Tailoring the treatment of inflammatory rheumatic diseases by a better stratification and characterization of the clinical patient heterogeneity. Findings from a systematic literature review and experts' consensus.

Inflammatory rheumatic diseases are different pathologic conditions associated with a deregulated immune response, codified along a spectrum of disorders, with autoinflammatory and autoimmune diseases as two-end phenotypes of this continuum. Despite pathogenic differences, inflammatory rheumatic diseases are commonly managed with a limited number of immunosuppressive drugs, sometimes with partial evidence or transferring physicians' knowledge in different patients. In addition, several randomized clinical trials, enrolling these patients, did not meet the primary pre-established outcomes and these findings could be linked to the underlying molecular diversities along the spectrum of inflammatory rheumatic disorders. In fact, the resulting patient heterogeneity may be driven by differences in underlying molecular pathology also resulting in variable responses to immunosuppressive drugs. Thus, the identification of different clinical subsets may possibly overcome the major obstacles that limit the development more effective therapeutic strategies for these patients with inflammatory rheumatic diseases. This clinical heterogeneity could require a diverse therapeutic management to improve patient outcomes and increase the frequency of clinical remission. Therefore, the importance of better patient stratification and characterization is increasingly pointed out according to the precision medicine principles, also suggesting a new approach for disease treatment. In fact, based on a better proposed patient profiling, clinicians could more appropriately balance the therapeutic management. On these bases, we synthetized and discussed the available literature about the patient profiling in regard to therapy in the context of inflammatory rheumatic diseases, mainly focusing on randomized clinical trials. We provided an overview of the importance of a better stratification and characterization of the clinical heterogeneity of patients with inflammatory rheumatic diseases identifying this point as crucial in improving the management of these patients.

Lysophosphatidic acid receptor 1 inhibition: a potential treatment target for pulmonary fibrosis.

Lysophosphatidic acid (LPA)-mediated activation of LPA receptor 1 (LPAR1) contributes to the pathophysiology of fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). These diseases are associated with high morbidity and mortality despite current treatment options. The LPA-producing enzyme autotaxin (ATX) and LPAR1 activation contribute to inflammation and mechanisms underlying fibrosis in preclinical fibrotic models. Additionally, elevated levels of LPA have been detected in bronchoalveolar lavage fluid from patients with IPF and in serum from patients with SSc. Thus, ATX and LPAR1 have gained considerable interest as pharmaceutical targets to combat fibrotic disease and inhibitors of these targets have been investigated in clinical trials for IPF and SSc. The goals of this review are to summarise the current literature on ATX and LPAR1 signalling in pulmonary fibrosis and to help differentiate the novel inhibitors in development. The mechanisms of action of ATX and LPAR1 inhibitors are described and preclinical studies and clinical trials of these agents are outlined. Because of their contribution to numerous physiologic events underlying fibrotic disease, ATX and LPAR1 inhibition presents a promising therapeutic strategy for IPF, SSc and other fibrotic diseases that may fulfil unmet needs of the current standard of care.

Evaluation of the Rheumatoid Arthritis Impact of Disease (RAID) Score in Assessing Rheumatoid Arthritis Activity in Teleconsultation.

OBJECTIVE: To evaluate the relevance of the Rheumatoid Arthritis Impact of Disease (RAID) score as a disease activity marker of rheumatoid arthritis (RA) in a teleconsultation setting. METHODS: A prospective, observational, 24-month, single-center study involving patients with RA who underwent teleconsultations was performed. The RAID score was sent to all patients by email and completed the day before the scheduled session. The RAID questionnaire was also completed just prior to the next scheduled face-to-face consultation. The same physician performed teleconsultation/in-person consultations and was unaware of the RAID results. RESULTS: We included 70 patients (mean age 50 [SD 14] yrs, mean disease duration 10 [SD 9] yrs). The RAID score correlated with the following items: patient global assessment (r 0.55, P < 0.001), patient-reported swollen joint count (r 0.50, P < 0.001), and Disease Activity Score in 28 joints based on C-reactive protein (DAS28-CRP) calculated with patient self-reported tender/swollen joints (r 0.74, P < 0.001). The RAID score completed during the next face-to-face consultation for 45 patients also correlated with the DAS28-CRP performed by the clinician (r 0.65, P < 0.001). A RAID score > 2 was associated with the best combination of sensitivity (94%) and specificity (43%) for the indication of rapid in-person consultation because of insufficiently controlled disease activity, with an area under the curve of 0.74. All 23 patients with RAID < 2 had no intercurrent flares; overall physician global assessment was 1.6 of 10 (SD 1.4), DAS28-CRP 1.5 (SD 0.2), and CRP 1.8 (SD 1.4) mg/L. CONCLUSION: Our findings reinforce the RAID score as a valuable tool in teleconsultation, exhibiting a good correlation with disease activity variables. Using a RAID score threshold of 2 during teleconsultations could distinguish patients with good disease control and those with the potential need for an in-person visit.

