuse proliferative glomerulonephritis, with subendothelial deposits forming wire-loop capillaries, is the most severe lupus nephritis.

Serologies. ANA is sensitive (over 95%) but not specific, so it is the screening test. Anti-dsDNA is specific and tracks disease activity, especially nephritis. Anti-Smith is specific but does not track activity.

Libman-Sacks endocarditis. Sterile verrucous vegetations on both sides of the mitral valve.

Antiphospholipid syndrome. Anticardiolipin, lupus anticoagulant, and anti-β2 glycoprotein I antibodies cause arterial and venous thrombosis and recurrent miscarriage. Anticardiolipin cross-reacts with the cardiolipin reagent of syphilis tests, giving a false-positive VDRL/RPR, and the PTT is paradoxically prolonged.

Lupus anticoagulant prolongs the PTT in vitro but causes clotting in vivo; these patients need anticoagulation, not factor replacement.

Drug-induced lupus. Marked by anti-histone antibodies; usually spares the kidneys and CNS and resolves after the drug is stopped. Culprits are hydralazine, procainamide, isoniazid, and minocycline; slow acetylators are at higher risk with the first three.

Sjögren syndrome and overlap disease

Sjögren syndrome. Lymphocytic destruction of exocrine glands, mainly in middle-aged women, either alone or secondary to RA or SLE. It causes keratoconjunctivitis sicca (dry eyes), xerostomia (dry mouth with dental caries), and parotid enlargement. Antibodies are anti-SSA (Ro) and anti-SSB (La); a lip (minor salivary gland) biopsy shows focal lymphocytic infiltrates. It raises the risk of B-cell (MALT) lymphoma.

Anti-SSA (Ro) is IgG, crosses the placenta, and causes neonatal lupus and congenital heart block.

Mixed connective tissue disease. An overlap of SLE, systemic sclerosis, and polymyositis with prominent Raynaud phenomenon and puffy hands, defined by high-titer anti-U1 RNP antibodies and often steroid-responsive.

Systemic sclerosis (scleroderma)

Mechanism. Autoimmune endothelial injury and fibroblast activation lead to excess collagen deposition in skin and viscera, with a small-vessel vasculopathy that underlies Raynaud phenomenon.

Limited systemic sclerosis (CREST). Skin involvement is limited to the face and distal extremities. Anti-centromere antibody is the marker, and pulmonary arterial hypertension is the feared late complication.

Diffuse systemic sclerosis. Widespread skin fibrosis including the trunk, plus early visceral disease: interstitial lung fibrosis, GI dysmotility, cardiac fibrosis, and scleroderma renal crisis. Markers are anti-Scl-70 (anti-DNA topoisomerase I) and anti-RNA polymerase III, and prognosis is worse than in limited disease.

Scleroderma renal crisis (malignant hypertension and acute kidney injury) is treated with ACE inhibitors; high-dose glucocorticoids can precipitate it.

Inflammatory myopathies

Shared picture. Polymyositis and dermatomyositis cause symmetric proximal muscle weakness (trouble combing hair or climbing stairs) with elevated CK and aldolase and anti-Jo-1 or anti-SRP antibodies (anti-Mi-2 is specific for dermatomyositis). Muscle biopsy distinguishes them, and glucocorticoids are first-line therapy.

Dermatomyositis skin and cancer. Skin signs are Gottron papules over the knuckles, a heliotrope (violaceous) eyelid rash, a shawl sign, and mechanic hands. Dermatomyositis is associated with occult malignancy (ovarian, lung, and GI cancers are classic), so adults need age-appropriate cancer screening.