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Correspondence
Ustekinumab inhibits Th1 and Th17 polarisation in a patient with giant cell arteritis
  1. Maxime Samson1,2,
  2. Thibault Ghesquière2,
  3. Sabine Berthier1,
  4. Bernard Bonnotte1,2
  1. 1 Department of Internal Medicine and Clinical Immunology, François Mitterrand Hospital, Dijon University Hospital, Dijon, France
  2. 2 INSERM, UMR1098, University of Bourgogne Franche-Comté, FHU INCREASE, Dijon, France
  1. Correspondence to Pr Bernard Bonnotte, Department of Internal Medicine and Clinical Immunology, François Mitterrand Hospital, Dijon University Hospital, 21000 Dijon, France; bernard.bonnotte{at}chu-dijon.fr

https://doi.org/10.1136/annrheumdis-2017-211622

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    Although glucocorticoids (GC) remain the corner stone of giant cell arteritis (GCA) treatment, GC-sparing strategies are needed because GC are responsible for side effects.1 Recent advances in the pathophysiology of GCA showed that CD4+ T cells are recruited in the arterial wall and polarised into Th1 and Th17 cells,2 3 the latter being sensitive to GC-mediated suppression, whereas Th1 response persists in GC-treated patients,2 which triggers the recruitment of macrophages4 and could be implicated in the occurrence of relapses when GC are tapered. Interleukin (IL)-12 and IL-23 are two cytokines involved in Th1 and Th17 polarisations, respectively.5 These two cytokines share a common subunit (p40), which allows ustekinumab, a humanised anti-p40 monoclonal antibody, to target both IL-12 and IL-23 pathways, thus disrupting in theory Th1 and Th17 immune responses.6 Recently, an open-label study reported on the efficacy and safety of ustekinumab in 14 patients with refractory GCA7 but data about T-cell polarisation were not available.

    Three years after the biopsy-proven diagnosis of GCA, a 70-year-old patient started azathioprine (100 mg/day) because of corticodependence. In July 2008, while azathioprine had been stopped, a relapse occurred: weakness, aortitis and C reactive protein (CRP) at 60 mg/L. Therefore, methotrexate was started in association with prednisone. Eighteen months later, the disease remained active (weakness, headache and CRP at 20 mg/L) despite 20 mg/week of methotrexate and 10 mg/day of prednisone. As tocilizumab was contraindicated because of a past history of sigmoiditis, methotrexate was stopped and ustekinumab was started (45 mg at week 0, week 4 and then every 12 weeks) in association with prednisone (10 mg/day). After 4 months of treatment, prednisone was decreased to 8 mg/day and the patient was free of GCA symptoms with a CRP level at 12 mg/L.

    Blood samples were obtained before and after 16 weeks of treatment with ustekinumab. Peripheral blood mononuclear cells (PBMCs) were obtained by Ficoll gradient centrifugation and flow cytometry analyses were performed. For intracellular staining of cytokines, PBMCs were stimulated for 4 hours with phorbol-12-myristate-23-acetate and ionomycin in the presence of brefeldin. Data were acquired on an LSRII cytometer and analysed with FlowJo software.

    We observed that the proportion of both Th1 and Th17 cells fell by 50% after three injections of ustekinumab (Th17: from 0.38% to 0.18% of total CD4+ cells; Th1: from 2.15% to 1.18% of total CD4+ cells). Consistently with the decrease in Th1 cells, the percentage of circulating cytotoxic T lymphocytes also fell from 32.3% to 11.4% of total CD3+CD8+ T cells. By contrast, Treg increased from 0.47% to 2.54% of total CD4+ T cells (figure 1).

    Figure 1
    Figure 1

    (A, B) flow cytometry analysis of the percentage of Treg (CD4+CD25highFoxP3+) among total CD4+T cells before (A) and after (B) treatment with ustekinumab. Dot plots show the CD25/FoxP3 staining after gating on CD4+T lymphocytes.C, D:flow cytometry analysis of the percentage of Th17 cells (CD3+CD4+IL-17+) among total CD3+CD4+T cells before (C) and after (D) treatment with ustekinumab. (E, F) flow cytometry analysis of the percentage of Th1 cells (CD3+CD4+IFN-γ+) among total CD3+CD4+T cells before (E) and after (F) treatment with ustekinumab. (G, H) flow cytometry analysis of the percentage of cytotoxic T lymphocytes (CTL: CD3+CD8+perforin+granzymeB+) among total CD3+CD8+T cells before (H) and after (H) treatment with ustekinumab. Dot plots show the perforin/granzyme B staining after gating on CD3+CD8+T lymphocytes.CTL, cytotoxic T lymphocyte; IFN, interferon; IL, interleukin.

