Bosentan in Dermatology: Clinical Applications and Safety

Background Bosentan, an orphan drug, is a dual endothelin receptor antagonist indicated in pulmonary hypertension and in the prevention of new digital ulcers (DU) in patients with systemic sclerosis and ongoing digital ulcer disease. Purpose To evaluate the effectiveness and safety of bosentan in the treatment of clinical manifestations associated with underlying autoimmune disease (Raynaud’s phenomenon (RP), DU and other location skin ulcers (SU)), all of them considered rare diseases. Material and methods Retrospective observational study including patients treated with bosentan from January 2012 to September 2014, on compassionate use. Variables collected were: sex, age, underlying disease, indication, previous treatments, dose and follow-up time. Effectiveness was evaluated as: absence of new ulcers, improvement of the basal ulcers and decrease in the number of RP episodes. The safety profile was determined according to the adverse reactions. Results 14 patients were included; follow up (median, range): 22 (2–55) months; sex: 10 (71%) female; age: 52 (25–81) years. All of them had previously been treated with first-line treatment until resistance or intolerance had developed. In 11 cases bosentan was indicated to treat RP and prevent/treat DU (4 systemic sclerosis, 3 pre-systemic sclerosis, 2 systemic lupus erythematosus (SLE), 1 dermatomyositis and 1 Buerger´s disease. Getting the next results: 63.6% effective (7), 18.2% ineffective (2) and 18.2% could not be evaluated. In the other 3 cases, bosentan was used to treat other location SUs (1 polyarteritis nodosa,1 SLE and 1 necrobiosis lipoidica) with 100% effectiveness. The treatment was discontinued in two cases due to digestive intolerance. In another two cases, the dose was adjusted as a consequence of an initial increase in the hepatic enzymes. Conclusion Bosentan may be considered an appropriate alternative in these diseases which have been refractory to conventional treatment. The number of patients is limited due to the low prevalence of these diseases and to the off-label use of the drug. Therefore, it could be said that value of research lies in the possibility of opening new therapeutic perspectives with this drug. References and/or Acknowledgements No conflict of interest.

Calcium channel blockers have been a treatment of first choice for patients with Raynaud's phenomenon (RP) for many years. The aim of the study: The aim of the study is to compare the therapeutic effect and safety of Diltiazem, Nifedipine and Felodipine in patients with primary and secondary RP and to determine their therapeutic effectiveness in patients with severe RP with digital ulcers. Patients and methods: For a period of six months 86 patients with RP were followed up - 19 with systemic sclerosis and 67 with primary RP. The patients are devided into three groups - treated with Diltiazem, Nifedipine and Felodipine. The first group (I) includes 28 patients (n=28) - 6 with scleroderma (3 patients with digital ulcers; n=3) and 22 patients with primary RP. They received Diltiazem at the dose of 60mg 3 times daily. The second group (II) includes 26 patients (n=26) - 6 with scleroderma (3 patients with digital ulcers; n=3) and 21 patients with primary RP. They received Nifedipine at the dose of 10mg 3 times daily. The third group (III) includes 32 patients (n=32) - 8 with scleroderma (4 patients with digital ulcers; n=4) and 24 patients with primary RP. They were treated with Felodipine at the dose of 5mg 2 times daily. For evaluation of the therapeutic efficacy of the medications was used VAS 100mm for global assessment of the severity of RP from the patient and the physician before the treatment and at the follow up. It was performed capillaroscopy. There were followed up also the adverse events in the course of treatment. Results: At the end of the second week we found significant decrease of values of VAS for the global assessment of severity of RP by the patients and by the doctor in groups of patients - I, II and III. In the three groups of patients the frequency and severity of vasospastic episodes was reduced as well as the degree of pain and disability. Capillaroscopy of nail-fold showed incresed blood flow at the end of the second week compared to baseline in the three groups of patients. Healing of digital ulcers we observed in four patients only in the group treated with Felodipine. These three calcium channel blockers that we used in the present study possess good therapeutic effect in patients with RP, which enhances in the sequence: Diltiazem. Scripta Scientifica Medica 2007;39(1):31-34

