[Severe small bowel involvement and chronic intestinal pseudo-obstruction in systemic sclerosis (scleroderma): Pathophysiological, diagnostic and therapeutic basis, including parenteral nutrition]. / Atteinte sévère de l'intestin grêle et pseudo-obstruction intestinale chronique au cours de la sclérodermie systémique : bases physiopathologiques, diagnostiques et thérapeutiques, dont la nutrition parentérale.

Gastrointestinal involvement in systemic sclerosis can be severe, reaching the critical point of chronic intestinal pseudo-obstruction, secondary to major disorders of small bowel motility. It is associated with some clinical and biological characteristics, in particular the positivity of anti-fibrillarin/U3RNP antibodies. Chronic intestinal pseudo-obstruction (CIPO) is complicated by a small intestinal bacterial overgrowth that requires cyclic antibiotic therapy. CIPO leads to a reduction of the food intake, due to painful symptoms, nausea and vomiting caused by meals, and ultimately to severe malnutrition. Meal splitting is often transiently effective and patients require exogenous nutritional support, mostly parenteral. Systemic sclerosis is not an obstacle to initiation and long-term continuation of parenteral nutrition and central venous catheter implantation is not associated with an increased risk of cutaneous or infectious complications. However, continuation of long-term parenteral nutrition requires monitoring in an expert nutrition center in order to adapt nutritional volumes and intakes and to limit potentially fatal cardiac and hepatobiliary complications. In addition to nutrition, prokinetic treatments, whose side effects must be known, can be associated. Invasive procedures, whose risk-benefit ratio must be carefully assessed, can also be used to treat symptoms exclusively.

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.

Systematic literature review informing the EULAR recommendations for the non-pharmacological management of systemic lupus erythematosus and systemic sclerosis.

Through this systematic literature review, we assembled evidence to inform the EULAR recommendations for the non-pharmacological management of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). We screened articles published between January 2000 and June 2021. Studies selected for data extraction (118 for SLE and 92 for SSc) were thematically categorised by the character of their intervention. Of 208 articles included, 51 were classified as robust in critical appraisal. Physical activity was the most studied management strategy and was found to be efficacious in both diseases. Patient education and self-management also constituted widely studied topics. Many studies on SLE found psychological interventions to improve quality of life. Studies on SSc found phototherapy and laser treatment to improve cutaneous disease manifestations. In summary, non-pharmacological management of SLE and SSc encompasses a wide range of interventions, which can be combined and provided either with or without adjunct pharmacological treatment but should not aim to substitute the latter when this is deemed required. While some management strategies i.e., physical exercise and patient education, are already established in current clinical practice in several centres, others e.g., phototherapy and laser treatment, show both feasibility and efficacy, yet require testing in more rigorous trials than those hitherto conducted.

Transcutaneous auricular branch vagal nerve stimulation as a non-invasive add-on therapeutic approach for pain in systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is an autoimmune disease with health-related quality of life (HRQoL) high impairment. Pain is of paramount importance to be targeted by therapeutical approaches. Our study aim was to perform an add-on device-based non-invasive neuromodulatory treatment through transcutaneous auricular vagal nerve stimulation (tVNS) in patients with SSc, assessing its effects on pain as primary endpoint and on inflammation, cardiovascular autonomic control and HRQoL. METHODS: Thirty-two patients with SSc were enrolled based on reported pain assessed through Numeric Rating Scale (NRS). Twenty-one (90% with limited cutaneous SSc) completed a randomised, cross-over, patient-blind trial, in which interventional and active control were used in random order for 4 weeks, interspersed with 4 weeks washout. NRS, Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) Item4 for pain interference, heart rate variability (HRV), serum cytokines and HRQoL questionnaires (Health Assessment Questionnaire, Patient Health Questionnaire-9, University of California, Los Angeles Gastrointestinal Tract, Pittsburgh Sleep Quality Index) were assessed at baseline, at T1 (after 1 month of tVNS or active control), at T2 (after washout) and at T3 (after 1 month of active control or tVNS). T-test for paired data and Wilcoxon signed-rank test for non-normally distributed parameters were performed to compare the effect of tVNS and active control. RESULTS: NRS pain was significantly reduced by tVNS and not by active control (Mean±SD: -27.7%±21.3% vs -7.7%±26.3%, p=0.002). Interleukin-6 was downregulated in tVNS versus active control (p=0.029). No significant differences were observed in tVNS versus active control for PROMIS-29 Item4, QoL scales and HRV with both spectral and symbolic analyses. CONCLUSION: tVNS demonstrated to be a safe and non-invasive add-on tool to reduce pain in SSc.

