Cryoglobulinemia

Landsteiner, 1903; Lerner & Watson, 1947

• Cryoglobulin disease, cryoglobulinemia, cryoglubulinemia

• Agglutination of immunoglobulins on exposure to cold (4°Celsius) with subsequent vasculitis of the small vessels → cryoglobulins
  • the process is reversible at 37°Celsius

Division into 3 types:

• Type I (approx.15%): Monoclonal cryoglobulin, mostly IgM (e.g. multiple myeloma, Waldenström's disease)
• Type II ( approx. 60%): Mono- and polyclonal immunoglobulins (hepatitis C, SLE, systemic scleroderma, Sjögren's syndrome)
• Type III (approx. 25%): Polyclonal immunoglobulins (mostly in autoimmune diseases, rheumatic disease)

1. Essential cryoglobulinaemia (idopathic)
2. Secondary cryoglobulinaemia:
   • Infections (over  80% of cases association to hepatitis C, syphilis) 
   • Autoimmune diseases (a. o. SLE, rheumatoid arthritis, ulcerative colitis)
   • Neoplasms (a. o. malignant lymphomas, plasmacytoma)
3. Association to hepatitis C, syphilis.a. SLE, rheumatoid arthritis, ulcerative colitis)
4. Neoplasms (a. o. malignant lymphoma, plasmacytoma)

• The clinic depends on the predominant immune complexes
  • Type I: especially acrocyanosis, necrosis of the acras, Raynaud's symptoms, erythema elevatum diutinum, livedo reticularis, livedo racemosa
  • Type II, III: Acrally accentuated, palpable small- and large-area purpura, muscle and joint complaints, polyneuropathy

• Late symptom or in severe course: glomerulonephritis

• Histories
• Clinical
• Lab:
  • Sharply elevated ESR at 37°Celsius, slowed at 4°Celsisus
  • Agglutination of immune complexes at cool temperatures
  • Cryoglobulin concentration mostly > 1 g/l (normal value < 100 mg/l)
• Eventual detection of hepatitis C infection, hepatitis serology
• Sample biopsy of the skin
• Immune electrophoresis

• Vasculitis of the small vessels (capillaries, venules, arterioles)
• Picture of a leukocytoclastic vasculitis
• Immune complex deposits (IgM and IgG) on the vessel walls of the skin
• Lymphocytic infiltrations within as well as perivascularly of the vessel walls

• Glomerulonephritis

• Chronic, recurrent course over months, years

• Avoid cold exposure
• Treatment of the underlying disease
  • including. for hepatitis C infection, interferon alpha and ribavirin
  • for malignancy, tumour search and treatment
• for severe course:
  • Prednisolone 0.25-0.5 mg/kg bw/day (Fauci regimen) leukocyte-adapted
  • Additive: cyclophosphamide 1-2 mg/kg bw/day
  • Alternatively, melphalan and prednisolone surge therapy; continuous therapy with chlorambucil 2-5 mg/day p.o
• For idiopathic cryoglobulinaemia
  • Symptomatic therapy approaches, e.g. NSAID ibuprofen 400-600 mg/day p.o.
• Rituximab can be used as a reserve agent

1. Baumgärtel MW. Diagnostik, klinisches Spektrum und Verlauf der Kryoglobulinämie. Eine Untersuchung anhand 1 640 konsekutiver Patienten einer hämatoimmunologischen Spezialambulanz. Dissertation der RWTH Aachen. 1998
2. Schwartzenberg S et al. (2003) Generalized vasculitis, thrombocytopenia, and transient lymphoproliferative disorder caused by idiopathic mixed cryoglobulinemia. Am J Med Sci 326: 47-50
3. Lospalluto J, Dorward B, Miller W, Jr, Ziff M. Cryoglobulinemia based on interaction between a gamma macroglobulin and 7S gamma globulin. Am J Med. 1962;32:142–145. doi: 10.1016/0002-9343(62)90191-2.
4. Dammacco F, Sansonno D. Mixed cryoglobulinemia as a model of systemic vasculitis. Clin Rev Allergy Immunol. 1997;15:97–119. doi: 10.1007/BF02828280.
5. Lunel F, Musset L, Cacoub P, Frangeul L, Cresta P, Perrin M, Grippon P, Hoang C, Valla D, Piette JC. Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology. 1994;106:1291–300.
6. Bonnet F et al. (2003) Prevalence of cryoglobulinemia and serological markers of autoimmunity in human immunodeficiency virus infected individuals: a cross-sectional study of 97 patients. J Rheumatol 30: 2005-2010