Insight into the Epidemiology of the Adult-onset Systemic Autoimmune Rheumatic Diseases in Egypt: A Descriptive Study of 8690 Patients.

BACKGROUND/OBJECTIVE: Although systemic autoimmune rheumatic diseases (SARDs) seem to be ubiquitous, Africa and the Middle East seem to be a remarkable exception with scarcity of data compared with the developed countries. Furthermore, most of the studies addressed a particular disease. This work aimed to shed light on the relative frequency and epidemiology of the different adult-onset SARDs in Egypt. METHODS: This is a retrospective hospital-based study including six university hospitals providing free health care services: Cairo, Alexandria, Tanta, Ismailia, Beni-Suef and Assiut University Hospitals. All available files for patients attending the outpatient clinics or admitted to the inpatient departments between January 2000 and December 2021 were retrospectively reviewed. Data about the patient's diagnosis, gender, age at disease onset, year of disease onset and residence were collected. RESULTS: The study included 8690 patients. Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Behçet's disease (BD) and spondyloarthropathies (SPA) represented the main SARDs in Egypt. They mainly affect young patients below the age of 40 years. RA and SLE mainly affect females; males are mainly affected by axial SPA and BD. There is an increasing incidence of SARDs during the study period. CONCLUSION: The study revealed the high burden of SARDs in Egypt, helping better allocation of economic resources for the management of diseases of the highest prevalence and those affecting the young reproductive age groups. Increased public and medical staff awareness about SARDs is recommended to help early referral of patients to rheumatologists and, hence, better estimation of their epidemiology.

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.

Systemic pharmacological treatment of digital ulcers in systemic sclerosis: a systematic literature review.

OBJECTIVE: To evaluate the evidence concerning systemic pharmacological treatments for SSc digital ulcers (DUs) to inform the development of evidence-based treatment guidelines. METHODS: A systematic literature review of seven databases was performed to identify all original research studies of adult patients with SSc DUs. Randomized controlled trials (RCTs) and prospective longitudinal observational studies (OBSs) were eligible for inclusion. Data were extracted, applying the patient, intervention, comparison, outcome framework, and risk of bias (RoB) was assessed. Due to study heterogeneity, narrative summaries were used to present data. RESULTS: Forty-seven studies that evaluated the treatment efficacy or safety of pharmacological therapies were identified among 4250 references. Data from 18 RCTs of 1927 patients and 29 OBSs of 661 patients, at various RoB (total 2588 patients) showed that i.v. iloprost, phosphodiesterase-5 inhibitors and atorvastatin are effective for the treatment of active DUs. Bosentan reduced the rate of future DUs in two RCTs (moderate RoB) and eight OBSs at low to high RoB. Two small studies (moderate RoB) indicate that Janus kinase inhibitors may be effective for the treatment of active DUs, otherwise there are no data to support the use of immunosuppression or anti-platelet agents in the management of DUs. CONCLUSION: There are several systemic treatments, across four medication classes, that are effective therapies for the management of SSc DUs. However, a lack of robust data means it is not possible to define the optimal treatment regimen for SSc DUs. The relatively low quality of evidence available has highlighted further areas of research need.

Examination of the Validity of Skin Ultrasound to Quantitate Skin Involvement for Multicenter Clinical Trials in Patients with Systemic Sclerosis (SSc): A Systematic Literature Review (SLR).

OBJECTIVE: The study objective was to conduct a systematic literature review (SLR) of ultrasound of the skin in patients with systemic sclerosis (SSc) to establish the degree to which ultrasound of the skin has been validated, using the Outcome Measures in Rheumatology (OMERACT) Filter. METHODS: We conducted an SLR of publications between 1950 and 2018, using PubMed and Cochrane library, to examine ultrasound validity to quantitate SSc skin involvement. Inclusion criteria were as follows: (1) in English; (2) used the 1980 or 2013 classification criteria for SSc criteria; (3) either a randomized controlled trial, an observational study, or a case study including more than 15 patients; (4) subjects 18 years of age or older; (5) for mixed patient populations, SSc results were separable; and (6) the ultrasound machine was clearly described. Exclusion criteria were as follows: (1) not in English; (2) data did not record at least one of the validation criteria; (3) subjects aged less than 18 years; (4) subjects had disease other than SSc (eg, localized scleroderma or scleroderma-like disease); (5) a letter to the editor or an editorial; and (6) involved a modified Rodnan skin score of less than 2. Descriptive statistics were generated for each criterion. RESULTS: From an initial 292 citations, 14 articles (1,055 patients) met inclusion and exclusion criteria. The status of validation for ultrasound was evaluated by using the OMERACT criteria of truth, discrimination, and feasibility (in turn divided into nine different criteria). Face, criterion, content, construct, reliability, and responsiveness criteria were met, and the feasibility criterion was partially met, whereas discrimination and reproducibility criteria were not met. CONCLUSION: Based on an SLR through December 31, 2018, ultrasound of the skin met some but not all validation criteria for use in clinical trials.