    Though our data came from only one patient, they are consistent with the reported efficacy of ustekinumab in GCA.7 Furthermore, they suggest that ustekinumab, by blocking both IL-12 and IL-23 pathways, could inhibit Th1, Th17 and cytotoxic immune responses and restore the quantitative deficiency of Treg, which is described in GCA.3 In terms of correction of T-cell homeostasis, the effect of ustekinumab could be more complete than that of tocilizumab, which is effective to treat GCA8 by targeting the Th17/Treg balance.9 10

    Acknowledgments

    The authors thank Marion Ciudad for her help in doing experiments. They thank Anabelle Legrand, Arlette Hamman and Serge Monier from the Plateforme de Cytométrie, Institut Férératif de Recherche 100, Université de Bourgogne. They also thank Philip Bastab22le for his help in writing the manuscript.

    References

    1. ↵
      2. Proven A ,
      3. Gabriel SE ,
      4. Orces C , et al
      . Glucocorticoid therapy in giant cell arteritis: duration and adverse outcomes. Arthritis Rheum 2003;49:703–8. doi:10.1002/art.11388
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      2. Deng J ,
      3. Ma-Krupa W ,
      4. Gewirtz AT , et al
      . Toll-like receptors 4 and 5 induce distinct types of vasculitis. Circ Res 2009;104:488–95. doi:10.1161/CIRCRESAHA.108.185777
      OpenUrlAbstract/FREE Full Text
    3. ↵
      2. Samson M ,
      3. Audia S ,
      4. Fraszczak J , et al
      . Th1 and Th17 lymphocytes expressing CD161 are implicated in giant cell arteritis and polymyalgia rheumatica pathogenesis. Arthritis Rheum 2012;64:3788–98. doi:10.1002/art.34647
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      2. Corbera-Bellalta M ,
      3. Planas-Rigol E ,
      4. Lozano E , et al
      . Blocking interferon γ reduces expression of chemokines CXCL9, CXCL10 and CXCL11 and decreases macrophage infiltration in ex vivo cultured arteries from patients with giant cell arteritis. Ann Rheum Dis 2016;75:1177–86. doi:10.1136/annrheumdis-2015-208371
      OpenUrlAbstract/FREE Full Text
    5. ↵
      2. Annunziato F ,
      3. Romagnani C ,
      4. Romagnani S
      . The 3 major types of innate and adaptive cell-mediated effector immunity. J Allergy Clin Immunol 2015;135:626–35. doi:10.1016/j.jaci.2014.11.001
      OpenUrlCrossRefPubMed
    6. ↵
      2. Teng MW ,
      3. Bowman EP ,
      4. McElwee JJ , et al
      . IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med 2015;21:719–29. doi:10.1038/nm.3895
      OpenUrlCrossRefPubMed
    7. ↵
      2. Conway R ,
      3. O’Neill L ,
      4. O’Flynn E , et al
      . Ustekinumab for the treatment of refractory giant cell arteritis. Ann Rheum Dis 2016;75:1578–9. doi:10.1136/annrheumdis-2016-209351
      OpenUrlFREE Full Text
    8. ↵
      2. Villiger PM ,
      3. Adler S ,
      4. Kuchen S , et al
      . Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2016;387:1921–7. doi:10.1016/S0140-6736(16)00560-2
      OpenUrl
    9. ↵
      2. Samson M ,
      3. Audia S ,
      4. Janikashvili N , et al
      . Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. Arthritis Rheum 2012;64:2499–503. doi:10.1002/art.34477
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      2. Miyabe C ,
      3. Miyabe Y ,
      4. Strle K , et al
      . An expanded population of pathogenic regulatory T cells in giant cell arteritis is abrogated by IL-6 blockade therapy. Ann Rheum Dis 2017;76:898–905. doi:10.1136/annrheumdis-2016-210070
      OpenUrlAbstract/FREE Full Text

    Footnotes

    • Contributors MS and TG did the experiments and collected data. SB included the patient. MS and BB wrote the manuscript.

    • Competing interests None declared.

    • Patient consent Obtained

    • Ethics approval The Institutional Review Board and the Ethics Committee of Dijon University Hospital.

    • Provenance and peer review Not commissioned; internally peer reviewed.

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