Doubt Cast on MGUS-Autoimmune Disease Link

Contrary to earlier studies, the not-entirely-rare condition known as monoclonal gammopathy of undetermined significance (MGUS) did not appear to raise risk for autoimmune disease when examined in the general population.

In a broad-based screening study performed in Iceland, rates of MGUS — an asymptomatic abnormality in bone marrow plasma cells, which then produce ineffectual but benign immunoglobulins — were no higher in people with autoimmune diseases than in otherwise healthy individuals (prevalence ratio 1.05, 95% CI 0.97-1.15), according to Ingigerdur Sverrisdottir, MD, of the University of Iceland in Reykjavik, and colleagues.

“Our findings have direct clinical relevance,” the researchers wrote in the Annals of Internal Medicine, “because they suggest that recommendations to routinely screen patients with autoimmune disease for MGUS may not be warranted.”

Yet while MGUS might have been exonerated as a promoter of autoimmune disease, the “undetermined significance” part of its name remains something of a misnomer. Not only does the new study come with important limitations, but it did not question earlier findings that MGUS often precedes development of multiple myeloma. “Each year, approximately 1% of patients with MGUS and 0.3% of patients with [light-chain] MGUS progress to [multiple myeloma] or other malignant conditions,” Sverrisdottir and colleagues noted. Overall, they observed, something like 3%-4% of older people have standard MGUS, while about 1% have the light-chain form.

It had been thought that MGUS is a factor in some cases of autoimmune disease, because observational studies found increased prevalence of MGUS in people with disorders such as rheumatoid arthritis, systemic sclerosis, and Sjögren’s syndrome. But, according to Sverrisdottir and colleagues, “patients seeking medical care are more likely to get tested for various conditions, including MGUS.” Consequently, they continued, the studies finding increased rates of MGUS in autoimmune disease patients “have a built-in ascertainment bias.”

A better approach, the group explained, would be to look for MGUS in conjunction with autoimmune disease in the general population. Exactly that type of data was available from a trial conducted in Iceland called iStopMM, which “aimed to investigate the benefits and harms of screening for MGUS” as a means of identifying people at heightened risk for multiple myeloma. This trial screened more than 75,000 Icelandic residents age 40 and older for MGUS starting in 2016 — representing roughly half of all Icelanders in that age group. Blood samples were tested for the so-called M protein, the hallmark deformed immunoglobulin produced in MGUS. Participants’ records in the country’s universal medical registry were then scanned for previous diagnoses or treatments for 42 different autoimmune diseases.

About 3,670 people with MGUS were identified in the screening; 298 individuals had a prior diagnosis of MGUS, but screening results were negative in 77. In the screening-positive population, 599 had some type of autoimmune disease. But that rate was nearly the same as was seen in the screening-negative group.

As well, when autoimmune diseases were stratified into four subtypes — autoantibody-positive, autoantibody-negative, organ-specific, and systemic — there was no suggestion of increased risk for MGUS in any of these in the screening population. Nor did the MGUS subtype (IgG, IgA, IgM, biclonal, or light-chain) seem to matter.

Sverrisdottir and colleagues did find roughly doubled rates of previously diagnosed autoimmune disease among the 298 people with a previous clinical diagnosis of MGUS, compared with MGUS-negative individuals. But that was most likely another example of the ascertainment bias inherent in people with autoimmune disease, the researchers argued.

Two substantial limitations were noted in their paper: the study’s conduct in Iceland, where the population is overwhelmingly white-Scandinavian, and its reliance on registry records. With regard to the latter, the researchers acknowledged, “the high accuracy of coding for chronic conditions shown in a validation study has not been demonstrated specifically for autoimmune diseases.” It was also possible that people with previous health conditions were more likely than others to agree to participate in iStopMM, which would introduce bias.

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