Attitudes and barriers to pulmonary arterial hypertension screening in systemic sclerosis patients: A survey of UK-based rheumatologists.

Objectives: The objectives were to explore rheumatologists' current clinical screening practices of pulmonary arterial hypertension in patients with systemic sclerosis in the United Kingdom and to identify barriers to screening and consider potential solutions. Methods: A survey of 31 questions was developed and included six sections: clinician demographics, the importance of screening, screening practices, barriers to screening, treatment and patient education. The survey was disseminated among rheumatologists working in the United Kingdom. Results: Forty-four rheumatologists working in the United Kingdom participated in the study, and the majority completed all the questions. Around one-third (37.0%) worked in specialised systemic sclerosis units (university or general hospitals (54.5% and 45.4%, respectively)). The majority recognised that systemic sclerosis-pulmonary arterial hypertension is a major cause of morbidity and mortality. Over half (60.0%) reported using the DETECT algorithm to screen for systemic sclerosis-pulmonary arterial hypertension, although other algorithms were also sometimes used. All of the respondents utilised transthoracic echocardiogram, and almost all (95.0%) performed pulmonary function tests for screening purposes. Various challenges and barriers were identified relating to systemic sclerosis-pulmonary arterial hypertension screening, with the difficulty in interpreting results from other hospitals and extended wait times for diagnostic tests being the most reported (76.0% and 74.0%, respectively). Most respondents agreed that access to key investigations (87.0%), ongoing clinician education (82.0%), multidisciplinary meetings (79.5%) and a better understanding of proposed screening algorithms (79.5%) could be potential solutions. Conclusion: Screening patients with systemic sclerosis for pulmonary arterial hypertension is crucial to improve survival, but variable practices exist among UK rheumatologists. Solutions include educating healthcare professionals on guidelines, sharing information between centres and integrating care services.

Biomarker analysis from the phase 2b randomized placebo-controlled trial of riociguat in early diffuse cutaneous systemic sclerosis.

OBJECTIVE: To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment. METHODS: Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. Alpha smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay. RESULTS: By week 14, cGMP increased by 94 ± 78% with riociguat and 10 ± 39% with placebo (p < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (p = 0.004 and p = 0.008, respectively). There were no differences in skin collagen markers between the 2 groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies were associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively). CONCLUSION: Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02283762.

The Performance of Pulmonary Function Tests in Predicting Systemic Sclerosis-Interstitial Lung Disease in the European Scleroderma Trial and Research Database.

BACKGROUND AND OBJECTIVES: In SSc, ILD is a major cause of morbidity and mortality. We aimed to investigate the performance of DLCO (diffusing capacity of lung carbon monoxide) and FVC (forced vital capacity) delta change (Δ) and baseline values in predicting the development of SSc-ILD. METHODS: Longitudinal data of DLCO, FVC, and ILD on the HRCT of SSc patients from the EUSTAR database were evaluated at baseline (t0) and after 12 (±4) (t1) and 24 (±4) (t2) months. RESULTS: 474/17805 patients were eligible for the study (403 females); 46 (9.7%) developed ILD at t2. Positivity for anti-topoisomerase antibodies (117 patients) showed an association with ILD development at t2 (p = 0.0031). Neither the mean t0 to t1 change (Δ) of DLCO nor the mean t0 to t1 FVCΔ predicted the appearance of ILD at t2. Investigating the possible role of baseline DLCO and FVC values in predicting ILD appearance after 24 (±4) months, we observed a moderate predictive capability of t0 DLCO < 80%, stronger than that of FVC < 80%. CONCLUSIONS: We suggest that an impaired baseline DLCO may be predictive of the appearance of ILD after 2 years of follow-up. This result advances the hypothesis that a reduction in gas exchange may be considered an early sign of lung involvement. However, further rigorous studies are warranted to understand the predictive role of DLCO evaluation in the course of SSc.

