Elevation of serum immunoglobulin free light chains during the preclinical period of rheumatoid arthritis

Abstract

Objective: Immunoglobulin free light chains (FLC) represent biomarkers of B cell activity in rheumatoid arthritis (RA) and are associated with all-cause mortality in the general population. Our objective was to evaluate the relationships of serum FLC to preclinical disease, RA characteristics, and mortality in RA compared to non-RA subjects.

Methods: A population-based study in Olmsted County, Minnesota, USA, was performed by crosslinking a large cohort in the general population having available serum FLC measurements with established RA incidence and prevalence cohorts. Serum κ, λ, and total FLC and their trends relative to RA incidence were compared between RA and non-RA subjects. Regression models were used to determine the associations between FLC, disease characteristics, and mortality, testing for differential effects of FLC on mortality in RA.

Results: Among 16,609 subjects, 270 fulfilled the criteria for RA at the time of FLC measurement. Mean total FLC were significantly higher in RA compared to non-RA subjects (4.2 vs 3.3 mg/dl, p < 0.001). FLC became elevated 3-5 years before the clinical onset of RA and remained elevated during followup. Polyclonal FLC were found to predict higher mortality in persons with RA, though elevation to the highest decile had a relatively lower effect on mortality in RA compared to non-RA subjects.

Conclusion: Elevation of serum FLC precedes the development of RA and may be useful in monitoring B cell activity and disease progression. FLC are associated with mortality among patients with RA as well as the general population.

Keywords: AUTOIMMUNITY; B CELL; BIOMARKERS; MORTALITY.

Figure 1

Study design illustrating the identification of subjects with RA with onset either before or after the FLC measurement. ACR = American College of Rheumatology; RA = rheumatoid arthritis; FLC = free light chain.

Figure 2

Evidence of preclinical activation of B-cell immunity in patients with RA compared to subjects in the general population. The graphs display trends in (upper) the concentration (mg/dL) of total FLC and in (lower) the percentage of patients with total FLCs ≥4.72 mg/dL, both relative to time from the RA incidence date. In the upper graph, the FLC data points for RA are shown along with a smooth line for trend in the 270 patients with RA (solid line) and a reference line for the 16,339 age- and sex-matched trend in the non-RA group (dashed line). A test for trend revealed that total FLCs increased over time (P<.001), and a test for change in slope at the time of RA incidence among the patients with RA revealed a significant change with a steeper rate of increase following RA incidence (P=.035). In the lower graph, the percentage of RA patients with total FLCs ≥4.72 mg/dL increased over time (solid red line with 95% confidence interval depicted as red dashed lines) and exceeded the age- and sex-matched trend in the non-RA group (solid black line). FLC = free light chains; RA = rheumatoid arthritis.

Figure 3

Lesser impact of the highest decile of polyclonal total FLCs on mortality in patients with RA compared to non-RA subjects. Shown are Kaplan-Meier curves comparing the survival experience between 15,431 non-RA subjects without (black dashed line) and with total FLCs ≥4.72 mg/dL (black solid line), and 252 patients with RA without and with serum FLCs in the highest decile (red dashed and red solid lines, respectively). All curves are age- and sex-adjusted to the age/sex distribution of the RA cohort.