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Controlling the digital ulcerative disease in systemic sclerosis is associated with improved hand function
Author’s Accepted Manuscript Controlling the digital ulcerative disease in systemic sclerosis is associated with improved hand functionControl of digital ulcerative disease in SSc with bosentan Luc Mouthon, Patrick H. Carpentier, Catherine Lok, Pierre Clerson, Virginie Gressin, Eric Hachulla, Alice Bérezné, Elisabeth Diot, Aurélie Khau Van Kien, Patrick Jego, Christian Agard, Anne Bénédicte Duval-Modeste, Agnès Sparsa, Eve Puzenat, Marie-Aleth Richard
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S0049-0172(17)30036-7 http://dx.doi.org/10.1016/j.semarthrit.2017.01.001 YSARH51136
To appear in: Seminars in Arthritis and Rheumatism Cite this article as: Luc Mouthon, Patrick H. Carpentier, Catherine Lok, Pierre Clerson, Virginie Gressin, Eric Hachulla, Alice Bérezné, Elisabeth Diot, Aurélie Khau Van Kien, Patrick Jego, Christian Agard, Anne Bénédicte Duval-Modeste, Agnès Sparsa, Eve Puzenat and Marie-Aleth Richard, Controlling the digital ulcerative disease in systemic sclerosis is associated with improved hand functionControl of digital ulcerative disease in SSc with bosentan, Seminars in Arthritis and Rheumatism, http://dx.doi.org/10.1016/j.semarthrit.2017.01.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Control of digital ulcerative disease in SSc
Controlling the digital ulcerative disease in systemic sclerosis is associated with improved hand function Running head: Control of digital ulcerative disease in SSc with bosentan Luc Mouthon1, MD, PhD; Patrick H. Carpentier2, MD; Catherine Lok3, MD; Pierre Clerson4, MD; Virginie Gressin5, MD; Eric Hachulla6, MD, PhD; Alice Bérezné1, MD; Elisabeth Diot7, MD, PhD; Aurélie Khau Van Kien8, MD; Patrick Jego9, MD, PhD; Christian Agard10, MD, PhD; Anne Bénédicte Duval-Modeste11, MD; Agnès Sparsa12, MD, PhD; Eve Puzenat13, MD; MarieAleth Richard14, MD, PhD, on behalf of the ECLIPSE study investigators Institutional addresses: 1Paris Descartes University, Cochin Hospital, Assistance PubliqueHôpitaux de Paris, Internal Medicine, Paris, France; 2University Hospital Grenoble, Vascular Medicine, Grenoble, France; 3University Hospital Amiens, Dermatology, Amiens, France; 4
Orgamétrie Biostatistics, Roubaix, France; 5Actelion Pharmaceuticals France, Paris, France;
6
Claude Huriez Hospital, Lille 2 University, Internal Medicine, Lille, France; 7Bretonneau
Hospital, Internal Medicine, Tours, France; 8Saint Eloi Hospital, Internal Medicine, Montpellier, France; 9University Hospital Rennes, Internal Medicine, Rennes, France; Nantes, Internal Medicine, Nantes, France; France;
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11
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University Hospital
University Hospital Rouen, Dermatology, Rouen,
University Hospital Limoges, Dermatology, Limoges, France ;
Hospital, Dermatology, Besançon, France;
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13
Saint Jacques
Aix-Marseille University, la Timone Hospital,
Assistance Publique-Hôpitaux de Marseille, Dermatology, Marseille, France. e-mail
addresses:
1
[email protected],
2
[email protected],
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[email protected], [email protected], [email protected],
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[email protected],
1
[email protected],
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[email protected], [email protected],
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[email protected], 10
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a-
[email protected],
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Control of digital ulcerative disease in SSc
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[email protected],
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[email protected],
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epuzenat@chu-
besancon.fr, [email protected] Financial support: This study was sponsored by Actelion Pharmaceuticals France. Actelion Pharmaceuticals France provided funding for logistical support, patient monitoring, project management, data management, and independent statistical analysis. Actelion Pharmaceuticals Ltd. provided funding for medical writing. Conflict of interest: Dr Mouthon reports grants from Actelion during the conduct of the study. Dr. Lok reports consulting fees from Actelion. Dr. Hachulla reports grants and personal fees from Actelion and GlaxoSmithKline, and personal fees from PFIZER, outside the submitted work. Dr Gressin is a full time employee of Actelion Pharmaceuticals France, as medical director. Dr Jego reports personal fees and non-financial support from Actelion, Pfizer, Lilly France, and GlaxoSmithKline, outside the submitted work. Drs. Carpentier and Richard report personal fees from Actelion during the conduct of the study. Drs Bérezné, Clerson, Diot, Khau Van Kien, Agard, Duval-Modeste, Sparsa, and Puzenat have nothing to disclose. Corresponding author: Luc Mouthon, MD, PhD. Service de Médecine Interne, Hôpital Cochin 27, Rue du Faubourg Saint-Jacques 75679 Paris Cedex 14 Tel: +33-(0)1 58 41 20 31; Fax: +33-(0)1 58 41 14 50; E-mail: [email protected]
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Abstract Objectives: Ischemic digital ulcers (DU) represent a major complication of systemic sclerosis (SSc). We investigated the impact of controlling the ulcerative disease on disability, pain, and quality of life in SSc patients receiving bosentan. Methods: ECLIPSE (Study AC-052-517) is a 2-year prospective, multicenter, observational study. Patients with SSc who experienced at least one DU in the previous year and received bosentan were included between October 2009 and March 2011. Disability scores (Cochin Hand Function Scale (CHFS), Health Assessment Questionnaire Disability Index (HAQ-DI)), pain scores (Visual Analog Scale), and quality of life scores (SF-36) were collected at inclusion and one year later (primary endpoint). A controlled ulcerative disease was defined by the absence of on-going/new DU episode between inclusion and one-year follow-up. Results: Data were available at one year for 120 patients out of 190 included. During follow-up, 46 (38.3%) patients experienced a new DU episode. The number of DU per patient decreased from 1.4±1.8 at inclusion to 0.6±1.6 (p < 0.0001) at 1 year. Disability scores decreased from 1.0±0.7 to 0.9±0.7 (p = 0.04) for the HAQ-DI and from 29±20 to 25±20 (p = 0.005) for the CHFS; the pain score decreased from 4.3±3.1 to 2.9±2.8 (p < 0.0001). This improvement was attributed to patients with a controlled ulcerative disease (48.3%), who significantly improved HAQ-DI (p = 0.04), CHFS (p = 0.04), and pain score (p = 0.046). Conclusions: In patients with SSc, control of the ulcerative disease for one year was associated with significant attenuation of hand disability.
Key words: systemic sclerosis; digital ulcers; hand; disability; bosentan.
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Clinical significance
What was already known before the study was performed?
SSc patients with active DU have reduced wrist and hand mobility and greater impairment of hand function compared with those patients without active DU. Hand disability develops as soon as one DU is present
What was learned from this study?
This prospective, observational study shows that the control of the ulcerative disease for one year (i.e. absence of active digital ulcer at the one-year assessment and no occurrence of new digital ulcer episode over the one-year follow-up) is associated with a significant attenuation of hand disability, as assessed by the Cochin Hand Function Scale (CHFS), independently of other factors limiting hand function. Functional improvement was attributed to patients with a controlled ulcerative disease (48.3%), who significantly improving health assessment questionnaire disability index (HAQ-DI) (p = 0.04), CHFS (p = 0.04), and visual analog scale for pain (p = 0.046).
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1
Introduction
Systemic sclerosis (SSc) is a connective tissue disease characterized by vascular hyper-reactivity and remodeling, cutaneous and visceral fibrosis, and immune system activation [1,2]. As vascular damage progresses, reduced perfusion of the skin and visceral microvascular beds leads to a state of chronic ischemia favoring fibroblast activation and extra-cellular matrix synthesis. Raynaud's phenomenon and digital ulcers (DUs) are typical manifestations of the underlying vasculopathy that characterizes SSc [3]. About 44-60% of patients with SSc experience one or more digital ulcers (DU) at some point in their disease course [4-8]. Ulcers on the fingertips and over the interphalangeal joints heal slowly with residual scars and digital resorption. They can be complicated by infection leading to osteitis, and progression to gangrene requiring amputation [4,6]. In addition, DU are painful, cause severe functional disability, and have a major impact on quality of life (QoL) [4,7]. Severe DU may necessitate hospitalization and time away from the workplace [6,7]. We recently reported that SSc patients with active DU have reduced wrist and hand mobility [9] and greater impairment of hand function [10] compared with those patients without active DU. Furthermore, hand disability develops as soon as one DU is present [10]. Patients’ education is key in DU prevention, with recommendation for reducing cold exposure, avoiding tobacco intake and vasoconstrictive agents, and preventing hand injury and repeated microtrauma. Pharmacological treatment for SSc-related digital vasculopathy is based on vasodilating medications to improve blood flow to ischemic areas. As such, the oral endothelin receptor antagonist bosentan is approved in Europe to prevent the occurrence of new DU in patients with on-going DU disease [11,12]. In two prospective randomized double-blind controlled trials (RAPIDS-1 [11] and RAPIDS-2 [12]), bosentan significantly reduced the number of new DU (in particular in patients with
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multiple DU) and improved overall hand function, although it did not improve the HAQ-DI nor accelerate the healing of DU. In the present prospective observational study, we investigated the impact of controlling the ulcerative disease on global disability, hand disability, pain, and QoL in patients with SSc treated with bosentan.
