The Association between Rheumatological Diseases and Monoclonal Gammopathy of Undetermined Significance

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Background: Monoclonal Gammopathy of Undetermined Significance (MGUS) is an asymptomatic clonal plasma cell disorder with the risk of progression to multiple myeloma (MM). Studies have shown that patients with rheumatological diseases (RD) are associated with an increased risk of progression of MGUS to MM. RD also exhibit higher prevalence of MGUS compared to the general population. Immunological dysregulation and chronic antigen stimulation from autoimmune activity are proposed mechanisms. We assessed the association between RD and MGUS development in the nationwide Veteran Health Administration database, thereby contributing to a deeper understanding of this relationship and its clinical implications. Methods: Patients with RD diagnosis (≥2 outpatient ICD 9/10 codes or ≥1 inpatient code) from 1999-2021 were included. Exclusions applied to patients with MGUS diagnosis (identified by a published natural language processing model), MM (ICD-9-CM/ICD-10-CM: C90/203.0/C90), non-Hodgkin lymphoma (202.85/C85), Waldenstrom's macroglobulinemia and other B-cell lymphomas (273.3/C88), or an amyloidosis (277/E85) prior to or <6 month of RD diagnosis. The first RD diagnosis was defined as the index date, with index age as the age at RD diagnosis. Follow-up time was from the index date to MGUS diagnosis/death/censoring (12/31/2021) which ever came first. Patients with RD were 1:2 matched to individuals without RD on their follow-up time (and determined their index date/age), followed by matching on their index age (±1 year). The same exclusion criteria were applied to individuals without RD. To account for potential bias due to more frequent care because of comorbidities, the cohort was further stratified by Charlson Comorbidity Index (CCI) at index date (high vs low based on median CCI). CCI was computed using ICD codes to identify diseases diagnosed <5 years before and 1 year after the index date. RD was categorized into antibody (Ab)-mediated and non-antibody (non-Ab) mediated RD. Stratified by CCI (high and low), multivariable logistic regression was conducted to analyze the association between RD (Ab and non-Ab mediated) and MGUS using multivariable-adjusted odds ratio (aOR). The covariates included sex, race (non-Hispanic White, non-Hispanic Black, Hispanic, Other), index age, body mass index (underweight, normal, overweight, obese), marital status (divorced/separated/widow, married, single), rurality (rural, urban), and CCI. Results: We analyzed data of 118,365 veterans; 39,455 had RD (80% non-ab-mediated, 20% Ab-mediated). Mean age was 54 years in both RD and non-RD groups by matching. Most patients were male (88.5% RD, 85.1% non-RD). Racial composition was similar: 56.5% non-Hispanic White, 26.0% non-Hispanic Black, and 6.9% Hispanic in the RD group, and 56.0%, 21.6%, 6.9% respectively in non-RD group. Median CCI was higher in the RD group (1 vs. 0). Most patients were obese (51.7% RD, 42.5% non-RD) or overweight (31.0% RD, 37.2% non-RD). In patients with high CCI (n=64,343), Ab-mediated RD (n=7,326) was associated with increased MGUS risk (aOR 2.1, 95% Confidence Interval [CI] 1.8-2.4, p<.0001) as was non-Ab mediated RD (n=20,830) (aOR 2.0, 95% CI 1.9-2.2, p<.0001) compared to patients without RD (n=36,187). In the low CCI group (n=54,022), non-Ab mediated RD (n=10,738) was associated with an increased risk of MGUS (aOR 4.4, 95% CI 3.3-5.7, p<0.0001) compared to patients without RD (n=42,723). There was not sufficient evidence to show that Ab-mediated RD (n=561) was associated with higher MGUS risk (aOR 2.6, 95% CI 0.49-13.7, p=0.26). Conclusions: In a retrospective cohort of US veterans, RD was associated with a higher incidence of MGUS. Both Ab-mediated and non-Ab mediated RD were associated with a higher risk of MGUS diagnosis in patients with higher burden of comorbidities. In patients with fewer comorbidities, only non-Ab-mediated RD was associated with MGUS, likely due to a small number of patients with Ab-mediated RD. Bias in MGUS assessment should be considered, as patients with RD may undergo more testing, leading to increased detection of MGUS. Future prospective studies are needed to evaluate this association and if presence of the RD increases risk of progression to MM.