Advanced Systemic Sclerosis Research Articles

Osteonecrosis of carpal bones in systemic sclerosis

Background. Systemic sclerosis (SSc) is a rare chronic disease, with unknown aetiology and complex pathogenesis. The hand is often implied in the main clinical findings, being affected primarily by the vascular component (Raynaud phenomenon, digital ulcers). One of the possible complications of the hand vasculopathy is osteonecrosis (ON) of the carpal bones. In these cases, the lunate is the most frequently affected, followed by the scaphoid. In the ON process, not only the vascular supply is important, but the nearby mechanical factors and anatomic variants of the wrist. Our objective was to reveal the most important aspects regarding the ON of the carpal bones in patients with SSc. Methods. A systematic literature review was performed through July 31, 2021 on Pubmed and Cochrane databases. The eligible articles were read in full text and were included in this paper, in the absence of exclusion criteria and after consensus between two reviewers. Results. Ten articles met the inclusion criteria, their main results being described in this review. In all studies, ON of the lunate and the scaphoid is associated with advanced SSc and severe Raynaud phenomenon. Conclusions. In conclusion, carpal ON is a rare complication of SSc, especially of the diffuse type. There is limited data on this condition, its prevalence being difficult to estimate due to the lack of symptoms.

Irinotecan and its metabolite SN38 inhibits procollagen I production of dermal fibroblasts from Systemic Sclerosis patients

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease characterized by a microangiopathy and fibrosis of the skin and internal organs. No treatment has been proved to be efficient in case of early or advanced SSc to prevent or reduce fibrosis. There are strong arguments for a key role of topo-I in the pathogenesis of diffuse SSc. Irinotecan, a semisynthetic derivative of Camptothecin, specifically target topo-I. This study was undertaken to evaluate the effects of noncytotoxic doses of irinotecan or its active metabolite SN38 on collagen production in SSc fibroblasts. Dermal fibroblasts from 4 patients with SSc and 2 healthy donors were cultured in the presence or absence of irinotecan or SN38. Procollagen I release was determined by ELISA and expression of a panel of genes involved in fibrosis was evaluated by qRT-PCR. Subcytotoxic doses of irinotecan and SN38 caused a significant and dose-dependent decrease of the procollagen I production in dermal fibroblasts from SSc patients, respectively − 48 ± 3%, p < 0.0001 and − 37 ± 6.2%, p = 0.0097. Both irinotecan and SN38 led to a global downregulation of genes involved in fibrosis such as COL1A1, COL1A2, MMP1 and ACTA2 in dermal fibroblasts from SSc patients (respectively − 27; − 20.5; − 30.2 and − 30% for irinotecan and − 61; − 55; − 50 and − 54% for SN38). SN38 increased significantly CCL2 mRNA level (+ 163%). The inhibitory effect of irinotecan and its active metabolite SN38 on collagen production by SSc fibroblasts, which occurs through regulating the levels of expression of genes mRNA, suggests that topoisomerase I inhibitors may be effective in limiting fibrosis in such patients.

New Autoantibody Specificities in Systemic Sclerosis and Very Early Systemic Sclerosis.

Chemokine (C-X-C motif) ligand 4 (CXCL4) is a biomarker of unfavorable prognosis in Systemic Sclerosis (SSc), a potentially severe autoimmune condition, characterized by vasculitis, fibrosis and interferon (IFN)-I-signature. We recently reported that autoantibodies to CXCL4 circulate in SSc patients and correlate with IFN-α. Here, we used shorter versions of CXCL4 and CXCL4-L1, the CXCL4 non-allelic variant, to search for autoantibodies exclusively reacting to one or the other CXCL4 form. Moreover, to address whether anti-CXCL4/CXCL4-L1 antibodies were present before SSc onset and predicted SSc-progression, we longitudinally studied two VEDOSS (Very Early Diagnosis of Systemic Sclerosis) patient cohorts, separating SSc-progressors from SSc-non-progressors. We found that anti-CXCL4-specific autoantibodies were present in both SSc and VEDOSS patients (both SSc-progressors and SSc-non-progressors). Anti-CXCL4-L1-specific autoantibodies were especially detected in long-standing SSc (lsSSc). Anti-CXCL4/CXCL4-L1 antibodies correlated with IFN-α and with specific SSc-skin features but only in lsSSc and not in early SSc (eaSSc) or VEDOSS. Thus, a broader antibody response, with reactivity spreading to CXCL4-L1, is characteristic of lsSSc. The early anti-CXCL4 autoantibody response seems qualitatively different from, and likely less pathogenic than, that observed in advanced SSc. Lastly, we confirm that anti-CXCL4 autoantibodies are SSc-biomarkers and uncover that also CXCL4-L1 becomes an autoantigen in lsSSc.