Deficiency and altered phenotype of mucosal-associated invariant T cells in systemic sclerosis.

Objective: Systemic sclerosis is an autoimmune disease characterized by fibrosis of the skin and internal organs including the lung. Mucosal-associated invariant T cells are innate-like T lymphocytes able to produce various cytokines and cytotoxic mediators such as granzyme B. A large body of evidence supports a role of mucosal-associated invariant T cells in autoimmune disease but more recent reports suggest also a potential role in fibrotic conditions. Therefore, we herein addressed the question as whether mucosal-associated invariant T cells may have an altered profile in systemic sclerosis. Methods: Mucosal-associated invariant T cell frequency was analyzed by flow cytometry, using fresh peripheral blood from 74 consecutive systemic sclerosis patients who were compared to 44 healthy donors. In addition, in-depth mucosal-associated invariant T cell phenotype and function were analyzed in unselected 29 women with systemic sclerosis who were compared to 23 healthy women donors. Results: Proportion of circulating mucosal-associated invariant T cells was significantly reduced by 68% in systemic sclerosis compared to healthy donors (0.78% in systemic sclerosis vs 2.5%, p < 0.0001). Within systemic sclerosis subsets, mucosal-associated invariant T cells were reduced in patients with interstitial lung disease (systemic sclerosis-interstitial lung disease) (0.56% vs 0.96% in patients without interstitial lung disease, p = 0.04). Moreover, in systemic sclerosis patients, mucosal-associated invariant T cells displayed an activated phenotype indicated by markedly increased CD69+ mucosal-associated invariant T cell frequency (20% mucosal-associated invariant T cell CD69+ compared to 9.4% in healthy donors, p = 0.0014). Interestingly, mucosal-associated invariant T cells from systemic sclerosis-interstitial lung disease patients had a more pronounced altered phenotype compared to systemic sclerosis without interstitial lung disease with a correlation between mucosal-associated invariant T cells expressing CCR6+ and mucosal-associated invariant T cell frequency (r = 0.8, p = 0.006). Conclusion: Circulating mucosal-associated invariant T cells were reduced and exhibited an activated phenotype in systemic sclerosis patients. This peripheral mucosal-associated invariant T cell deficiency may be related to enhanced apoptosis and/or homing in inflamed tissue, particularly in systemic sclerosis-interstitial lung disease patients.

Is cyclophosphamide still the gold standard in early severe rapidly progressive systemic sclerosis?

Cyclophosphamide (CYC) has been a gold standard of treatment for severe progressive Systemic Sclerosis (SSc), especially in patients with concomitant interstitial lung disease (ILD). This approach was based on results of several interventional studies, including randomized control trials, which mainly addressed SSc-ILD as a primary end point and skin involvement as a second one. The use of CYC is time-limited due to significant adverse events. More recently, other immunosuppressive and biological agents showed efficacy but better safety profile in patients with SSc and SSc-ILD. With regards to other end-points, post-hoc analyses, systematic reviews and metalysis showed that CYC had limited influence on patients' quality of life, event-free survival and mortality. Comprehensive patient's stratification according to a molecular, cellular and phenotypic pattern may help in choosing of personalized medicine with more ambitious treatment effect and should be the future direction. According to the above available data and even if scientific evidence may be missing, experts' opinion has changed the attitude to CYC as an anchor drug in the management of severe SSc. Indeed, CYC has been pushed to the second and even third treatment option after mycophenolate mofetil, tocilizumab or rituximab. This position became obvious during debate on this topic at CORA meeting 2023.

Real-World Effectiveness and Safety of SDZ ETN, an Etanercept Biosimilar, in Patients with Rheumatic Diseases: Final Results from Multi-Country COMPACT Study.

