Monoclonal Gammopathy in Autoimmune Diseases: Marker, Consequence, Pathogenetic Factor—Or Coincidence?

The possible association between monoclonal gammopathy and autoimmune/immune-mediated diseases has received increasing attention in recent years. Several observational studies have reported an increased prevalence of monoclonal gammopathy in certain autoimmune conditions, particularly primary Sjögren’s syndrome, rheumatoid arthritis, and systemic lupus erythematosus. However, recent population-based screening data from the iStopMM study found no significant association between autoimmune disease and screen-detected MGUS after adjustment for age and sex, suggesting that ascertainment bias may partly explain associations observed in clinically identified cohorts. The underlying mechanisms may include chronic antigen stimulation, sustained B-cell activation, germinal-center dysregulation, increased T follicular helper cell activity, and BAFF/APRIL-, IL-6-, NF-κB-, and STAT3-mediated signaling pathways. Based on current evidence, the relationship between monoclonal gammopathy and autoimmunity can be interpreted according to four potentially overlapping models: monoclonal gammopathy may serve as a marker of chronic immune activation, develop as a consequence of persistent autoimmune inflammation, act as a pathogenetic factor through the direct effects of the monoclonal immunoglobulin or the underlying clonal B-cell/plasma-cell population, or represent a coincidental finding related to factors such as age, genetic background, or increased diagnostic surveillance. This review summarizes the major epidemiological, pathogenetic, and clinical evidence supporting these interpretations and discusses their potential diagnostic, prognostic, and therapeutic implications. Finally, we highlight key directions for future research, including longitudinal single-cell and spatial omics approaches, further characterization of the BAFF/APRIL axis, and investigation of PANoptosis as a potential link between chronic inflammation and clonal plasma-cell disorders.