Stem Cell Therapy as a Treatment for Autoimmune Disease-Updates in Lupus, Scleroderma, and Multiple Sclerosis.

Evidence for hematopoietic stem cell transplantation (HCT) in autoimmune disease has been building since the 1990s; however, many clinicians may not yet be aware of its applications to autoimmune disease. We review the basic tenets of HCT and evidence for autologous HCT in multiple sclerosis (MS), systemic sclerosis (SSc), and lupus with an emphasis on recent advanced phase trials. In MS, the phase 3 randomized MIST trial and the phase 2 randomized ASTIMS trial demonstrated the efficacy of autologous HCT in refractory MS over disease-modifying therapies and mitoxantrone, respectively. In SSc, the phase 3 randomized ASTIS trial and the phase 2 randomized SCOT trial demonstrated the efficacy of autologous HCT in advanced SSc compared to cyclophosphamide. The evidence for HCT in autoimmune diseases continues to grow, particularly in MS and SSc. In lupus, large, comparative trials are still needed. Across autoimmune diseases, questions that still remain to be answered include optimizing patient selection to limit TRM, the appropriate use of MAC, and the necessity for graft manipulation. Furthermore, collaboration between disease-specific and transplant physicians is imperative to expand the appropriate use of HCT in routine clinical practice.

Evolving Symptom Characteristics of Raynaud's Phenomenon in Systemic Sclerosis and Their Association With Physician and Patient-Reported Assessments of Disease Severity.

Assessment of Raynaud's phenomenon (RP) in systemic sclerosis (SSc) is reliant on self-report. The Raynaud's Condition Score (RCS) diary assumes discrete episodic RP attacks, although not all SSc patients identify with this paradigm. We investigated the clinical associations of SSc-RP symptom characteristics and the evolution of SSc-RP symptoms with disease progression. A cross-sectional study at UK and US sites captured digital color changes of SSc-RP and patients' ability to identify with diagrammatic representations (and descriptive stems) of 4 distinct theoretical SSc-RP patterns (progressing severity A through D) reflecting progressively severe SSc-RP experiences. SSc-RP self-management and symptom evolution were explored. Patient demographics, the clinical phenotype, the Scleroderma Health Assessment Questionnaire (SHAQ), the 2-week RCS diary, and patient and physician global assessments were collected. We enrolled 107 patients with SSc (with questionnaires returned by 94). A higher number of self-reported digital color changes of SSc-RP were associated with increased SSc-RP symptom severity but not with the SSc clinical phenotype. Patients could identify with distinct patterns of SSc-RP. These patterns were associated with disease duration, global disease severity, and conceptually linked physician and patient assessments of peripheral vascular severity (e.g., SHAQ RP subscale and RCS diary parameters), but not with conceptually unrelated outcomes (e.g., SHAQ breathing subscale). SSc-RP characteristics and symptom severity evolve during the disease course. Patients identify with distinct patterns of SSc-RP that may relate to progression of the obliterative microangiopathy of SSc. Difficulty distinguishing discrete SSc-RP attacks from persistent digital ischemia in patients with advanced SSc could influence diary-based approaches to assessing SSc-RP, with implications for future clinical trials.

CATHETER ABLATION OF VENTRICULAR TACHYCARDIAS ORIGINATING FROM RIGHT VENTRICULAR SCAR IN A PATIENT WITH SYSTEMIC SCLEROSIS

Sustained ventricular tachycardia (VT) in systemic sclerosis (SSc) patients is uncommon. The pathophysiology behind the predilection of the right ventricle (RV) for SSc-associated scarring remains to be elucidated. A 68-year-old woman with advanced SSc was admitted with progressive dyspnea and

