Background Abnormalities in B-cell population distribution were recently reported in polymyalgia rheumatica (PMR), which improved with glucocorticoïds. Data about cytokine involvement in PMR pathophysiology are scarce and contradictory.
Objectives Our objective was to analyze the subsets of lymphocytes and level of cytokines in patients with PMR and to follow their evolution after tocilizumab treatment.
Methods The TENOR study [Clinicaltrials.gov (NCT01713842)] was an open labeled prospective trial including patients with recent PMR fulfilling the Chuang criteria. Patients had active disease and were glucocorticoïds (GCs) free. Patients with suspected giant cell arteritis were excluded. Patients were treated with tocilizumab infusions (week 0, 4 and 8) without GCs (period 1) and then by low-dose GCs from week 12 to week 24 (period 2). Peripheral blood lymphocyte profiling was performed by multicolor flow cytometry in 18 patients at week (W) 0 (before first tocilizumab infusion), W2, W12 and W24. Cytokine levels were estimated using membrane cytokine array enabling detection of 34 different cytokines. Interleukine (IL) 6 and 10 levels were evaluated by ELISA at W0 and W12. They were compared to 16 sex and age-matched healthy controls (HC).
Results At baseline, total lymphocyte (p=0.31), T cell (p=0.46), B cell (p=0.08) and NK cell (p=0.905) levels were similar between PMR patients and HC. Transitional B cells (CD24high, CD38high) and mature-naïve B cells (CD24low, CD38low) were lower in patients with PMR than in HC, 3±6 vs 6±6 per mm3 (p=0.01) and 46±41 vs 92±53 per mm3 (p=0.01), respectively. After tocilizumab, total lymphocyte count slightly increased (1739±539/mm3 at W0, 2030±591/mm3 at W2, 2068±775/mm3 at W12, and 2031±584/mm3 at W24, p<0.01). The absolute number and proportion of CD4+ T cells and NK cells were unaffected by the treatment. In contrast, both absolute number and proportion of B cells increased between W0 and W12, respectively from 176±105/mm3 to 260±192/mm3 (p=0.004) and from 10.1% to 13.0% (p<0.001). Among B-cell subsets, these modifications were mainly attributable to the variations of the memory compartment. Unswitched (IgD+CD27+) and switched (IgD-CD27+) memory B-cell absolute number and proportions significantly increased after tocilizumab (p<0.001). After cytokines detection using membrane cytokine array only IL-6 level was significantly different between patients and HC. IL-6 and IL-10 levels were measured in ELISA. IL-6 level was higher in patients (112±78 pg/ml) than in HC (13±13) (p<0.0001) and was found associated with disease activity measured by PMR-AS (r=0.628; p=0.006). IL-6 decrease in patients treated with tocilizumab infusion was not significant.
Conclusions The drastic clinical improvement following tocilizumab monotherapy in PMR patients is paralleled by an increase in peripheral blood memory B cells. These observations suggest that B cells are involved in disease pathophysiology, and that IL-6 blockade could restore B-cell homeostasis.
Disclosure of Interest None declared