Effect of sildenafil on digital ulcers in systemic sclerosis: analysis from a single centre pilot study.
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ABSTRACT: Objective
In this pilot study, the effect of sildenafil on digital ulcer (DU) healing and related clinical symptoms was analysed.Methods
A total of 19 patients with systemic sclerosis (SSc) were treated with maximally tolerated sildenafil doses up to 6 months. Primary outcome was the healing of DUs. Changes in other clinical symptoms were also evaluated.Results
In all, 49 DUs were present at baseline; this decreased to 17 ulcers (p<0.001) at the end of sildenafil treatment. Furthermore, the visual analogue scale (VAS) score for Raynaud's phenomenon (RP), pain and activity improved (p=0.003, p=0.002 and p=0.05, respectively). A total of 9 patients developed 12 new DUs during sildenafil treatment.Conclusions
This study indicates an effect of sildenafil on DU healing in patients with SSc and an improvement of RP and associated symptoms that should be validated in controlled studies.
SUBMITTER: Brueckner CS
PROVIDER: S-EPMC2938897 | biostudies-literature | 2010 Aug
REPOSITORIES: biostudies-literature
Publications
Effect of sildenafil on digital ulcers in systemic sclerosis: analysis from a single centre pilot study.
Brueckner Claudia S CS Becker Mike O MO Kroencke Thomas T Huscher Doerte D Scherer Hans Ulrich HU Worm Margitta M Burmester Gerd G Riemekasten Gabriela G
Annals of the rheumatic diseases 20091108 8
<h4>Objective</h4>In this pilot study, the effect of sildenafil on digital ulcer (DU) healing and related clinical symptoms was analysed.<h4>Methods</h4>A total of 19 patients with systemic sclerosis (SSc) were treated with maximally tolerated sildenafil doses up to 6 months. Primary outcome was the healing of DUs. Changes in other clinical symptoms were also evaluated.<h4>Results</h4>In all, 49 DUs were present at baseline; this decreased to 17 ulcers (p<0.001) at the end of sildenafil treatmen ...[more]
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Project description:Systemic sclerosis is a disease where microcirculation damage is critical in their beginning and vascular complications have similar pathogenic findings. Digital ulcers are a frequent complication in systemic sclerosis patients and pulmonary hypertension is one of the leading causes of death. The use of bosentan has been shown to be useful for the treatment of pulmonary arterial hypertension and to prevent new digital ulcers. However, is unknown if bosentan can prevent pulmonary hypertension. Our objective was to determine if bosentan is useful to prevent pulmonary hypertension in SSc patients. A retrospective study in 237 systemic sclerosis patients with digital ulcers history treated or not with bosentan to prevent it was made. We analyzed the occurrence of pulmonary hypertension defined by an echocardiogram pulmonary arterial pressure > 40 mmHg in the entire cohort. Demographic, clinical, and treatment variables were recorded for all patients. Statistical significance was denoted by p values < 0.05. Fifty-nine patients were treated with bosentan a median of 34 months. 13.8% of treated patients had pulmonary hypertension vs 23.7% of untreated patients (p 0.13) during the follow up. In multivariate analysis patients not treated with bosentan had 3.9fold-increased risk of pulmonary hypertension compared with patients under bosentan treatment (p < 0.02). Moreover the percentage carbon monoxide diffusing capacity (DLCO) in bosentan treated patients did not decrease from baseline to the end of follow-up (61.8±14% vs 57±20.1%, p = 0.89). We concluded that Systemic sclerosis patients with digital ulcers treated with bosentan seems to have less risk to develop pulmonary hypertension and to stabilize DLCO.
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Project description:ObjectiveTo evaluate the evidence concerning systemic pharmacological treatments for SSc digital ulcers (DUs) to inform the development of evidence-based treatment guidelines.MethodsA systematic literature review of seven databases was performed to identify all original research studies of adult patients with SSc DUs. Randomized controlled trials (RCTs) and prospective longitudinal observational studies (OBSs) were eligible for inclusion. Data were extracted, applying the patient, intervention, comparison, outcome framework, and risk of bias (RoB) was assessed. Due to study heterogeneity, narrative summaries were used to present data.ResultsForty-seven studies that evaluated the treatment efficacy or safety of pharmacological therapies were identified among 4250 references. Data from 18 RCTs of 1927 patients and 29 OBSs of 661 patients, at various RoB (total 2588 patients) showed that i.v. iloprost, phosphodiesterase-5 inhibitors and atorvastatin are effective for the treatment of active DUs. Bosentan reduced the rate of future DUs in two RCTs (moderate RoB) and eight OBSs at low to high RoB. Two small studies (moderate RoB) indicate that Janus kinase inhibitors may be effective for the treatment of active DUs, otherwise there are no data to support the use of immunosuppression or anti-platelet agents in the management of DUs.ConclusionThere are several systemic treatments, across four medication classes, that are effective therapies for the management of SSc DUs. However, a lack of robust data means it is not possible to define the optimal treatment regimen for SSc DUs. The relatively low quality of evidence available has highlighted further areas of research need.
