Complications of monoclonal Igs

Even in the absence of overt lymphoid proliferation, it is necessary to look for the presence of the possible complications associated with the presence of the monoclonal protein itself. These “downstream” manifestations can be the consequence of high levels of monoclonal Ig, particular physicochemical properties, or autoantibody activity.

Hyperviscosity, impaired haemostasis and dilutional anaemia Circulating monoclonal Ig can cause hyperviscosity, hypervolaemia and haemostatic abnormalities. These disturbances depend on the quantity of Ig (in practice over 30 g/L) and the size of the molecule. These complications are mainly encountered with monoclonal IgM, since the molecule is 5 times larger than the other Igs, but is also seen with monoclonal IgA and some IgGs with a tendency to spontaneous aggregation.

Magnetic resonance imaging (MRI) of the spine of a patient with myeloma and vertebral compression

The manifestations of this « large molecule » syndrome, particularly mental status changes caused by the hyperviscosity of the blood, may require rapid intervention to reduce serum levels of the monoclonal Ig. This can be achieved through plasma exchange and is sometimes urgently required.

Renal manifestations: amyloidosis and Ig deposition diseases.

Renal failure is a frequent and serious complication of myeloma. Determination of serum creatinine concentration is essential for its diagnosis and as part of patient monitoring. It is mainly caused by the precipitation of light chains inside tubules. The renal risk depends on the concentration of light chains present in the urine and on their intrinsic capacity to precipitate. Reduced urinary flow and acidic urine are risk factors. Its prevention requires avoiding any dehydration, by maintaining adequate fluid intake at all times, preferably using alkaline fluids. It can be precipitated or exacerbated by non-steroidal anti-inflammatory drugs, which are too often prescribed for bone pain, and by the injection of iodinated contrast medium for radiological examinations, including CT scans. With certain exceptions, these products are contraindicated in patients excreting significant amounts of urinary light chains.

The renal complications of monoclonal Igs are not confined to obstruction of the renal tubules. Patients with proteinuria consisting mainly of albumin rather than light chains, possibly associated with hypoalbuminaemia and oedema (nephrotic syndrome), may have glomerular injury and must be investigated for the presence of Ig deposition. The deposits usually have a fibrillar structure, AL amyloidosis being the most frequent form. More rarely, disorganized granular deposits form along the basal, glomerular and especially tubule membranes, characterizing Ig deposition disease or Randall disease. In both cases, Ig is not only deposited in the kidney, and very many extrarenal symptoms (e.g. carpal tunnel syndrome, macroglossia, hepatomegaly, various cutaneous signs) can reveal their presence and/or have prognostic significance (cardiac manifestations). Simple biopsies taken from the skin, abdominal fat or gingiva should be examined for the presence of Ig deposition before considering histological examination of the kidneys (or liver), which should stains specific for amyloidoses (Congo red) and immunohistochemical analysis to confirm AL amyloidosis.

Autoantibody activity of monoclonal Igs: mixed cryoglobulinaemia, cold agglutinin disease and macroglobulinaemia-associated neuropathy

 Monoclonal Igs, mainly of the IgM class, can be autoantibodies but generally cause no symptoms. In some cases however, the autoantibody activity has deleterious consequences, due to either formation of antigen-antibody complexes (which is the case in mixed cryoglobulinaemia) or a directly harmful effect of the monoclonal autoantibody, for example on red blood cells (cold agglutinin IgM) or peripheral nerves (anti-myelin IgM).

Mixed cryoglobulinaemia results from the precipitation of complexes at low temperatures, consisting of a monoclonal IgM called rheumatoid factor (which means that it recognizes the terminal portion of any IgG molecule) and polyclonal IgG. These complexes can damage vessel walls causing vasculitis and often affect the skin (vascular purpura). One of the major causes of mixed cryoglobulinaemia is infection with hepatitis C virus.

Cold agglutinin disease is due to the presence of a monoclonal IgM that recognizes sugars on the membrane of red blood cells, especially when the temperature falls. The main manifestation of the disease is ischaemia of the extremities, due to erythrocyte agglutination and acute intravascular destruction of red blood cells. Exposure to cold predisposes to or precipitates the symptoms (mainly acrocyanosis and passage of dark urine due to haemoglobinuria). The direct Coombs test is always positive for complement, and cold agglutinins are detected in the indirect Coombs test, often at a high titre. At the time of diagnosis, the level of monoclonal IgM in the serum is usually low (less than 5 g/L) and a lymphoid clone undetectable. The clinical course is variable, but prevention, avoiding exposure to cold and advising optimum protection of the extremities from the cold, is often sufficient to limit the frequency and severity of haemolytic crises.

Peripheral neuropathy is a complication of about 5% of monoclonal IgMs. It usually presents as symmetrical (predominantly sensory) polyneuropathy of insidious onset that progresses very slowly. The sensory disorders are distal and affect the lower extremities first. Ataxia and tremor are common tell-tale signs. Demyelinating neuropathy with secondary axonal degeneration is seen on electromyography. These neuropathies frequently the presenting sign for low-level monoclonal IgM without overt lymphoid proliferation, and testing for monoclonal IgM must be performed systematically whenever such peripheral neuropathy is demonstrated.

Most IgMs associated with neuropathy recognize a minor myelin glycoprotein called MAG (myelin-associated glycoprotein). Other autoantibody activities have been demonstrated besides anti-myelin IgMs. In particular, antibodies against the gangliosides GM1 and asialo-GM1 are found in patients with a motor neuropathy resembling amyotrophic lateral sclerosis. It is important to recognize this entity, because it appears to be improved by intravenous Ig infusions much more frequently than other disorders.

In addition to type II cryoglobulinaemia, cold agglutinin disease and neuropathies with monoclonal IgM, other complications associated with monoclonal Ig are caused by pathogenic autoantibody activities against factor VIII or other clotting factors, or against lipoproteins, leading to xanthomas. In other cases the mechanism is less clear (acquired angioedema with monoclonal IgM). Furthermore, certain situations are almost always associated with the presence of a monoclonal Ig, without there being any known link between the immunochemical anomaly and the pathophysiology of the symptoms. Examples include dermatological conditions such as papular mucinosis, capillary leak syndrome marked by unexpected onset of hypovolaemic shock with haemoconcentration due to sudden extravasation of plasma proteins, and Schnitzler syndrome, in which urticarial vasculitis is associated with monoclonal IgM.