[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.

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.

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.

Role of Vitamin D in Systemic Sclerosis: A Systematic Literature Review.

BACKGROUND: Systemic sclerosis (SSc) is a chronic multisystem autoimmune condition defined by a complex pathobiology, comprising excessive fibrosis of skin and internal organs, peripheral vasculopathy with endothelial cell dysfunction, inadequate vascular repair and neovascularization, and aberrant immunity. Vitamin D is a steroid hormone with pleiotropic effects beyond its traditional role in calcium and bone homeostasis. Since vitamin D has immunomodulatory, cardioprotective, and antifibrotic properties, it could potentially interfere with SSc pathogenesis. Suboptimal vitamin D levels are classically recognized in scleroderma, irrespective of clinical and serological phenotype. AIM: This systematic review is aimed at investigating and clarifying the role of vitamin D in SSc and emphasizing the association of vitamin D status with different clinical settings. METHODS AND RESULTS: A systematic online search was performed, using PubMed databases to collect articles on the topic of vitamin D in SSc. The final analysis included 40 eligible articles. CONCLUSIONS: Hypovitaminosis D is common in SSc patients and could be associated with clinical and serologic patterns of the disease. Intervention for low serum vitamin D levels in SSc pathogenesis remains controversial, as well as the significance of vitamin D supplementation in such patients.

Natural Formulations: Novel Viewpoint for Scleroderma Adjunct Treatment.

BACKGROUND: Scleroderma is a complex disease involving autoimmune, vascular, and connective tissues, with unknown etiology that can progress through any organ systems. OBJECTIVE: Yet, no cure is available; the thorough treatment of scleroderma and current treatments are based on controlling inflammation. Nowadays, medicinal plants/natural-based formulations are emerging as important regulators of many diseases, including autoimmune diseases. Here, we provided an overview of scleroderma, also focused on recent studies on medicinal plants/natural-based formulations that are beneficial in scleroderma treatment/prevention. METHODS: This study is the result of a search in PubMed, Scopus, and Cochrane Library with "scleroderma", "systemic sclerosis", "plant", "herb", and "phytochemical" keywords. Finally, 22 articles were selected from a total of 1513 results entered in this study. RESULTS: Natural products can modulate the inflammatory and/or oxidative mediators, regulate the production or function of the immune cells, and control the collagen synthesis, thereby attenuating the experimental and clinical manifestation of the disease. CONCLUSION: Natural compounds can be considered an adjunct treatment for scleroderma to improve the quality of life of patients suffering from this disease.

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.

[Silica-induced scleroderma in miners in former uranium ore mining (Wismut AG)]. / Quarzinduzierte Sklerodermie bei Bergleuten im früheren Uranerzbergbau (Wismut AG).

As part of the reappraisal of the legacy of Wismut AG, 12 patients with silica-induced scleroderma among underground uranium ore mine workers (Wismut AG) under long-term exposure to silica fine dust, as well as radon and its daughter products, during the 1960s and 1970s are reported on. Silica-induced scleroderma is clinically, serologically and immunologically indistinguishable from idiopathic systemic sclerosis. In experimental studies, endothelial cells, monocytes and fibroblasts, as well as their synthesis rates and the release of cytokines and chemokines, were activated by silica fine dust in a way that is consistent with the pathophysiological processes in idiopathic systemic sclerosis. It was not possible to achieve recognition of silica-induced systemic sclerosis as an occupational disease in Germany.

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.

Paediatric morphoea: a holistic review. Part 2: diagnosis, measures of disease activity, management and natural history.

Paediatric morphoea is a debilitating fibrosing disorder of uncertain aetiology, affecting the skin and subcutaneous tissues. Defining optimum management strategies in paediatric morphoea remains an ongoing challenge, owing to the varied presentations and a relative paucity of paediatric-specific studies. We performed a literature search on PubMed, MEDLINE and Google Scholar, using keywords such as 'pediatric morphea', 'juvenile localised scleroderma' and 'juvenile systemic sclerosis'. Relevant studies, including randomized trials, reviews of standard current guidelines and original research articles, were selected and results analysed before summarizing them. In Part 1 of this review, we described the epidemiology, aetiopathogenesis and clinical classification; in this part, we discuss the diagnosis, markers of disease activity, management and natural history in paediatric morphoea.

Vitamin D and Cytokine Profiles in Patients With Systemic Sclerosis.