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2
Patients and methods
2.1 Study design ECLIPSE (Evaluation of the impact of recurrent ischemic DU on hand disability in patients with SSc) is a prospective, longitudinal, observational, multicenter study with a 2-year follow-up and a primary endpoint at 1 year. The design of the study and the inclusion characteristics of the patients have been described previously [10]. The initial hypothesis of the study was that each new DU episode was associated with a cumulative increase in disability, where a DU episode was defined as a period with at least one active DU between two DU-free periods. However, this approach, based on the number of new DU episodes, does not take in consideration the impact of long-lasting and/or successive DU without DU-free intervals. Therefore, we propose a new definition of disease control: the ulcerative disease is considered as controlled when the patient has no active DU at endpoint and no new DU episode over the follow-up. We subsequently investigated whether disease control over 1 year was associated with preserved functioning and QoL. The study was conducted in compliance with the Good Clinical Practices protocol and Declaration of Helsinki principles. In accordance with French law, formal approval from an ethical committee was not required for this observational study. Patients gave their oral consent to participate.
2.2 Patients The study enrolled patients, aged ≥ 18 years, with limited or diffuse cutaneous SSc according to the 1980 American College of Rheumatology (ACR) [13] or Leroy and Medsger [14] criteria. Enrollment in the study occurred between October 2009 and March 2011, i.e. before the availability of the new ACR/EULAR classification criteria [15]. Eligible patients had to have
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experienced at least one predominantly ischemic DU (new or on-going) during the previous year, whether or not they presented active DU at inclusion. A predominantly ischemic DU was defined as an ulcer located on the pulpar face of the fingers, distal to the proximal interphalangeal joints, and not facing a calcinosis or bone profile (DU not satisfying these conditions were considered as predominantly mechanical DU) [11]. All DU described in the manuscript refer to predominantly ischemic DU identified by a trained physician, unless otherwise specified. Moreover, patients had to be eligible for bosentan therapy as approved by the European Medicines Agency [16]. Treatment with bosentan was on-going or may have been started at entry in the study.
2.3 Patients evaluation After the inclusion visit, visits were scheduled at 1 and 2 years as recommended by the French health authorities [17]. Additional visits could be planned following the healing or the appearance of DU. SSc/DU disease characteristics were collected from the patient’s history as previously described [10]. Patients were allowed to continue their usual treatment for SSc and/or DU in addition to bosentan. Clinical examination included the description of the DU episode if present and looked for potential mechanical causes of hand disability. DU complications (osteitis, infection, gangrene) were recorded at each visit. Global disability was assessed by the Health Assessment Questionnaire (HAQ) that evaluates 20 items related to daily activities divided into 8 domains scored between 0 (no disability) and 3 (maximal disability) [18,19]. The highest score reported in each domain determines the score for that domain. The disability index (HAQ-DI) is expressed on a scale of 0 to 3 units, representing an average score across the domains.
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Hand disability was assessed by the Cochin Hand Function Scale (CHFS) based on 18 items related to daily activities, each scored on a scale of 0 (performed without difficulty) to 5 (impossible to do). The total score is obtained by adding individual scores (range 0-90) [20-22]. QoL was evaluated with the Medical Outcomes Study 36-item Short-Form Health Survey (SF36v2 acute, France) that investigates 8 scales related to QoL. Scale scores are normalized to a mean of 50 and standard deviation of 10 based on the normal US population [23]. Scale scores are summarized in two summary measures: the Physical Component Summary (PCS) and Mental Component Summary (MCS) [24,25]. Scale scores and summary measures are reported on a scale from 0 (poorest) to 100 (best). Pain was rated on a 10-point Visual Analog Scale (VAS) [26]. Skin thickness was assessed with the modified Rodnan skin score, which grades 17 body areas on a scale of 0 (uninvolved skin) to 3 (severe skin thickening) following clinical palpation [27].
2.4 Statistical analysis Data are presented as absolute numbers, percentages, means with corresponding standard deviations, or medians with corresponding 25th and 75th percentiles [inter-quartile range (IQR)]. Comparisons were tested with variance analysis (ANOVA) with baseline adjustment for comparisons between subgroups at one year. The annual incidence rate of DU episodes was estimated from a Poisson regression model with the follow-up duration as offset term. Univariate regression analyses adjusted for differences at baseline were performed to compare the 2 groups of patients with and without a controlled disease and identify relevant covariates impacting the CHFS. The following covariates were considered: 1) mechanical DU including DU located on the dorsal surface of the fingers, DU complicating calcinosis, DU located on bone profile, 2) presence of sequelae including loss of substance, auto-amputation, surgical amputation, digital sympathectomy, and arthrodesis, 3) other non-ischemic factors including
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tendinous retractions, non-ulcerative calcinosis, ankylosis of the distal, proximal interphalangeal joints, ankylosis of the metacarpo-phalangeal joints. A multivariate regression analysis was then conducted to identify independent risk factors associated with an increased CHFS. A p value <0.05 was considered as statistically significant. Statistical analyses were performed with the SAS software version 9.1.
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3
Results
3.1 Study population A total of 194 patients were recruited at 53 centers in France. Four patients had no history of DU within the preceding year and were excluded from the analysis (Figure 1). Among the 190 included patients, 120 (63.2%) had one year of follow-up under bosentan therapy. The characteristics of these 120 patients (Table 1) were similar to those of the overall cohort, which was described previously [10] and no statistically significant difference was observed between the patients with and those without one-year-follow-up. Patients were 54.2 years old at inclusion and 70.0% were women. At inclusion, 73 patients (60.8%) had an active DU. All 120 patients were treated with bosentan and the mean daily dosage was 195±63 mg: 45 patients started bosentan within 2 months of inclusion and 75 were previously treated with bosentan. At one year, 58 patients (48.3%) had a controlled disease (57.8% of patients starting bosentan at inclusion and 42.7% of those on previous bosentan had a controlled disease; p = 0.11). Patients with an uncontrolled disease were more likely to have diffuse SSc with anti-topoisomerase 1 (Scl-70) antibodies and a high modified Rodnan skin score, and to present with at least one organ involvement; these patients also had experienced a higher number of previous DU episodes. Patients could present with additional factors limiting hand function, along with ischemic DU (Table 2), including presence of mechanical DU, sequelae from previous DU and other nonischemic factors. Patients with an uncontrolled ulcerative disease more frequently reported nonischemic DU on bone profile, tendinous retraction, non-ulcerative calcinosis, and ankylosis of distal interphalangeal joints. At 2 years, many patients were lost to follow-up and the data are not presented.
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3.2 Changes in DU numbers after one year of follow-up During the one-year follow-up, 46 (38.3%) patients experienced a new DU episode and the incidence of the event was 0.6 event/patient-year [95% confidence interval: 0.44-0.81]. The proportion of patients with at least one active DU decreased from 60.8% at inclusion to 22.5% at one year (p < 0.0001), and the mean number of DU per patient decreased from 1.4±1.8 to 0.6±1.6 (p < 0.0001) on both hands and from 0.82±1.08 to 0.33±0.96 (p < 0.0001) on the dominant hand. The distribution of DU per finger on both hands is presented in Figure 2 for the 79 patients with active DU at inclusion and/or at one year. Among the 73 patients (60.8%) with an active DU at inclusion, 2 (2.7%) had osteitis, 9 (12.3%) had cutaneous infection, and 4 (5.5%) had gangrene. After one year, among the 27 patients (22.5%) with an active DU, these complications were reported for 0 (0%), 5 (18.5%) and 1 (3.7%) patients, respectively.
3.3 Changes in functional assessments after one year of follow up After one year of follow-up, disability and pain had receded (Table 3). The HAQ-DI decreased from 1.0±0.7 to 0.9±0.7 (p = 0.04). For 42 (35.6%) patients, the improvement was above 0.21, the minimally important difference for the HAQ-DI [28,29]; 28 (66.7%) of these patients were in the group with controlled ulcerative disease (p = 0.02). The CHFS decreased from 29±20 to 25± 20 (p = 0.005), and the VAS from 4.3±3.1 to 2.9±2.8 (p < 0.0001). These improvements in functional scores observed in the overall patient population were attributed to improvements in the population with a controlled ulcerative disease. The PCS and MCS of the SF-36 did not increase significantly (p = 0.92 and p = 0.22, respectively) but improvement was observed for the bodily pain (p = 0.04) and mental health (p = 0.01) scales. After adjustment for differences at inclusion, the magnitude of the improvements was still higher in the population with a controlled ulcerative disease for the HAQ-DI (p = 0.04), the CHFS (p = 0.04), the VAS (p = 0.046) and the PCS of the SF-36 (p = 0.049).
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3.4 Impact of various factors limiting hand function on the CHFS Univariate regression analyses were performed to compare the 2 groups of patients with and without a controlled disease and to identify relevant covariates impacting the CHFS. Factors potentially limiting hand function in addition to ischemic DU (Table 2) were tested: ulcerative disease control (p = 0.052) and loss of substance (p = 0.084) were identified as potential contributors to the CHFS, although without reaching statistical significance. After inclusion of these 2 variables in the final model, the control of the ulcerative disease was the only significant variable impacting the CHFS (p = 0.048).
3.5 Safety and treatment discontinuation During the one-year follow-up, 21 (17.5%) patients out of the 120 analyzed at 1 year discontinued bosentan for an adverse event, including 5 patients presenting elevated aminotransferases. Among the 99 patients remaining on bosentan, the drug dosage at 1 year was decreased for 1 patient (1.0%), stable for 67 (69.8%), and increased for 28 (29.2%). Out of the 21 patients who stopped bosentan during the one-year of follow-up, 12 (57.1%) had a controlled disease at one year. This proportion was 46/99 (46.5%) for those patients continuing bosentan treatment for one year (p = 0.37).