INTRODUCTION: COMPACT, a non-interventional study, evaluated the persistence, effectiveness, safety and patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA), axial-spondyloarthritis (axSpA) or psoriatic arthritis (PsA) treated with SDZ ETN (etanercept [ETN] biosimilar) in Europe and Canada. METHODS: Patients (aged ≥ 18 years) who have been treated with SDZ ETN were categorised on the basis of prior treatment status (groups A-D): patients in clinical remission or with low disease activity under treatment with reference ETN or biosimilar ETN and switched to SDZ ETN; patients who received non-ETN targeted therapies and switched to SDZ ETN; biologic-naïve patients who started SDZ ETN after conventional therapy failure; or disease-modifying anti-rheumatic drug (DMARD)-naïve patients with RA considered suitable for treatment initiation with a biologic and started on treatment with SDZ ETN. The primary endpoint was drug persistence, defined as time from study enrolment until discontinuation of SDZ ETN treatment. RESULTS: Of the 1466 patients recruited, 844 (57.6%) had RA, 334 (22.8%) had axSpA and 288 (19.6%) had PsA. Patients had an ongoing SDZ ETN treatment at the time of enrolment for an observed average of 138 days (range 1-841); 22.7% of patients discontinued SDZ ETN through 12 months of study observation. Overall, all the patients receiving SDZ ETN showed good treatment persistence at 12 months with discontinuation rates of 15.2%, 25.7% and 27.8% in groups A, B and C, respectively. Across all patient groups, no major differences were observed in the disease activity and PRO scores between baseline and month 12. Injection-site reactions were low across the treatment groups. CONCLUSION: These results support the effectiveness and safety of SDZ ETN treatment in patients with RA, axSpA or PsA in real-life conditions. The treatment persistence rates observed were consistent with previously published reports of patients treated with reference or other biosimilar ETN. No new safety signals were identified.

Effects of B Cell Depletion by CD19-Targeted Chimeric Antigen Receptor T Cells in a Murine Model of Systemic Sclerosis.

OBJECTIVE: Our goal was to study the tolerance and efficacy of two B cell depletion strategies, including one with CD19-targeted chimeric antigen receptor (CAR) T cells, in a preclinical model mimicking the severe lung damages observed in systemic sclerosis. METHODS: B cell depletion strategies were evaluated in the Fra-2 transgenic (Tg) mouse model. We considered a first group of 16 untreated mice, a second group of 15 mice receiving a single dose of anti-CD20 monoclonal antibody (mAb), and a third group of 8 mice receiving CD19-targeted CAR-T cells in combination with anti-CD20 monoclonal antibody. After six weeks of clinical evaluation, different validated markers of inflammation, lung fibrosis, and pulmonary vascular remodeling were assessed. RESULTS: CD19-targeted CAR-T cells infusion in combination with anti-CD20 mAb resulted in a deeper B cell depletion than anti-CD20 mAb alone in the peripheral blood and lesional lungs of Fra-2 Tg mice. CAR-T cell infusion worsened the clinical score and increased mortality in Fra-2 Tg mice. In line with the above findings, CAR-T cell infusion significantly increased lung collagen content, the histological fibrosis score, and right ventricular systolic pressure. CAR-T cells accumulated in lesional lungs and promoted T activation and inflammatory cytokine production. Treatment with anti-CD20 mAb in monotherapy had no impact on lung inflammation-driven fibrosis and pulmonary hypertension. CONCLUSION: B cell therapies failed to show efficacy in the Fra2 Tg mice. The exacerbated Fra-2 lung inflammatory burden stimulated accumulation and expansion of activated CD19-targeted CAR-T cells, secondarily inducing T cell activation and systemic inflammation, finally leading to disease worsening.

Effects of nintedanib in patients with limited cutaneous systemic sclerosis and interstitial lung disease.

OBJECTIVES: To investigate the course of interstitial lung disease (ILD) and the effects of nintedanib in patients with limited cutaneous systemic sclerosis (lcSSc). METHODS: In the SENSCIS trial, patients with SSc-ILD were randomized to receive nintedanib or placebo. Patients who completed the SENSCIS trial were eligible to enter SENSCIS-ON, in which all patients received open-label nintedanib. RESULTS: Among 277 patients with lcSSc treated in the SENSCIS trial, the rate (s.e.) of decline in forced vital capacity (FVC; ml/year) over 52 weeks was -74.5 (19.2) in the placebo group and -49.1 (19.8) in the nintedanib group (difference: 25.3 [95% CI -28.9, 79.6]). Among 249 patients with data at week 52, mean (s.e.) change in FVC at week 52 was -86.4 (21.1) ml in the placebo group and -39.1 (22.2) ml in the nintedanib group. Among 183 patients with lcSSc who participated in SENSCIS-ON and had data at week 52, mean (s.e.) change in FVC from baseline to week 52 of SENSCIS-ON was -41.5 (24.0) ml in patients who took placebo in the SENSCIS trial and initiated nintedanib in SENSCIS-ON and -45.1 (19.1) ml in patients who took nintedanib in the SENSCIS trial and continued it in SENSCIS-ON. CONCLUSION: Patients with lcSSc may develop progressive fibrosing ILD. By targeting pulmonary fibrosis, nintedanib slows decline in lung function in patients with lcSSc and ILD. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov), NCT02597933 and NCT03313180.