Ultrasonographic imaging of systemic sclerosis digital ulcers: A systematic literature review and validation steps.

INTRODUCTION/BACKGROUND: Skin ulcers are a complex array of clinical manifestations of systemic sclerosis (SSc) and are often difficult to treat. However, the definition of SSc-skin ulcers has to date not been promising, demonstrating poor reliability and accuracy. There are emerging data that ultrasound has significant potential to evaluate SSc-skin ulcers. OBJECTIVE: To perform a systematic literature review (SLR) to understand the degree to which ultrasound of SSc skin ulcers has been validated according to OMERACT criteria. METHODS: In a SLR, we investigated the Cochrane Library, Web of Science and Pubmed databases for manuscripts from inception to 1st April 2020. Inclusion and exclusion criteria included manuscripts on SSc patients aged over 16 years, performing SSc-related skin ulcer evaluation with ultrasound machines. Papers on animal model, diseases other than SSc, venous ulcers were excluded. Data extraction used a uniform case report form which collected data on patient demographics, disease activity, description of the ultrasound machine and procedures and the degree to which domains of validity were fulfilled. Manuscript evaluation and extraction was performed by two independent assessors, with a third author being consulted in case of disagreement. RESULTS: amongst 308 manuscripts that were identified, 6 published manuscripts/ posters fulfilled the inclusion/exclusion criteria and were extracted. Face validity was found. Three studies developed an US definition of SSc-ulcers across patients (content validity); one study evaluated the concordance between US image and clinical assessment. Criterion validity was shown by one study and ultrasound detected improvement (sensitivity to change) of SSc-skin ulcer in response to therapy. Feasibility was demonstrated by US use for skin ulcers in multiple settings (the 6 manuuscripts/posters). CONCLUSION: This systematic literature review shows that ultrasound for skin ulcers in SSc has been partially validated. It has face, content, criterion validity, responsiveness and reasonable feasibility. Further validation for construct validity, reliability and discrimination is required.

Erratum to the impact of slice-reduced computed tomography on histogram based densitometry assessment of lung fibrosis in patients with systemic sclerosis.

[This corrects the article DOI: 10.21037/jtd.2018.04.39.].

Preliminary Validation of the Digital Ulcer Clinical Assessment Score in Systemic Sclerosis.

OBJECTIVE: To date, "healed/non-healed" and clinical judgment are the only available assessment tools for digital ulcers (DU) in patients with systemic sclerosis (SSc). The aim of our study is to examine a preliminary composite DU clinical assessment score (DUCAS) for SSc for face, content, and construct validity. METHODS: Patients with SSc presenting at least 1 finger DU were enrolled and assessed with the Health Assessment Questionnaire-Disability Index, Cochin scale, visual analog scale (VAS) for DU-related pain, patient global DU status, and global assessment as patient-reported outcomes (PRO), and physician VAS for DU status (phyGDU) as an SSc-DU expert physician/nurse measure. The DUCAS included 7 DU-related variables selected by a committee of SSc DU experts and weighted on a clinical basis. Face validity was examined by consensus and partial construct validity was tested through convergent correlation with other measures of hand function, using Spearman's correlations. A range of patients with SSc was examined. A linear regression model with backward stepwise analysis was used to determine the relationship of individual variables with the primary clinical parameter, phyGDU. RESULTS: Forty-four patients with SSc (9 males, mean age 55 ± 15 yrs, mean disease duration 9.9 ± 5.8 yrs) were enrolled in the study. Overall DUCAS showed significant positive correlations with all abovementioned PRO (r > 0.4, p < 0.01). When all scores and scales were modeled, only DUCAS significantly predicted phyGDU (r = 0.59, R2 = 0.354, Akaike information criterion = 385.4). CONCLUSION: Preliminarily, we suggest that the DUCAS may be a new clinical score for SSc-related DU, having face and content validity and convergent/divergent correlations (construct validity). These early data suggest that this score deserves further evaluation.