Immersion Ultrasound Therapy in Combination with Manual Therapy in the Treatment of Ischemic Digital Ulcers in Systemic Sclerosis.

Background and Objectives: Digital ulcers (DUs) are the most common complication in patients with Systemic Sclerosis (SSc). They cause pain with hand dysfunction and negatively impact activities of daily and working life. Our study aims to evaluate the efficacy of a combined treatment of manual therapy and ultrasound therapy in SSc patients with ischemic DU (IDU) compared to manual therapy alone. Materials and Methods: We conducted a before-and-after study (non-randomized study). We enrolled a consecutive series of IDU patients undergoing rehabilitation treatment and divided them into two groups: a treatment group consisting of patients undergoing a combination of manual therapy and US water immersion and a standard care group consisting of patients subjected to manual therapy alone. At the time of the first visit (T0) and at the end of the 4-week rehabilitation period (T1), we evaluated functional capacity, pain intensity, ulcer evolution, and quality of life. Results: In the treatment group, we observed a statistically significant improvement in the functional capacity of the hand (DHI: 28.15 ± 11.0 vs. 19.05 ± 8.83; p < 0.05), pain (NRS: 5.55 ± 1.2 vs. 2.9 ± 1.09; p < 0.05), and PSST score (24.4 ± 4.0 vs. 16.2 ± 2.36; p < 0.05). In the standard care group, we observed a statistically significant improvement only for the functional capacity of the hand (DHI: 28.85 ± 9.72 vs. 22.7 ± 7.68; p < 0.05). Finally, from the comparison between the treatment group and the standard care group, we observed statistically significant improvements in pain (2.9 ± 1.09 vs. 4.5 ± 1.07; p < 0.05) and in the PSST scale (16.2 ± 2.36 vs. 20.4 ± 4.02; p < 0.05). Furthermore, at the end of treatment in the treatment group, 15 ulcers (62.5%) were completely healed, while in the standard care group, only 3 ulcers were completely healed (14.3%). Conclusions: Combined treatment with manual therapy and ultrasound therapy appears to be useful in the management of IDU in patients with scleroderma.

Expanding the Treatment Team: What Is the Role for Occupational Therapy, Physical Therapy, Wound Care, and Nutritional Support in Systemic Sclerosis?

The optimal systemic sclerosis (SSc) care plan includes an occupational therapist and physical therapist as well as wound care experts and a registered dietitian if indicated. Screening instruments for functional and work disability, hand and mouth limitations, malnutrition, and dietary intake can identify the need for ancillary support services. Telemedicine can assist in developing effective ancillary treatment plans. Reimbursement for services may limit access for patients with SSc to expand their care team but a focus on prevention rather than management of damage is recognized as an important unmet need in SSc. In this review, the role of a comprehensive care team for SSc is discussed.

Physical Therapy in Systemic Sclerosis: The Patient Perspective.