Systemic sclerosis (SSc) is a systemic disease, characterized by fibrosis and vasculopathy, with variable internal organ involvement. Skin is very often involved, namely digital ulcers (DU), seldom treatment resistant, responsible for important functional limitation. The DU can evolve from sclerodactily with superficial ulcers, isquemic lesions, deep necrosis, gangrene, loss of tissue, and consequently, to finger amputation. The authors describe the case of a 36 year old female patient, with SSc diagnosed 6 years previously, with skin, lung and gut manifestations. The patient showed uncontrolled Raynaud's phenomenon (RF), despite the adequate treatment using nifedidpine and general local warming measures, with progressively worsening DU and isquemia, especially in cold seasons. Bosentan, 62.5 mg twice daily was started, and a significant improvement in the peripheral isquemic lesions was achieved. The ulcers' healing was fast, the patient totally recovered function and regained quality of life, and no further lesions developed. The authors review the RF and DU in SSc, as well as the use of bosentan, an endotheline receptor antagonist, and its indications. Although it is not formally approved, the use of bosentan in SS has shown benefits in reducing the incidence of DU, and despite no influence in the healing process, this drug prevents the development of new lesions.

Sudden winter iloprost withdrawal in scleroderma patients during COVID-19 pandemic

To report the novel finding of a significant improvement in Raynaud's phenomenon symptoms with clonazepam in a patient with systemic sclerosis. A 45-year-old female with limited scleroderma and chronic renal failure was admitted to our hospital due to hyponatremia (sodium 103 mEq/L). Her hyponatremia was treated by intravenous infusion of NaCl 3%. Clonazepam, which had been prescribed previously for anxiety and insomnia, was discontinued. Three weeks after she was discharged from the hospital, the patient presented with the complaint of increased severity of Raynaud's phenomenon and digital ulcers. She told us that her fingertip ulcers had been healed while she was taking clonazepam and that episodes of Raynaud's phenomenon had increased after discontinuation of the drug. Clonazepam 1 mg twice daily was restarted, and Raynaud's phenomenon and fingertip ulcers resolved within a month. On 2 occasions after that time, we discontinued clonazepam and replaced it with alprazolam, as the patient believed alprazolam was more beneficial in alleviating anxiety. Episodes of Raynaud's phenomenon and new digital ulcers recurred on both of these occasions, and clonazepam was restarted. At the time of writing, no severe episodes of Raynaud's phenomenon or fingertip ulcers have occurred with clonazepam treatment. Raynaud's phenomenon and recurrent digital ulcers are a manifestation of vascular disease in patients with systemic sclerosis and lead to pain, impaired function, and tissue loss. Few drugs have previously been shown to affect digital ulcers in the setting of scleroderma. Our patient experienced a significant and sustained improvement in Raynaud's phenomenon and digital ulcers following the initiation of clonazepam. To our knowledge, as of March 2007, this is the first reported use of clonazepam in Raynaud's phenomenon and digital ulcer. While its therapeutic mechanism remains unclear, clonazepam may offer some advantages compared with current agents. We report a case of Raynaud's phenomenon and digital ulcers responding to clonazepam. Further research is warranted to test the robustness of this preliminary finding.

Nerve conduction velocities in the lower extremity in patients with Raynaud's phenomenon and clinical applications

Raynaud's phenomenon (RP) and digital ulcers (DUs) impact the quality of life (QoL) of systemic sclerosis (SSc) patients. Calcium channel blockers (CCBs) and phosphodiesterase-5 inhibitors (PDE-5i) have been used to improve blood flow. However, vasodilators are limited in patients with low blood pressure. We aimed to determine the eficacy and safety of 2% isosorbide dinitrate (ISDN) cream as an adjunctive for treating DUs and RP. A cohort study was conducted at the Scleroderma Clinic at Khon Kaen University's Srinagarind Hospital in Khon Kaen, Thailand between January 2021 and December 2022. The study included adult SSc patients, who had received 2% ISDN cream for treatment of DUs or RP as adjuvant and with/or without receiving CCBs and/or PDE-5i as a background treatment for DUs and RP. Patients had to have follow-up data between 2 and 4 months after starting treatment. The median treatment duration was 2.8 months. Dosages of sustained-release nifedipine ranged from 10-80 mg and sildenafil ranged from 12.5-150 mg. Topical 2% ISDN cream was thinly applied three times a day. The treatment responses of DUs (ulcer size and pain) and RP (frequency and duration of attack) were according to patients' self-assessment, categorized into 3 levels Improvement Stable and Worsening. Before and after the treatment period of 2% ISDN cream the Quality of life was evaluated by using the EuroQoL five dimensions (EQ-5D) assessment by attending physicians. In terms of anxiety, QoL, as evaluated by the EQ-5D, significantly improved after treatment with 2% ISDN cream in patients with DUs compared to before treatment. When used as an adjunct to CCB, 2% ISDN cream resulted in stability or improvement of RP in 43.2% of patients, DUs in 41.4% of patients, and both RP and DUs in 41.0% of patients. When used as an adjunct to PDE-5i as background therapy, it resulted in stability or improvement of RP in 13.5% of patients, DUs in 13.8% of patients, and both RP and DUs in 15.4% of patients. Topical 2% ISDN cream may help to reduce anxiety when DUs were improved and improve overall QoL.