| S-EPMC10691932 | biostudies-literature
Project description:Digital ulcers (DUs) comprise the main manifestation of vasculopathy and are a major cause of disability in patients with systemic sclerosis (SSc). A literature search in Web of Science, PubMed and Directory of Open Access Journals was performed in December 2022 to identify articles published in the last decade regarding the management of DUs. Prostacyclin analogues, endothelin antagonists and phosphodiesterase 5 inhibitors have shown promising results both as a stand-alone treatment and in combination for the treatment of existing and prevention of new DUs. Moreover, autologous fat grafting and botulinum toxin injections, although not readily available, can be of use in recalcitrant cases. Many investigational treatments with promising results could pave the way for a paradigm shift in the treatment of DUs in the future. Despite these recent advances, challenges remain. Better-designed trials are of paramount importance to optimise DU treatment in the years to come. Key Points • DUs are a major cause of pain and reduced quality of life in patients with SSc. • Prostacyclin analogues and endothelin antagonists have shown promising results both as a stand-alone treatment and in combination for the treatment of existing and prevention of new DUs. • In the future, a combination of more powerful vasodilatory drugs, perhaps in conjunction with topical approaches, may improve outcomes.
| S-EPMC10497679 | biostudies-literature
Project description:Digital ulcers (DU) are a common, severe vascular manifestation of systemic sclerosis (SSc) with few effective treatment options. Using data from the Australian Scleroderma Cohort Study (ASCS), we sought to evaluate the effect of calcium channel blockers (CCB) on the treatment and prevention of DU.Using data from 1953 participants, with a median of 4.34 years of follow-up, we used generalised estimating equations to evaluate the clinical characteristics associated with CCB use and ascertain the risk factors for the presence of DU at subsequent study visits. A time-dependent Cox-proportional hazard model was applied to evaluate the risk of future occurrence of DU with CCB use.Sixty-six percent of participants received CCB and patients with a history of DU were more likely to be prescribed a CCB (76.76% vs 53.70%, p < 0.01). CCB use was more frequent in patients with severe complications of DU including chronic DU (OR 1.47, p = 0.02), need for hospitalisation for iloprost (OR 1.30, p = 0.01) or antibiotics (OR 1.36, p = 0.04) and digital amputation (OR 1.48, p < 0.01). Use of CCB was more likely in patients who experienced DU at subsequent study visits (OR 1.32, p < 0.01) and was not associated with a decreased risk of the development of a first DU (HR 0.94, p = 0.65).CCB are frequently used in the management of SSc in the ASCS and their use is associated with severe peripheral vascular manifestations of SSc. However, our results suggest that CCB may not be effective in the healing or prevention of DU.
| S-EPMC10774194 | biostudies-literature
Project description:BackgroundSystemic sclerosis (SSc) is a rare disabling connective tissue disease with few available treatment options. Diffuse cutaneous systemic sclerosis (dcSSc) is associated with high mortality. A previous experiment has shown that JAK2 inhibitor can significantly improve skin fibrosis in bleomycin (BLM)-induced murine model, including reducing dermal thickening and collagen accumulation. We aimed to describe the efficacy of oral JAK1/2 inhibitor baricitinib in SSc patients, especially focusing on skin fibrosis and microvascular manifestations.MethodsWe described the different effects of oral selective JAK1, JAK2, or JAK3 inhibitor treatment in a BLM-induced skin fibrosis mouse model. Furthermore, 10 adult patients with dcSSc were treated with baricitinib. We assessed the changes in modified rodman skin score (mRSS) and digital ulcer net burden at week 12 and 24 from baseline. We also compared the absolute changes in scores on the Scleroderma Health Assessment Questionnaire (SHAQ) and a total score on the St. George's Respiratory Questionnaire (SGRQ) over a 24-week period.ResultsIn the experimental mouse model of skin fibrosis, a JAK1 and JAK2 inhibitor ameliorated skin fibrosis, and a JAK2 inhibitor had the most obvious effect. Treatment with the JAK2 inhibitor also blunted the capillary rarefaction. We demonstrated that skin fibrosis and digital ulcers were significantly relieved in 10 SSc patients treated with baricitinib. The mRSS significantly improved at week 12 from baseline, with a mean change in mRSS of -8.3 [95% confidence interval (CI), -12.03 to -4.574; p = 0.0007] and improved greater at week 24 to -11.67 (95% CI, -16.84 to -6.496; p = 0.0008). Among the four patients with digital ulcers (DU), three were completely healed at week 24, the number of ulcers in another patient was significantly reduced, and there was no patient with new ulcers. Only one adverse event (AE) of herpes zoster was observed.ConclusionsOur results indicate that selective JAK1 and JAK2 inhibitor alleviates skin fibrosis, and oral JAK1/2 inhibitor baricitinib is a potentially effective treatment for dcSSc patients with skin fibrosis and DU. Baricitinib was well-tolerated by most patients in this study. Additional large clinical trials are needed to confirm our pilot findings.Chinese clinical trial registry numberChiCTR2000030995.