Heart and systemic sclerosis-findings from a national cohort study.

OBJECTIVES: Heart involvement is one of the leading causes of death in systemic sclerosis (SSc). The prevalence of SSc-related cardiac involvement is poorly known. Our objective was to investigate the prevalence and prognosis burden of different heart diseases in a nationwide cohort of patients with SSc. METHODS: We used data from a multicentric prospective study using the French SSc national database. Focusing on SSc-related cardiac involvement, we aimed to determine its incidence and risk factors. RESULTS: Over the 3528 patients with SSc 312 (10.9%) had SSc-related cardiac involvement at baseline. They tended to have a diffuse SSc subtype more frequently, more severe clinical features, and presented more cardiovascular risk factors. From the 1646 patients available for follow-up analysis, SSc-related cardiac involvement was associated with an increased risk of death. There was no significant difference in overall survival between SSc-related cardiac involvement, ischaemic heart disease or pulmonary arterial hypertension. Regarding survival analysis, 98 patients developed SSc-related cardiac involvement at five years (5-year event rate: 11.15%). Regarding reduced LVEF < 50% and left ventricular diastolic dysfunction, the 5-year event rate was 2.49% and 5.84% respectively. Pericarditis cumulative incidence at five years was 3%. Diffuse SSc subtype was a risk factor for SSc-related cardiac involvement and pericarditis. Female sex was associated with less left ventricular diastolic dysfunction incidence. CONCLUSIONS: Our results describe the incidence and prognostic burden of SSc-related cardiac involvement at a large scale, with gender and diffuse SSc subtype as risk factors. Further analyses should assess the potential impact of treatment on these various cardiac outcomes.

Should complete B-cell depletion be maintained in patients treated long-term with rituximab for rheumatoid arthritis?

OBJECTIVE: To determine whether persistent complete B cell (BC) depletion was associated with a better clinical response in rheumatoid arthritis (RA) patients long-term treated with rituximab (RTX). METHODS: We conducted a retrospective study including RA patients admitted for a new infusion between 2019 and 2021. The primary end point was the comparison of the mean DAS28-CRP at each of the 4 last infusion visits between patients with persistent complete BC depletion (mean CD19 counts <18/µL at each of the last 4 visits) or without persistent complete BC depletion (mean CD19 counts of the last 4 visits ≥18/µL). Secondary endpoints included DAS28, pain/fatigue VAS, CRP, gammaglobulins and the frequency of self-reported RA flares. RESULTS: Of the 126 patients in maintenance therapy with RTX (exposure period: 76 ± 5 months, n 14 ± 7 infusions received), 43 (34%) had persistent complete BC depletion at each of the 4 last infusions. The mean DAS28-CRP calculated at each of the 4 last infusion visits did not significantly differ according to persistence or not of complete BC depletion. This result remained unchanged after adjusting for antibody status, number of previous therapies, number of RTX infusion and cumulative RTX dose. All secondary outcomes were also not significantly different between both groups. CONCLUSION: Maintaining complete BC depletion does not appear to be a therapeutic target to achieve in RA patients in long-term maintenance therapy with RTX. There is a limited benefit of monitoring CD19 in RA patients long term treated with RTX and having achieved low disease activity/remission.

Phenotyping by persistent inflammation in systemic sclerosis associated interstitial lung disease: a EUSTAR database analysis.

