Effectiveness of bosentan in the treatment of systemic sclerosis-related digital ulcers: Systematic review and meta-analysis
Marziyeh Hosseinbalam1, Rasool Nouri2, Ziba Farajzadegan3, Peyman Mottaghi1
1 Department of Internal Medicine, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran
2 Health Information Technology Research Center, School of Management and Medical Information Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
3 Department of Community Medicine, Faculty of Medicine, Child Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
|Date of Submission||27-May-2022|
|Date of Decision||16-Jul-2022|
|Date of Acceptance||26-Jul-2022|
|Date of Web Publication||31-Jan-2023|
Department of Internal Medicine, Medical School, Isfahan University of Medical Sciences, Isfahan
Source of Support: None, Conflict of Interest: None
Materials and Methods: The aim of the present systematic review and meta-analysis was to evaluate the therapeutic efficacy of bosentan, a dual endothelin receptor antagonist, for systemic sclerosis (SSc) patients with digital ulcers (DUs). Methods: A systematic search of MEDLINE, Embase, Web of Science, and Scopus was done using appropriate keywords till September 2021. Weighted mean difference (WMD) as the effect of therapeutic efficacy of bosentan on continuous outcomes was an estimate. Furthermore, the pooled prevalence of diffuse SSc and limited SSc was computed. Fixed or random effects models when appropriate were used for data synthesis. Results: Totally, 469 patients, with a mean age ranging from 48.1 to 63.7 years, from 8 studies were included in the systematic review and meta-analysis. The pooled frequency of diffuse SSc and limited SSc was 56% (95% confidence interval [CI]: 39%, 73%) and 44% (95% CI: 27%, 61%). The pooled prevalence of new DUs following bosentan treatment was 21% (95% CI: 10%, 33%). The results of the meta-analysis showed a pooled mean decrease of WMD: −0.09 (95% CI: −0.020, 0.02, P= 0.10), WMD: −2.82 (95% CI: −5.91, 0.27, P= 0.07), and WMD: −6.65 (95% CI: −9.49, −3.82, P< 0.001) in mean SSc-Health Assessment Questionnaire, pain, and Rodnan score, respectively. Our meta-analysis also indicated a significant pooled decrease in the number of new DUs in SSc patients compared to placebo subjects (WMD: −0.89 [95% CI: −1.40, −0.37; P= 0.001]) and baseline values (WMD: −1.34 (95% CI: −1.95, −0.73; P< 0.001). Conclusion: Bosentan possibly is an efficacious treatment option for SSc-related DUs. Although further large-scale randomized clinical trials are required to confirm the preliminary finding and underlying mechanisms of action.
Keywords: Bosentan, digital ulcer, meta-analysis, systemic sclerosis, treatment
|How to cite this article:|
Hosseinbalam M, Nouri R, Farajzadegan Z, Mottaghi P. Effectiveness of bosentan in the treatment of systemic sclerosis-related digital ulcers: Systematic review and meta-analysis. J Res Med Sci 2023;28:3
|How to cite this URL:|
Hosseinbalam M, Nouri R, Farajzadegan Z, Mottaghi P. Effectiveness of bosentan in the treatment of systemic sclerosis-related digital ulcers: Systematic review and meta-analysis. J Res Med Sci [serial online] 2023 [cited 2023 Mar 20];28:3. Available from: https://www.jmsjournal.net/text.asp?2023/28/1/3/368852
| Introduction|| |
Systemic sclerosis (SSc) is a disease of connective tissue manifested by cutaneous and visceral fibrosis and vascular abnormalities. There are two major subtypes of SSc according to the skin involvement comprising diffuse cutaneous SSc (DcSSc) and limited cutaneous SSc (LcSSc). The diffuse form progresses rapidly and involves skin and internal organs extensively. While LcSSc is dominated by vascular diseases and its cutaneous involvement is limited to hands and face. Digital ulcers (DUs) have been known as the most common presentations of vasculopathy with a prevalence of 40%–50%. It is believed that the presence of DUs in SSc patients is a predictor of severe disease course and decreased survival., In addition, DUs are associated with great pain, decreased quality of life, and functional disability., Thus, its effective clinical management is of great importance.
