Efficacy In Systemic Sclerosis Research Articles

P137 A multinational survey to identify the clinicians perspectives concerning proton pump inhibitors in patients with systemic sclerosis

Abstract Background/Aims Proton Pump Inhibitors (PPIs) are widely used in Systemic Sclerosis (SSc) for the treatment of gastroesophageal reflux disease (GERD). However, there is scarce evidence to support their use while long-term safety has been questioned. The aim of our study was to identify healthcare providers’ perspectives and experience regarding PPIs therapy in SSc patients. Methods An online survey in English language targeting clinicians involved in the care of SSc patients, was developed and distributed through social media and international physician networks. The survey was launched on 27th November 2022 and kept open for three weeks. Results Responses from 227 clinicians from 36 countries were recorded: most of them (86%) were between 30-70 years and gender was equally represented (F: 52%; M: 48%). The majority ‘agreed’ (41%) or ‘strongly agreed’ (45%) that GERD is a major cause of morbidity in SSc. Lifestyle modifications and non-pharmacological approaches alone were seldom (16%) considered effective. Only half of respondents ‘agreed’ (43%) or ‘strongly agreed’ (11%) there is solid evidence supporting PPIs efficacy in SSc. A range of PPIs was prescribed by clinicians, most frequently pantoprazole (74%), esomeprazole (72%), omeprazole (72%), and lansoprazole (68%). The most common reasons for PPIs prescription (Table 1) were symptomatic GERD unresponsive to lifestyle modification (95%), objective evidence of GERD (82%), and hoarseness or respiratory symptoms (71%). Multiple concerns were raised about PPI long-term safety. The three highest (mean, 10 being very concerned) reasons were: small intestinal bacterial overgrowth (5.5), osteoporosis (5.4), and drug interactions (5.2). There were significant differences in attitudes towards surgery for refractory GERD: ‘strongly disagreed’ (14%), ‘disagreed’ (26%) ‘neutral’ (52%), ‘agreed’ (13%), ‘strongly agreed’ (3%). Furthermore, half of respondents had concerns about potential complications (i.e., worsening of dysphagia): ‘disagreed’ (26%) or ‘strongly disagreed’ (6%), ‘neutral (52%), ‘agreed’ (13%), ‘strongly agreed’ (3%). Conclusion Our survey confirms that PPIs are frequently prescribed for GERD in SSc patients, despite the absence of randomized clinical trials demonstrating their efficacy and safety. Clinicians are concerned about side effects, especially regarding long-term use. There is significant heterogeneity in attitudes towards surgery for refractory GERD. Future research and practical treatment recommendation are urgently needed. Disclosure G. Bandini: None. A. Alunno: None. F. Oliveira Pinheiro: None. C. Campochiaro: None. I. Galetti: None. P. Matucci Cerinic: None. B. Ruaro: None. A. Moggi Pignone: None. L. Dagna: None. M. Matucci Cerinic: None. Z. McMahan: None. M. Hughes: None.

Xanthohumol attenuates collagen synthesis in scleroderma skin fibroblasts by ROS/Nrf2/TGFβ1/Smad3 pathway

Skin fibrosis, the most obvious clinical manifestation of systemic sclerosis (SSc), has a high unmet need for treatment. Xanthohumol (Xn) has been shown to have beneficial effects on fibrotic diseases, but its efficacy in SSc remains unreported. This study aims to elucidate the effects and mechanisms of Xn on collagen synthesis in SSc skin fibroblasts (SScF). We found increased collagen production in SScF cultured in vitro, accompanied by dysregulated levels of oxidative stress. Cell experiments showed that Xn inhibited cell proliferation and promoted apoptosis. In addition, Xn was shown for the first time to upregulate reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (Nrf2)levels in SScF, and when combined with the ROS scavenger N-acetylcysteine (NAC), Nrf2 expression was decreased. Importantly, we demonstrated that Xn significantly attenuated collagen synthesis by blocking the fibrotic classical transforming growth factor beta 1 (TGFβ1)/Smad3 pathway, which interestingly was upregulated when combined with the Nrf2 inhibitor 385. Taken together, Xn suppressed the TGFβ1/Smad3 pathway to ameliorate collagen overproduction by promoting ROS-induced oxidative stress damage and activating Nrf2, suggesting that Xn administration may be an emerging therapeutic strategy for skin fibrosis in SSc.