| S-EPMC9208297 | biostudies-literature
Project description:ObjectiveTo assess the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on digital ulcer (DU) healing in systemic sclerosis (SSc).MethodsRandomised, placebo-controlled study in patients with SSc to assess the effect of sildenafil 20 mg or placebo, three times daily for 12 weeks, on ischaemic DU healing. The primary end point was the time to healing for each DU. Time to healing was compared between groups using Cox models for clustered data (two-sided tests, p=0.05).ResultsIntention-to-treat analysis involved 83 patients with a total of 192 DUs (89 in the sildenafil group and 103 in the placebo group). The HR for DU healing was 1.33 (0.88 to 2.00) (p=0.18) and 1.27 (0.85 to 1.89) (p=0.25) when adjusted for the number of DUs at entry, in favour of sildenafil. In the per protocol population, the HRs were 1.49 (0.98 to 2.28) (p=0.06) and 1.43 (0.93 to 2.19) p=0.10. The mean number of DUs per patient was lower in the sildenafil group compared with the placebo group at week (W) 8 (1.23±1.61 vs 1.79±2.40 p=0.04) and W12 (0.86±1.62 vs 1.51±2.68, p=0.01) resulting from a greater healing rate (p=0.01 at W8 and p=0.03 at W12).ConclusionsThe primary end point was not reached in intention-to-treat, partly because of an unexpectedly high healing rate in the placebo group. We found a significant decrease in the number of DUs in favour of sildenafil compared with placebo at W8 and W12, confirming a sildenafil benefit.Trial registration numberNCT01295736.
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Project description:BackgroundTo determine the frequency and clinical characteristics of systemic sclerosis-related digital ulcers, and associated direct health care costs, quality of life, and survival.MethodsDigital ulcers (DUs) were defined as an area with a visually discernible depth and a loss of continuity of epithelial coverage. DU severity was calculated based on the physician reported highest number of new DUs at clinical review (mild = 1-5 DUs, moderate 6-10 DUs, severe > 10 DUs). Healthcare use was captured through data linkage, wherein SSc clinical data captured prospectively in a dedicated clinical database were linked with health services databases to capture hospital admissions, emergency department (ED) presentations and ambulatory care (MBS) utilization and cost for the period 2008-2015. Healthcare cost determinants were estimated using logistic regression.ResultsAmong 1085 SSc patients, 48.6% experienced a DU over a mean follow-up of 5.2 ± 2.5 years. Those who developed DUs were more likely to have diffuse disease subtype (34.9% vs 18.2%, p < 0.001), anti-Scl-70 antibody (18.9% vs 9.3%, p < 0.001), and a younger age at SSc onset (43.6 ± 13.9 vs 48.8 ± 14.0 years, p < 0.001) in addition to reduced health-related quality of life (HRQoL) measured by the SF-36 but without a significant impact on survival. SSc patients with a history of a DU utilized significantly more healthcare resources per annum than those without a DU, including hospitalizations, ED presentation, and ambulatory care services. Total healthcare services, excluding medications, were associated with an annual excess cost per DU patient of AUD$12,474 (8574-25,677), p < 0.001, driven by hospital admission and ED presentation costs.ConclusionDUs place a large burden on the patient and healthcare system through reduced HRQoL and increased healthcare resource utilization and associated cost.
