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Observational Study
. 2017 Jul;76(7):1207-1218.
doi: 10.1136/annrheumdis-2016-210503. Epub 2017 Feb 10.

Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS)

Ariane L Herrick  1   2 , Xiaoyan Pan  3 , Sébastien Peytrignet  3 , Mark Lunt  3 , Roger Hesselstrand  4 , Luc Mouthon  5 , Alan Silman  6 , Edith Brown  7 , László Czirják  8 , Jörg H W Distler  9 , Oliver Distler  10 , Kim Fligelstone  11 , William J Gregory  12 , Rachel Ochiel  11 , Madelon Vonk  13 , Codrina Ancuţa  14 , Voon H Ong  15 , Dominique Farge  16 , Marie Hudson  17 , Marco Matucci-Cerinic  18 , Alexandra Balbir-Gurman  19 , Øyvind Midtvedt  20 , Alison C Jordan  21 , Paresh Jobanputra  21 , Wendy Stevens  22 , Pia Moinzadeh  23 , Frances C Hall  24 , Christian Agard  25 , Marina E Anderson  26 , Elisabeth Diot  27 , Rajan Madhok  28 , Mohammed Akil  29 , Maya H Buch  30 , Lorinda Chung  31 , Nemanja Damjanov  32 , Harsha Gunawardena  33 , Peter Lanyon  34 , Yasmeen Ahmad  35 , Kuntal Chakravarty  36 , Søren Jacobsen  37 , Alexander J MacGregor  38 , Neil McHugh  39 , Ulf Müller-Ladner  40 , Gabriela Riemekasten  41 , Michael Becker  42 , Janet Roddy  43 , Patricia E Carreira  44 , Anne Laure Fauchais  45 , Eric Hachulla  46 , Jennifer Hamilton  47 , Murat İnanç  48 , John S McLaren  49 , Jacob M van Laar  50 , Sanjay Pathare  51 , Susannah Proudman  52 , Anna Rudin  53 , Joanne Sahhar  54 , Brigitte Coppere  55 , Christine Serratrice  56 , Tom Sheeran  57 , Douglas J Veale  58 , Claire Grange  59 , Georges-Selim Trad  60 , Christopher P Denton  15
Affiliations
Observational Study

Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS)

Ariane L Herrick et al. Ann Rheum Dis. 2017 Jul.

Abstract

Objectives: The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches.

Methods: This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival.

Results: Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: -4.0 (-5.2 to -2.7) units for methotrexate, -4.1 (-5.3 to -2.9) for MMF, -3.3 (-4.9 to -1.7) for cyclophosphamide and -2.2 (-4.0 to -0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months.

Conclusions: These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed.

Trial registration number: NCT02339441.

Keywords: Cyclophosphamide; Methotrexate; Systemic Sclerosis; Treatment.

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Conflict of interest statement

Competing interests: ALH has done consultancy work for Actelion, served on a Data Safety Monitoring Board for Apricus, received research funding and speaker's fees from Actelion, and speaker's fees from GSK. JHWD has consultancy relationships and/or has received research funding from Actelion, BMS, Celgene, Bayer Pharma, Boehringer Ingelheim, JB Therapeutics, Sanofi-Aventis, Novartis, UCB, GSK, Array Biopharma, Active Biotech, Galapagos, Inventiva, Medac, Pfizer, Anamar and RuiYi and is stock owner of 4D Science GmbH. OD has received consultancy fees from 4D Science, Actelion, Active Biotech, Bayer, Biogenidec, BMS, Boehringer Ingelheim, EpiPharm, Ergonex, espeRare Foundation, Genentech/Roche, GSK, Inventiva, Lilly, Medac, Medimmune, Pharmacyclics, Pfizer, Serodapharm, and Sinoxa and received research grants from Actelion, Bayer, Boehringer Ingelheim, Ergonex, Pfizer and Sanofi, and has a patent mir-29 for the treatment of systemic sclerosis licenced. WG has received teaching fees from Pfizer. FH has received research funding from Actelion. MEA has undertaken advisory board work and received honoraria from Actelion, and received speaker's fees from Bristol-Myers Squibb. LC has done advisory board work for Gilead and served Data Safety Monitoring Boards for Cytori and Reata. HG has done consultancy work and received honoraria from Actelion. UM-L is funded in part bu EUSTAR/EULAR. JMvL has received honoraria from Eli Lilly, Pfizer, Roche, MSD and BMS. AR receives funding from AstraZeneca. CPD has done consultancy for GSK, Actelion, Bayer, Inventiva and Merck-Serono, received research grant funding from GSK, Actelion, CSL Behring and Inventiva, received speaker's fees from Bayer and given trial advice to Merck-Serono.

Figures

Figure 1
Figure 1
Progression of patients through the study.
Figure 2
Figure 2
Modified Rodnan skin score (mRSS) during baseline and follow-up visits, by initial protocol. For each group of patients, according to their initial protocol, the distribution of the skin score is illustrated on the left-hand side by box and whisker plots (indicating the median and IQR) at baseline, 12 and 24 months. On the right-hand side, the distribution of individual 1-year changes in the skin score is described by histograms and a kernel density estimate. In addition, a vertical green line indicates the value of the average 1-year change in the skin score, irrespective of treatment choice. The bottom panel in the figure describes the estimated changes in mRSS (with 95% CI) according to initial protocol, based on the results from the adjusted model (described in table 3).
Figure 3
Figure 3
Kaplan-Meier estimated survival curves by treatment group.
See this image and copyright information in PMC

References

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