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Observational Study
. 2020 Feb 18;22(1):30.
doi: 10.1186/s13075-020-2113-6.

Early trajectories of skin thickening are associated with severity and mortality in systemic sclerosis

Emmanuel Ledoult  1   2   3 , David Launay  1   2   3 , Hélène Béhal  4 , Luc Mouthon  5 , Grégory Pugnet  6 , Jean-Christophe Lega  7 , Christian Agard  8 , Yannick Allanore  9 , Patrick Jego  10 , Anne-Laure Fauchais  11 , Jean-Robert Harlé  12 , Sabine Berthier  13 , Achille Aouba  14 , Arsène Mekinian  15 , Elisabeth Diot  16 , Marie-Elise Truchetet  17 , Carine Boulon  18 , Alain Duhamel  4 , Eric Hachulla  1   2   3 , Vincent Sobanski  19   20   21 ; French National Scleroderma Cohort Network
Collaborators, Affiliations
Observational Study

Early trajectories of skin thickening are associated with severity and mortality in systemic sclerosis

Emmanuel Ledoult et al. Arthritis Res Ther. .

Abstract

Background: Systemic sclerosis (SSc) is a severe and highly heterogeneous disease. The modified Rodnan skin score (mRSS) is a widely used tool for the assessment of the extent and degree of skin thickness. This study aimed to identify the classes of patients with early similar skin thickening trajectories without any a priori assumptions and study their associations with organ involvement and survival.

Methods: From the French SSc national cohort, patients with a disease duration of less than 2 years at inclusion and with at least 2 mRSS available within the first 4 years of follow-up were enrolled. Classes of patients with similar mRSS trajectories were identified based on a latent class mixed model. The clinical characteristics and survival rate were compared between the obtained classes.

Results: A total of 198 patients fulfilled the inclusion criteria, with a total of 641 mRSS available. The median disease duration and follow-up were 0.8 (interquartile range 0.4; 1.2) and 6.3 (3.8; 8.9) years, respectively. Individual trajectories of mRSS were highly heterogeneous between patients. Models with 1-6 latent classes of trajectories were sequentially assessed, and the 5-class model represented the best fit to data. Each class was characterized by a unique global trajectory of mRSS. The median disease duration did not differ significantly between classes. Baseline organ involvement was more frequent in classes with significant change over time (classes 2-5) than in class 1 (low baseline mRSS without significant change over time). Using Cox regression, we observed a progressively increasing risk of death from classes 1 to 5.

Conclusions: Early identification of clinical phenotype based on skin thickening trajectories could predict morbi-mortality in SSc. This study suggested that mRSS trajectories characterization might be pivotal for clinical practice and future trial designs.

Keywords: Clinical heterogeneity; Modified Rodnan skin score; Skin thickening trajectories; Systemic sclerosis.

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Conflict of interest statement

David Launay reports grants and personal fees from Actelion, Shire, CSL Behring, GSK, and Roche; personal fees from Boehringer Ingelheim; and grants from Octapharma outside the submitted work. Christian Agard reports grants and personal fees from Roche-Chugai and Boehringer Ingelheim outside the submitted work. Yannick Allanore reports grants from Inventiva and Sanofi; personal fees from Bayer, Boehringer Ingelheim, Chemomab, Inventiva, Roche, and Sanofi. Nadine Magy-Bertrand reports grants from GSK outside the submitted work. Olivier Lidove reports grants and personal fees from Amicus, Genzyme/Sanofi, and Shire HGT outside the submitted work. Francois Maurier reports personal fees from Actelion, and Chugaï; non-financial support from Amgen, Janssen, GSK, and Novartis outside the submitted work. Eric Hachulla reports grants from CSL Behring, Grifols and Octapharma; personal fees from Actelion, Bayer, Boehringer Ingelheim, GSK, Roche-Chugai, and Sanofi-Genzyme; grants from Actelion, GSK, and Roche-Chugai outside of the submitted work. Vincent Sobanski reports personal fees from Grifols; grants from Actelion, CSL Behring, Grifols, GSK, Octapharma, Pfizer, and Shire outside the submitted work. The other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow-chart. RP: Raynaud’s phenomenon; mRSS: modified Rodnan skin score
Fig. 2
Fig. 2
The 5-class LCMM results. (Left) All individual trajectories and the average trend estimated using B-splines. (Right) Results of the 5-class LCMM. Time 0 was defined by the date of baseline mRSS record. mRSS: modified Rodnan skin score
Fig. 3
Fig. 3
Clinical characteristics of the 5 trajectory classes of the 5-class LCMM. a Each class’ spaghetti-plot of the 5-class LCMM with the modeled trajectory estimated using B-splines. Time 0 was defined by the date of the baseline mRSS record. mRSS: modified Rodnan skin score. b Graphs representing the autoantibodies in each class. ACA: anti-centromere antibodies; RNAP3: anti-RNA polymerase III antibodies; ATA: anti-topoisomerase I antibodies; others: no specific SSc target antibodies. c Graphs illustrating the main organ involvement in each class. DU: digital ulcers; GIT: gastrointestinal tracts; ILD: interstitial lung disease; PH: pulmonary hypertension; SRC: scleroderma renal crisis
Fig. 4
Fig. 4
Survival of the 5 trajectory classes of the 5-class LCMM. a Kaplan-Meier curves of 5-class LCMM (p = 0.025). Time 0 was defined by the date of the first non-Raynaud’s Phenomenon symptom. b Forest plot showing mortality hazard ratios and 95% confidence intervals for the 5 trajectory classes before (top) or after (bottom) adjusting for sex and age. Broken line shows the hazard ratio for the reference group
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