It is very challenging to find and evaluate efficacious treatment options for SSc because the pathophysiology of the disease is complex and not fully understood. An increased serum level of endothelin-1 (ET-1), which is a naturally occurring vasoconstrictor, has been reported in patients with SSc, suggesting its role in the vascular pathogenesis of the disease. Recently, bosentan, a dual endothelin receptor (ER) antagonist which prevents the binding of ET-1 to its receptors, has been introduced for the treatment of pulmonary hypertension in patients with SSc., Furthermore, it has been known that bosentan prevents the onset of DUs in several studies comprising two double-blind randomized controlled trial (RCT). Korn et al. in a multicenter RCT evaluated the effect of bosentan on the prevention of DUs in patients with SSc. The results of the study indicated that the mean number of new ulcers decreased significantly in patients treated with bosentan after 16 weeks. An improvement in hand function was also observed in bosentan-treated patients. Matucci-Cerinic et al. also reported a significant reduction in the number of new DUs compared to placebo; however, their results failed to show any improvement in pain and disability. Given the low prevalence of SSc and the small sample size of related studies, the present systematic review and meta-analysis aimed to estimate pooled data regarding bosentan efficacy in the treatment of DUs in patients with SSc.
| Methods|| |
A systematic search of MEDLINE, Embase, Web of Sciences, and Scopus databases was done to identify the studies investigating the therapeutic effect of bosentan in patients with digital ulcers from inception to September 2021. The following terms were used: “Bosentan” OR “Farantan” OR “Sentobiox” OR “Tracleer” OR “'Endothelin receptor antagonist” OR “ET-1antagonist” OR “stayveer” AND “Finger ulcer” OR “'Digital ulcer” OR “Gangrene” OR “Calcinosis” OR “Raynaud” AND “Scleroderma” OR “'Systemic sclerosis” OR “Dermatosclerosis” OR “Sclerema” OR “scleroderma adultorum” OR “scleroderma” OR “skin sclerosis.” After removing duplicates, an independent screen of the titles and abstracts was done by two independent reviewers (M.H and R.N) and relevant articles were short-listed. To determine the eligibility of short-listed articles, their full texts were screened by the same reviewers and any disagreement was resolved by consensus with a third review author (P.M). The reference list of included studies was manually searched to find relevant studies.
Eligibility criteria and data extraction
All observational and interventional studies concerning the therapeutic efficacy of bosentan for SSc patients with DUs published in English were included in the present systematic review and meta-analysis. The exclusion criteria were (1) editorials, case reports, conference reports, and review articles; (2) unavailable data or full texts; (3) studies on subjects younger than 18 years old or those diagnosed with other connective tissue disorders than SSc; and (4) studies investigating the treatment of SSc-related DUs with bosentan in combination with other medications. Two independent researchers (M.H and R.N) extracted data from the included studies. The following variables were extracted: the first author, the publication year, the study design, region, sample size, population demographics (age and sex), condition information, and outcomes comprising the prevalence of new DUs as well as the mean of pain, Rodnan score, and SSc-Health Assessment Questionnaire score (SSc-HAQ).
Data synthesis and statistical analysis
Mean changes were calculated as follows: Measure at end of the treatment period minus measure at baseline. The weighted mean difference (WMD) along with a 95% confidence interval (CI) for WMD was calculated to assess the effects of treatment on continuous outcomes. For those studies that did not report standard error of the means (SEMs) values, the computation was done based on the available data using the following standard formula: (SEM = Standard deviation (SD)/square root of the number of subjects. SDs of the mean difference were calculated as: SD = square root ([SD pretreatment]2+ [SD posttreatment]2− [2 R × SD pretreatment × SD posttreatment]), considering a correlation coefficient R = 0.6.
To estimate the pooled prevalence and corresponding 95% CI, weighted prevalence rates were calculated using the “MetaProp program” in STATA software. Heterogeneity of the included studies was assessed using Higgins' I2 statistic and Cochran Q test and expressed as percentage. Values of 25%, 50%, and 75% for I2 were considered low, medium, and high levels of heterogeneity, respectively. Data were pooled using fixed effects when heterogeneity was low and random effects model in case of high levels of heterogeneity among included studies. Possible sources of heterogeneity were explored by sensitivity analyses and meta-regression. Publication bias was tested using Egger's and Begg's test and visual inspection of the funnel plot. In the existence of a bias, trim-and-fill analysis was conducted to detect the contribution of the bias to the overall effect. All data synthesis was performed using STATA version 14 (STATA, College Station, TX, USA).