Efficacy and safety of biological drugs in interstitial lung disease associated with connective tissue diseases

ABSTRACT Introduction Interstitial lung disease (ILD) is one of the most important manifestations of connective tissue diseases (CTD) due to its association with high morbidity and mortality. Areas covered Literature review focused on the evidence on efficacy and safety of biological therapy. Expert opinion Rituximab (RTX) is the most studied drug, though tocilizumab (TCZ) has methodologically more robust evidence, whereas abatacept (ABA) has only anecdotal reports. RTX studies suggest a clinically relevant effect on lung function and fibrosis in refractory to conventional treatment patients, with a good safety profile. Its multi-level efficacy in systemic sclerosis and the potentially more favorable response of anti-synthetase syndrome, especially when administered early in acute-onset or exacerbated ILD stand out over current standard of care, pending the availability of randomized controlled clinical trials. The significant and clinically meaningful benefit found in lung function and fibrosis with TCZ in faSScinate and focuSSced trials represents a change with respect to the usual practice, reinforcing the importance of treatment in early subclinical or clinical SSc-ILD patients with risk factors for ILD progression. This evidence has led to the inclusion of both RTX and TCZ in the expert-based therapeutic algorithms or recommendations for CTD-ILD management.

Mesenchymal stromal cells-derived extracellular vesicles alleviate systemic sclerosis via miR-29a-3p

Systemic sclerosis (SSc) is a potentially lethal disease with no curative treatment. Mesenchymal stromal cells (MSCs) have proved efficacy in SSc but no data is available on MSC-derived extracellular vesicles (EVs) in this multi-organ fibrosis disease. Small size (ssEVs) and large size EVs (lsEVs) were isolated from murine MSCs or human adipose tissue-derived MSCs (ASCs). Control antagomiR (Ct) or antagomiR-29a-3p (A29a) were transfected in MSCs and ASCs before EV production. EVs were injected in the HOCl-induced SSc model at day 21 and euthanasized at day 42. We found that both ssEVs and lsEVs were effective to slow-down the course of the disease. All disease parameters improved in skin and lungs. Interestingly, down-regulating miR-29a-3p in MSCs totally abolished therapeutic efficacy. Besides, we demonstrated a similar efficacy of human ASC-EVs and importantly, EVs from A29a-transfected ASCs failed to improve skin fibrosis. We identified Dnmt3a, Pdgfrbb, Bcl2, Bcl-xl as target genes of miR-29a-3p whose regulation was associated with skin fibrosis improvement. Our study highlights the therapeutic role of miR-29a-3p in SSc and the importance of regulating methylation and apoptosis.

Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial

A phase 2 trial of tocilizumab showed preliminary evidence of efficacy in systemic sclerosis. We assessed skin fibrosis and systemic sclerosis-associated interstitial lung disease (SSc-ILD) in a phase 3 trial to investigate the safety and efficacy of tocilizumab, an anti-interleukin-6 receptor antibody, in the treatment of systemic sclerosis. In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial, participants were recruited from 75 sites in 20 countries across Europe, North America, Latin America, and Japan. Adults with diffuse cutaneous systemic sclerosis for 60 months or less and a modified Rodnan skin score (mRSS) of 10-35 at screening were randomly assigned (1:1) with a voice-web-response system to receive subcutaneous tocilizumab 162 mg or placebo weekly for 48 weeks, stratified by IL-6 levels; participants and investigators were masked to treatment group. The primary endpoint was the difference in change from baseline to week 48 in mRSS. Percentage of predicted forced vital capacity (FVC% predicted) at week 48, time to treatment failure, and patient-reported and physician-reported outcomes were secondary endpoints. This trial is registered with ClinicalTrials.gov (number NCT02453256) and is closed to accrual. Between Nov 20, 2015, and Feb 14, 2017, 210 individuals were randomly assigned to receive tocilizumab (n=104) or placebo (n=106). In the intention-to-treat population, least squares mean [LSM] change from baseline to week 48 in mRSS was -6·14 for tocilizumab and -4·41 for placebo (adjusted difference -1·73 [95% CI -3·78 to 0·32]; p=0·10). The shift in distribution of change from baseline in FVC% predicted at week 48 favoured tocilizumab (van Elteren nominal p=0·002 vs placebo), with a difference in LSM of 4·2 (95% CI 2·0-6·4; nominal p=0·0002), as did time to treatment failure (hazard ratio 0·63 [95% CI 0·37-1·06]; nominal p=0·08). Change in LSM from baseline to week 48 in Health Assessment Questionnaire-Disability Index and in patient-global and physician-global visual analogue scale assessments did not differ between tocilizumab and placebo. In the safety set, infections were the most common adverse events (54 [52%] of 104 participants in the tocilizumab group, 53 [50%] of 106 in the placebo group). Serious adverse events were reported in 13 participants treated with tocilizumab and 18 with placebo, primarily infections (three events, eight events) and cardiac events (two events, seven events). The primary skin fibrosis endpoint was not met. Findings for the secondary endpoint of FVC% predicted indicate that tocilizumab might preserve lung function in people with early SSc-ILD and elevated acute-phase reactants. Safety was consistent with the known profile of tocilizumab. F Hoffmann-La Roche Ltd.

Arsenic trioxide induces regulatory functions of plasmacytoid dendritic cells through interferon-α inhibition

Arsenic trioxide (As2O3) is recently found to have therapeutic potential in systemic sclerosis (SSc), a life-threatening multi-system fibrosing autoimmune disease with type I interferon (IFN-I) signature. Chronically activated plasmacytoid dendritic cells (pDCs) are responsible for IFN-I secretion and are closely related with fibrosis establishment in SSc. In this study, we showed that high concentrations of As2O3 induced apoptosis of pDCs via mitochondrial pathway with increased BAX/BCL-2 ratio, while independent of reactive oxygen species generation. Notably, at clinical relevant concentrations, As2O3 preferentially inhibited IFN-α secretion as compared to other cytokines such as TNF-α, probably due to potent down-regulation of the total protein and mRNA expression, as well as phosphorylation of the interferon regulatory factor 7 (IRF7). In addition, As2O3 induced a suppressive phenotype, and in combination with cytokine inhibition, it down-regulated pDCs’ capacity to induce CD4+ T cell proliferation, Th1/Th22 polarization, and B cell differentiation towards plasmablasts. Moreover, chronically activated pDCs from SSc patients were not resistant to the selective IFN-α inhibition, and regulatory phenotype induced by As2O3. Collectively, our data suggest that As2O3 could target pDCs and exert its treatment efficacy in SSc, and more autoimmune disorders with IFN-I signature.

Ajulemic acid: potential treatment for chronic inflammation.

Ajulemic acid (AJA, CT‐3, IP‐751, JBT‐101, anabasum) is a first‐in‐class, synthetic, orally active, cannabinoid‐derived drug that preferentially binds to the CB2 receptor and is nonpsychoactive. In preclinical studies, and in Phase 1 and 2 clinical trials, AJA showed a favorable safety, tolerability, and pharmacokinetic profile. It also demonstrated significant efficacy in preclinical models of inflammation and fibrosis. It suppresses tissue scarring and stimulates endogenous eicosanoids that resolve chronic inflammation and fibrosis without causing immunosuppression. AJA is currently being developed for use in 4 separate but related indications including systemic sclerosis (SSc), cystic fibrosis, dermatomyositis (DM), and systemic lupus erythematosus. Phase 2 clinical trials in the first 3 targets demonstrated that it is safe, is a potential treatment for these orphan diseases and appears to be a potent inflammation‐resolving drug with a unique mechanism of action, distinct from the nonsteroidal anti‐inflammatory drug (NSAID), and will be useful for treating a wide range of chronic inflammatory diseases. It may be considered to be a disease‐modifying drug unlike most NSAIDs that only provide symptomatic relief. AJA is currently being evaluated in 24‐month open‐label extension studies in SSc and in skin‐predominant DM. A Phase 3 multicenter trial to demonstrate safety and efficacy in SSc has recently been initiated.