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4
Discussion
The ECLIPSE study is a prospective, longitudinal, observational, multicenter study, which provides insight on the course of ulcerative disease and the concomitant evolution of hand disability, pain and quality of life in a large cohort of 120 SSc patients. Patients were receiving bosentan for the treatment of ulcerative disease at inclusion in the study for a mean duration of 16 months and all but 21 pursued the treatment over the follow-up period. We here present data after a one-year follow-up period. Using a definition of controlled disease that is not limited to the development of new DU but also takes into account DU that do not heal, we report that 48.3% of the patients had a controlled disease over the one-year follow-up (i.e. they did not have an active DU at the one-year assessment and had not experienced a new DU episode over the follow-up period). The control of the ulcerative disease over one year was associated with a significant improvement of hand function as assessed by the CHFS. Patients who had a controlled disease also improved significantly in terms of global disability and pain, as assessed by the HAQ-DI and VAS, respectively. The HAQ-DI, CHFS and VAS have been widely used in patients with SSc to show that DU play a major role in the occurrence of disability [7,9,18,30]. In the present study, two SF-36 scales (bodily pain and mental health) were improved after one year, which is in line with the deterioration in bodily pain and mental health observed in the presence of active DU in previous studies with a different population [7] and with the ECLIPSE population at inclusion [10]. One of the explanations for the absence of improvement of the SF36 summaries (PCS and MCS) could be that these parameters are too general and not sensitive to the changes observed in our patient population. The VAS for pain and the SF-36 bodily pain scale indicated significantly less pain at one year and statistical significance was maintained for the VAS in the subgroup of patients with an uncontrolled disease. Such an impact on pain had not been observed in the two prospective
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randomized double-blind controlled trials (RAPIDS-1 [11] and RAPIDS-2 [12]), investigating the effects of bosentan treatment over a shorter period of time (4 and 6 months). In patients with SSc and DU, hand disability is a major component of global disability, highlighting the need to specifically assess hand disability in these patients [22]. Some of the items on the HAQ-DI are not considered major problems by patients with SSc, although we did observe a significant albeit small improvement in this index. The CHFS, on the other hand, is hand-function specific and appears particularly appropriate to evaluate hand disability in SSc [21,22]. Thus, the CHFS has good construct validity in SSc with an excellent inter-observer reliability [21], and effect size (ES) and standardized response mean (SRM) values of –0.16 and –0.24, respectively [31], which is a definite advantage in multicenter studies. We previously observed that SSc patients with active DU have reduced wrist and hand mobility [9] and greater impairment of hand function [10] as compared with those patients without active DU. In line with this finding, Zelenietz et al. [32] reported that the HAQ-DI improved when a DU healed and worsened when a DU occurred, although the functional impact of DU was best detected by the subset of the HAQ related to hand function. In the present study, impairment of hand function as assessed with the CHFS was significantly related to the presence of active DU and was unlikely to be due to other factors potentially limiting hand function [10]. Furthermore, hand function was altered as soon as one DU was present. In our study, at the one-year assessment, the magnitude of the improvement in the CHFS significantly differed between patients with and patients without a controlled disease, which suggests that an uncontrolled disease (i.e. persistent/recurring DU) contributes to severe hand disability. Patients with an uncontrolled ulcerative disease had a more severe SSc/DU disease at inclusion: they were more likely to have diffuse SSc, increased modified Rodnan skin score, and at least one organ involvement, in particular pulmonary fibrosis and involvement of the esophagus. This
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is in line with what is known of the diffuse form of SSc, which is more frequently associated with visceral involvement [33] and presence of DU [4,5,7,34,35]. Pulmonary fibrosis and involvement of the esophagus have been reported to impact on the presence of DU in other studies [35]. Patients with an uncontrolled ulcerative disease also more frequently reported tendinous retractions, a feature that has been associated with disability and also occurs more frequently in patients with diffuse SSc [36]. These patients also often had detectable antitopoisomerase 1 (Scl-70) antibodies, consistent with the increased incidence of DU observed in patients with anti-Scl-70 antibody positivity [5,8,34,35]. Thus, the presence of a number of baseline clinical parameters, in particular diffuse versus limited SSc, allows anticipating the development of an uncontrolled ulcerative disease. Powerful vasodilator therapies prescribed for the treatment of pulmonary arterial hypertension have been used with some success in the management of severe DU [37-40]. The two prospective randomized double-blind controlled trials (RAPIDS-1 [11] and RAPIDS-2 [12]), indicated that 4 to 6 months of bosentan treatment significantly reduced the number of new DU, although it did not accelerate DU healing. Thus, it is well accepted that bosentan may improve digital ulcerative disease through the prevention of the occurrence of new DU. Our results suggest that controlling of the ulcerative disease in patients treated with bosentan may improve patient function over a longer term (one year). Patient global and hand disability is reduced and pain is alleviated. We also observed that complications such as infection, osteitis, and gangrene were less frequent at 1 year. This is an important benefit for the patients as complications of DU can be painful and severe often leading to hospitalization and prolonged treatment. During the one-year follow-up, treatment with bosentan was well tolerated: 21 (17.5% out of 120 analyzed at 1 year) patients discontinued bosentan for an adverse event, including 5 patients presenting elevated aminotransferases, which is comparable with the frequency of abnormal liver function tests seen in previous studies of bosentan in patients with DU [11,12]. January 12, 2017
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A limitation of the study is the high rate of patients lost to follow-up: only 120 patients were evaluated at one year out of 190 included into the study. However, demographics and clinical characteristics were similar in both groups and the lack of follow-up for these 70 patients may not be a major limitation to study interpretation. The clinical assessment of DU is challenging and presents a high inter-observer variability [41]. We defined the location of DU (distal to the proximal interphalangeal joints) and the type of DU (ischemic versus mechanic DU) but we did not impose a strict definition for active DU and study investigators may have had different opinions on what constitute an active DU.
Conclusion In patients with SSc, hand function worsening is caused by the occurrence of recent or active DU. The control of the ulcerative disease for one year characterized by the absence of any active DU at endpoint and any new DU episode over the follow-up was associated with a significant attenuation of hand disability, as assessed by the CHFS, independently of additional factors limiting hand function.
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5
Acknowledgements
The authors thank the investigators who have contributed to the conduct of this study (Appendix). Medical writing assistance was provided by Sylvie I. Ertel (Sundgau Medical Writers, France). Luc Mouthon and Alice Bérezné are members of the Département HospitaloUniversitaire (DHU) AUToimmune and HORmonal diseaseS. Appendix: the ECLIPSE Investigators: Lok C., Thuillier D.: Amiens; Le Clec'h C.: Angers; Duchêne F.: Belfort; Puzenat E.: Besancon; Prey S., Solanilla A.: Bordeaux; Bourgault-Villada I.: Boulogne Billancourt; Le Hello C., Bienvenu, B.: Caen; Berthier S., Muller G.: Dijon; Remond B.: Evreux; Carpentier P.: Grenoble; Damade R.: Le Coudray; Beneton-Benhard N., Maillard H.: Le Mans; Barcat D.: Libourne; Hachulla E., Hatron P.Y.: Lille; Sparsa A., Doffoel-Hantz V., Fauchais A.L.: Limoges; Geffray L.: Lisieux; Coppéré B., Jullien D.: Lyon; Granier F.: Mantes-la-Jolie; Harle J.R., Granel B., M.A. Richard: Marseille; Maurier F.: Metz; Cohen J.D., Khau Van Kien A.: Montpellier; Granel Brocard F.: Nancy; Agard C: Nantes; Queyrel V.: Nice; Corondan A.: Orléans; Bérezné A., Mouthon L., Crickx B., Picard Dahan C., Eguia B., Francès C., Emmerich J., Fiessinger J.N., Mathian A., Lazareth I., Michon-Pasturel U.: Paris; Viallard J.F.: Pessac; Wierzbicka-Hainaut E: Poitiers; Fleuret C.: Quimper; Léonard-Lefèbvre F., Reguiai Z.: Reims; Jego P., Perdriger A.: Rennes; Modeste Duval A.B.: Rouen; Bonnin A.: Royan; Chatelus E., Poindron V.: Strasbourg; Diot E.: Tours; Bica-Chicinas D., Roger M.: Troyes; Wahl D., Zuily S.: Vandoeuvre-les-Nancy.
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Control of digital ulcerative disease in SSc
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Control of digital ulcerative disease in SSc
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Control of digital ulcerative disease in SSc
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Control of digital ulcerative disease in SSc
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of agreement between rheumatologists in defining digital ulceration in systemic sclerosis, Arthritis Rheum 60 (2009) 878-882.
Figure 1: Distribution of patients Figure 2: Distribution of digital ulcers (DU) at inclusion (A) and at one year (B). Data is presented for 79 patients with active DU at inclusion and/or at one year.