OBJECTIVE: To assess the use, satisfaction, needs, and preferences regarding physical therapy (PT) in patients with systemic sclerosis (SSc). METHODS: A total of 405 SSc patients, treated in the Leiden University Medical Center multidisciplinary care program and fulfilling American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 SSc criteria, received a questionnaire containing 37 questions on use and satisfaction regarding PT over a 2-year period, and their needs and preferences for future PT. RESULTS: A total of 204 SSc patients (median age 63 years, 81% female) completed the questionnaire. One hundred twenty-eight patients (63%) had used or were using PT in a primary care setting. For 39% of patients not using PT, lack of referral or lack of knowledge was the reason for not using it. The most frequently reported active treatments were muscle-strengthening (n = 92 [72%]), range of motion (n = 77 [60%]), and aerobic exercises (n = 72 [56%]). Specific SSc hand- and mouth-opening exercises were reported by 20 (15%) and 7 (6%) patients, respectively. Manual treatment (massage or passive mobilization) was reported by 83 patients (65%). The mean ± SD satisfaction score (range 0-10) was 8.2 ± 1.6. Regarding patients' needs, 96 patients (47%) of the total group wanted to receive more information concerning PT, and 128 (63%) wanted to continue, start, or restart PT in the near future, with 56 of the 128 patients (44%) favoring individual treatment on a continuous basis. CONCLUSION: We observed a significant variation in the use and content of PT for SSc patients in a primary care setting. Our results suggest potential underuse of PT care, in particular for hand and oral dysfunction, and underpin the need for initiatives to improve the quality and accessibility of PT care for SSc patients.

Extracorporeal photopheresis for systemic sclerosis: A meta-analysis of randomized clinical trials.

Systemic sclerosis (scleroderma) (SSc) is a rare autoimmune disorder characterized by excessive production of collagen. Extracorporeal photopheresis (photochemotherapy, phototherapy) (ECP) involves repeated exposure of peripheral blood lymphocytes to ultraviolet A (UVA) radiation. The rationale for treating patients with SSc by ECP lies in its presumed immunomodulatory effects, though, rigorous data on the specific effects of ECP are limited, particularly in patients with SSc. The objective was to evaluate the effects of extracorporeal photopheresis as a treatment modality for patients with SSc. We searched the databases CENTRAL and MEDLINE on 13 March 2022 and included randomized clinical trials (RCTs) on patients diagnosed with SSc and treated with ECP. Primary outcome was the change of skin scores. We applied independent extraction and judgment by multiple observers. We conducted a meta-analysis applying the inverse variance method and the random effects model; the main outcome measure was standard mean difference of skin scores. We identified three relevant RCTs including 162 randomized (132 analyzed) people who received ECP in a simple parallel design. Pooled data of the three studies were indifferent. We estimated a standard mean difference from baseline of -0.11 (95% confidence interval -0.45 to 0.23), p = 0.54, I2  = 0%. We did not identify serious treatment-related adverse events. The evidence base for extracorporeal photopheresis on skin scores in patients with systemic sclerosis was not high enough to support a superior effect when compared to no treatment, sham photopheresis, or D-penicillamine.

Efficacy and safety of mesenchymal stem cells in the treatment of systemic sclerosis: a systematic review and meta-analysis.

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease with high morbidity and mortality characterized by fibrosis of the skin and internal organs. Some studies have investigated the use of stem cells to treat SSc. Herein, a systematic review and meta-analysis was conducted to determine the efficacy and safety of mesenchymal stem cells (MSCs) in the treatment of SSc. METHODS: PubMed, Embase, Cochrane Library, Web of Science, OVID, China National Knowledge Infrastructure and Wanfang databases were searched up to February 1, 2021. Literature screening, data extraction and quality assessment were conducted independently by two researchers in according to the inclusion and exclusion criteria. The discrepancies were resolved by a third researcher. RESULTS: A total of 9 studies encompassing 133 SSc patients were included in the study. Compared to the baseline after treatment with MSCs: 1. The modified Rodnan skin score (mRSS) was significantly reduced in patients with SSc (P < 0.00001). 2. MSCs decreased the number of digital ulcer, mouth handicap scale, and visual analog scale of hand pain in SSc patients (P = 0.0007 and P = 0.03, respectively). 3. No statistical differences were detected in Raynaud's condition score and Cochin hand function scale score at 6 months of MSCs therapy (P = 0.5 and P = 0.62). 4. After 12 months of follow-up, MSCs improve carbon monoxide diffusing capacity and forced vital capacity of SSc patients (P < 0.05). 5. Overall, MSCs application was safe; a few cases exhibited swelling at the injection site, diarrhea and arthralgia, which had self-recovery, and no severe adverse events occurred in the included trials. CONCLUSIONS: MSC therapy improves the degree of skin thickening, lung function, and mouth opening and relieves finger ulcers and pain in patients with SSc without severe adverse events. Thus, MSCs or MSCs combined with plasma and traditional medicine might be an effective and promising treatment of SSc patients. PROSPERO registration number: CRD42020200350.