INTRODUCTION: Hypovitaminosis D has been frequently described in systemic sclerosis (SSc). Cytokines are important mediators of tissue damage and clinical dysfunction in SSc and may be influenced by vitamin D levels. OBJECTIVE: To evaluate the serum levels of vitamin D and its correlation with the clinical features and cytokine profiles in SSc patients. METHODS: Case-control study, including 50 SSc patients and 35 healthy non matched controls. Serum levels of 25(OH) vitamin D were measured by chemiluminescence assay, and serum concentrations of interleukin 2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor, and interferon γ were determined by flow cytometry. RESULTS: Fourteen patients (28%) had diffuse cutaneous SSc, 94% were female, 80% European derived, with a mean age of 57.2 ± 12.8 years. The serum vitamin D levels in SSc patients were 23.9 ± 8.5 ng/mL and 30.2 ± 6.2 ng/mL in the control group (standardized mean difference -6.19; 95% confidence interval, -9.9 to -2.3; p = 0.002), despite the more frequent supplementation of vitamin D in SSc patients (p = 0.014). No significant associations were found among vitamin D concentrations and cytokine levels. Serum levels of IL-6 were significantly elevated in SSc patients (p = 0.024) and were positively correlated with the modified Rodnan skin score (rs = 0.291, p =0.041). CONCLUSIONS: Despite lower vitamin D levels in SSc patients, there was no clear association with any cytokine. Serum levels of IL-6 were significantly elevated and positively correlated with the extent of skin involvement in SSc patients.

Vitamin D serum levels and the risk of digital ulcers in systemic sclerosis: A longitudinal study.

AIM: Low levels of vitamin D (25OHD) have been found to associated with digital ulcers (DUs) in systemic sclerosis (SSc), although only cross-sectional studies have been performed. We aimed to investigate if variations in vitamin D serum levels over time affect DU in SSc. METHODS: This is a retrospective study on 65 patients. 25OHD was measured in 2011 and 2016 and its variations correlated with DU. RESULTS: The mean age of our cohort was 58 (SD 12) years with a mean disease duration of 9.5 (5.3) years. Most of our patients had a limited SSc (69.2%). At baseline 50.8% and 41.5% after 5 years had 25OHD <30 ng/mL. Patients receiving supplementation (8750 IU/wk) at baseline numbered 39 (60.0%) and 45 (69.2%) at the end of follow up. Nevertheless, 31 (47.7%) had a decrease of 25OHD in 5 years. In univariate analysis, patients with incident DU had a decrease in 25OHD as compared to patients with no incident DU (-17.4 [37.0] vs 13.0 [89.5], P = 0.018). No differences in 25OHD variations were found for other disease characteristics. In multivariate analysis correcting for previous DU and modified Rodnan Skin Score at baseline, patients with a decrease in 25OHD had an increased risk of developing DU (odds ratio 16.6; 95% CI 1.7-164.5, P = 0.017). CONCLUSIONS: A decrease in 25OHD is associated with the risk of developing DUs. In addition, vitamin D supplementation with the doses currently recommended may be insufficient in SSc. Further studies in wider cohorts are needed to confirm these results.

Challenges in the diagnosis and treatment of disabling pansclerotic morphea of childhood: case-based review.

Disabling pansclerotic morphea of childhood (DPMC) is a rare subtype of juvenile localized scleroderma (JLS) characterized by pansclerosis mainly affecting children under the age of 14. This aggressive disease has a poor prognosis due to the rapid progression of deep musculoskeletal atrophy resulting in cutaneous ulceration and severe joint contractures. We describe the challenges in treating a previously well 5-year-old male who has refractory symptoms of DPMC. Over the 29 months, since his initial presentation, we trialed over ten therapies. There was subjective improvement with prednisolone and mycophenolate mofetil (MMF). However, other therapies including biologics and tyrosine kinase inhibitors (TKI) were ineffective. The patient has been referred for hematopoietic stem cell transplant given ongoing disease progression. We conducted a literature search focusing on English articles with keywords including DPMC. Publications with limited information or describing cases aged 20 and above were excluded. Thirty-seven case reports were identified and the reported treatments were evaluated. Methotrexate and corticosteroids have been the most commonly utilized. MMF has been anecdotally effective. Biologics, TKI, and Janus kinase inhibitors lack evidence in DPMC, but have had demonstrated efficacy in similar pathologies including systemic sclerosis, and, thus, have been used for DPMC. Phototherapy has been documented to be reducing skin thickness and stiffness of plaques. Eventually, most children require multi-modal and high-dose immunosuppressive therapies to reduce the inflammation inflicted by the disease. Long-term antibiotics and nutritional support are important in the ongoing care of these patients.

Characteristics and Outcomes of Patients With Systemic Sclerosis (Scleroderma) Requiring Renal Replacement Therapy in Europe: Results From the ERA-EDTA Registry.