Systemic Sclerosis and Pleural Effusion in a Patient with Ankylosing Spondylitis

Systemic sclerosis (SSc) is a chronic autoimmune disorder characterized by endothelial and fibroblast dysfunction, resulting in progressive fibrosis of the skin and internal organs. Ankylosing spondylitis (AS) is an arthritic condition affecting the axial skeleton and peripheral joints. An association between SSc and AS is relatively rare, as the two diseases share few characteristics. Here, we present a case of limited SSc in a 44-year-old man who exhibited low-grade AS, and discuss several cases of coexisting SSc and AS in the literature. Patients with both diseases showed several common features, including male predominance, middle age, and combined interstitial lung disease. However, unlike our case, the patients reported in the literature had advanced ankylosis and diffuse SSc. Keywords: Scleroderma, Systemic; Ankylosing spondylitis; Lung diseas, Interstitial 중심 단어: ì „ì‹ ê²½í™”ì¦; 강직척추염; 간질성 폐질환

Thermography Improves Clinical Assessment in Patients with Systemic Sclerosis Treated with Ozone Therapy.

Objective. Treatment of scleroderma is challenging and limited. The aim of our study was to evaluate the usefulness of thermography in assessment of the clinical condition (joints movability and skin thickness) in clinically advanced patients with systemic sclerosis before and after ozone therapy. Method. The study included 42 patients aged 32 to 73 years with advanced systemic sclerosis hospitalized in the university clinic between 2003 and 2006. Thermography and clinical examinations were conducted at baseline and after two series of bath in water with ozone. Results. The comparison of results showed significant increase in skin temperature by 2.5°C, significant increase in interphalangeal joints movability by 18 degrees, and significant decrease in skin score by 14.7 points. The skin temperature was correlated with skin score (r = −0.59) and joints movability (r = +0.8). Conclusions. Ozone therapy shows positive effect on clinical parameters and skin temperature as measured with thermography. The study indicated possibility of introducing ozonotherapy as an independent therapy in cases with low level of progression or during remission periods and as additional treatment in patients with advanced disease requiring immunosuppressive treatment. Thermography is useful in assessment of skin condition showing strong correlation between skin temperature and clinical parameters.

Prevalence and risk factors for left ventricular diastolic dysfunction in a scleroderma cohort

Objectives: Left ventricular diastolic dysfunction (LVDD) is more common in systemic sclerosis (SSc) compared to the general population. Focal myocardial ischaemia and fibrosis may be important in its pathogenesis. LVDD is associated with increased mortality and little is known about the risk factors. Advanced SSc lung complications may accompany LVDD.Method: We conducted a cross-sectional study of 300 SSc outpatients with and without LVDD, seen between May 2012 and May 2014, and performed univariate and multivariate regression analyses to determine clinical factors associated with LVDD. LVDD was confirmed by the latest echocardiogram (tissue Doppler imaging) reports. Interstitial lung disease (ILD) was confirmed by high-resolution computed tomography (HRCT) and pulmonary hypertension (PH) was diagnosed by right heart catheterization (RHC).Results: Of the 300 SSc patients, there were 133 (44%) with LVDD. In the univariate analysis, advanced age, disease duration (from the onset of Raynaud’s phenomenon), anti-centromere antibody, the presence of SSc lung complications, systemic hypertension, smoking, valvular heart disease, chronic kidney and thyroid diseases were all significantly associated with LVDD. However, in the multivariate regression analysis, advanced age was the most significant factor associated with LVDD, followed by systemic hypertension and SSc lung complications. There were significantly more deaths in the LVDD group (p < 0.0001).Conclusions: LVDD was more prevalent in the SSc population, especially in those with advanced age, systemic hypertension, or SSc-pulmonary complications. SSc patients with pulmonary fibrosis or pulmonary hypertension had more advanced LVDD and higher mortality. More effective therapy is needed to improve the outcome in this population.

Regulatory T Cells in Systemic Sclerosis: a Comprehensive Review.

Systemic sclerosis (SSc) is a chronic inflammatory disease with complex pathogenesis, based on the sophisticated interplay of injury to the vascular endothelium, exaggerated tissue regeneration and fibrosis, and extensive immune abnormalities. The role of regulatory T cells (Tregs) in the development of SSc has started being studied during the last decade with new aspects being disclosed continuously, in parallel with the better understanding of Tregs physiology. There is a general agreement in the medical literature regarding the decreased functional capacity of circulating Tregs in SSc. Some patients, particularly those with active disease, may have increased numbers of circulating Tregs, representing the inhibitory response of the immune system to its inappropriate activation or occurring as a compensatory move for Tregs' decreased suppressive ability. Decreased pool of circulating Tregs can be seen in other SSc patients, with even lower Treg percentages seen in patients with long-standing disease. Skin-resident Tregs are depleted in advanced SSc but can be active and have a role in earlier disease stages. In addition to diminished suppressive ability, Tregs can contribute to SSc evolution by their microenvironment-dependent transformation to pathogenic effector T cells of Th17 or Th2 lineages with respective pro-inflammatory or pro-fibrotic activity. The current data on the effects of existing treatment modalities, including autologous stem cell transplantation, on Tregs function in SSc, is controversial, not being sufficiently elaborated.