Physical therapy in patients with systemic sclerosis: physical therapists' perspectives on current delivery and educational needs.

OBJECTIVE: To assess the perspectives of physical therapists treating patients with systemic sclerosis (SSc) on their current practice and educational needs. METHOD: In July 2019, 405 SSc patients attending a multidisciplinary SSc programme received a survey on physical therapy. Patients who indicated having received physical therapy in the past 2 years were asked to invite their treating physical therapist to complete a questionnaire including sociodemographic characteristics, referral process, content of treatment, perceived knowledge and skills, and educational needs (mostly yes/no answers). RESULTS: Forty-eight of 80 possibly eligible physical therapists treating SSc patients returned the questionnaire [median age 44 years (interquartile range 35-58); 52% female; median number of SSc patients currently treated: 1 (range 1-4)]. Eighty-one per cent (n = 39) of physical therapists had received a referral, with 69% (n = 27/39) judging its content as insufficient. The most often provided types of exercises were range of motion (96%), muscle-strengthening (85%), and aerobic (71%) exercises, followed by hand (42%) and mouth (10%) exercises. Concerning manual treatment, 65% performed either massage or passive mobilization. Regarding competences, 65% indicated feeling capable of treating SSc patients. Nevertheless, 85% expressed the need for an information website on physical therapy in SSc, and 77% for postgraduate education on SSc. CONCLUSION: Primary care physical therapists treating patients with SSc used a wide range of treatment modalities. Although most stated that they treated very few patients, the majority felt capable of treating SSc patients. Nevertheless, the large majority expressed a need for additional information and educational activities concerning SSc.

Nutrition and connective tissue disease.

Despite an incomplete overall understanding, nutrition plays an important role in connective tissue disease. Assessment of patients with connective tissue disease for nutritional status and metabolic disturbances may significantly contribute to patient outcomes. Several studies have indicated the multifactorial role of macronutrients, micronutrients, and supplements in the setting of connective tissue disease. There is additional evidence regarding the roles of weight, obesity, and malnutrition. This contribution reviews a growing body of data regarding nutrition in the development and treatment of various connective tissue diseases, including systemic lupus erythematosus, dermatomyositis, and systemic sclerosis.

Efficacy of local oxygen-ozone therapy for the treatment of digital ulcer refractory to medical therapy in systemic sclerosis: A randomized controlled study.

BACKGROUND: This study aimed to investigate the efficacy of local oxygen-ozone therapy in systemic sclerosis (SSc) patients with digital ulcers (DUs) who were resistant to medical therapy and had impairment in activities of daily living. METHODS: Participants' demographic data, and clinical parameters were recorded. Twenty-five SSc patients with DUs were randomized to the ozone group (I) (n = 13) to receive medical treatment plus local oxygen-ozone therapy and the control group (II) (n = 12) to receive medical treatment only. Hand functions were assessed using the Health Assessment Questionnaire (HAQ) and the Modified Hand Mobility in Scleroderma (HAMISm) test. Clinical parameters, HAQ, and mHAMIS scores were re-evaluated in participants 4 weeks after the initiation of treatment. RESULTS: Demographic and clinical characteristics of the two groups showed no significant differences. At 4 weeks after the initial treatment, the efficacy rate was significantly higher in the ozone group than that in the control group (92% versus 42% P = 0.010). Clinical parameters, HAQ, and HAMISm scores were significantly improved in the treatment group compared to those in the control group (P < 0.05). CONCLUSION: Local oxygen-ozone therapy was effective in the treatment of SSc patients with resistant DUs and improved clinical parameters and functional disability.