RATIONALE & OBJECTIVE: Data for outcomes of patients with end-stage renal disease (ESRD) secondary to systemic sclerosis (scleroderma) requiring renal replacement therapy (RRT) are limited. We examined the incidence and prevalence of ESRD due to scleroderma in Europe and the outcomes among these patients following initiation of RRT. STUDY DESIGN: Registry study of incidence and prevalence and a matched cohort study of clinical outcomes. SETTING & PARTICIPANTS: Patients represented in any of 19 renal registries that provided data to the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry between 2002 and 2013. PREDICTOR: Scleroderma as the identified cause of ESRD. OUTCOMES: Incidence and prevalence of ESRD from scleroderma. Recovery from RRT dependence, patient survival after ESRD, and graft survival after kidney transplantation. ANALYTICAL APPROACH: Incidence and prevalence were calculated using population data from the European Union and standardized to population characteristics in 2005. Patient and graft survival were compared with 2 age- and sex-matched control groups without scleroderma: (1) diabetes mellitus as the cause of ESRD and (2) conditions other than diabetes mellitus as the cause of ESRD. Survival analyses were performed using Kaplan-Meier analysis and Cox regression. RESULTS: 342 patients with scleroderma (0.14% of all incident RRT patients) were included. Between 2002 and 2013, the range of adjusted annual incidence and prevalence rates of RRT for ESRD due to scleroderma were 0.11 to 0.26 and 0.73 to 0.95 per million population, respectively. Recovery of independent kidney function was greatest in the scleroderma group (7.6% vs 0.7% in diabetes mellitus and 2.0% in other primary kidney diseases control group patients, both P<0.001), though time required to achieve recovery was longer. The 5-year survival probability from day 91 of RRT among patients with scleroderma was 38.9% (95% CI, 32.0%-45.8%), whereas 5-year posttransplantation patient survival and 5-year allograft survival were 88.2% (95% CI, 75.3%-94.6%) and 72.4% (95% CI, 55.0%-84.0%), respectively. Adjusted mortality from day 91 on RRT was higher among patients with scleroderma than observed in both control groups (HRs of 1.25 [95% CI, 1.05-1.48] and 2.00 [95% CI, 1.69-2.39]). In contrast, patient and graft survival after kidney transplantation did not differ between patients with scleroderma and control groups. LIMITATIONS: No data for extrarenal manifestations, treatment, or recurrence. CONCLUSIONS: Survival of patients with scleroderma who receive dialysis for more than 90 days was worse than for those with other causes of ESRD. Patient survival after transplantation was similar to that observed among patients with ESRD due to other conditions. Patients with scleroderma had a higher rate of recovery from RRT dependence than controls.

The challenge of pet therapy in systemic sclerosis: evidence for an impact on pain, anxiety, neuroticism and social interaction.

OBJECTIVES: The aim of our study was to evaluate the effect of animal-assisted intervention (AAI), a complementary support to traditional therapies focused on the interaction between animals and human beings, in improving psychological trait, anxiety and pain in a cohort of systemic sclerosis (SSc) patients. METHODS: 42 SSc patients, undergoing iloprost intravenous infusion, were divided in three groups: 1) 14 patients submitted to 20 AAI sessions; 2) 14 patients engaged in alternative social activity (control group 1 - C1); and 3) 14 patients without any alternative activity (control group 2 - C2). All patients underwent Visual Analog Scale (VAS), the State-anxiety (STAI-S) and emotional faces at the beginning (s0) and at the end (s1) of each single session, while General Anxiety State-Trait Anxiety Inventory (STAI-T), Beck Depression Inventory (BDI), Social Interaction Anxiety Scale (SIAS), Eysenck Personality Questionnaire-Revised (EPQ-R), the Social Phobia Scale (SPS), the Toronto Alexythymia Scale (TAS-20), the Thought Control Questionnaire (TCQ) were administered at baseline (t0) and at the end of the project (t1). RESULTS: AAI group showed a significant decrease of the anxiety state level in respect to the two control groups (p<0.001). VAS scale resulted lower both in AAI (p < 0.001) and C1 group (p<0.01). Moreover, STAI-T and TAS scores were significantly reduced in AAI group (p<0.001). TCQ scale showed that patients treated with AAI, compared to control group C2, had greater capacity to avoid unpleasant and unwanted thoughts (p<0.05). In AAI group, the EPQ-R test revealed an enhancement of extroversion trait compared to both control groups (p<0.05). CONCLUSIONS: Our data show that AAI significantly reduces pain perception, anxiety, neuroticism and ameliorates patients' social interaction, therefore it may be a useful to allow a better compliance to traditional therapies.

Prognostic profile of systemic sclerosis: analysis of the clinical EUSTAR cohort in China.