The impact of slice-reduced computed tomography on histogram-based densitometry assessment of lung fibrosis in patients with systemic sclerosis.

Background: To evaluate usability of slice-reduced sequential computed tomography (CT) compared to standard high-resolution CT (HRCT) in patients with systemic sclerosis (SSc) for qualitative and quantitative assessment of interstitial lung disease (ILD) with respect to (I) detection of lung parenchymal abnormalities, (II) qualitative and semiquantitative visual assessment, (III) quantification of ILD by histograms and (IV) accuracy for the 20%-cut off discrimination. Methods: From standard chest HRCT of 60 SSc patients sequential 9-slice-computed tomography (reduced HRCT) was retrospectively reconstructed. ILD was assessed by visual scoring and quantitative histogram parameters. Results from standard and reduced HRCT were compared using non-parametric tests and analysed by univariate linear regression analyses. Results: With respect to the detection of parenchymal abnormalities, only the detection of intrapulmonary bronchiectasis was significantly lower in reduced HRCT compared to standard HRCT (P=0.039). No differences were found comparing visual scores for fibrosis severity and extension from standard and reduced HRCT (P=0.051-0.073). All scores correlated significantly (P<0.001) to histogram parameters derived from both, standard and reduced HRCT. Significant higher values of kurtosis and skewness for reduced HRCT were found (both P<0.001). In contrast to standard HRCT histogram parameters from reduced HRCT showed significant discrimination at cut-off 20% fibrosis (sensitivity 88% kurtosis and skewness; specificity 81% kurtosis and 86% skewness; cut-off kurtosis ≤26, cut-off skewness ≤4; both P<0.001). Conclusions: Reduced HRCT is a robust method to assess lung fibrosis in SSc with minimal radiation dose with no difference in scoring assessment of lung fibrosis severity and extension in comparison to standard HRCT. In contrast to standard HRCT histogram parameters derived from the approach of reduced HRCT could discriminate at a threshold of 20% lung fibrosis with high sensitivity and specificity. Hence it might be used to detect early disease progression of lung fibrosis in context of monitoring and treatment of SSc patients.

Ultrasound characterization of cutaneous ulcers in systemic sclerosis.

Skin ulcers in scleroderma (SSc) patients are considered a major challenge, both in clinical assessment and treatment decisions. The objective of our study is to assess ultrasonographic (US) morphology of skin ulcers in SSc patients and evaluate if US will be of value in enhancing our clinical information and influence our management plans. We examined a convenience sample of 21 skin ulcers reported in 10 SSc patients by US. We used a previously published US definition of normal skin and developed a preliminary US definition of skin ulcer. Skin ulcers were evaluated by gray scale (GS) and power Doppler (PD) and separated into ulcer and non-ulcer lesions; pain and ulcer measures were obtained using visual analogue scales (VAS). Lesions were characterized and ulcers were clinically and sonographically measured. Ten patients presenting with 21 skin lesions were examined by US. Applying our US definition of skin ulcer, all ulcers were available to measure by ultrasound. Eight lesions were sonographically defined as ulcers, and 13 lesions as non-ulcer lesions. Three ulcers had high PD signals suggestive of infection requiring antibiotic treatment and were monitored for 2 weeks showing a decrease of the pain, VAS, and PD signals. Five lesions showed subclinical calcinosis. This is the first study to show the promising role of US in defining skin ulcers of SSc patients. US may support the assessment of morphology and extent of skin ulcers in SSc and can be a helpful tool for detecting underlying pathology.

Scleroderma renal crisis and renal involvement in systemic sclerosis.

This corrects the article DOI: 10.1038/nrneph.2016.124.

Scleroderma renal crisis and renal involvement in systemic sclerosis.

Scleroderma renal crisis (SRC) is a rare, potentially life-threatening complication that affects 2-15% of patients with systemic sclerosis (SSc, also known as scleroderma). SRC typically presents in patients with early, rapidly progressive, diffuse cutaneous SSc within the first 3-5 years after the onset of a non-Raynaud sign or symptom. SRC is characterized by an acute, usually symptomatic increase in blood pressure, a rise in serum creatinine levels, oliguria and thrombotic microangiopathy in about 50% of patients. The prognosis of SRC substantially improved in the 1980s with the introduction of angiotensin-converting-enzyme inhibitors for rapid blood pressure control, with additional antihypertensive agents as required. However, the survival of patients with SRC can still be improved. Current patient survival is 70-82% at 1 year, but decreases to 50-60% at 5 years despite dialysis support. Patients with SRC who show no signs of renal functional recovery despite timely blood pressure control are candidates for transplantation. In this Review, we discuss progress made in the identification and proactive management of patients at risk of SRC and make recommendations aimed at optimizing management for those who progress to chronic kidney failure.