Preliminary safety and efficacy profile of prucalopride in the treatment of systemic sclerosis (SSc)-related intestinal involvement: results from the open label cross-over PROGASS study

BackgroundProkinetics are used to treat enteric dismotility symptoms in systemic sclerosis (SSc) patients, but they often lack adequate efficacy. The most effective prokinetics belonging to the serotonin (5-HT4) receptor agonists class were withdrawn due to cardiac toxicity in relation to modest 5-HT4 receptor affinity. Prucalopride is a high-affinity 5-HT4 receptor agonist with no major cardiac issues, for which the efficacy in SSc has not yet been assessed.MethodsForty patients with self-reported mild to moderately severe enteric symptoms were enrolled in a cross-over 2 × 2 study. Subjects were randomized 1:1 to prucalopride 2 mg/day or no treatment for one month and vice versa after a 2-week washout period. Before and after each sequence the patients compiled the University of California Los Angeles gastrointestinal tract (UCLA GIT) 2.0 questionnaire and the numbers of complete intestinal movements were recorded. Oro-cecal transit time (OCTT) was evaluated by lactulose breath test in a subgroup of patients. Data were evaluated by mixed linear models corrected for the number of laxatives used during the study periods.ResultsThere were 29 subjects who completed the study; 7 subjects withdrew due to side-effects and 4 subjects were not compliant with the study procedures. As compared to dummy treatment, prucalopride was associated with more intestinal evacuations (p < 0.001), improvement of UCLA GIT constipation (-0.672 ± 0.112 vs 0.086 ± 0.115; p < 0.001), reflux (-0.409 ± 0.094 vs 0.01 ± 0.096; p < 0.005) and bloating (-0.418 ± 0.088 vs -0.084 ± 0.09; p = 0.01) scores. Treatment was ranked moderately to more than moderately effective by 22 patients (72.4%). OCTT was significantly reduced during prucalopruide consumption (prucalopride: -20.1 ± 20.1 vs no treatment: 45.8 ± 21.3 minutes; treatment effect = -65.9 minutes; p = 0.035).ConclusionsThe safety profile of prucalopride in SSc is similar to what is known from the literature. In patients with mild to severe gastrointestinal problems, prucalopride may be effective in treating dismotility symptoms, increasing the number of complete bowel movements and improving bowel transit, reducing reflux disease and bloating.Trial registrationEU Clinical Trial Registry, EudraCT2012-005348-92. Registered on 19 February 2013.

Perceived Functioning Has Ethnic-specific Associations in Systemic Sclerosis: Another Dimension of Personalized Medicine

To measure self-reported physical and mental functioning and associated clinical features at study entry in 3 ethnic groups with systemic sclerosis (SSc). Sixty Hispanic, 39 African American, and 104 Caucasian patients with recent-onset SSc (< 5 yrs) were assessed for perceived physical and mental functioning, using the Medical Outcomes Study Short Form-36 (SF-36) and Scleroderma-Health Assessment Questionnaire (Scleroderma-HAQ). Socioeconomic, demographic, clinical, immunologic, immunogenetic, behavioral, and psychological variables (Interpersonal Support Evaluation List, ISEL; Illness Behavior Questionnaire, IBQ; and Arthritis Helplessness Index, AHI) were analyzed by linear regression models for associations with SF-36 and mHAQ scores as dependent variables. Perceived physical functioning scores had ethnic-specific associations with AHI > fatigue scores > IBQ > clinical variables (hypertension, skin score, and percentage predicted DLCO). Scleroderma-HAQ scores had ethnic-specific associations with IBQ > AHI scores > most clinical and laboratory variables. Decreased mental component summary (MCS) scores associated with AHI > ISEL. Ethnic-specific immunogenetic variables HLA-DQB1*0202 (Caucasian) and HLA-DRB 1*11 (African American), and HLA-DQA1*0501 (Hispanic) also associated with MCS. Antinuclear autoantibodies, anti-topoisomerase I, and RNA polymerases I and III also demonstrated associations with functioning in African American and Hispanic groups. Clinical, psychosocial, and immunogenetic variables had ethnic-specific associations with perceived physical and mental functioning. Consideration of ethnic-specific psychological and behavioral support in designing more personalized, relevant therapeutic interventions for the patient may improve therapeutic efficacy in SSc.

