Hit hard and early: analysing the effects of high-dose methylprednisolone on nailfold capillary changes and biomarkers in very early systemic sclerosis: study protocol for a 12-week randomised controlled trial

Wieneke M T van den Hombergh, Brigit E Kersten, Hanneke K A Knaapen-Hans, Rogier M Thurlings, Peter M van der Kraan, Frank H J van den Hoogen, Jaap Fransen, Madelon C Vonk, Wieneke M T van den Hombergh, Brigit E Kersten, Hanneke K A Knaapen-Hans, Rogier M Thurlings, Peter M van der Kraan, Frank H J van den Hoogen, Jaap Fransen, Madelon C Vonk

Abstract

Background: Mounting evidence indicates that inflammatory mechanisms drive systemic sclerosis (SSc) vasculopathy and fibrosis, especially early in the disease. Therefore, patients with very early SSc could benefit from early treatments targeting inflammation. Glucocorticoids are among the most potent anti-inflammatory and immunosuppressive agents. Several studies have demonstrated a mixed response to treatment with glucocorticoids in SSc, probably because it is seldom initiated at very early stages of the disease. We hypothesise that by inhibiting the inflammatory process driving SSc disease progression, glucocorticoid treatments will induce remission in patients with very early SSc.

Methods/design: This study is a 12-week, randomised, double-blind, placebo-controlled trial analysing the effects of high-dose intravenous methylprednisolone in very early SSc. Thirty patients who fulfil the criteria for very early SSc will be randomly assigned in a 2:1 ratio to receive either intravenous methylprednisolone or a placebo on three consecutive days over three consecutive months. In this study, the primary endpoint will be the change in capillary density between the baseline and after 12 weeks of treatment. The secondary outcomes of this study are a change in selected biomarkers, other changes in the nailfold capillaries, signs of established SSc and changes in physical function, general health and utilities, as reported through questionnaires.

Discussion: This trial is the first aiming to treat very early SSc and is promising because it targets the very early stages of the disease process by using an inexpensive and relatively safe treatment known to be highly effective against inflammation. The use of vasculopathy and inflammatory biomarkers as well as clinical signs and symptoms as the endpoints in our study enables us to meet the patient need for markers of disease activity. If it is possible to prevent clinically significant disease in patients with very early SSc by using a safe treatment, this will cause a paradigm shift in scleroderma care and research.

Trial registration: ClinicalTrials.gov Identifier: NCT03059979 . Registered on 20 February 2017.

Keywords: Methylprednisolone; Nailfold capillaroscopy; Randomised controlled trial; Systemic sclerosis; Very early diagnosis of systemic sclerosis.

Conflict of interest statement

Ethics approval and consent to participate

The study received ethical review board approval: CMO Regio Arnhem-Nijmegen (2015–004613-24).

Informed consent from all participants in the study is obtained by one of the study doctors.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Study visits and procedures. Pulmonary function tests consisting of vital capacity, total lung capacity and carbon monoxide (CO) diffusion capacity. Plasma biomarkers consist of CXCL4, interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNFα), IL-6, ET-1, intercellular adhesion molecule 1 (ICAM-1) and vascular endothelial growth factor (VEGF). Abbreviation: HRCT high-resolution computer tomography