BACKGROUND: Systemic sclerosis is a disease that has significant clinical heterogeneity. This study aims to determine the causes and risk factors of death in a single center European League Against Rheumatism Scleroderma Trials and Research Group (EUSTAR) cohort at the Peking Union Medical College Hospital (PUMCH) in China. METHODS: Patients clinically diagnosed with systemic sclerosis (SSc) between Feb 2009 and Dec 2015 were prospectively recruited from the EUSTAR database and Chinese Rheumatism Data Center (CRDC) of the PUMCH. Baseline and follow-up data were collected. Kaplan-Meier analysis was used to estimate survival, and Cox proportional hazards regression analysis was used to identify factors associated with mortality. RESULTS: A total of 448 patients were included in the cohort, of whom 56.7% had limited cutaneous systemic sclerosis (lcSSc). The average age at diagnosis was 42.8 ± 12.1 years. The prevalence of interstitial lung disease (ILD) was 382/447 (85.5%). Among 402 patients, 348 of them took glucocorticoid during the disease course; 374 patients received immunosuppressors. Across 2167 patient-years, 40 patients died. Of these, 27 deaths were attributable to SSc, with pulmonary arterial hypertension (PAH) being the leading cause of death. The median survival time was 53 months. Survival rates from disease diagnosis were 97.0%, 94.6%, 91.1% and 87.8% at 1, 3, 5 and 10 years, respectively. Independent prognostic factors for mortality were PAH (HR 6.248, 95% CI 2.855, 13.674) and arrhythmia (HR 4.729, 95% CI 1.588, 14.082). Tripterygium wilfordii Hook F (TwHF) (log-rank test 7.851, p 0.005) and methotrexate (MTX) (log-rank test 7.925, p = 0.005) were found in survival analysis to be protective treatments against mortality. Patients who used cyclophosphamide (CTX) during the disease course had poorer prognosis (log-rank test 5.177, p = 0.023). CONCLUSIONS: In china, although there is a high prevalence of ILD in patients with SSc (85.5%), most of them have reserved pulmonary function, which means that interstitial lung disease (ILD) is not the most important factor in the death of patients with SSc and also is not a risk factor for poor prognosis. Only ILD with pulmonary dysfunction is associated with poor outcome. The 10-year cumulative rate (87.8%) in patients with SSc in China is slightly lower than the Europe, and pulmonary arterial hypertension (PAH) and arrhythmia at baseline are independent prognostic factors, whereas PAH instead of ILD is the leading cause of death in patients with SSc. Interestingly, the Chinese traditional medicine TwHF, as a protective factor for survival deserves further study.

Diagnostic criteria, severity classification and guidelines of localized scleroderma.

We established diagnostic criteria and severity classification of localized scleroderma because there is no established diagnostic criteria or widely accepted severity classification of the disease. Also, there has been no clinical guideline for localized scleroderma, so we established its clinical guideline ahead of all over the world. In particular, the clinical guideline was established by clinical questions based on evidence-based medicine according to the New Minds Clinical Practice Guideline Creation Manual (version 1.0). We aimed to make the guideline easy to use and reliable based on the newest evidence, and to present guidance as specific as possible for various clinical problems in treatment of localized scleroderma.

Intestinal Involvement in Systemic Sclerosis: A Clinical Review.

Systemic sclerosis (SSc) is a chronic systemic disease characterized by microvasculopathy, autoantibodies, and extensive fibrosis. Intestinal involvement is frequent in SSc and represents a significant cause of morbidity. The pathogenesis of intestinal involvement includes vascular damage, nerve dysfunction, smooth muscle atrophy, and fibrosis, causing hypomotility, which leads to small intestinal bacterial overgrowth (SIBO), malabsorption, malnutrition, diarrhea, pseudo-obstruction, constipation, pneumatosis intestinalis, and fecal incontinence. Manifestations are often troublesome and reduce quality of life and life expectancy. Assessment of intestinal involvement includes screening for small intestine hypomotility, malnutrition, SIBO, and anorectal dysfunction. Current management of intestinal manifestations is largely inadequate. Patients with diarrhea are managed with low-fat diet, medium-chain triglycerides, avoidance of lactulose and fructose, and control of bacterial overgrowth with antibiotics for SIBO. In diarrhea/malabsorption, bile acid sequestrant and pancreatic enzyme supplementation may help, and nutritional support is needed. General measures are applied for constipation, and intestine rest plus antibiotics for pseudo-obstruction. Fecal incontinence is managed with measures for associated SIBO, or constipation, and with behavioral therapies. Pneumatosis intestinalis is usually an incidental finding that does not require any specific treatment. Immunomoduation should be considered early in intestinal involvement. Multidisciplinary approach of intestinal manifestations in SSc by gastroenterologists and rheumatologists is required for optimum management.