Raynaud's Phenomenon: A Brush Up!

Although there is abundant evidence of vascular perturbation from studies of peripheral blood in systemic sclerosis (SSc), there are few data about the ability to use biomarkers of vascular injury and growth factors to predict vascular outcomes and response to therapy. We sought to explore the association between candidate vascular biomarkers and digital ulcerations (DU) in a clinical trial context. We examined 19 circulating vascular, angiogenic, and inflammatory biomarkers in 124 patients with scleroderma and DU who participated in a randomized controlled trial of oral treprostinil diolamine (ClinicalTrials.gov identifier NCT00775463). Correlation, regression, and random forest analyses were conducted to assess biomarker relationships in response to drug treatment. Over the 20-week trial, 82 (66%) patients had their cardinal ulcer completely heal, 54 (44%) developed new ulcers, and 72 (58%) had complete healing of all ulcers; mean change in ulcer burden comparing week 20 with baseline was - 0.36 ± 1.70. Nineteen biomarkers were analyzed for their association and ability to predict clinical DU outcomes. After adjusting for multiple comparisons, no individual biomarker (baseline level, week 20 level, or change over time) was significantly associated with any of the clinical outcomes, suggesting that traditional vascular, angiogenic or inflammatory drivers are not predictive of ulcer fate. The lack of strong response to any of the vascular, angiogenic, or inflammatory markers suggest that these pathways are not primary drivers in the development of DU clinical outcomes in a SSc population with prevalent DU. • Currently we lack robust biomarkers to predict vascular outcomes or response to therapy in scleroderma patients with Raynaud's phenomenon.• Longitudinal assessment of vascular biomarkers in a clinical trial setting provides a unique opportunity to define biomarkers that predict vascular outcomes.• In a randomized controlled trial of oral treprostinil diolamine for treatment of scleroderma-associated digital ulcers, biomarkers involved in several vascular, inflammatory, and angiogenic pathways did not predict short-term clinical response to therapy or digital ulcer outcomes.• Further study of these and other biomarkers should be considered in Raynaud's clinical trials in scleroderma patients without prevalent digital ulcers.

To perform a systematic literature review (SLR) aimed at evaluating the efficacy and safety of pharmacological and non-pharmacological treatments for Raynaud's phenomenon (RP) and digital ulcers (DU) in patients with systemic sclerosis (SSc) and other connective tissue diseases (CTD), in order to inform the Portuguese recommendations for managing RP and DU in these patients. A SLR was conducted until May 2022 to identify studies assessing the efficacy and safety of pharmacological and non-pharmacological interventions for RP and DU in SSc and other CTD. Eligible study designs included randomized controlled trials (RCTs), controlled clinical trials, and their extensions for assessing efficacy and safety of interventions. Observational studies with a comparator were included for evaluating the efficacy and safety of non-pharmacological interventions and safety of pharmacological interventions. The risk of bias of each study was assessed using standard tools. Out of 71 publications meeting the inclusion criteria, 59 evaluated pharmacological and 12 non-pharmacological interventions. We found moderate quality evidence supporting the efficacy of calcium channel blockers, phosphodiesterase-5 inhibitors, and intravenous prostacyclin analogues in reducing RP frequency, severity, and duration. Intravenous iloprost had a small to moderate effect size in improving DU healing. Phosphodiesterase-5 inhibitors were effective in reducing total DU count, new DU occurrence, and enhancing DU healing. Bosentan effectively prevented new DU in SSc patients. No new safety concerns were associated with these treatments. The studies on non-pharmacological interventions were, in general, of low quality, and had a small sample size. Warming measures decreased frequency and duration of RP attacks; laser therapy improved RP-related outcomes; local oxygen-ozone therapy improved RP outcomes as an add-on therapy; bone marrow mononuclear cell implantation improved DU-associated pain; periarterial sympathectomy and vascular bypass reduced DU number and finger amputation risk. The available evidence supports the efficacy and safety of pharmacological interventions, namely nifedipine, sildenafil, iloprost, and bosentan in treating RP and DU in patients with SSc and other CTD. Scarce and low-quality evidence does support the use of some non-pharmacological interventions but with only a modest effect size. This SLR underscores the limited availability of high-quality evidence for determining the optimal treatment.

