Still Disease, IgG4-Related Disease & Relapsing Polychondritis
Three great imitators: fever with ferritin, masses that melt, cartilage under attack
Adult-onset Still disease
Presentation. An IL-1–driven autoinflammatory disease of young adults. Fever spikes to ≥39°C once daily (quotidian), often in the evening, and returns to normal between spikes. An evanescent salmon-pink macular rash on the trunk and limbs appears with the fever and can be provoked by scratching (Koebner phenomenon). Other features are arthralgia or arthritis (often the wrists), sore throat, lymphadenopathy, splenomegaly, and serositis.
Laboratory picture. Neutrophilic leukocytosis (≥10,000/μL with ≥80% neutrophils), transaminitis, and markedly elevated ferritin—often in the thousands, with a low glycosylated fraction—while ANA and RF are negative. SLE differs by causing cytopenias, low complement, and anti-dsDNA.
Still disease is a diagnosis of exclusion. Rule out infection (blood cultures, viral studies, echocardiography for endocarditis), lymphoma (imaging and node biopsy), and rheumatic fever (ASO) before labeling the fever.
Treatment. NSAIDs suffice for mild disease, but most patients need glucocorticoids. IL-1 blockade (anakinra, a recombinant IL-1 receptor antagonist, or canakinumab) or IL-6 receptor blockade (tocilizumab) is now started early to spare steroids and is essential for steroid-refractory or steroid-dependent disease. Methotrexate spares steroids in chronic articular disease.
Macrophage activation syndrome
Macrophage activation syndrome is secondary hemophagocytic lymphohistiocytosis and the most dangerous complication of Still disease. Persistent fever is accompanied by falling platelet and white cell counts, falling ESR and fibrinogen (fibrinogen, the main driver of the ESR, is consumed), rising triglycerides, AST, and LDH, and ferritin that often exceeds 10,000 ng/mL; marrow may show hemophagocytosis. A "normalizing" ESR in a febrile patient is a warning sign, not improvement. Treat urgently with pulse glucocorticoids and anakinra, adding cyclosporine if needed.
| Marker | Active Still disease | MAS |
|---|---|---|
| Platelets and WBC | High (reactive) | Falling (cytopenias) |
| ESR and fibrinogen | High (acute phase) | Falling (consumption) |
| Ferritin | High, often thousands | Extreme and rising, often >10,000 ng/mL |
| Triglycerides, AST, LDH | Mildly abnormal | Rising |
IgG4-related disease
Concept. An immune-mediated fibroinflammatory disorder, often of older men, that swells organs into tumor-like masses, alone or in several organs at once.
| Site | Presentation | Main mimic |
|---|---|---|
| Pancreas | Type 1 autoimmune pancreatitis: painless obstructive jaundice, diffuse "sausage" pancreas with a capsule-like rim | Pancreatic adenocarcinoma |
| Bile ducts | IgG4-related sclerosing cholangitis | PSC, cholangiocarcinoma |
| Lacrimal and salivary glands | Symmetric enlargement (Mikulicz disease) | Sjögren disease, lymphoma |
| Orbit | Orbital pseudotumor with proptosis | Orbital lymphoma |
| Retroperitoneum | Fibrosis encasing aorta and ureters → hydronephrosis | Retroperitoneal malignancy |
| Thyroid | Riedel thyroiditis: stony-hard, fixed gland that can compress the trachea | Anaplastic carcinoma, lymphoma |
Excluding cancer. Pancreatic cancer typically forms a focal hypodense mass with upstream duct dilation and atrophy, vascular invasion, or liver metastases, and it does not respond to steroids. Because serum IgG4 is neither sensitive nor specific, obtain tissue (e.g., EUS-guided biopsy) before treating.
Histology. A dense lymphoplasmacytic infiltrate rich in IgG4+ plasma cells, storiform (cartwheel) fibrosis, obliterative phlebitis, and eosinophils. Granulomas point elsewhere, such as sarcoidosis or tuberculosis.
Treatment. Glucocorticoids produce brisk improvement within weeks—a response that itself supports the diagnosis. Relapse is common, so rituximab is used for relapse or steroid sparing. Early treatment prevents irreversible fibrosis.
Relapsing polychondritis and VEXAS
Cartilage inflammation. Relapsing polychondritis causes recurrent attacks of auricular chondritis—a red, tender pinna that spares the cartilage-free lobule, unlike cellulitis—plus nasal chondritis leading to saddle nose, costochondritis, and nonerosive arthritis.
Organ threats. Laryngotracheobronchial chondritis causes hoarseness, anterior neck tenderness, and stridor; cartilage destruction produces tracheomalacia or fixed stenosis, dynamic airway collapse, recurrent pneumonia, and respiratory failure—a leading cause of death. Screen every patient with PFTs (flow-volume loops) and dynamic expiratory CT. Other targets are the eye (scleritis, episcleritis, uveitis), inner ear (sensorineural hearing loss, vertigo), and aortic valve (regurgitation).
VEXAS syndrome. In older men, RP-like chondritis with fevers, macrocytic anemia, myelodysplastic syndrome, vacuolated marrow precursors, and thrombosis suggests VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic): an acquired mutation in the X-linked UBA1 gene, which encodes the E1 ubiquitin-activating enzyme, within blood stem cells. Unlike familial Mediterranean fever (germline MEFV mutations), it is not inherited.
Treatment. Glucocorticoids, with methotrexate as a steroid-sparing agent; severe airway or organ disease needs stronger immunosuppression.