| Results|| |
The systematic search found a total of 1257 results [Figure 1]. After removing 243 duplicates, 1104 titles and abstracts remained to screen. Ultimately, 16 full texts were retrieved for further examination. A total of eight articles met our inclusion criteria, comprising three RCTs,,, four prospective,,,, and one retrospective study conducted between 2004 and 2021. Details of the included studies in the systematic review and meta-analysis are summarized in [Table 1]. Four studies were from Europe and North America,,,, two from Asia,, one from Eurasia, and one from South America. Eligible studies included a total of 469 SSc patients with a mean age ranging from 48.1 to 63.7 years. Investigated subjects were mainly women with a frequency ranging from 61.5% to 100%.
|Table 1: Detailed characteristics of included studies in the systematic review and meta-analysis|
Click here to view
The frequency of DcSSc and LcSSc ranged from 33.3% and 25.8% to 74.2%, and 66.6%, respectively. The results of meta-analysis indicated that overall frequency of DcSSc and LcSSc were 56% (95% CI: 39%, 73%) [Figure 2]a and 44% (95% CI: 27%, 61%) (I2 = 73.03%, P< 0.001) [Figure 2]c. There was no publication bias according to Egger's test (P > 0.05) and visual inspection of the funnel plot [Figure 2]b and [Figure 2]d. As shown in [Table 2], meta-regression analysis found no statistically significant association between mean age, disease duration, and sample size, as confounding, variables with the frequency of DcSSc and LcSSc (P > 0.05).
|Figure 2: Forest plot for the frequency of diffuse cutaneous systemic sclerosis (a), Eager's funnel plot asymmetry test for publication bias (b), Forest plot for the frequency of limited cutaneous systemic sclerosis (c), Eager's funnel plot asymmetry test for publication bias (d)|
Click here to view
Prevalence of new DUs after bosentan treatment was assessed in seven studies ranging from 0% to 66.3%.,,,,,, Fixed random effect meta-analysis across eligible studies showed a pooled prevalence of new DUs of 21% (95% CI: 10%, 33%; I2 = 75.93%, P< 0.001) [Figure 3]a. The results of Egger's test (P = 0.03) and funnel plot showed a significant publication bias [Figure 3]b and after trim-and-fill analysis for correction of publication bias, results did not change. The meta-regression test failed to show any significant association between mean age, disease duration, DcSSc, and LcSSc frequency with the prevalence of new DUs after bosentan treatment (P > 0.05) [Table 2].
|Figure 3: Forest plot of the effect of bosentan treatment on the prevalence of new digital ulcers (a), Eager's funnel plot asymmetry test for publication bias (b)|
Click here to view
The weighted mean difference (WMD) of SSc-HAQ score following bosentan treatment was reported in four studies.,,, Our results indicated a nonsignificant pooled WMD decrease of − 0.09 (95%CI: −0.020,0.02, P= 0.1; I2 = 0%, P= 0.96) in SSc-HAQ score [Figure 4]a. In addition, a nonsignificant publication bias was suggested according to Egger's test (P > 0.05) and funnel plot [Figure 4]b. Meta-regression did not show a statistically significant association between mean age, disease duration, DcSSc, and LcSSc frequency with the mean difference of SSc-HAQ score after bosentan treatment (P > 0.05) [Table 2].
|Figure 4: Forest plot of the effect of bosentan treatment on systemic sclerosis-HAQ score (a), Eager's funnel plot asymmetry test for publication bias (b). HAQ = Health Assessment Questionnaire|
Click here to view
According to our meta-analysis results, a pooled WMD decrease of − 2.82 (95% CI: −5.91, 0.27; P= 0.07, I2 = 0%, P= 0.77) and − 6.65 (95% CI: −9.49, −3.82; P< 0.001, I2 = 89.9%, P< 0.001) was also observed in mean pain and Rodnan score, respectively [Figure 5]a and [Figure 5]b. The mean age and disease duration were not statistically contributed to the mean difference of Rodnan score after bosentan treatment (P > 0.05) [Table 2].
|Figure 5: Forest plot of the effect of bosentan treatment on pain (a) and Rodnan score (b)|
Click here to view
Two studies reported changes in the mean number of DUs compared to the placebo group, or baseline values., Our meta-analysis indicated a significant pooled WMD of − 0.89 (95% CI: −1.40, −0.37; P= 0.001, I2 = 5.8%, P= 0.36) in the number of new DUs in the SSc group compared to the placebo group. In addition, a significant pooled WMD of new DUs compared to baseline values was observed (WMD: −1.34 (95% CI: −1.95, −0.73; P< 0.001, I2 = 54.0%, P= 0.04)).
| Discussion|| |
Bosentan has been approved for the treatment of DUs in Europe recently; however, its efficacy in the healing of DUs is a matter of debate. Thus, the present systematic review and meta-analysis were performed to investigate the effect of bosentan treatment on various outcomes of SSC patients with DUs.