| S-EPMC6929369 | biostudies-literature
Project description:ObjectiveDigital ulcers (DUs) are often a primary end point in systemic sclerosis (SSc; scleroderma) clinical trials, although the reliability of rheumatologists grading DUs is poor to moderate at best. DU assessment in recent trials has been based upon visual inspection alone, which potentially misses "real-world" clinical contextual information. Our aim was to investigate whether this clinical information improves the reliability of rheumatologists grading DUs. A secondary aim was to assess agreement between patients and rheumatologists.MethodsEighty images of a range of digital lesions were collected from patients with SSc with the clinical context: pain (severity and temporal relationship), lesion duration, and discharge (patient reported and clinician observed). Raters received all images either with or without the clinical context, and graded these images (using a custom-built interface) on an ordinal scale of severity: no ulcer, inactive ulcer, or active ulcer. Patients also graded their lesion(s) on the same scale.ResultsFifty-one rheumatologists from 15 countries completed the study (26 without and 25 with context): 4,590 (including 510 repeated) image gradings were obtained. Context did not significantly increase (without and with context) either intra- (0.64, 0.71) or interrater (0.32, 0.36) reliability. Pain (visual analog scale and temporal relationship) and discharge (patient reported and clinician observed) were associated with increased lesion severity, and duration with reduced severity. Agreement between individual patients and rheumatologists was poor without and with context (0.19, 0.28).ConclusionThe overall intra- and interrater reliability of DU grading did not significantly improve with the clinical context. Agreement between patients and rheumatologists was poor.
| S-EPMC5006886 | biostudies-literature
Project description:BACKGROUND:To determine the effect of riociguat, an oral, selective soluble guanylate cyclase stimulator, on the net digital ulcer (DU) burden in systemic sclerosis (SSc). METHODS:Participants with SSc-related active or painful indeterminate DUs were recruited in a multicenter, double-blind, randomized, placebo-controlled, proof-of-concept trial. Eligible participants were required to have at least one visible, active ischemic DU or painful indeterminate DU at screening, located at or distal to the proximal interphalangeal joint and that developed or worsened within 8 weeks prior to screening. Participants were randomized 1:1 to placebo or riociguat in individualized doses (maximum of 2.5 mg three times daily) during an 8-week titration period, followed by an 8-week stable dosing period. This was followed by an optional 16-week open-label extension phase for participants with active DU/reoccurrence of DUs within 1 month of the end of the main treatment phase. The primary endpoint was the change from baseline to week 16 in net ulcer burden (NUB), analyzed using ANCOVA. Other endpoints included plasma biomarkers and proportion of participants with treatment-emergent adverse events (AEs). RESULTS:Seventeen participants (eight placebo, nine riociguat) were randomized at five centers. Six participants in each group transitioned to the open-label extension. Baseline characteristics were comparable between the treatment groups, except participants randomized to placebo were older and had longer disease duration (p < 0.05). At baseline, the mean (SD) NUB was 2.5 (2.0) in the placebo and 2.4 (1.4) in the riociguat. No significant treatment difference was observed in the change from baseline to 16 weeks in NUB (adjusted mean treatment difference - 0.24, 95% CI (- 1.46, 0.99), p = 0.70). Four participants experienced five serious AE (four in riociguat and one in placebo); none was considered related to study medication. Statistically significant elevation of cGMP was observed at 16 weeks in the riociguat group (p = 0.05); no other biomarkers showed significant changes. In the open-label extension, participants in the riociguat-riociguat arm had complete healing of their DUs. CONCLUSION:In participants with SSc-DU, treatment with riociguat did not reduce the number of DU net burden compared with placebo at 16 weeks. Open-label extension suggests that longer duration is needed to promote DU healing, which needs to be confirmed in a new trial. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02915835 . Registered on September 27, 2016.
| S-EPMC6724329 | biostudies-literature
Project description:BackgroundLocally acting, well-tolerated treatments for systemic sclerosis (SSc) digital ulcers (DUs) are needed.ObjectivesOur primary aim was to investigate the safety, feasibility, and tolerability of a novel low-level light therapy (LTTT). A secondary aim was to tentatively assess efficacy.MethodsA custom-built device comprising infrared (850 nm), red (660 nm), and violet (405 nm) LEDs was utilized. DUs were irradiated with 10 J/cm2 twice weekly for 3 weeks, with follow-up at weeks 4 and 8. Any safety concerns were documented. Patient opinion on time to deliver, feasibility, and pain visual analogue score (VAS; 0-100, 100 most severe) was collected. Patient and clinician DU global assessment VAS were documented. DUs were evaluated by laser Doppler perfusion imaging pre- and post-irradiation.ResultsIn all, 14 DUs in eight patients received a total of 46 light exposures, with no safety concerns. All patients considered LTTT 'took just the right amount of time' and was 'feasible', with a low associated mean pain VAS of 1.6 (SD: 5.2). Patient and clinician global DC VAS improved during the study (mean change: -7.1 and -5.2, respectively, both p < .001). DU perfusion significantly increased post-irradiation.ConclusionsLTTT for DUs is safe, feasible, and well tolerated. There was an early tentative suggestion of treatment efficacy.
| S-EPMC6484448 | biostudies-literature