January 12, 2017
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Control of digital ulcerative disease in SSc
Table 1. Demographics and clinical characteristics at inclusion Included patients
All patients Patients with Patients with
p-
with data
controlled
uncontrolled
value
at 1 year
disease
disease
*
(n = 190)
(n = 120)
¶
(n = 58 )
§
(n = 62 )
Age, years
52.8±14.6
54.2±14.9
53.5±14.2
55.0±15.5
0.58
Female gender
132 (69.5)
84 (70.0)
41 (70.7)
43 (69.4)
0.87
43.0±14.7
44.3±15.1
43.7±14.9
44.9±15.4
0.66
limited SSc
109 (57.4)
69 (57.5)
39 (67.2)
30 (48.4)
0.04
diffuse SSc
81 (42.6)
51 (42.5)
19 (32.8)
32 (51.6)
Time since RP
11.0 [5-20]
12 [4-20]
12 [4-23]
12 [4-19]
0.49
Time since first non RP
8.0 [3-14]
8 [3-15]
7 [2-15]
8.5 [4-15]
0.86
4.8 [2-10]
4 [1-10]
3 [1-10]
5 [3-10]
0.36
At least 1 organ involvement
160 (84.2)
100 (83.3)
44 (75.9)
56 (90.3)
0.03
Pulmonary fibrosis
86 (45.3)
50 (41.7)
18 (31.0)
32 (51.6)
0.02
PAH†
22 (11.6)
13 (10.8)
4 (6.9)
9 (14.5)
0.18
6 (3.2)
2 (1.7)
1 (1.7)
1 (1.6)
0.96
Esophagus involvement
140 (73.7)
88 (73.3)
37 (63.8)
51 (82.3)
0.02
Gastrointestinal involvement
52 (27.4)
31 (25.8)
11 (19.0)
20 (32.3)
0.10
14.2±8.8
14.2±8.6
12.6±8.2
15.7±8.7
0.049
108 (57.4)
68 (57.1)
27 (46.6)
41 (67.2)
0.02
(n = 188)
(n = 119)
2.0±2.0
1.9±2.0
Demographics
Clinical characteristics Age at SSc diagnosis, years Disease form
Disease duration, years
symptom Time since first DU Organ involvement
History of renal crisis
Skin involvement Modified Rodnan Skin Score Ulcerative disease > 5 DU episodes† since first DU DU episodes† during last year
January 12, 2017
(n = 61) 1.8±2.2
1.9±1.9
0.73
24
Control of digital ulcerative disease in SSc Immunological characteristics Anti-topoisomerase 1 (Scl-
97 (51.6)
59 (50.0)
20 (35.1)
39 (63.9)
0.003
70) antibodies
(n = 188)
(n = 118)
(n = 57)
(n = 61)
Anti-centromere antibodies
54 (29.8)
37 (33.0)
22 (39.3)
15 (26.8)
(n = 181)
(n = 112)
(n = 56)
(n = 56)
190 (100)
120 (100)
58 (100)
62 (100)
15.3±21.5
15.6±22.0
14.7±23.6
16.4±20.6
0.69
Intermittent iloprost
35 (18.4)
24 (20)
12 (20.7)
12 (19.4)
0.86
Calcium channel blockers
42 (60.9)
25 (55.6)
14 (58.3)
11 (52.4)
0.69
(n = 69)
(n = 45)
(n = 24)
(n = 21)
0.16
Treatment for DU Bosentan Treatment duration, months
Values are expressed as mean ± standard deviation, median with first and third quartiles [Q1;Q3], or number of patients (percentage). Number of patients with the assessment (n) is provided when different from the number of patients in group. *p-values are provided for comparison between patients with controlled and uncontrolled disease. ¶
Including 12 patients who discontinued bosentan
§ †
Including 9 patients who discontinued bosentan A DU episode is defined as a period with at least one active DU between two DU-free periods.
DU: digital ulcers;
: pulmonary arterial hypertension; R : Raynaud’s phenomenon; SSc:
systemic sclerosis.
January 12, 2017
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Control of digital ulcerative disease in SSc
Table 2. Factors limiting hand function in addition to ischemic DU All patients
Patients with a
Patients with an
p-
with data
controlled
uncontrolled
value*
at 1 year
disease
disease
(n = 120)
¶
(n = 58 )
(n = 62§)
22 (18.3)
11 (19.0)
11 (17.7)
0.86
6 (5.0)
1 (1.7)
5 (8.1)
0.21
14 (11.7)
3 (5.2)
11 (17.7)
0.03
Non-ischemic DU Located on the dorsal surface of the fingers Complicating calcinosis On bone profile
Sequelae from previous DU (on one hand a least) Loss of substance
73 (60.8)
36 (62.1)
37 (60.0)
0.79
Auto-amputation
10 (8.3)
3 (5.2)
7 (11.3)
0.33
Surgical amputation
13 (10.8)
7 (12.1)
6 (9.7)
0.67
Digital sympathectomy
4 (3.3)
0
4 (6.5)
0.12
Arthrodesis
2 (1.7)
0
2 (3.2)
0.50
Tendinous retractions
52 (43.3)
16 (27.6)
36 (58.1)
0.0008
Non-ulcerative calcinosis
16 (13.3)
4 (6.9)
12 (19.4)
0.04
Ankylosis
81 (67.5)
34 (58.6)
47 (75.8)
0.04
63 (52.5)
26 (44.8)
37 (59.7)
0.10
35 (29.2)
16 (27.6)
19 (30.7)
0.71
Other non-ischemic factors
of
distal
interphalangeal joints Ankylosis of proximal interphalangeal joints Ankylosis of metacarpophalangeal joints Values are expressed as number of patients (percentage). *p-values are provided for comparison between patients with controlled and uncontrolled disease. ¶
Including 12 patients who discontinued bosentan
§
Including 9 patients who discontinued bosentan
DU: digital ulcers.
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Control of digital ulcerative disease in SSc
Table 3. Changes in functional scores
HAQ-DI (range 0-3)
All patients with
Patients with a
Patients with an
data at 1 year
controlled disease
uncontrolled disease
(n = 120)
(n = 58¶)
(n = 62§)
At
At
At
At
At
At
inclusion
Month 12
inclusion
Month 12
inclusion
Month 12
1.0±0.7
0.9±0.7
0.9±0.7
0.7±0.7
1.0±0.7
1.0±0.7
(n = 118) p = 0.04
(n = 60) p = 0.01
p = 0.76
p = 0.04 (change between subgroups) CHFS (range 0-90)
29±20
25±20
(n = 111)
30±22
22±20
(n = 54)
p = 0.005
29±18
28±20
(n = 57)
p = 0.001
p = 0.50
p = 0.04 (change between subgroups) VAS (range 0-10)
4.3±3.1
2.9± 1.8
4.2±3.7
2.3±2.2
4.5±3.1
3.4±3.2
(n = 110)
(n = 115)
(n = 53)
(n = 58)
(n = 57)
(n = 57)
p < 0.0001
p = 0.0004
p = 0.04
p = 0.046 (change between subgroups) SF-36 PCS (range 0-100)
39±9
39±10
41±10
41±10
38±7
37±8
(n = 116)
(n = 114)
(n = 56)
(n = 57)
(n = 60)
(n = 57)
p = 0.92
p = 0.29
p = 0.32
p = 0.049 (change between subgroups) Physical Functioning
55±29
56±30
p = 0.81 Role-Physical
50±30
51±27
p = 0.62 Bodily Pain
44±24
49±23
p = 0.04
January 12, 2017
62±30
62±31
p = 0.81 47±33
53±30
p = 0.10 44±27
53±25
p = 0.01
49±28
49±28
p = 0.55 52±26
49±24
p = 0.41 44±21
45±20
p = 0.88
27
Control of digital ulcerative disease in SSc
p = 0.03 (change between subgroups) General Health
41±19
41±20
42±18
p = 0.70 SF-36 MCS (range 0-100)
42±21
p = 0.73
40±20
39±19
p = 0.43
38±12
40±12
37±11
38±11
39±13
41±13
(n = 116)
(n = 114)
(n = 56)
(n = 57)
(n = 60)
(n = 57)
p = 0.22
p = 0.26
p = 0.24
p = 0.87 (change between subgroups) Vitality
40±20
40±21
40±20
p = 0.91 Social Functioning
59±26
63±26
p = 0.96 59±27
p = 0.12 Role-Emotional
59±32
59±30
51±21
55±21
63±26
p = 0.20 56±34
p = 0.78 Mental Health
40±22
58±31
p = 0.53 52±17
p = 0.01
55±20
p = 0.10
40±20
41±20
p = 0.91 59±26
63±25
p = 0.37 62±29
59±29
p = 0.35 51±24
56±22
p = 0.05
Values are expressed as mean ± standard deviation. Number of patients with the assessment (n) is provided when different from the number of patients in group. Comparisons were tested with variance analysis (ANOVA) with baseline adjustment for comparisons between subgroups at one year (for the SF-36 scales, p-values for comparisons between subgroups are only presented when significant). ¶
Including 12 patients who discontinued bosentan
§
Including 9 patients who discontinued bosentan
CHFS: Cochin Hand Function Scale, DU: digital ulcers, HAQ-DI: Health Assessment Questionnaire Disability Index, SF-36 PCS/MCS: Medical Outcomes Study 36-item Short-Form Physical/Mental Component Summary, VAS: visual analog scale.