Treatment of Raynaud phenomenon and ischemic ulcers associated to systemic sclerosis with hyperbaric oxygen.

We describe 4 patients with Raynaud's phenomenon associated with systemic sclerosis, 3 with ischaemic ulcers, successfully treated with hyperbaric oxygen. This therapy has been useful in the treatment of chronic wounds due to its anti-inflammatory, antimicrobial and angiogenic effects. Hyperbaric oxygen treatment could be a therapeutic option in patients with Raynaud's phenomenon refractory to conventional treatment.

Locoregional Treatments for Digital Ulcers in Systemic Sclerosis: A Systematic Review.

The management of digital ulcers in systemic sclerosis is difficult. While the 2017 European League Against Rheumatism (EULAR) guidelines clearly defined the use of systemic therapies for digital ulcers, little is known about the efficacy of locoregional treatments. The aim of this review is to systematically assess the spectrum of published locoregional therapies for digital ulcers. A total of 58 studies were included. Among the different locoregional treatment strategies described, injections of fat-derived cells and botulinum toxin showed promising results in the reduction of pain and the number of digital ulcers. By contrast, this review found that sympathectomy yielded disappointing results, with low rates of effectiveness and frequent recurrence. For other treatments, such as hyperbaric oxygen therapy, phototherapy (ultraviolet A), low-level light therapy, intermittent compression, Waon therapy, extracorporeal shockwave, vitamin E gel, and topical dimethyl sulphoxide, the conflicting results or limited published data reflected the low level of evidence. Larger randomized clinical trials are required to confirm the validity of promising techniques.

Review of the Current Medical and Surgical Treatment Options for Microstomia in Patients With Scleroderma.

BACKGROUND: Most patients with scleroderma suffer from microstomia, which can have debilitating consequences on their quality of life. Unfortunately, treatment options remain limited. No specific guidelines exist; hence, microstomia remains a challenge to treat in this patient population. OBJECTIVE: This review aims to evaluate the different medical and surgical treatment modalities currently available for microstomia in patients with scleroderma and make recommendations for future research. MATERIALS AND METHODS: A search of PubMed, Ovid MEDLINE, and Ovid Embase was conducted to identify articles discussing the treatment of microstomia in scleroderma. Twenty articles discussing surgical therapy and one article discussing medical therapy were reviewed. RESULTS: Mostly because of a scarcity of high-level evidence, no individual therapy has documented long-term efficacy. Some treatments demonstrate positive results and warrant further research. CONCLUSION: Given the variability of results, specific recommendations for the treatment of microstomia in patients with scleroderma are difficult to establish. A multifaceted approach that includes surgical and medical therapy is likely the best option to improve oral aperture in this patient population. Surgical treatments such as neurotoxins, autologous fat grafting, and ultraviolet A1 phototherapy may hold the most potential for improvement.

ARTERIAL INSUFFICIENCIES: Hyperbaric Oxygen Therapy for Selected Problem Wounds.

The use of hyperbaric oxygen (HBO2) for the treatment of selected problem wounds has focused almost entirely on the diabetic foot ulcer (DFU) in recent years. The prevalence of DFUs in today's patient population and the reimbursement available for the treatment of DFUs have given it priority status in discussions about problem wounds, but there are sound fundamental reasons why additional oxygen may have benefits in the treatment of non-DFU wounds.

Investigation of the effectiveness of Tai Chi exercise program in patients with scleroderma: A randomized controlled study.