There are very few epidemiological studies to investigate the incidence and prevalence of SSc, and there is considerable variability in prevalence and incidence estimates of available epidemiological reports. However, the results of previous studies indicated a higher prevalence of the disease in populations of European origin., To the best of our knowledge, no previous study has investigated the global prevalence of two main subtypes of SSc. SSc is usually subdivided into DcSSc and LcSSc with higher skin involvement and mortality risk in diffuse subjects. According to our findings, the pooled frequency of DcSSc and LcSSc in subjects treated with bosentan was 56% and 44%, respectively. The higher frequency of DcSSc in the present systematic review and meta-analysis is probably due to the inclusion of more severe cases for bosentan treatment in research studies.
The frequency of new DUs after bosentan treatment was highly variable across included studies in the present systematic review and meta-analysis which is possibly owing to differences in studied populations and study designs. Our study estimated the pooled prevalence of new DUs to be 21% after bosentan treatment. However, the net value of new DUs frequency is not a good indicator for evaluating the efficacy of bosentan treatment. Rather, changes in the frequency of new DUs after bosentan treatment compared to baseline values can give us an accurate assessment of the effect of this treatment on the reduction of new DUs frequency. Therefore, using the available data, the change in the mean of new DUs compared to placebo or baseline values was examined. Our results showed a significant pooled weighted mean decrease of 0.89 and 1.34 in the number of new DUs compared to the placebo group and baseline values, respectively.
SSc-HAQ is one of the most widely used tools to assess the disability caused by SSc. This 20-item questionnaire comprises HAQ and five visual analog scales of Reynold's phenomenon, DUs, gastrointestinal symptoms, lung symptoms, and disease severity. The final score of the questionnaire ranged from 0 to 3 and five 15-cm length visual analog scales. Some studies have evaluated the SSc-HAQ score to assess an improvement in the disability and function of SSc patients following bosentan treatment. Our results indicated that bosentan treatment resulted in a decrease in SSc-HAQ WMD; however, the difference was not significant. Meta-regression analysis also failed to show the confounding role of age, disease duration, and the prevalence of SSc on the SSc-HAQ mean difference.
In DcSSc patients, skin thickness has been proposed as an indicator of disease activity, severity, and mortality. As skin thickening in early dcSSc is often associated with internal organ involvement and increased mortality. The modified Rodnan score is used for estimating skin thickness in SSc patients. This score can also be used in research studies as a primary or secondary outcome to address the efficacy of various treatment options. According to our findings, bosentan treatment was associated with a significant reduction in Rodnan score. However, no statistically significant reduction was observed in pain score, assessed by the Visual Analog Scale.
The present systematic review and meta-analysis have several limitations that should be acknowledged. First, a few eligible studies were included in the review. Second, substantial heterogeneity was observed in the investigated outcomes. The meta-regression was performed to assess the influence of several variables; however, it could not quantify the confounding role of age, disease duration, sample size, and SSc subtypes frequency. However, the preliminary results of this study can be used as a guide for future studies.
| Conclusion|| |
The findings of the current study showed that bosentan treatment maybe an efficacious approach for the reduction of new DUs and skin involvement of SSc, although further randomized clinical trials are required to examine the effect of the treatment on the quality of life, function, and SSc-related pain.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Matucci-Cerinic M, Kahaleh B, Wigley FM. Review: Evidence that systemic sclerosis is a vascular disease. Arthritis Rheum 2013;65:1953-62.
Amanzi L, Braschi F, Fiori G, Galluccio F, Miniati I, Guiducci S, et al.
Digital ulcers in scleroderma: Staging, characteristics and sub-setting through observation of 1614 digital lesions. Rheumatology (Oxford) 2010;49:1374-82.
Hachulla E, Clerson P, Launay D, Lambert M, Morell-Dubois S, Queyrel V, et al.
Natural history of ischemic digital ulcers in systemic sclerosis: Single-center retrospective longitudinal study. J Rheumatol 2007;34:2423-30.
Mihai C, Landewé R, van der Heijde D, Walker UA, Constantin PI, Gherghe AM, et al.
Digital ulcers predict a worse disease course in patients with systemic sclerosis. Ann Rheum Dis 2016;75:681-6.
Meunier P, Dequidt L, Barnetche T, Lazaro E, Duffau P, Richez C, et al.
