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The relevance of monoclonal gammopathy in relation to rheumatic disorders has recently been reviewed.1 Monoclonal gammopathy or paraproteins can be detected in healthy adults and in different disease entities like amyloidosis, malignant proliferative disorders,2 associated with hepatitis C infections,3 and rheumatic diseases.4 The overall incidence of paraproteins in adults is about 1%.5 This incidence is higher in people over 70 and increases with age.6 When a paraprotein is detected and no underlying disease is present, the condition is referred to as a monoclonal gammopathy of undetermined significance.
Owing to their immunochemical properties, paraproteins can be precipitated by lowering the temperature below 37°C. In this way they form an essential part of the so-called cryoglobulins. When cryoglobulins are detected in the serum of a patient, this finding is usually associated with the coexistence of paraproteins. Recently, three patients with a clinical picture of a necrotising vasculitis associated with an essential cryoglobulinaemia (type 1) were admitted to our department. The causative relationship between the cryoglobulinaemia and the clinical symptoms was shown by the reduced severity of the clinical signs when paraprotein levels were decreased.
Patient A was a 69 year old man who, in May 1999, developed extremely painful purpura of the upper part of the third finger of his left hand. In the following days the upper part of his finger became necrotic. Angiography of his arteries showed normal vessels. Immune electrophoresis showed the presence of 8 g/l of an M component (IgGλ). An assay for the detection of cryoglobulinaemia was positive.
Laboratory examinations showed a normal plasma viscosity; antinuclear antibodies could not be detected and neither could rheumatoid factor. Complement components showed decreased C1q levels 46 IE/ml (normal 81–128), C3 1.3 g/l (normal 0.9–1.8), and low C4 levels 35 mg/l (normal 150–400). Virus serology was negative for cytomegalovirus, hepatitis A, B, and C. A skin biopsy of non-affected skin showed no evidence for vasculitis, but thrombus formation was detected in one artery. A diagnosis of multiple myeloma was ruled out by extensive laboratory examination.
Treatment was started with prednisone 60 mg daily and chlorambucil 8 mg daily until the M component concentration reached a plateau. During this treatment the skin lesions on his foot disappeared and his finger became necrotic The M component decreased to 5 g/l. After almost a year of follow up he is still free of complaints.
Patient B was a 60 year old man who was admitted to our hospital in January 2000 with arthritis of the small joints and severe Raynaud's phenomenon of his ears, which affected him so severely that he could not leave his house. Furthermore, he felt short of breath when breathing cold air. Physical examination showed purpura skin lesions on both helices of his ears. A paraprotein was detected with an M component of 4 g/l. The presence of a cryoglobulinaemia was shown, which consisted exclusively of the M component (IgGκ). Further laboratory examination showed very low levels of the complement component C1q <15 IE/ml (normal 81–128), C3 1.42 g/l (normal 0.9–1.8), and C4 300 mg/l (normal 150–400). Virus serology was positive for cytomegalovirus and negative for hepatitis A, B, and C. Plasma viscosity was normal. No evidence for multiple myeloma and/or lymphoma was obtained. A skin biopsy of the non-affected skin showed only a slight perivascular infiltrate, and no evidence for a necrotising vasculitis was seen. He was treated with chlorambucil 8 mg daily, which after two weeks was switched to melphalan (6 mg/m2) and prednisone (60 mg/m2) every four weeks for six months. The M component fell to 2 g/l and the severe Raynaud's phenomenon disappeared.
Patient C was a 78 year old woman who was admitted to our hospital in May 2000 with cyanosis in both feet, indicating possible arterial occlusion in both legs. Both feet were cold and very painful. Angiography showed normal vessels, which strongly suggested vasculitis of the end arterial vessels of her feet.
Laboratory examination showed a paraprotein (8 g/l) combined with a cryoglobulinaemia consisting of the monoclonal protein (IgGλ). Other laboratory examinations showed no abnormalities. Virus serology showed only a positive cytomegalovirus titre. She was treated with chlorambucil (8 mg/day) and prednisone (60 mg/day), which improved the necrosis of her legs. The necrosis of her right leg disappeared and on the left foot the necrosis began to demarcate to the upper part of her foot. While waiting for the complete demarcation so that an amputation could be planned, she developed a sepsis and died.
Few patients with essential cryoglobulinaemia type 1 have been reported. Until now a defined clinical syndrome could never be associated with classification of the cryoglobulins. Overall Raynaud's phenomenon and necrosis of the skin has been described as in our three patients. None of our three patients showed abnormalities on angiographic examination, which may indicate that only the small vessels are affected in the disease process.
In our patients we were able to show that the cryoglobulins were formed by the monoclonal immunoglobulin. When the serum concentration of the paraproteins was reduced, the disease symptoms in our patients improved. These cases suggest that a paraprotein found in patients with a rheumatic syndrome is not only indicative of a developing malignancy or other disease but may also be interpreted as a causative agent. We conclude that paraproteins seen in rheumatic syndromes have a role in the pathogenesis and should be treated when serious symptoms are present.
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