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Cytokines are critical in initiating and perpetuating the chronic inflammatory response in primary Sjögren's syndrome (pSS).1 Rituximab has beneficial effects on disease activity in pSS patients2 and results in a rise in B cell activating factor (BAFF) levels.3 Whether (elevated) levels of other (proinflammatory) cytokines are affected was addressed in this study. This information is important for understanding of the effect of rituximab in pSS.
Twenty-eight patients with early-onset pSS2 treated with rituximab (n=18) or placebo (n=10), and 10 age-matched and sex-matched healthy controls (HCs) were assessed for presence of cytokines/chemokines in serum, using a multiplex-25 bead array assay (Invitrogen, Breda, The Netherlands). The following cytokines and chemokines were analysed: GM-CSF, IL-1β, IL-1Ra, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p40/p70, IL-13, IL-15, IL-17, IFN-α, IFN-γ, TNF-α, MCP-1/CCL2, MIP-1α/CCL3; MIP-1β/CCL4, RANTES/CCL5, Eotaxin/CCL11, MIG/CXCL9 and IP-10/CXCL10.
At baseline, levels for nearly all cytokines/chemokines were significantly higher in pSS patients than HCs (table 1; Mann–Whitney U test, p<0.05); only levels of IL-8, IFN-γ and RANTES/CCL5 did not differ (Mann–Whitney U test, p>0.05). We could not confirm that patients with germinal centres have generally higher cytokine levels in the peripheral blood.4
Treatment with rituximab results in a rapid, temporarily depletion of B-cells in peripheral blood.5 Linear mixed effect analysis showed a significant treatment effect between rituximab-treated patients and placebo-treated patients for serum levels of GM-CSF, IL-1Ra, IL-6, IL-10, IFN-α, TNF-α, MIP-1β/CCL4 and MIG/CXCL9 (p<0.05). Subsequent analysis shows that this difference is due to a decrease of cytokine/chemokine levels after rituximab treatment. Levels of these cytokines/chemokines were significantly decreased, compared with baseline levels, at 5–12 weeks after rituximab treatment (Wilcoxon matched pairs test, p<0.01), when B-cells are virtually absent in peripheral blood.5 After this initial decrease, levels gradually returned towards baseline levels at 36–48 weeks after treatment (figure 1). Cytokine/chemokine serum levels remained almost unaffected in placebo-treated patients, with an exception of MIP-1β/CCL4 and IL-6, which were significantly (Wilcoxon matched pairs test, p<0.05) higher at 36 weeks and 48 weeks after placebo treatment, respectively (figure 1C,G). This may reflect the ongoing disease process in placebo-treated patients and suggests that these cytokines play an important role in pathogenesis.
Decrease in cytokine levels after rituximab treatment might be explained by indirect effects as a consequence of B-cell depletion. For example, autoantibody levels to SSA and SSB combined with material released from apoptotic cells are potent inducers of IFN-α by plasmacytoid dendritic cells.6 A decrease in autoantibody levels after rituximab treatment could therefore lead to lower serum IFN-α levels, which could subsequently result in a decrease of IL-R1a and MIG/CXCL9.7 ,8 B-cells are not only involved in immunoglobulin production but are also responsible for production of certain cytokines/chemokines, including GM-CSF, IL-6, TNF-α and IL-10.9 ,10 Therefore, the decrease of cytokine and chemokine levels in pSS patients treated with rituximab could, at least in part, be explained by a direct effect of removal of cytokine producing B-cells.11 The drop in certain cytokine and chemokine levels may contribute to improvement of disease progression and various clinical parameters as found after rituximab treatment of pSS patients.2 The effect on decreased cytokine/chemokine levels is among others reflected by reduced numbers of germinal centres and lymphoepithelial lesions in parotid gland tissue (manuscript in preparation). The results from our study may have implications for the development of new treatment modalities, which are eagerly awaited.12 Based upon our findings, we anticipate that more specific treatment approaches (eg, blockade of IL-6) might be beneficial for pSS patients.
RPEP and WHA contributed equally to this work.
ClinicalTrials.gov identifier: NCT00363350
Contributors None of the authors have financial interests that could create a potential competing interest or the appearance of a conflict of interest with regard to the work.
Funding Supported by unconditional grants of Roche (Woerden, The Netherlands) and the Jan-Kornelis de Cock foundation (Groningen, The Netherlands).
Competing interests None.
Patient consent Obtained.
Ethics approval The ethics committee of the University Medical Center Groningen (METC approval: 05.229).
Provenance and peer review Not commissioned; externally peer reviewed.