SAT0218 Efficacy of Bosentan for The Treatment of Digital Ulcers in Patients with Systemic Autoimmune Diseases

Peripheral vasculopathy in Raynaud phenomenon: Vascular disease biomarkers

To document disease activity and functional status in patients with scleroderma (systemic sclerosis [SSc]) and Raynaud's phenomenon (RP) and to determine the sensitivity to change, reliability, ease of use, and validity of various outcome measures in these patients. Patients with SSc and moderate-to-severe RP participating in a multicenter RP treatment trial completed daily diaries documenting the frequency and duration of RP attacks and recorded a daily Raynaud's Condition Score (RCS). Mean scores for the 2-week periods prior to baseline (week 0), end of trial (week 6), and posttrial followup (week 12) were calculated. At weeks 0, 6, and 12, physicians completed 3 global assessment scales and performed clinical assessments of digital ulcers and infarcts; patients completed the Health Assessment Questionnaire (HAQ), the Arthritis Impact Measurement Scales 2 (AIMS2) mood and tension subscales, 5 specific SSc/RP-related visual analog scales (VAS), and 3 other VAS global assessments. We used these measures to document baseline disease activity and to assess their construct validity, sensitivity to change, and reliability in trial data. Two hundred eighty-one patients (248 women, 33 men; mean age 50.4 years [range 18-82 years]) from 14 centers participated. Forty-eight percent had limited cutaneous SSc; 52% had diffuse cutaneous SSc. Fifty-nine patients (21%) had digital ulcers at baseline. Patients had 3.89 +/- 2.33 (mean +/- SD) daily RP attacks (range 0.8-14.6), with a duration of 82.1 +/- 91.6 minutes/attack. RCS for RP activity (possible range 0-10) was 4.30 +/- 1.92. HAQ scores (0-3 scale) indicated substantial disability at baseline (total disability 0.86, pain 1.19), especially among the subscales pertaining to hand function (grip, eating, dressing). AIMS2 mood and tension scores were fairly high, as were many of the VAS scores. Patients with digital ulcers had worse RCS, pain, HAQ disability (overall, grip, eating, and dressing), physician's global assessment, and tension, but no significant difference in the frequency of RP, duration of RP, patient's global assessment, or mood, compared with patients without digital ulcers. VAS scores for digital ulcers as rated by the patients were not consistent with the physician's ratings. Factor analysis of the 18 measures showed strong associations among variables in 4 distinct domains: disease activity, RP measures, digital ulcer measures, and mood/tension. Reliability of the RCS, HAQ pain and disability scales, and AIMS2 mood and tension subscales was high. The RP measures demonstrated good sensitivity to change (effect sizes 0.33-0.76). Our findings demonstrate that the significant activity, disability, pain, and psychological impact of RP and digital ulcers in SSc can be measured by a small set of valid and reliable outcome measures. These outcome measures provide information beyond the quantitative metrics of RP attacks. We propose a core set of measures for use in clinical trials of RP in SSc patients that includes the RCS, patient and physician VAS ratings of RP activity, a digital ulcer/infarct measure, measures of disability and pain (HAQ), and measures of psychological function (AIMS2).