January 12, 2017
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PII: DOI: Reference:
www.elsevier.com/locate/semarthrit
S0049-0172(17)30036-7 http://dx.doi.org/10.1016/j.semarthrit.2017.01.001 YSARH51136
To appear in: Seminars in Arthritis and Rheumatism Cite this article as: Luc Mouthon, Patrick H. Carpentier, Catherine Lok, Pierre Clerson, Virginie Gressin, Eric Hachulla, Alice Bérezné, Elisabeth Diot, Aurélie Khau Van Kien, Patrick Jego, Christian Agard, Anne Bénédicte Duval-Modeste, Agnès Sparsa, Eve Puzenat and Marie-Aleth Richard, Controlling the digital ulcerative disease in systemic sclerosis is associated with improved hand functionControl of digital ulcerative disease in SSc with bosentan, Seminars in Arthritis and Rheumatism, http://dx.doi.org/10.1016/j.semarthrit.2017.01.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Control of digital ulcerative disease in SSc
Controlling the digital ulcerative disease in systemic sclerosis is associated with improved hand function Running head: Control of digital ulcerative disease in SSc with bosentan Luc Mouthon1, MD, PhD; Patrick H. Carpentier2, MD; Catherine Lok3, MD; Pierre Clerson4, MD; Virginie Gressin5, MD; Eric Hachulla6, MD, PhD; Alice Bérezné1, MD; Elisabeth Diot7, MD, PhD; Aurélie Khau Van Kien8, MD; Patrick Jego9, MD, PhD; Christian Agard10, MD, PhD; Anne Bénédicte Duval-Modeste11, MD; Agnès Sparsa12, MD, PhD; Eve Puzenat13, MD; MarieAleth Richard14, MD, PhD, on behalf of the ECLIPSE study investigators Institutional addresses: 1Paris Descartes University, Cochin Hospital, Assistance PubliqueHôpitaux de Paris, Internal Medicine, Paris, France; 2University Hospital Grenoble, Vascular Medicine, Grenoble, France; 3University Hospital Amiens, Dermatology, Amiens, France; 4
Orgamétrie Biostatistics, Roubaix, France; 5Actelion Pharmaceuticals France, Paris, France;
6
Claude Huriez Hospital, Lille 2 University, Internal Medicine, Lille, France; 7Bretonneau
Hospital, Internal Medicine, Tours, France; 8Saint Eloi Hospital, Internal Medicine, Montpellier, France; 9University Hospital Rennes, Internal Medicine, Rennes, France; Nantes, Internal Medicine, Nantes, France; France;
12
11
10
University Hospital
University Hospital Rouen, Dermatology, Rouen,
University Hospital Limoges, Dermatology, Limoges, France ;
Hospital, Dermatology, Besançon, France;
14
13
Saint Jacques
Aix-Marseille University, la Timone Hospital,
Assistance Publique-Hôpitaux de Marseille, Dermatology, Marseille, France. e-mail
addresses:
1
[email protected],
2
[email protected],
3
[email protected], [email protected], [email protected],
6
[email protected],
1
[email protected],
7
[email protected], [email protected],
January 12, 2017
[email protected], 10
8
a-
[email protected],
1
Control of digital ulcerative disease in SSc
11
[email protected],
12
[email protected],
13
epuzenat@chu-
besancon.fr, [email protected] Financial support: This study was sponsored by Actelion Pharmaceuticals France. Actelion Pharmaceuticals France provided funding for logistical support, patient monitoring, project management, data management, and independent statistical analysis. Actelion Pharmaceuticals Ltd. provided funding for medical writing. Conflict of interest: Dr Mouthon reports grants from Actelion during the conduct of the study. Dr. Lok reports consulting fees from Actelion. Dr. Hachulla reports grants and personal fees from Actelion and GlaxoSmithKline, and personal fees from PFIZER, outside the submitted work. Dr Gressin is a full time employee of Actelion Pharmaceuticals France, as medical director. Dr Jego reports personal fees and non-financial support from Actelion, Pfizer, Lilly France, and GlaxoSmithKline, outside the submitted work. Drs. Carpentier and Richard report personal fees from Actelion during the conduct of the study. Drs Bérezné, Clerson, Diot, Khau Van Kien, Agard, Duval-Modeste, Sparsa, and Puzenat have nothing to disclose. Corresponding author: Luc Mouthon, MD, PhD. Service de Médecine Interne, Hôpital Cochin 27, Rue du Faubourg Saint-Jacques 75679 Paris Cedex 14 Tel: +33-(0)1 58 41 20 31; Fax: +33-(0)1 58 41 14 50; E-mail: [email protected]
January 12, 2017
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Control of digital ulcerative disease in SSc
Abstract Objectives: Ischemic digital ulcers (DU) represent a major complication of systemic sclerosis (SSc). We investigated the impact of controlling the ulcerative disease on disability, pain, and quality of life in SSc patients receiving bosentan. Methods: ECLIPSE (Study AC-052-517) is a 2-year prospective, multicenter, observational study. Patients with SSc who experienced at least one DU in the previous year and received bosentan were included between October 2009 and March 2011. Disability scores (Cochin Hand Function Scale (CHFS), Health Assessment Questionnaire Disability Index (HAQ-DI)), pain scores (Visual Analog Scale), and quality of life scores (SF-36) were collected at inclusion and one year later (primary endpoint). A controlled ulcerative disease was defined by the absence of on-going/new DU episode between inclusion and one-year follow-up. Results: Data were available at one year for 120 patients out of 190 included. During follow-up, 46 (38.3%) patients experienced a new DU episode. The number of DU per patient decreased from 1.4±1.8 at inclusion to 0.6±1.6 (p < 0.0001) at 1 year. Disability scores decreased from 1.0±0.7 to 0.9±0.7 (p = 0.04) for the HAQ-DI and from 29±20 to 25±20 (p = 0.005) for the CHFS; the pain score decreased from 4.3±3.1 to 2.9±2.8 (p < 0.0001). This improvement was attributed to patients with a controlled ulcerative disease (48.3%), who significantly improved HAQ-DI (p = 0.04), CHFS (p = 0.04), and pain score (p = 0.046). Conclusions: In patients with SSc, control of the ulcerative disease for one year was associated with significant attenuation of hand disability.
Key words: systemic sclerosis; digital ulcers; hand; disability; bosentan.
January 12, 2017
3
Control of digital ulcerative disease in SSc
Clinical significance
What was already known before the study was performed?
SSc patients with active DU have reduced wrist and hand mobility and greater impairment of hand function compared with those patients without active DU. Hand disability develops as soon as one DU is present
What was learned from this study?
This prospective, observational study shows that the control of the ulcerative disease for one year (i.e. absence of active digital ulcer at the one-year assessment and no occurrence of new digital ulcer episode over the one-year follow-up) is associated with a significant attenuation of hand disability, as assessed by the Cochin Hand Function Scale (CHFS), independently of other factors limiting hand function. Functional improvement was attributed to patients with a controlled ulcerative disease (48.3%), who significantly improving health assessment questionnaire disability index (HAQ-DI) (p = 0.04), CHFS (p = 0.04), and visual analog scale for pain (p = 0.046).
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Control of digital ulcerative disease in SSc
1
Introduction
Systemic sclerosis (SSc) is a connective tissue disease characterized by vascular hyper-reactivity and remodeling, cutaneous and visceral fibrosis, and immune system activation [1,2]. As vascular damage progresses, reduced perfusion of the skin and visceral microvascular beds leads to a state of chronic ischemia favoring fibroblast activation and extra-cellular matrix synthesis. Raynaud's phenomenon and digital ulcers (DUs) are typical manifestations of the underlying vasculopathy that characterizes SSc [3]. About 44-60% of patients with SSc experience one or more digital ulcers (DU) at some point in their disease course [4-8]. Ulcers on the fingertips and over the interphalangeal joints heal slowly with residual scars and digital resorption. They can be complicated by infection leading to osteitis, and progression to gangrene requiring amputation [4,6]. In addition, DU are painful, cause severe functional disability, and have a major impact on quality of life (QoL) [4,7]. Severe DU may necessitate hospitalization and time away from the workplace [6,7]. We recently reported that SSc patients with active DU have reduced wrist and hand mobility [9] and greater impairment of hand function [10] compared with those patients without active DU. Furthermore, hand disability develops as soon as one DU is present [10]. Patients’ education is key in DU prevention, with recommendation for reducing cold exposure, avoiding tobacco intake and vasoconstrictive agents, and preventing hand injury and repeated microtrauma. Pharmacological treatment for SSc-related digital vasculopathy is based on vasodilating medications to improve blood flow to ischemic areas. As such, the oral endothelin receptor antagonist bosentan is approved in Europe to prevent the occurrence of new DU in patients with on-going DU disease [11,12]. In two prospective randomized double-blind controlled trials (RAPIDS-1 [11] and RAPIDS-2 [12]), bosentan significantly reduced the number of new DU (in particular in patients with
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Control of digital ulcerative disease in SSc
multiple DU) and improved overall hand function, although it did not improve the HAQ-DI nor accelerate the healing of DU. In the present prospective observational study, we investigated the impact of controlling the ulcerative disease on global disability, hand disability, pain, and QoL in patients with SSc treated with bosentan.
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2
Patients and methods
2.1 Study design ECLIPSE (Evaluation of the impact of recurrent ischemic DU on hand disability in patients with SSc) is a prospective, longitudinal, observational, multicenter study with a 2-year follow-up and a primary endpoint at 1 year. The design of the study and the inclusion characteristics of the patients have been described previously [10]. The initial hypothesis of the study was that each new DU episode was associated with a cumulative increase in disability, where a DU episode was defined as a period with at least one active DU between two DU-free periods. However, this approach, based on the number of new DU episodes, does not take in consideration the impact of long-lasting and/or successive DU without DU-free intervals. Therefore, we propose a new definition of disease control: the ulcerative disease is considered as controlled when the patient has no active DU at endpoint and no new DU episode over the follow-up. We subsequently investigated whether disease control over 1 year was associated with preserved functioning and QoL. The study was conducted in compliance with the Good Clinical Practices protocol and Declaration of Helsinki principles. In accordance with French law, formal approval from an ethical committee was not required for this observational study. Patients gave their oral consent to participate.