BACKGROUND: and Purpose: There were studies showing the positive effects of Tai Chi on sleep, fatigue, endurance, balance, anxiety and depression in rheumatologic diseases. The aim of this study was to investigate the effects of Tai Chi exercise program on trunk endurance, balance, sleep, fatigue, anxiety and depression in patients with systemic sclerosis (SSc). MATERIALS AND METHODS: 28 patients were randomly divided into two groups as Tai Chi (n:14, 53.35 ± 10.86 years) and home exercise group (n:14, 52.64 ± 9.45 years). Trunk Lateral Endurance Test, Berg Balance Scale, Pittsburg Sleep Quality Index, Fatigue Severity Scale and Fatigue Impact Scale, Hospital Anxiety and Depression Scale was used for assesment. All evaluations were performed at baseline and at the end of the 10th week. RESULTS: After training, a statistically significant difference was observed in all parameters in Tai Chi group (p:0.00); there was a significant difference in trunk endurance and sleep quality in the home exercise group (p:0.00-0.03) compared to pre-training. When the delta values between groups were compared, Tai Chi group was superior to home exercise group in all parameters except trunk endurance (p:0.00-0.01). No side effects were observed during the exercises. CONCLUSION: As a result of our study; Tai Chi has a possitive effect on endurance, balance, sleep quality, fatique, anxiety and depression in patients with SSc. Tai Chi should be included in rehabilitation programs as a safe alternative type of exercise to improve trunk endurance, balance, sleep quality and reduce fatigue, anxiety and depression in patients with SSc.

Frontiers in translational systemic sclerosis research: A focus on the unmet 'cutaneous' clinical needs (Viewpoint).

This viewpoint considers four cutaneous unmet clinical needs of patients with systemic sclerosis (SSc), namely the rapidly progressive skin thickening (scleroderma) which occurs early on in diffuse cutaneous disease; digital (finger and toe) ulcers; calcinosis; and cutaneous telangiectases. All four problems cause pain, disability and/or disfigurement, all impact on quality of life, and for each, we require effective treatments. For each unmet need, we give a brief description of the clinical problem (including clinical burden), pathophysiology and current treatment, followed by a personal viewpoint of the key questions which research must address. For the painful, debilitating skin thickening of early diffuse cutaneous SSc, studies are required to decide whether corticosteroids are effective and safe (current opinion is divided) and whether phototherapy approaches have a role. Also, we need to develop and validate reliable outcome measures for clinical trials of promising new therapies: these could be composite indices, novel non-invasive imaging methods and patient-reported outcome measures, possibly in combination as they provide complementary information. For digital ulcers, again we require validated outcome measures for clinical trials. We also need to explore local (including topical) treatments, which are free from systemic adverse effects, and preventative strategies for high-risk patients. For calcinosis, we need to better understand pathophysiology, to validate outcome measures and to develop topical treatments. For telangiectases, we need to "use" these highly accessible lesions to help unravel the vascular pathophysiology of SSc and explore their different properties as potential biomarkers.

The need for a holistic approach for SSc-ILD - achievements and ambiguity in a devastating disease.

Systemic sclerosis (SSc) is a multi-organ autoimmune disease with complex interactions between immune-mediated inflammatory processes and vascular pathology leading to small vessel obliteration, promoting uncontrolled fibrosis of skin and internal organs. Interstitial lung disease (ILD) is a common but highly variable manifestation of SSc and is associated with high morbidity and mortality. Treatment approaches have focused on immunosuppressive therapies, which have shown some efficacy on lung function. Recently, a large phase 3 trial showed that treatment with nintedanib was associated with a reduction in lung function decline. None of the conducted randomized clinical trials have so far shown convincing efficacy on other outcome measures including quality of life determined by patient reported outcomes. Little evidence is available for non-pharmacological treatment and supportive care specifically for SSc-ILD patients, including pulmonary rehabilitation, supplemental oxygen, symptom relief and adequate information. Improved management of SSc-ILD patients based on a holistic approach is necessary to support patients in maintaining as much quality of life as possible throughout the disease course and to improve long-term outcomes.