Pulmonary artery hypertension (PAH) remains the leading cause of morbidity and mortality in systemic sclerosis, while Raynaud's phenomenon and digital ulcers significantly add to the morbidity in systemic sclerosis (SSc). This study was undertaken to evaluate the role of sildenafil in PAH, Raynaud's phenomenon, and digital ulcers in systemic sclerosis patients. A prospective, open-label, uncontrolled pilot study was done at a tertiary care centre in India to study the safety and efficacy of oral sildenafil in PAH, Raynaud's phenomenon, digital infarcts, and ulcers in SSc. Seventeen patients fulfilling ACR classification criteria for scleroderma and having PAH were recruited. Six-minute walk test, WHO class of dyspnoea, severity of Raynaud's phenomenon, and 2D ECHO were performed in all the study subjects at baseline and at 3 months post-treatment. All patients were treated with oral sildenafil 25 mg three times a day for a period of 3 months. The pre- and post-treatment values of mean pulmonary artery pressure (PAP), 6-min walk test, WHO class of dyspnoea, and severity of Raynaud's phenomenon were compared to look for any significant change. Sixteen patients who completed 3-month follow-up had shown statistically significant improvement in 6-min walk test, WHO class of dyspnoea, severity of Raynaud's phenomenon, and mPAP. Also, there was no occurrence of new digital infarcts or ulcers, and existing ulcers showed signs of healing. Sildenafil is highly efficacious cheaper and safe alternative to other available therapies for SSc-associated PAH, Raynaud's phenomenon, and digital infarcts/ulcers.

ObjectivesSystemic sclerosis (SSc) is a heterogeneous complex autoimmune connective tissue disease with variable presentation as a consequence of multisystem involvement. One of the key features of SSc is Raynaud's phenomenon along with vascular endothelial dysfunction that leads to digital ulcers (DUs). Raynaud's tends to be triggered by decreasing thermal gradient exposure, while stress and smoking also play a role. DUs arising as a consequence of severe Raynaud's and vasculopathy are a major cause of morbidity and disability in SSc. We set out to determine the relationship between smoking, Raynaud's phenomenon, DUs, and skin thickness in our Waikato Systemic Sclerosis cohort.MethodsThe Waikato Systemic Sclerosis (SSc) database was used to extract data. Variables collected included demographics, age of diagnosis, SSc subtypes, age at first non-Raynaud's phenomenon, medications used for treatment of Raynaud's phenomenon or ulcers, and maximal modified Rodnan skin score (mRSS). Raynaud's phenomenon and finger DUs (severity for each over the past week and since diagnosis) and a Scleroderma Health Assessment Questionnaire (SHAQ) visual analog 10 cm scale were collected. The lead rheumatologist completed a physician's assessment of Raynaud's and the disease severity questionnaire.ResultsOf the cohort of 143 patients, 100 patients were eligible to complete the questionnaires. Seventy-five patients returned completed questionnaires. Of these, the majority were female (88%), 52 (69.3%) had limited cutaneous systemic sclerosis (lcSSc), 17 (22.7%) had diffuse cutaneous systemic sclerosis (dcSSc), and 6 (8%) had an overlap syndrome. Thirty-six (48%) had a smoking history (in the time frame of collection of serial data). Mean ± standard deviation (SD) pack-years smoked were 17.11 ± 15.29 years. Thirty-five participants had a history of DUs, with a median of 4 DU (range 1–20). Of 17 patients with dcSSc, 12 (70.6%) had ulcers in comparison with 17 of 52 (32.7%) patients with lcSSc. There was a significant relationship between SSc subtype and the number with ulcers (X2 = 10.1, P = 0.007). There was also a significant relationship between physician severity of Raynaud's and presence of ulcers (t = 6.1, P < 0.001), which was not evident between patients’ severity of Raynaud's and presence of ulcers (t = 1.9, P = 0.06). On the SHAQ score, smokers had significantly worse Raynaud's phenomenon over the prior week (t = 3.08, P = 0.03) and were more likely to note DUs over the preceding week, although the latter was not statistically significant (t = 1.95, P = 0.055). There was no association between smoking and skin thickness as measured by mRSS (r = 0.23, P = 0.19).ConclusionOur study demonstrates that smokers have had worse Raynaud's phenomenon over the past week and they were also more likely to note DUs with a trend toward significance but not statistically significant most likely due to our small sample size. Our study also demonstrated that patients with dcSSc had more ulcers in comparison with lcSSc. This study justifies physicians strongly recommending smoking cessation in patients with SSc.