You are here

Article Text

Article menu

Download PDFPDF

Letters
Predominantly proinflammatory cytokines decrease after B cell depletion therapy in patients with primary Sjögren's syndrome
  1. R P E Pollard1,
  2. W H Abdulahad2,
  3. H Bootsma2,
  4. P M Meiners1,
  5. F K L Spijkervet1,
  6. M G Huitema2,
  7. J G M Burgerhof3,
  8. A Vissink1,
  9. F G M Kroese2
  1. 1 Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  2. 2 Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  3. 3 Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  1. Correspondence to Professor A Vissink, Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, PO-Box 30.001, Groningen 9700 RB, The Netherlands; a.vissink{at}umcg.nl

https://doi.org/10.1136/annrheumdis-2013-203447

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    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

    View this table:
    Table 1

    Serum cytokine and chemokine levels (median (IQR) values in pg/mL) of 10 HCs and 28 pSS patients at baseline as measured by multiplex-25 bead array cytokine assay

    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.

    Figure 1
    Figure 1

    Cytokine and chemokine serum levels of healthy controls and effect of rituximab treatment in primary Sjögren's syndrome patients. The horizontal lines indicate the median values in pg/mL. Only cytokines and chemokines that showed a significant treatment effect of rituximab treatment compared with placebo treatment are shown. (A) GM-CSF; (B) IL-1Ra; (C) IL-6; (D) IL-10; (E) IFN-α; (F) TNF-α; (G) MIP-1β (CCL4); (H) MIG (CXCL9). *Indicates significant differences compared with baseline values (p<0.05).

    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.

    References

    1. ↵
      1. Roescher N,
      2. Tak PP,
      3. Illei GG
      . Cytokines in Sjögren's syndrome. Oral Dis 2009;15:519–26.
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      1. Meijer JM,
      2. Meiners PM,
      3. Vissink A,
      4. et al
      . Effectiveness of rituximab treatment in primary Sjögren's syndrome a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010;62:960–8.
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      1. Pollard RP,
      2. Abdulahad WH,
      3. Vissink A,
      4. et al
      . Serum levels of BAFF, but not APRIL, are increased after rituximab treatment in patients with primary Sjögren's syndrome: data from a placebo-controlled clinical trial. Ann Rheum Dis 2013;72:146–8.
      OpenUrlFREE Full Text
    4. ↵
      1. Reksten TR,
      2. Jonsson MV,
      3. Szyszko EA,
      4. et al
      . Cytokine and autoantibody profiling related to histopathological features in primary Sjögren's syndrome. Rheumatology 2009;48:1102–6.
      OpenUrlAbstract/FREE Full Text
    5. ↵
      1. Abdulahad WH,
      2. Meijer JM,
      3. Kroese FGM,
      4. et al
      . B cell reconstitution and T helper cell balance after rituximab treatment of active primary Sjögren's syndrome a double- blind, placebo-controlled study. Arthritis Rheum 2011;63:1116–23.
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      1. Bave U,
      2. Nordmark G,
      3. Lovgren T,
      4. et al
      . Activation of the type I interferon system in primary Sjögren's syndrome: a possible etiopathogenic mechanism. Arthritis Rheum 2005;52:1185–95.
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      1. Thacker SG,
      2. Berthier CC,
      3. Mattinzoli D,
      4. et al
      . The detrimental effects of IFN-alpha on vasculogenesis in lupus are mediated by repression of IL-1 pathways: potential role in atherogenesis and renal vascular rarefaction. J Immunol 2010; 185:4457–69.
      OpenUrlAbstract/FREE Full Text
    8. ↵
      1. Bauer JW,
      2. Baechler EC,
      3. Petri M,
      4. et al
      . Elevated serum levels of interferon-regulated chemokines are biomarkers for active human systemic lupus erythematosus. PLoS Med 2006;3:e491.
      OpenUrlCrossRefPubMed
    9. ↵
      1. Harris DP,
      2. Haynes L,
      3. Sayles PC,
      4. et al
      . Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat Immunol 2000;1:475–82.
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      1. Lund FE,
      2. Garvy BA,
      3. Randall TD,
      4. et al
      . Regulatory roles for cytokine-producing B cells in infection and autoimmune disease. Curr Dir Autoimmun 2005;8:25–54.
      OpenUrlPubMed
    11. ↵
      1. Barr TA,
      2. Shen P,
      3. Brown S,
      4. et al
      . B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells. J Exp Med 2012;209:1001–10.
      OpenUrlAbstract/FREE Full Text
    12. ↵
      1. Kallenberg CG,
      2. Vissink A,
      3. Kroese FG,
      4. et al
      . What have we learned from clinical trials in primary Sjögren's syndrome about pathogenesis? Arthritis Res Ther 2011;13:205.
      OpenUrlCrossRefPubMed
    View Abstract

    Footnotes

    • 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.