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cryoglobulinemia (cryoglobulinemic vasculitis)

Classification: See individual types: - type 1 cryoglobulinemia (monoclonal IgM) [3] - type 2 cryoglobulinemia - mixed cryoglobulins with monoclonal rheumatoid factor - polyclonal IgG + monoclonal IgM rheumatoid factor [3] - type 3 cryoglobulinemia - mixed cryoglobulins with polyclonal rheumatoid factor - polyclonal IgG + polyclonal IgM rheumatoid factor [3] Etiology: - hepatitis C (mixed cryoglobulinemia) most common - HIV infection - lymphoproliferative disorder, lymphoma, leukemia - plasma cell dyscrasia - IgM MGUS [3] - Waldenstrom's macroglobulinemia [3] - multiple myeloma - systemic lupus erythematosus - rheumatoid arthritis - vasculitis Pathology: - vasculitis - membranoproliferative glomerulonephritis Clinical manifestations: 1) cutaneous symptoms (100%) [6] a) vascular purpura 55%, palpable purpura b) erythematous macules [3]; not maculopapular rash [3] c) lower extremities d) distal necrosis 14% (types 1 & 2) - digital ischemia, earlobe infarctions [3] e) urticaria 10% (types 1 & 3) f) livedo reticularis 8-14% (type 3) g) leg ulcers 5% (types 1 & 3) h) skin nodules or skin ulcers 2) Raynaud's phenomenon 50% 3) acrocyanosis 9% (types 1 & 2 > type 3) 4) articular manifestations 35-70% (type 3 > 2 > 1) [6] - arthralgias 5) renal symptoms 21-55% (type 2 > 1 > 3) [6] - variable: mild hematuria & proteinuria - nephrotic syndrome - membranoproliferative glomerulonephritis [3] - rapidly progressive glomerulonephritis [3] 6) neurologic symptoms 17% (type 3 > 1 > 2) - sensory or sensorimotor polyneuropathy [3] - mononeuritis multiplex [3] 7) pulmonary crackles less common [10] 8) hemorrhage 7% (types 1 & 2, 1 > 2) 9) abdominal pain 2-5% (type 3) 10) arterial thrombosis 1-5% (type 1) 11) lymphadenopathy 12) hepatosplenomegaly [5] 13) not associated with acute febrile onset [3] Laboratory: 1) blood collection & specimen processing a) blood collected in pre-warmed tubes b) kept at 37 degrees during clotting to keep cryoglobulins from precipitating with clot c) serum separated from clot at 37 degrees d) incubation at 4 degrees C for 72 hours 2) cryoglobulins in serum/plasma - trace amounts of cryoglobulins may be found in normal individuals 3) serum protein electrophoresis to identify cryoglobulin as monoclonal or polyclonal 5) serum complement levels are generally decreased (type 2 & 3), serum complement C4 more than serum complement C3 6) rheumatoid factor strongly positive (type 2 & 3) 7) serum transaminases may be elevated 8) hepatitis serology - hepatitis C serology 9) urinalysis with urine microscopy - active urinary sediment, erythrocyte casts, 9) see ARUP consult [7] Management: 1) therapy directed at underlying disease 2) idiopathic or essential cryoglobulinemia a) prednisone b) other immunosuppressive agents c) short course of therapy 3) hepatitis C-associated cryoglobulinemia a) ledipasvir & sofosbuvir for treatment of hepatitis C - 90% effective [3] b) peginterferon-alfa (Pegasys, Pegintron) + ribavirin - older recommenation, 75% effective c) disease may recur if antiviral therapy discontinued & hepatitis C virus not eradicated [3] 4) hyperviscosity responds to plasmapheresis

Interactions

disease interactions

Related

autoimmune disease cryofibrinogenemia cryoglobulin

Specific

mixed cryoglobulinemia type 1 (monoclonal) cryoglobulinemia type 2 (mixed) cryoglobulinemia type 3 (mixed) cryoglobulinemia

General

lymphoproliferative disorder paraproteinemia (monoclonal gammopathy) vasculitis

References

  1. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 527
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 849
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2022. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  4. Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 1307
  5. Brahn E, Scoville CD Biochemical markers of disease activity. Baillieres Clin Rheumatol 1988 2:153 PMID: 2458192
  6. Khasnis A and Langford CA. Update on vasculitis. J Allergy Clin Immunol 2009 Jun; 123:1226. PMID: 19501230
  7. ARUP Consult: Cryoglobulinemia The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/cryoglobulinemia
  8. Ramos-Casals M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias. Lancet. 2012 Jan 28;379(9813):348-60 PMID: 21868085
  9. Cacoub P, Comarmond C, Domont F, Savey L, Saadoun D. Cryoglobulinemia Vasculitis. Am J Med. 2015 Sep;128(9):950-5. Review. PMID: 25837517
  10. NEJM Knowledge+ Hematology