BACKGROUND: Systemic sclerosis (SSc) is a heterogeneous disease with frequently associated interstitial lung disease (SSc-ILD). We aimed to determine the prognostic potential of phenotyping patients with SSc and SSc-ILD by inflammation and to describe disease trajectories stratified by inflammation and immunosuppressive treatment. METHODS: Patients from the European Scleroderma Trials and Research (EUSTAR) group cohort were allocated to persistent inflammatory, intermediate and non-inflammatory phenotypes if C-reactive protein (CRP) levels were ≥5 mg/L at ≥80%, at 20-80% and at <20% of visits, respectively. Cox regression models were used to analyse mortality risk and mixed effect models to describe trajectories of FVC and diffusing capacity for carbon monoxide (DLCO) %-predicted stratified by inflammation and immunosuppressive treatment. RESULTS: 2971 patients with SSc and 1171 patients with SSc-ILD had at least three CRP measurements available. Patients with SSc-ILD with a persistent inflammatory phenotype had a 6.7 times higher risk of mortality within 5 years compared with those with a persistent non-inflammatory phenotype (95% CI 3 to 15). In the inflammatory phenotype, FVC %-predicted was declining without (-1.11 (95% CI -2.14 to -0.08)/year), but stable with immunosuppressive treatment (-0.00 (95% CI -0.92 to 0.92)/year). In the non-inflammatory phenotype, patients with and without immunosuppressive treatment had a significant decline in FVC %-predicted, which was more pronounced in those with immunosuppressive treatment (-1.26 (95% CI -1.87 to -0.64) and -0.84 (95% CI -1.35 to -0.33)/year, respectively). CONCLUSIONS: Phenotyping by persistent inflammation provides valuable prognostic information, independent of demographics, disease duration, cutaneous subtype, treatment and SSc-ILD severity. The findings from this study support early immunosuppressive treatment in patients with SSc-ILD with persistent inflammation.

Surgical management of digital ulcers in systemic sclerosis: A systematic literature review.

BACKGROUND: There is a strong rationale to develop locally-acting surgical treatments for digital ulcers (DUs) in patients with systemic sclerosis (SSc). Our aim was to examine the safety and efficacy of local surgical management for SSc-DU. METHODS: A systematic literature review was carried out until to August 2022 using 7 different databases. Original research studies concerning adult patients with SSc-DUs, and local surgical treatments were analysed using the PICO framework. We included randomized controlled trials, prospective/retrospective studies, and case series (minimum of 3 patients) References were independently screened by two reviewers including assessment of the risk of bias using validated tools. RESULTS: Out of 899, 13eligible articles were included. Autologous fat (adipose tissue AT) grafting was the surgical modality most identified (7 studies, 1 randomized controlled double blinded trial and 6 prospective open-label single arm studies). The healing rate (HR) with autologous fat grafting (4 studies) was 66-100 %. Three studies reported autologous adipose-derived stromal vascular fraction grafting: HR of 32-60 %. Bone marrow derived cell transplantation in a single study showed 100 % healing rate over 4-24 weeks. Surgical sympathectomy was examined in 3 studies, prospective without comparator with a median healing rate of 81 %. Two surgical studies (of direct microsurgical revascularisation and microsurgical arteriolysis) showed 100 % healing of ulcers, with no complications. CONCLUSION: Several surgical approaches for SSc-DUs have demonstrated some degree of safety and effectiveness for DU healing. However, there are significant methodological issues. Future studies are warranted to rigorously investigate surgical interventions for SSc-DUs.

Non-surgical local treatments of digital ulcers in systemic sclerosis: a systematic literature review.

INTRODUCTION: Digital ulcers (DUs) are difficult to treat in patients with systemic sclerosis (SSc) and systemic (i.e., pharmacological) therapy is currently considered the 'standard of care'. Our aim was to examine the safety and efficacy of local, non-surgical treatment for SSc-DUs. METHODS: A systematic literature review (SLR) of original research articles up to August, 29 2022 was performed according to the PICO framework. References were independently screened by two reviewers and risk of bias was assed using validated tools. Due to study heterogeneity narrative summaries are used to present data. RESULTS: Among 899 retrieved references, 14 articles were included (2 randomised trials (RTs), and 12 observational (OBS) studies). The most frequently studied procedure (5 studies) was botulin A toxin (hand or single finger) injection with a reported healing rate (HR) of 71%-100%. Amniotic and hydrocolloid membranes were examined in one study each and associated with a good HR. Tadalafil 2% cream was studied in a single study with a reduction in the number of DUs. Vitamin E gel was associated with a reduction in ulcer healing time. Low-level light therapy, hydrodissection and corticosteroid injection, extracorporeal shock wave (ESW) and photobiomodulation were evaluated in a single study each and showed a positive trend. Dimethyl sulfoxide was associated with significant local toxicity. CONCLUSIONS: A range of non-surgical, local treatments for SSc-DUs have been explored and showed efficacy to some extent. We have identified methodological flaws that should be avoided in the design of future studies to explore locally-acting treatments for SSc-DUs.