2.2 Patients The study enrolled patients, aged ≥ 18 years, with limited or diffuse cutaneous SSc according to the 1980 American College of Rheumatology (ACR) [13] or Leroy and Medsger [14] criteria. Enrollment in the study occurred between October 2009 and March 2011, i.e. before the availability of the new ACR/EULAR classification criteria [15]. Eligible patients had to have
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Control of digital ulcerative disease in SSc
experienced at least one predominantly ischemic DU (new or on-going) during the previous year, whether or not they presented active DU at inclusion. A predominantly ischemic DU was defined as an ulcer located on the pulpar face of the fingers, distal to the proximal interphalangeal joints, and not facing a calcinosis or bone profile (DU not satisfying these conditions were considered as predominantly mechanical DU) [11]. All DU described in the manuscript refer to predominantly ischemic DU identified by a trained physician, unless otherwise specified. Moreover, patients had to be eligible for bosentan therapy as approved by the European Medicines Agency [16]. Treatment with bosentan was on-going or may have been started at entry in the study.
2.3 Patients evaluation After the inclusion visit, visits were scheduled at 1 and 2 years as recommended by the French health authorities [17]. Additional visits could be planned following the healing or the appearance of DU. SSc/DU disease characteristics were collected from the patient’s history as previously described [10]. Patients were allowed to continue their usual treatment for SSc and/or DU in addition to bosentan. Clinical examination included the description of the DU episode if present and looked for potential mechanical causes of hand disability. DU complications (osteitis, infection, gangrene) were recorded at each visit. Global disability was assessed by the Health Assessment Questionnaire (HAQ) that evaluates 20 items related to daily activities divided into 8 domains scored between 0 (no disability) and 3 (maximal disability) [18,19]. The highest score reported in each domain determines the score for that domain. The disability index (HAQ-DI) is expressed on a scale of 0 to 3 units, representing an average score across the domains.
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Hand disability was assessed by the Cochin Hand Function Scale (CHFS) based on 18 items related to daily activities, each scored on a scale of 0 (performed without difficulty) to 5 (impossible to do). The total score is obtained by adding individual scores (range 0-90) [20-22]. QoL was evaluated with the Medical Outcomes Study 36-item Short-Form Health Survey (SF36v2 acute, France) that investigates 8 scales related to QoL. Scale scores are normalized to a mean of 50 and standard deviation of 10 based on the normal US population [23]. Scale scores are summarized in two summary measures: the Physical Component Summary (PCS) and Mental Component Summary (MCS) [24,25]. Scale scores and summary measures are reported on a scale from 0 (poorest) to 100 (best). Pain was rated on a 10-point Visual Analog Scale (VAS) [26]. Skin thickness was assessed with the modified Rodnan skin score, which grades 17 body areas on a scale of 0 (uninvolved skin) to 3 (severe skin thickening) following clinical palpation [27].
2.4 Statistical analysis Data are presented as absolute numbers, percentages, means with corresponding standard deviations, or medians with corresponding 25th and 75th percentiles [inter-quartile range (IQR)]. Comparisons were tested with variance analysis (ANOVA) with baseline adjustment for comparisons between subgroups at one year. The annual incidence rate of DU episodes was estimated from a Poisson regression model with the follow-up duration as offset term. Univariate regression analyses adjusted for differences at baseline were performed to compare the 2 groups of patients with and without a controlled disease and identify relevant covariates impacting the CHFS. The following covariates were considered: 1) mechanical DU including DU located on the dorsal surface of the fingers, DU complicating calcinosis, DU located on bone profile, 2) presence of sequelae including loss of substance, auto-amputation, surgical amputation, digital sympathectomy, and arthrodesis, 3) other non-ischemic factors including
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Control of digital ulcerative disease in SSc
tendinous retractions, non-ulcerative calcinosis, ankylosis of the distal, proximal interphalangeal joints, ankylosis of the metacarpo-phalangeal joints. A multivariate regression analysis was then conducted to identify independent risk factors associated with an increased CHFS. A p value <0.05 was considered as statistically significant. Statistical analyses were performed with the SAS software version 9.1.
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3
Results
3.1 Study population A total of 194 patients were recruited at 53 centers in France. Four patients had no history of DU within the preceding year and were excluded from the analysis (Figure 1). Among the 190 included patients, 120 (63.2%) had one year of follow-up under bosentan therapy. The characteristics of these 120 patients (Table 1) were similar to those of the overall cohort, which was described previously [10] and no statistically significant difference was observed between the patients with and those without one-year-follow-up. Patients were 54.2 years old at inclusion and 70.0% were women. At inclusion, 73 patients (60.8%) had an active DU. All 120 patients were treated with bosentan and the mean daily dosage was 195±63 mg: 45 patients started bosentan within 2 months of inclusion and 75 were previously treated with bosentan. At one year, 58 patients (48.3%) had a controlled disease (57.8% of patients starting bosentan at inclusion and 42.7% of those on previous bosentan had a controlled disease; p = 0.11). Patients with an uncontrolled disease were more likely to have diffuse SSc with anti-topoisomerase 1 (Scl-70) antibodies and a high modified Rodnan skin score, and to present with at least one organ involvement; these patients also had experienced a higher number of previous DU episodes. Patients could present with additional factors limiting hand function, along with ischemic DU (Table 2), including presence of mechanical DU, sequelae from previous DU and other nonischemic factors. Patients with an uncontrolled ulcerative disease more frequently reported nonischemic DU on bone profile, tendinous retraction, non-ulcerative calcinosis, and ankylosis of distal interphalangeal joints. At 2 years, many patients were lost to follow-up and the data are not presented.
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3.2 Changes in DU numbers after one year of follow-up During the one-year follow-up, 46 (38.3%) patients experienced a new DU episode and the incidence of the event was 0.6 event/patient-year [95% confidence interval: 0.44-0.81]. The proportion of patients with at least one active DU decreased from 60.8% at inclusion to 22.5% at one year (p < 0.0001), and the mean number of DU per patient decreased from 1.4±1.8 to 0.6±1.6 (p < 0.0001) on both hands and from 0.82±1.08 to 0.33±0.96 (p < 0.0001) on the dominant hand. The distribution of DU per finger on both hands is presented in Figure 2 for the 79 patients with active DU at inclusion and/or at one year. Among the 73 patients (60.8%) with an active DU at inclusion, 2 (2.7%) had osteitis, 9 (12.3%) had cutaneous infection, and 4 (5.5%) had gangrene. After one year, among the 27 patients (22.5%) with an active DU, these complications were reported for 0 (0%), 5 (18.5%) and 1 (3.7%) patients, respectively.
3.3 Changes in functional assessments after one year of follow up After one year of follow-up, disability and pain had receded (Table 3). The HAQ-DI decreased from 1.0±0.7 to 0.9±0.7 (p = 0.04). For 42 (35.6%) patients, the improvement was above 0.21, the minimally important difference for the HAQ-DI [28,29]; 28 (66.7%) of these patients were in the group with controlled ulcerative disease (p = 0.02). The CHFS decreased from 29±20 to 25± 20 (p = 0.005), and the VAS from 4.3±3.1 to 2.9±2.8 (p < 0.0001). These improvements in functional scores observed in the overall patient population were attributed to improvements in the population with a controlled ulcerative disease. The PCS and MCS of the SF-36 did not increase significantly (p = 0.92 and p = 0.22, respectively) but improvement was observed for the bodily pain (p = 0.04) and mental health (p = 0.01) scales. After adjustment for differences at inclusion, the magnitude of the improvements was still higher in the population with a controlled ulcerative disease for the HAQ-DI (p = 0.04), the CHFS (p = 0.04), the VAS (p = 0.046) and the PCS of the SF-36 (p = 0.049).
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3.4 Impact of various factors limiting hand function on the CHFS Univariate regression analyses were performed to compare the 2 groups of patients with and without a controlled disease and to identify relevant covariates impacting the CHFS. Factors potentially limiting hand function in addition to ischemic DU (Table 2) were tested: ulcerative disease control (p = 0.052) and loss of substance (p = 0.084) were identified as potential contributors to the CHFS, although without reaching statistical significance. After inclusion of these 2 variables in the final model, the control of the ulcerative disease was the only significant variable impacting the CHFS (p = 0.048).
3.5 Safety and treatment discontinuation During the one-year follow-up, 21 (17.5%) patients out of the 120 analyzed at 1 year discontinued bosentan for an adverse event, including 5 patients presenting elevated aminotransferases. Among the 99 patients remaining on bosentan, the drug dosage at 1 year was decreased for 1 patient (1.0%), stable for 67 (69.8%), and increased for 28 (29.2%). Out of the 21 patients who stopped bosentan during the one-year of follow-up, 12 (57.1%) had a controlled disease at one year. This proportion was 46/99 (46.5%) for those patients continuing bosentan treatment for one year (p = 0.37).
