NOTE

🌱 created from: hematology

cryoglobulinemia

One Name for Two Diseases

Cacoub P. Cryoglobulinemia — One Name for Two Diseases. New England Journal of Medicine. Published online October 17, 2024.

Overview of Cryoglobulinemia

• Pathologic condition characterized by precipitation of circulating immunoglobulins at temperatures below 4°C
• Proteins discovered by Wintrobe and Buell in 1933; later identified as gamma globulins by Lerner and Watson

Evolution of Understanding

• Initial descriptions emerged in the late 1960s, leading to better understanding
• Conditions categorized into lymphomas, Waldenström’s macroglobulinemia, and essential forms

Classification and Types_of_cryoglobulinemia

Therapeutic Approaches and Prognosis

• Empirical therapeutic approaches involve different combinations of drugs
• Glucocorticoids, immunosuppressants, and plasma exchange used
• Inconsistent outcomes and poor prognosis

Therapeutic Approaches	Prognosis
Glucocorticoids, immunosuppressants	Poor prognosis
Plasma exchange	Inconsistent outcomes

Main Causes of Cryoglobulinemia

IMMUNE COMPLEX (IC)–ASSOCIATED SMALL-VESSEL VASCULITIS

• Epidemiology: ~1/100,000, but prevalence varies with HCV rates; ♀ >♂

• Etiologies_of_cryoglobulinemia

(idiopathic in ~10%)

• Pathophysiology_of_cryoglobulinemia

• Clinical manifestations_of_cryoglobulinemia (most Pts w/o sx)

• Dx studies

✓ Cryoglobulins (keep blood warmed to 37°C en route to lab to avoid false ⊖, loss of RF and ↓↓ C3, C4). Cryocrit quantifies cryoprotein but not always indicative of disease activity. May see false ↑ in WBC or plt on automated CBC due to precipitation.

Type I: ✓ serum viscosity, symptomatic if ≥4.0 centipoise; complement normal.

Type II: ↓ C4, variable C3, ↑ ESR, ⊕ RF. ✓ HCV, HBV, HIV in mixed cryoglobulinemia. Bx: hyaline thrombi; small vessel leukocytoclastic vasculitis w/ mononuclear infiltrate.

• Treatment (Blood 2017;129:289; J Inflamm Res 2017;10:49): Rx underlying disorder. Heme malig → chemoradiation; HCV → antivirals; CTD → DMARD/steroids ± RTX. Type I: plasma exchange if hyperviscosity; steroids, alkylating agents, RTX, chemo. For mixed cryo, steroids and RTX; CYC or plasma exchange for major organ involvement.

Connective tissue disease–associated vasculitis

• Small-vessel vasculitis a/w RA, SLE, or Sjögren’s syndrome

• Clinical sx: distal arteritis (digital ischemia, livedo reticularis, palpable purpura, cutaneous ulceration); visceral arteritis (pericarditis, mesenteric ischemia); peripheral neuropathy

• Dx studies: skin/sural nerve bx, EMG, angiography; ↓ C3, C4 in SLE; ⊕ RF, anti-CCP in RA

• Treatment: steroids, cyclophosphamide, MTX (other DMARDs)

Cutaneous leukocytoclastic angiitis (Arthritis Rheumatol 2018;70:171)

• Most common type of vasculitis; heterogeneous group of clinical syndromes due to IC deposition in capillaries, venules, and arterioles; includes hypersensitivity vasculitis

• Etiol: drugs (PCN, ASA, amphetamines, levamisole, thiazides, chemicals, immunizations, etc.); infection (Strep, Staph, endocarditis, TB, hepatitis); malignancy (paraneoplastic)

• Clinical manifestations: abrupt onset of palpable purpura and transient arthralgias after exposure to the offending agent; visceral involvement rare but can be severe

• Dx studies: ↑ ESR, ↓ complement levels, eosinophilia; ✓ U/A; skin biopsy → leukocytoclastic vasculitis w/o IgA deposition in skin (to distinguish from IgA vasculitis); if etiology not clear, consider ANCA, cryoglobulins, hepatitis serologies, ANA, RF

• Treatment: withdrawal of offending agent ± rapid prednisone taper