A case of advanced systemic sclerosis with severe GERD successfully treated with acotiamide

The majority of systemic sclerosis (SSc) patients have gastrointestinal tract involvement, but therapies of prokinetic agents are usually unsatisfactory. Patients are often compromised by the use of steroid; therefore, a surgical indication including fundoplication has been controversial. There is no report that advanced SSc with severe gastroesophageal reflux disease (GERD) is successfully treated with acotiamide, which is the acetylcholinesterase (AChE) inhibitor designed for functional dyspepsia (FD). We report a 44-year-old woman of SSc with severe GERD successfully treated with acotiamide. She had received medical treatment in our hospital since 2003. She had been aware of the significant gastroesophageal reflux symptoms (e.g., heartburn, chest pain, and dysphagia) due to the development of esophageal hardening associated with SSc since 2014. As a result of upper gastrointestinal series, upper gastrointestinal endoscopy, and 24-h pH monitoring and frequency scale for the symptoms of the GERD (FSSG) scoring, she has been diagnosed with GERD associated with SSc. First of all, she started to take prokinetic agents Rikkunshito and mosapride and proton pump inhibitor; there was no change in reflux symptoms. So, we started to prescribe her the acotiamide.After oral administration started, reflux symptoms have been improved. Five months after oral administration, FSSG score, a questionnaire for evaluation of the symptoms of GERD, was improved. Since its introduction of acotiamide, the patient has kept free from symptoms for 6 months.

The Impact of Medical Nutrition Therapy for Patients with Advanced Systemic Sclerosis (MNT PASS)

Methods: Eighteen patients with SSc with unintentional weight loss and GI symptoms were consented and recruited. Nutrition symptomology (abridged Patient Generated Subjective Global Assessment), GI symptoms (UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tracker), health-related quality of life (CDC HRQOL), anthropometrics, diet (24-hour recall) and body composition (dual energy x-ray absorptiometry) were assessed at baseline and 6 weeks following MNT that emphasized greater caloric intake, improved protein distribution and texture alterations. Descriptive statistics (frequencies, means standard deviations), T-tests and c2 tests were conducted.

FRI0507 Dual Energy Computed Tomography for the Evaluation of Calcinosis in Systemic Sclerosis

BackgroundCalcinosis, the deposition of calcified material in the skin and subcutaneous soft tissues, is frequently seen in up to 40% patients with SSc (1, 2). Calcium hydroxyapatite (3) is the...

SAT0301 Vasospastic Severity and Digital Ischemia during Cooling is Related to Nail-Fold Capillaroscopic Pattern in Patients with Secondary Raynaud Phenomenon and Systemic Sclerosis

BackgroundMicroangiopathy, assessed as specific nail-fold capillaroscopic patterns (NCP), is a key feature and currently diagnostic criterion in the development of systemic sclerosis (SSc). In advanced SSc, NCP severity correlates clearly...

Mandibular resorption in progressive systemic sclerosis: a report of three cases

Progressive systemic sclerosis is a generalized collagen disorder, which is characterized by fibrosis that involves skin, muscles and other organ systems like the gastrointestinal tract, lungs, heart and kidneys. Its oral manifestations include features like restricted mouth opening, widening of periodontal ligament space, pseudoankylosis, malocclusion and mandibular resorption. Mandibular resorption in systemic sclerosis is relatively uncommon and is reported only in 10% of cases. The purpose of reporting these three cases is to highlight the importance of screening all patients with advanced systemic sclerosis with panoramic radiographs. Panoramic radiographs are essential for early detection of resorption in the mandible to prevent possible consequences like pathological fractures, osteomyelitis and neuropathies.

Mechanism of sustained monomorphic ventricular tachycardia in systemic sclerosis

Three patients with advanced systemic sclerosis and recurrent or incessant monomorphic ventricular tachycardia underwent cardiac electrophysiologic studies. Biventricular transcatheter mapping showed findings most compatible with a reentrant mechanism, which was effectively treated with transcatheter ablation.