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4
Discussion
The ECLIPSE study is a prospective, longitudinal, observational, multicenter study, which provides insight on the course of ulcerative disease and the concomitant evolution of hand disability, pain and quality of life in a large cohort of 120 SSc patients. Patients were receiving bosentan for the treatment of ulcerative disease at inclusion in the study for a mean duration of 16 months and all but 21 pursued the treatment over the follow-up period. We here present data after a one-year follow-up period. Using a definition of controlled disease that is not limited to the development of new DU but also takes into account DU that do not heal, we report that 48.3% of the patients had a controlled disease over the one-year follow-up (i.e. they did not have an active DU at the one-year assessment and had not experienced a new DU episode over the follow-up period). The control of the ulcerative disease over one year was associated with a significant improvement of hand function as assessed by the CHFS. Patients who had a controlled disease also improved significantly in terms of global disability and pain, as assessed by the HAQ-DI and VAS, respectively. The HAQ-DI, CHFS and VAS have been widely used in patients with SSc to show that DU play a major role in the occurrence of disability [7,9,18,30]. In the present study, two SF-36 scales (bodily pain and mental health) were improved after one year, which is in line with the deterioration in bodily pain and mental health observed in the presence of active DU in previous studies with a different population [7] and with the ECLIPSE population at inclusion [10]. One of the explanations for the absence of improvement of the SF36 summaries (PCS and MCS) could be that these parameters are too general and not sensitive to the changes observed in our patient population. The VAS for pain and the SF-36 bodily pain scale indicated significantly less pain at one year and statistical significance was maintained for the VAS in the subgroup of patients with an uncontrolled disease. Such an impact on pain had not been observed in the two prospective
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Control of digital ulcerative disease in SSc
randomized double-blind controlled trials (RAPIDS-1 [11] and RAPIDS-2 [12]), investigating the effects of bosentan treatment over a shorter period of time (4 and 6 months). In patients with SSc and DU, hand disability is a major component of global disability, highlighting the need to specifically assess hand disability in these patients [22]. Some of the items on the HAQ-DI are not considered major problems by patients with SSc, although we did observe a significant albeit small improvement in this index. The CHFS, on the other hand, is hand-function specific and appears particularly appropriate to evaluate hand disability in SSc [21,22]. Thus, the CHFS has good construct validity in SSc with an excellent inter-observer reliability [21], and effect size (ES) and standardized response mean (SRM) values of –0.16 and –0.24, respectively [31], which is a definite advantage in multicenter studies. We previously observed that SSc patients with active DU have reduced wrist and hand mobility [9] and greater impairment of hand function [10] as compared with those patients without active DU. In line with this finding, Zelenietz et al. [32] reported that the HAQ-DI improved when a DU healed and worsened when a DU occurred, although the functional impact of DU was best detected by the subset of the HAQ related to hand function. In the present study, impairment of hand function as assessed with the CHFS was significantly related to the presence of active DU and was unlikely to be due to other factors potentially limiting hand function [10]. Furthermore, hand function was altered as soon as one DU was present. In our study, at the one-year assessment, the magnitude of the improvement in the CHFS significantly differed between patients with and patients without a controlled disease, which suggests that an uncontrolled disease (i.e. persistent/recurring DU) contributes to severe hand disability. Patients with an uncontrolled ulcerative disease had a more severe SSc/DU disease at inclusion: they were more likely to have diffuse SSc, increased modified Rodnan skin score, and at least one organ involvement, in particular pulmonary fibrosis and involvement of the esophagus. This
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Control of digital ulcerative disease in SSc
is in line with what is known of the diffuse form of SSc, which is more frequently associated with visceral involvement [33] and presence of DU [4,5,7,34,35]. Pulmonary fibrosis and involvement of the esophagus have been reported to impact on the presence of DU in other studies [35]. Patients with an uncontrolled ulcerative disease also more frequently reported tendinous retractions, a feature that has been associated with disability and also occurs more frequently in patients with diffuse SSc [36]. These patients also often had detectable antitopoisomerase 1 (Scl-70) antibodies, consistent with the increased incidence of DU observed in patients with anti-Scl-70 antibody positivity [5,8,34,35]. Thus, the presence of a number of baseline clinical parameters, in particular diffuse versus limited SSc, allows anticipating the development of an uncontrolled ulcerative disease. Powerful vasodilator therapies prescribed for the treatment of pulmonary arterial hypertension have been used with some success in the management of severe DU [37-40]. The two prospective randomized double-blind controlled trials (RAPIDS-1 [11] and RAPIDS-2 [12]), indicated that 4 to 6 months of bosentan treatment significantly reduced the number of new DU, although it did not accelerate DU healing. Thus, it is well accepted that bosentan may improve digital ulcerative disease through the prevention of the occurrence of new DU. Our results suggest that controlling of the ulcerative disease in patients treated with bosentan may improve patient function over a longer term (one year). Patient global and hand disability is reduced and pain is alleviated. We also observed that complications such as infection, osteitis, and gangrene were less frequent at 1 year. This is an important benefit for the patients as complications of DU can be painful and severe often leading to hospitalization and prolonged treatment. During the one-year follow-up, treatment with bosentan was well tolerated: 21 (17.5% out of 120 analyzed at 1 year) patients discontinued bosentan for an adverse event, including 5 patients presenting elevated aminotransferases, which is comparable with the frequency of abnormal liver function tests seen in previous studies of bosentan in patients with DU [11,12]. January 12, 2017
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Control of digital ulcerative disease in SSc
A limitation of the study is the high rate of patients lost to follow-up: only 120 patients were evaluated at one year out of 190 included into the study. However, demographics and clinical characteristics were similar in both groups and the lack of follow-up for these 70 patients may not be a major limitation to study interpretation. The clinical assessment of DU is challenging and presents a high inter-observer variability [41]. We defined the location of DU (distal to the proximal interphalangeal joints) and the type of DU (ischemic versus mechanic DU) but we did not impose a strict definition for active DU and study investigators may have had different opinions on what constitute an active DU.
Conclusion In patients with SSc, hand function worsening is caused by the occurrence of recent or active DU. The control of the ulcerative disease for one year characterized by the absence of any active DU at endpoint and any new DU episode over the follow-up was associated with a significant attenuation of hand disability, as assessed by the CHFS, independently of additional factors limiting hand function.
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5
Acknowledgements
The authors thank the investigators who have contributed to the conduct of this study (Appendix). Medical writing assistance was provided by Sylvie I. Ertel (Sundgau Medical Writers, France). Luc Mouthon and Alice Bérezné are members of the Département HospitaloUniversitaire (DHU) AUToimmune and HORmonal diseaseS. Appendix: the ECLIPSE Investigators: Lok C., Thuillier D.: Amiens; Le Clec'h C.: Angers; Duchêne F.: Belfort; Puzenat E.: Besancon; Prey S., Solanilla A.: Bordeaux; Bourgault-Villada I.: Boulogne Billancourt; Le Hello C., Bienvenu, B.: Caen; Berthier S., Muller G.: Dijon; Remond B.: Evreux; Carpentier P.: Grenoble; Damade R.: Le Coudray; Beneton-Benhard N., Maillard H.: Le Mans; Barcat D.: Libourne; Hachulla E., Hatron P.Y.: Lille; Sparsa A., Doffoel-Hantz V., Fauchais A.L.: Limoges; Geffray L.: Lisieux; Coppéré B., Jullien D.: Lyon; Granier F.: Mantes-la-Jolie; Harle J.R., Granel B., M.A. Richard: Marseille; Maurier F.: Metz; Cohen J.D., Khau Van Kien A.: Montpellier; Granel Brocard F.: Nancy; Agard C: Nantes; Queyrel V.: Nice; Corondan A.: Orléans; Bérezné A., Mouthon L., Crickx B., Picard Dahan C., Eguia B., Francès C., Emmerich J., Fiessinger J.N., Mathian A., Lazareth I., Michon-Pasturel U.: Paris; Viallard J.F.: Pessac; Wierzbicka-Hainaut E: Poitiers; Fleuret C.: Quimper; Léonard-Lefèbvre F., Reguiai Z.: Reims; Jego P., Perdriger A.: Rennes; Modeste Duval A.B.: Rouen; Bonnin A.: Royan; Chatelus E., Poindron V.: Strasbourg; Diot E.: Tours; Bica-Chicinas D., Roger M.: Troyes; Wahl D., Zuily S.: Vandoeuvre-les-Nancy.
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Questionnaire between patients with and without digital ulcers in systemic sclerosis: a post hoc analysis of pooled data from two randomised controlled trials in digital ulcers using bosentan, Ann Rheum Dis 69 (2010) 2055-2056. [33]
T. Krieg, K. Takehara, Skin disease: a cardinal feature of systemic sclerosis,
Rheumatology (Oxford) 48 Suppl 3 (2009) iii14-18. [34]
U.A. Walker, A. Tyndall, L. Czirjak, C. Denton, D. Farge-Bancel, O. Kowal-Bielecka et
al., Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database, Ann Rheum Dis 66 (2007) 754-763.
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Control of digital ulcerative disease in SSc
[35]
C. Sunderkotter, I. Herrgott, C. Bruckner, P. Moinzadeh, C. Pfeiffer, J. Gerss et al.,
Comparison of patients with and without digital ulcers in systemic sclerosis: detection of possible risk factors, Br J Dermatol 160 (2009) 835-843. [36]
J. Avouac, H. Guerini, J. Wipff, N. Assous, A. Chevrot, A. Kahan et al., Radiological
hand involvement in systemic sclerosis, Ann Rheum Dis 65 (2006) 1088-1092. [37]
F.M. Wigley, J.R. Seibold, R.A. Wise, D.A. McCloskey, W.P. Dole, Intravenous iloprost
treatment of Raynaud's phenomenon and ischemic ulcers secondary to systemic sclerosis, J Rheumatol 19 (1992) 1407-1414. [38]
F.M. Wigley, R.A. Wise, J.R. Seibold, D.A. McCloskey, G. Kujala, T.A. Medsger, Jr. et
al., Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis. A multicenter, placebo-controlled, double-blind study, Ann Intern Med 120 (1994) 199-206. [39]
C.S. Brueckner, M.O. Becker, T. Kroencke, D. Huscher, H.U. Scherer, M. Worm et al.,
Effect of sildenafil on digital ulcers in systemic sclerosis: analysis from a single centre pilot study, Ann Rheum Dis 69 (2010) 1475-1478. [40]
A. Della Rossa, M. Doveri, A. D'Ascanio, A. Tavoni, A. Consensi, R. Neri et al., Oral
sildenafil in skin ulcers secondary to systemic sclerosis, Scand J Rheumatol 40 (2011) 323-325. [41]
A.L. Herrick, C. Roberts, A. Tracey, A. Silman, M. Anderson, M. Goodfield et al., Lack
of agreement between rheumatologists in defining digital ulceration in systemic sclerosis, Arthritis Rheum 60 (2009) 878-882.
Figure 1: Distribution of patients Figure 2: Distribution of digital ulcers (DU) at inclusion (A) and at one year (B). Data is presented for 79 patients with active DU at inclusion and/or at one year.
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23
Control of digital ulcerative disease in SSc
Table 1. Demographics and clinical characteristics at inclusion Included patients
All patients Patients with Patients with
p-
with data
controlled
uncontrolled
value
at 1 year
disease
disease
*
(n = 190)
(n = 120)
¶
(n = 58 )
§
(n = 62 )
Age, years
52.8±14.6
54.2±14.9
53.5±14.2
55.0±15.5
0.58
Female gender
132 (69.5)
84 (70.0)
41 (70.7)
43 (69.4)
0.87
43.0±14.7
44.3±15.1
43.7±14.9
44.9±15.4
0.66
limited SSc
109 (57.4)
69 (57.5)
39 (67.2)
30 (48.4)
0.04
diffuse SSc
81 (42.6)
51 (42.5)
19 (32.8)
32 (51.6)
Time since RP
11.0 [5-20]
12 [4-20]
12 [4-23]
12 [4-19]
0.49
Time since first non RP
8.0 [3-14]
8 [3-15]
7 [2-15]
8.5 [4-15]
0.86
4.8 [2-10]
4 [1-10]
3 [1-10]
5 [3-10]
0.36
At least 1 organ involvement
160 (84.2)
100 (83.3)
44 (75.9)
56 (90.3)
0.03
Pulmonary fibrosis
86 (45.3)
50 (41.7)
18 (31.0)
32 (51.6)
0.02
PAH†
22 (11.6)
13 (10.8)
4 (6.9)
9 (14.5)
0.18
6 (3.2)
2 (1.7)
1 (1.7)
1 (1.6)
0.96
Esophagus involvement
140 (73.7)
88 (73.3)
37 (63.8)
51 (82.3)
0.02
Gastrointestinal involvement
52 (27.4)
31 (25.8)
11 (19.0)
20 (32.3)
0.10
14.2±8.8
14.2±8.6
12.6±8.2
15.7±8.7
0.049
108 (57.4)
68 (57.1)
27 (46.6)
41 (67.2)
0.02
(n = 188)
(n = 119)
2.0±2.0
1.9±2.0
Demographics
Clinical characteristics Age at SSc diagnosis, years Disease form
Disease duration, years
symptom Time since first DU Organ involvement
History of renal crisis
Skin involvement Modified Rodnan Skin Score Ulcerative disease > 5 DU episodes† since first DU DU episodes† during last year
January 12, 2017
(n = 61) 1.8±2.2
1.9±1.9
0.73
24
Control of digital ulcerative disease in SSc Immunological characteristics Anti-topoisomerase 1 (Scl-
97 (51.6)
59 (50.0)
20 (35.1)
39 (63.9)
0.003
70) antibodies
(n = 188)
(n = 118)
(n = 57)
(n = 61)
Anti-centromere antibodies
54 (29.8)
37 (33.0)
22 (39.3)
15 (26.8)
(n = 181)
(n = 112)
(n = 56)
(n = 56)
190 (100)
120 (100)
58 (100)
62 (100)
15.3±21.5
15.6±22.0
14.7±23.6
16.4±20.6
0.69
Intermittent iloprost
35 (18.4)
24 (20)
12 (20.7)
12 (19.4)
0.86
Calcium channel blockers
42 (60.9)
25 (55.6)
14 (58.3)
11 (52.4)
0.69
(n = 69)
(n = 45)
(n = 24)
(n = 21)
0.16
Treatment for DU Bosentan Treatment duration, months
Values are expressed as mean ± standard deviation, median with first and third quartiles [Q1;Q3], or number of patients (percentage). Number of patients with the assessment (n) is provided when different from the number of patients in group. *p-values are provided for comparison between patients with controlled and uncontrolled disease. ¶
Including 12 patients who discontinued bosentan
§ †
Including 9 patients who discontinued bosentan A DU episode is defined as a period with at least one active DU between two DU-free periods.
DU: digital ulcers;
: pulmonary arterial hypertension; R : Raynaud’s phenomenon; SSc:
systemic sclerosis.
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Control of digital ulcerative disease in SSc
Table 2. Factors limiting hand function in addition to ischemic DU All patients
Patients with a
Patients with an
p-
with data
controlled
uncontrolled
value*
at 1 year
disease
disease
(n = 120)
¶
(n = 58 )
(n = 62§)
22 (18.3)
11 (19.0)
11 (17.7)
0.86
6 (5.0)
1 (1.7)
5 (8.1)
0.21
14 (11.7)
3 (5.2)
11 (17.7)
0.03
Non-ischemic DU Located on the dorsal surface of the fingers Complicating calcinosis On bone profile
Sequelae from previous DU (on one hand a least) Loss of substance
73 (60.8)
36 (62.1)
37 (60.0)
0.79
Auto-amputation
10 (8.3)
3 (5.2)
7 (11.3)
0.33
Surgical amputation
13 (10.8)
7 (12.1)
6 (9.7)
0.67
Digital sympathectomy
4 (3.3)
0
4 (6.5)
0.12
Arthrodesis
2 (1.7)
0
2 (3.2)
0.50
Tendinous retractions
52 (43.3)
16 (27.6)
36 (58.1)
0.0008
Non-ulcerative calcinosis
16 (13.3)
4 (6.9)
12 (19.4)
0.04
Ankylosis
81 (67.5)
34 (58.6)
47 (75.8)
0.04
63 (52.5)
26 (44.8)
37 (59.7)
0.10
35 (29.2)
16 (27.6)
19 (30.7)
0.71
Other non-ischemic factors
of
distal
interphalangeal joints Ankylosis of proximal interphalangeal joints Ankylosis of metacarpophalangeal joints Values are expressed as number of patients (percentage). *p-values are provided for comparison between patients with controlled and uncontrolled disease. ¶
Including 12 patients who discontinued bosentan
§
Including 9 patients who discontinued bosentan
DU: digital ulcers.
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Control of digital ulcerative disease in SSc
Table 3. Changes in functional scores
HAQ-DI (range 0-3)
All patients with
Patients with a
Patients with an
data at 1 year
controlled disease
uncontrolled disease
(n = 120)
(n = 58¶)
(n = 62§)
At
At
At
At
At
At
inclusion
Month 12
inclusion
Month 12
inclusion
Month 12
1.0±0.7
0.9±0.7
0.9±0.7
0.7±0.7
1.0±0.7
1.0±0.7
(n = 118) p = 0.04
(n = 60) p = 0.01
p = 0.76
p = 0.04 (change between subgroups) CHFS (range 0-90)
29±20
25±20
(n = 111)
30±22
22±20
(n = 54)
p = 0.005
29±18
28±20
(n = 57)
p = 0.001
p = 0.50
p = 0.04 (change between subgroups) VAS (range 0-10)
4.3±3.1
2.9± 1.8
4.2±3.7
2.3±2.2
4.5±3.1
3.4±3.2
(n = 110)
(n = 115)
(n = 53)
(n = 58)
(n = 57)
(n = 57)
p < 0.0001
p = 0.0004
p = 0.04
p = 0.046 (change between subgroups) SF-36 PCS (range 0-100)
39±9
39±10
41±10
41±10
38±7
37±8
(n = 116)
(n = 114)
(n = 56)
(n = 57)
(n = 60)
(n = 57)
p = 0.92
p = 0.29
p = 0.32
p = 0.049 (change between subgroups) Physical Functioning
55±29
56±30
p = 0.81 Role-Physical
50±30
51±27
p = 0.62 Bodily Pain
44±24
49±23
p = 0.04
January 12, 2017
62±30
62±31
p = 0.81 47±33
53±30
p = 0.10 44±27
53±25
p = 0.01
49±28
49±28
p = 0.55 52±26
49±24
p = 0.41 44±21
45±20
p = 0.88
27
Control of digital ulcerative disease in SSc
p = 0.03 (change between subgroups) General Health
41±19
41±20
42±18
p = 0.70 SF-36 MCS (range 0-100)
42±21
p = 0.73
40±20
39±19
p = 0.43
38±12
40±12
37±11
38±11
39±13
41±13
(n = 116)
(n = 114)
(n = 56)
(n = 57)
(n = 60)
(n = 57)
p = 0.22
p = 0.26
p = 0.24
p = 0.87 (change between subgroups) Vitality
40±20
40±21
40±20
p = 0.91 Social Functioning
59±26
63±26
p = 0.96 59±27
p = 0.12 Role-Emotional
59±32
59±30
51±21
55±21
63±26
p = 0.20 56±34
p = 0.78 Mental Health
40±22
58±31
p = 0.53 52±17
p = 0.01
55±20
p = 0.10
40±20
41±20
p = 0.91 59±26
63±25
p = 0.37 62±29
59±29
p = 0.35 51±24
56±22
p = 0.05
Values are expressed as mean ± standard deviation. Number of patients with the assessment (n) is provided when different from the number of patients in group. Comparisons were tested with variance analysis (ANOVA) with baseline adjustment for comparisons between subgroups at one year (for the SF-36 scales, p-values for comparisons between subgroups are only presented when significant). ¶
Including 12 patients who discontinued bosentan
§
Including 9 patients who discontinued bosentan
CHFS: Cochin Hand Function Scale, DU: digital ulcers, HAQ-DI: Health Assessment Questionnaire Disability Index, SF-36 PCS/MCS: Medical Outcomes Study 36-item Short-Form Physical/Mental Component Summary, VAS: visual analog scale.
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28