References

    1. Kowal-Bielecka O, Landewe R, Avouac J, Chwiesko S, Miniati I, Czirjak L, et al. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR scleroderma trials and research group (EUSTAR) Ann Rheum Dis. 2009;68(5):620–628. doi: 10.1136/ard.2008.096677.
    1. Geyer M, Muller-Ladner U. The pathogenesis of systemic sclerosis revisited. Clin Rev Allergy Immunol. 2011;40(2):92–103. doi: 10.1007/s12016-009-8193-3.
    1. van Bon L, Affandi AJ, Broen J, Christmann RB, Marijnissen RJ, Stawski L, et al. Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N Engl J Med. 2014;370(5):433–443. doi: 10.1056/NEJMoa1114576.
    1. Radstake TR, Gorlova O, Rueda B, Martin JE, Alizadeh BZ, Palomino-Morales R, et al. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet. 2010;42(5):426–429. doi: 10.1038/ng.565.
    1. Greenblatt MB, Aliprantis AO. The immune pathogenesis of scleroderma: context is everything. Curr Rheumatol Rep. 2013;15(1):297. doi: 10.1007/s11926-012-0297-8.
    1. Hua-Huy T, Dinh-Xuan AT. Cellular and molecular mechanisms in the pathophysiology of systemic sclerosis. Pathol Biol (Paris) 2015;63(2):61–68. doi: 10.1016/j.patbio.2015.03.003.
    1. Xing X, Yang J, Yang X, Wei Y, Zhu L, Gao D, et al. IL-17A induces endothelial inflammation in systemic sclerosis via the ERK signaling pathway. PLoS One. 2013;8(12):e85032. doi: 10.1371/journal.pone.0085032.
    1. Lafyatis R, York M. Innate immunity and inflammation in systemic sclerosis. Curr Opin Rheumatol. 2009;21(6):617–622. doi: 10.1097/BOR.0b013e32832fd69e.
    1. Marie I, Mouthon L. Therapy of polymyositis and dermatomyositis. Autoimmun Rev. 2011;11(1):6–13. doi: 10.1016/j.autrev.2011.06.007.
    1. Hahn BH, Kantor OS, Osterland CK. Azathioprine plus prednisone compared with prednisone alone in the treatment of systemic lupus erythematosus. Report of a prospective controlled trial in 24 patients. Ann Intern Med. 1975;83(5):597–605. doi: 10.7326/0003-4819-83-5-597.
    1. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med. 2005;353(16):1711–1723. doi: 10.1056/NEJMra050541.
    1. Iudici M, van der Goes MC, Valentini G, Bijlsma JW. Glucocorticoids in systemic sclerosis: weighing the benefits and risks - a systematic review. Clin Exp Rheumatol. 2013;31(2 Suppl 76):157–165.
    1. Czirjak L, Matucci-Cerinic M. Beyond Raynaud's phenomenon hides very early systemic sclerosis: the assessment of organ involvement is always mandatory. Rheumatology (Oxford) 2011;50(2):250–251. doi: 10.1093/rheumatology/keq374.
    1. Griffiths B, Miles S, Moss H, Robertson R, Veale D, Emery P. Systemic sclerosis and interstitial lung disease: a pilot study using pulse intravenous methylprednisolone and cyclophosphamide to assess the effect on high resolution computed tomography scan and lung function. J Rheumatol. 2002;29(11):2371–2378.
    1. Vanthuyne M, Blockmans D, Westhovens R, Roufosse F, Cogan E, Coche E, et al. A pilot study of mycophenolate mofetil combined to intravenous methylprednisolone pulses and oral low-dose glucocorticoids in severe early systemic sclerosis. Clin Exp Rheumatol. 2007;25(2):287–292.
    1. Minier T, Guiducci S, Bellando-Randone S, Bruni C, Lepri G, Czirjak L, et al. Preliminary analysis of the very early diagnosis of systemic sclerosis (VEDOSS) EUSTAR multicentre study: evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis. Ann Rheum Dis. 2014;73(12):2087–2093. doi: 10.1136/annrheumdis-2013-203716.
    1. Matucci-Cerinic M, Bellando-Randone S, Lepri G, Bruni C, Guiducci S. Very early versus early disease: the evolving definition of the 'many faces' of systemic sclerosis. Ann Rheum Dis. 2013;72(3):319–321. doi: 10.1136/annrheumdis-2012-202295.
    1. Smith V, Decuman S, Sulli A, Bonroy C, Piettte Y, Deschepper E, et al. Do worsening scleroderma capillaroscopic patterns predict future severe organ involvement?a pilot study. Ann Rheum Dis. 2012;71(10):1636–1639. doi: 10.1136/annrheumdis-2011-200780.
    1. van Laar JM, Farge D, Tyndall A. Autologous stem cell transplantation international scleroderma (ASTIS) trial: hope on the horizon for patients with severe systemic sclerosis. Ann Rheum Dis. 2005;64(10):1515. doi: 10.1136/ard.2005.043240.
    1. Miniati I, Guiducci S, Conforti ML, Rogai V, Fiori G, Cinelli M, et al. Autologous stem cell transplantation improves microcirculation in systemic sclerosis. Ann Rheum Dis. 2009;68(1):94–98. doi: 10.1136/ard.2007.082495.
    1. Valentini G, Marcoccia A, Cuomo G, Vettori S, Iudici M, Bondanini F, et al. Early systemic sclerosis: analysis of the disease course in patients with marker autoantibody and/or capillaroscopic positivity. Arthritis Care Res (Hoboken). 2014;66(10):1520–1527. doi: 10.1002/acr.22304.
    1. Kowal-Bielecka O. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017;76(8):1327–1339. doi: 10.1136/annrheumdis-2016-209909.
    1. Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science. 1995;270(5234):286–290. doi: 10.1126/science.270.5234.286.
    1. Davies CA, Jeziorska M, Freemont AJ, Herrick AL. The differential expression of VEGF, VEGFR-2, and GLUT-1 proteins in disease subtypes of systemic sclerosis. Hum Pathol. 2006;37(2):190–197. doi: 10.1016/j.humpath.2005.10.007.
    1. Stratton RJ, Coghlan JG, Pearson JD, Burns A, Sweny P, Abraham DJ, et al. Different patterns of endothelial cell activation in renal and pulmonary vascular disease in scleroderma. QJM. 1998;91(8):561–566. doi: 10.1093/qjmed/91.8.561.
    1. Greenberg SA, Higgs BW, Morehouse C, Walsh RJ, Kong SW, Brohawn P, et al. Relationship between disease activity and type 1 interferon- and other cytokine-inducible gene expression in blood in dermatomyositis and polymyositis. Genes Immun. 2012;13(3):207–213. doi: 10.1038/gene.2011.61.
    1. Higgs BW, Liu Z, White B, Zhu W, White WI, Morehouse C, et al. Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway. Ann Rheum Dis. 2011;70(11):2029–2036. doi: 10.1136/ard.2011.150326.
    1. van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2013;72(11):1747–1755. doi: 10.1136/annrheumdis-2013-204424.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner