Cryoglobulins and skin D89.1

Occurrence of circulating serum proteins (cryoglobulins) that precipitate in cold conditions. These are immunoglobulins (mostly IgM) with the property of precipitating at 4ºC and re-solubilizing when rewarmed to 37ºC. About 80% of patients have an underlying hematologic disease as the cause, in most cases MGUS.

There are three types:

• Type I: Monoclonal cryoglobulins(paraproteins), mostly IgM, approx. 15%: Occurs mainly in multiple myeloma and Waldenström's disease.
• Type II: Mono- and polyclonal mixed cryoglobulins with monoclonal IgM rheumatoid factor and polyclonal IgG (monoclonal IgG or IgA rheumatoid factors in the precipitate are rarer): this type accounts for about 60% of cases of cryoglobulinemia. Hepatitis C infection is considered the most common cause. It is also clinically present in systemic scleroderma, Sjögren's syndrome, systemic lupus erythematosus and (more rarely) in chronic polyarthritis. It has also been described to occur in long-term infectious diseases and in rare cases in Waldenström 's disease.
• Type III: Exclusively polyclonal cryoglobulins (mostly circulating immune complexes in autoimmune diseases or infections): this type is present in about 25% of all cryoglobulin cases. Clinically occurring in systemic scleroderma, SLE, less frequently in chronic polyarthritis and chronic infectious diseases.

Autoimmune diseases: systemic lupus erythematosus, Sjögren's syndrome, polyarteritis nodosa, rheumatoid arthritis, lymphocytic leukemia, malignant lymphogranulomatosis, sarcoidosis, ulcerative colitis.

Infections: e.g. hepatitis B, hepatitis C, infectious mononucleosis, toxoplasmosis, syphilis, Borrelia infections, cytomegalovirus infection, subacute bacterial endocarditis.

Other: Chronic liver disease, arthritis after intestinal bypass.

• Skin changes with the different types of cryoglobulins:
  • V.a. in type I: acrocyanosis after cold exposure, cold urticaria, Raynaud's phenomenon, necrosis and (acral) ulcerations of fingers, toes, ears and nose, erythema elevatum diutinum, livedo reticularis, livedo racemosa.
  • V.a. type II and III: purpura, fatigue, arthralgias, glomerulonephritis, nerve damage with dysesthesias. However, the clinical symptoms mentioned in type I may also occur.
• Extracutaneous manifestations: arthralgias, myalgias, nephropathies, neuropathies (IgM-associated polyneuropathy-anti-MAG antibodies), anemia (IgM-associated cold agglutinin disease is responsible for 15% of all hemolytic anemias; pathophysiologically, anemia is complementassociated and occurs mainly extravascularly. The severity of the anemia depends on the thermal amplitude of the antibody = the binding ability of the antibody to the erythrocytes at a certain temperature). Hemoglobinuria.

BSG strongly accelerated at 37 °C, slowed down at 4 °C. Precipitation of cryoglobulins in serum at refrigerator temperatures (hours to days). Cryoglobulin concentration usually > 1 g/l (standard value < 100 mg/l). Frequently anaemia, haemoglobinuria, false-positive syphilisserology.

Treatment of the underlying disease, see there in each case.

In essential mixed cryoglobulinemia (type II): cyclophosphamide (e.g. Endoxan) 1-2 mg/kg bw/day in combination with prednisolone 0.25-0.5 mg/kg bw/day (Fauci regimen) leukocyte-adapted. Alternatively: Melphalan (e.g. Alkeran) and prednisolone shock therapy as in plasmocytoma or continuous therapy with chlorambucil (e.g. Leukeran, 2-5 mg/day p.o.).

In idiopathic cryoglobulinemia: symptomatic therapy approaches, e.g. NSA such as ibuprofen (e.g. Ibuprofen Heumann) 400-600 mg/day p.o.; no immunosuppression.

In paraneoplastic forms, e.g. type I cryoglobulinemia and malignancy-associated cryofibrinogenemia: tumor search and tumor-adaptive treatment.

In autoimmune forms ( lupus erythematosus, systemic; Sjögren's syndrome; chronic polyarthritis (rheumatoid arthritis): treatment of the underlying disease taking into account cryoglobulin-induced organ damage.

In chronic HBV and HCV infections: 3 times 5 million IU of interferon alfa-2a or interferon alfa-2b.

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