Cryoglobulins and skin D89.1

Occurrence of circulating serum proteins (cryoglobulins) that precipitate in the cold. These are immunoglobulins (mostly IgM) with the property of precipitating at 4ºC and dissolving again when rewarmed to 37ºC. Around 80% of patients have an underlying haematological disease as the cause, in most cases MGUS or multiple myeloma.

A distinction is made between three types:

• Type I: Monoclonal cryoglobulins(paraproteins), mostly IgM, approx. 15%: Occurrence mainly in monoclonal gammopathy of unclear siognificans (MGUS), multiple myeloma or Waldenström's disease.
• Type II: monoclonal 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 approx. 60% of cases of cryoglobulinaemia. Hepatitis C infection is the most common cause. It also occurs clinically in systemic scleroderma, Sjögren's syndrome, systemic lupus erythematosus and (more rarely) in chronic polyarthritis. Occurrence has also been described 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 approx. 25% of all cryoglobulin cases. Clinically occurring in systemic scleroderma, SLE, less frequently in chronic polyarthritis and also in chronic infectious diseases.

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

Lymphoproliferative diseases: MGUS, multiple myeloma, Waldenström's disease, lymphatic leukemia, malignant lymphogranulomatosis.

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

Other: Chronic liver diseases, arthritis after intestinal bypass.

Skin changes with the different types of cryoglobulins:

• Especially with type I: acrocyanosis after cold exposure, cold urticaria, Raynaud's phenomenon, necrosis and (acral) ulcerations on fingers, toes, ears and nose due to an occlusive vasculopathy of the small and medium-sized vessels, erythema elevatum diutinum, livedo reticularis, livedo racemosa. Less common are sensory neuropathy, arthritides, glomerulonephritis or thrombotic vascular occlusion. Rare is a palpable purpura and thus a small vessel vasculitis (purpura is rather an indication of type II/III).
• Especially type II and III: purpura (small vessel vasculitis), fatigue, arthralgia, glomerulonephritis, nerve damage with dysesthesia. However, the clinical symptoms mentioned for type I can 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, the anemia is complement-associated and occurs mainly extravascularly. The severity of the anemia depends on the thermal amplitude of the antibody = the ability of the antibody to bind 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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