The role of DMARDs in systemic sclerosis therapy

The aim of this review is to evaluate the evidence for disease-modifying anti-rheumatic drugs (DMARDs) for treatment of systemic sclerosis (SSc). In the previously published trials, DMARD therapy was usually initiated for severe skin thickening, organ involvement and alveolitis. These studies suggest beneficial effects of methotrexate, azathioprine, ciclosporine A and cyclophosphamide therapy in SSc patients. However, many of these data were derived from retrospective analyses with low numbers of patients, short-term follow-up and often without an appropriate control group. Finally, some of these studies led to inconsistent results. At the present time there is no DMARD therapy of proven efficacy in SSc. Immunosuppressive therapy should only be considered in patients with early diffuse disease, overlap syndromes or pulmonary fibrosis. Current expert recommendations suggest a therapy with methotrexate for skin thickening or cyclophosphamide for acute alveolitis. However, more clinical trials with larger numbers of patients with recent onset SSc are needed.

Ein praktischer Ansatz zur Therapie der systemischen Sklerose

Systemic sclerosis (SSc) is characterised by vascular abnormalities, fibrosis, inflammatory changes, and atrophy affecting the skin and several internal organs. The course of the disease is highly variable from patient to patient, and the different organ manifestations may show a different stage of activity and damage. More extensive skin involvement coincides with more severe internal organ manifestation(s) resulting in an unfavourable outcome of disease. Subset classification and organ system involvements should be carefully determined before introducing the therapy. Prognostic evaluation, including the staging of disease severity, damage, activity and the definition of longitudinal disease behaviour of the organ manifestations (by serial investigations) is also crucial. Theoretically the treatment should focus on both the early reduction of inflammatory phenomena and influence of vascular symptoms to prevent the development of tissue fibrosis and atrophy. Major internal organ manifestations including gastro-oesophageal reflux, scleroderma renal involvement, different cardio-respiratory disorders should also be carefully looked for, and early signs of internal organ involvements should be recognized and treated. There is no disease modifying drug therapy of proven efficacy in SSc but an individualized, well designed therapy may be remarkably efficient in terms of improving the prognosis and quality of life of patients. Education of patients is also compelling.

Double-blind, placebo-controlled study of oral calcitriol for the treatment of localized and systemic scleroderma

Background: Various treatments including corticosteroids, nonsteroidal anti-inflammatory drugs, D-penicillamine, interferon gamma, cyclosporine, and cytostatic drugs have been used with limited success in both morphea and systemic sclerosis (SSc). Objective: We investigated the effect of treatment with oral calcitriol in patients with localized or systemic scleroderma. Methods: A randomized, double-blind, placebo-controlled study of 9 months' duration with a 6-month follow-up was performed at the Department of Dermatology. A total of 27 patients (7 patients with SSc and 20 with morphea) were selected on a minimal skin score of 3 for patients with morphea and 12 for those with SSc. Each patient received calcitriol (0.75 μg/day for 6 months plus 1.25 μg/day for 3 months) or placebo for 9 months. Efficacy parameters included skin score, measurement of serum markers of collagen synthesis and degradation and, additional for the patients with SSc, oral aperture measurements, lung function studies, and esophagus motility. Results: The skin score in patients with morphea after 9 months' treatment showed no significant difference between the placebo and calcitriol groups (mean percentage reduction [SD] in skin score in the placebo group was −29.3 [57.9]; in the calcitriol group it was −19.4 [46.6]). The small group of patients with SSc was inadequate to allow us to draw any conclusions regarding efficacy. No significant change was found in the serum markers of collagen metabolism. Conclusion: In this study calcitriol was not more effective than placebo in patients with morphea. Because of the small group of patients with SSc treated, no conclusions regarding efficacy in SSc can be drawn. (J Am Acad Dermatol 2000;43:1017-23.)