Monoclonal gammopathy (MG) encompasses a spectrum of conditions ranging from benign to malignant clonal B-cell proliferations. While MG is traditionally associated with hematologic malignancies, its role in autoimmune and rheumatologic diseases is increasingly recognized. This review proposes the novel concept of “monoclonal gammopathy of rheumatologic significance (MGRhS)” that refers to a non-malignant or pre-malignant systemic condition related to a monoclonal immunoglobulin and clonal B cells, capable of producing multi-organ damage or influencing the therapeutic management of rheumatologic diseases. MG of clinical significance is characterized by the production of monoclonal proteins causing organ damage and modulating immune responses. These proteins contribute to rheumatologic conditions or peculiar phenotypes, including cryoglobulinemic vasculitis, Sjögren's disease, and other autoimmune disorders. The review explores pathogenic mechanisms linking MG with these diseases, emphasizing early detection and accurate classification to guide therapeutic strategies. The manuscript addresses the implications of incidental MG detection in rheumatologic patients, particularly in the context of biologic therapies. Practical guidance is provided on identifying MGRhS, assessing its impact, and tailoring management to prevent complications. This analysis aims to advance understanding of MGRhS as a distinct clinical entity, encouraging a multidisciplinary approach to its management. The integration of novel diagnostic tools and targeted therapies is essential to improve outcomes and address the complexity of this condition.