Increased risk of mortality in systemic sclerosis-associated digital ulcers: A systematic review and meta-analysis. J Eur Acad Dermatol Venereol 2019;33:405-9.
Ennis H, Vail A, Wragg E, Taylor A, Moore T, Murray A, et al.
A prospective study of systemic sclerosis-related digital ulcers: Prevalence, location, and functional impact. Scand J Rheumatol 2013;42:483-6.
Bérezné A, Seror R, Morell-Dubois S, de Menthon M, Fois E, Dzeing-Ella A, et al.
Impact of systemic sclerosis on occupational and professional activity with attention to patients with digital ulcers. Arthritis Care Res (Hoboken) 2011;63:277-85.
Biondi ML, Marasini B, Bassani C, Agastoni A. Increased plasma endothelin levels in patients with Raynaud's phenomenon. N Engl J Med 1991;324:1139-40.
Korn JH, Mayes M, Matucci Cerinic M, Rainisio M, Pope J, Hachulla E, et al.
Digital ulcers in systemic sclerosis: Prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 2004;50:3985-93.
Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et al.
Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896-903.
Matucci-Cerinic M, Denton CP, Furst DE, Mayes MD, Hsu VM, Carpentier P, et al.
Bosentan treatment of digital ulcers related to systemic sclerosis: Results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 2011;70:32-8.
Nyaga VN, Arbyn M, Aerts M. Metaprop: A Stata command to perform meta-analysis of binomial data. Arch Public Health 2014;72:39.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.
Begg CB. A measure to aid in the interpretation of published clinical trials. Stat Med 1985;4:1-9.
Lee KA, Park S, Kim BY, Kim YS, Ju JH, Son CN, et al.
Effects of bosentan in the treatment of digital ulcers in Korean patients with systemic sclerosis: A longitudinal, multicenter, uncontrolled trial. J Clin Rheumatol 2021;27:e599-601.
Küçükşahin O, Yildizgören MT, Gerede DM, Maraş Y, Erten Ş. Bosentan for digital ulcers in patients with systemic sclerosis: Single center experience. Arch Rheumatol 2016;31:229-33.
Mariz HD, Corrêa MJ, Kayser C. Bosentan in the treatment of refractory extremities ulcers in systemic sclerosis. Rev Bras Reumatol 2009;49:254-64.
Funauchi M, Kishimoto K, Shimazu H, Nagare Y, Hino S, Yano T, et al.
Effects of bosentan on the skin lesions: An observational study from a single center in Japan. Rheumatol Int 2009;29:769-75.
García de la Peña-Lefebvre P, Rodríguez Rubio S, Valero Expósito M, Carmona L, Gámir Gámir ML, Beltrán Gutiérrez J, et al.
Long-term experience of bosentan for treating ulcers and healed ulcers in systemic sclerosis patients. Rheumatology (Oxford) 2008;47:464-6.
Roman Ivorra JA, Simeon CP, Alegre Sancho JJ, Egurbide MV, Castillo MJ, Lloria X, et al.
Bosentan in clinical practice for treating digital and other ischemic ulcers in Spanish patients with systemic sclerosis: IBER-DU cohort study. J Rheumatol 2011;38:1631-5.
Ingegnoli F, Ughi N, Mihai C. Update on the epidemiology, risk factors, and disease outcomes of systemic sclerosis. Best Pract Res Clin Rheumatol 2018;32:223-40.
Barnes J, Mayes MD. Epidemiology of systemic sclerosis: Incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol 2012;24:165-70.
Steen VD, Medsger TA Jr. The value of the Health Assessment Questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time. Arthritis Rheum 1997;40:1984-91.
Pope J. Measures of systemic sclerosis (scleroderma): Health Assessment Questionnaire (HAQ) and Scleroderma HAQ (SHAQ), physician- and patient-rated global assessments, Symptom Burden Index (SBI), University of California, Los Angeles, Scleroderma Clinical Trials Consortium Gastrointestinal Scale (UCLA SCTC GIT) 2.0, Baseline Dyspnea Index (BDI) and Transition Dyspnea Index (TDI) (Mahler's Index), Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR), and Raynaud's Condition Score (RCS). Arthritis Care Res (Hoboken) 2011;63 Suppl 11:S98-111.
Khanna D, Furst DE, Clements PJ, Allanore Y, Baron M, Czirjak L, et al.
Standardization of the modified Rodnan skin score for use in clinical trials of systemic sclerosis. J Scleroderma Relat Disord 2017;2:11-8.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]