Brief Report: Pulmonary Function Tests: High Rate of False-Negative Results in the Early Detection and Screening of Scleroderma-Related Interstitial Lung Disease.

OBJECTIVE: Validated methods for the screening and early diagnosis of systemic sclerosis (SSc; scleroderma)-related interstitial lung disease (ILD) are needed. The aim of this study was to evaluate the performance of pulmonary function tests (PFTs) compared with that of high-resolution computed tomography (HRCT) of the chest for the detection of SSc-related ILD in clinical practice, and to identify predictors of lung involvement that is functionally occult but significant on HRCT. METHODS: Prospectively enrolled patients with SSc were assessed according to the European League Against Rheumatism (EULAR)/EULAR Scleroderma Trial and Research standards. The assessment included PFTs and HRCT. The HRCT images were evaluated in a blinded manner by 2 experienced radiologists. The performance parameters of PFTs for the diagnosis of SSc-related ILD were calculated. Predictors of significant ILD as determined by HRCT in patients with normal forced vital capacity (FVC) values were identified through logistic regression. RESULTS: Among the 102 patients, 64 (63.0%) showed significant ILD on HRCT, while only 27 (26.0%) had an FVC <80% of predicted, and 54 (53.0%) had a decrease in the results of at least 1 PFT. Forty (62.5%) of 64 patients with significant ILD on HRCT had a normal FVC value, translating into a high false-negative rate. Notably, 5 of 40 patients with a normal FVC value had severe, functionally occult lung fibrosis; in 2 of these patients, the results of all of the PFTs were within normal limits. Patients with normal FVC values despite evidence of fibrosis on HRCT more frequently had anti-Scl-70 antibodies and diffuse SSc and less frequently had anticentromere antibodies (ACAs) compared with patients with both normal FVC values and normal HRCT results. CONCLUSION: The derived evidence-based data reveal a high risk of missing significant SSc-related ILD when relying solely on PFTs. More comprehensive screening algorithms for early detection are warranted. In particular, additional imaging investigations for the early detection of SSc-related ILD should be considered in ACA-negative patients with normal FVC values.

Vascular endothelial growth factor aggravates fibrosis and vasculopathy in experimental models of systemic sclerosis.

OBJECTIVES: High levels of vascular endothelial growth factor (VEGF), a key angiogenic factor, are present in patients with systemic sclerosis (SSc), but its role in the pathogenesis of fibrosis and its contribution to the disturbed angiogenesis of SSc remains hypothetical. METHODS: Mono (+/-) and double (+/+) VEGF transgenic (tg) mice and their wildtype (wt) controls were analysed. The bleomycin model was applied to VEGF tg mice to evaluate effects of VEGF under proinflammatory conditions. Additionally, tight skin (TSK) 1/VEGF+/+ mice were generated to mimic later non-inflammatory stages of SSc. RESULTS: VEGF+/+, but not VEGF+/- tg mice, spontaneously developed significant skin fibrosis, indicating profibrotic effect of VEGF in a gene-dosing manner. In the proinflammatory bleomycin model, the profibrotic effect became more pronounced with induction of skin fibrosis in VEGF+/- tg mice and even more enhanced fibrosis in VEGF+/+ tg mice. Analysis in TSK1/VEGF+/+ mice showed similar profibrotic effects of VEGF also under non-inflammatory in vivo conditions. In vitro analysis revealed that VEGF is able to directly induce collagen synthesis in dermal fibroblasts. Additionally, there was an inverse gene-dosing effect on the efficacy of angiogenesis in that a higher number of microvessels was observed in VEGF+/- tg mice than in VEGF+/+ tg mice. CONCLUSIONS: These data provide the first evidence for VEGF as a novel molecular link between fibrosis and vasculopathy in the pathogenesis of SSc. They suggest that high levels of VEGF potently induce fibrosis in inflammatory and non-inflammatory stages, and also contribute to the relatively insufficient angiogenesis characteristic for SSc.

Novel Aspects in the Pathophysiology of Peripheral Vasculopathy in Systemic Sclerosis.

Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by fibrosis, autoimmunity and vascular damage. Although fibrosis is often considered the main feature of the disease, there is evidence that the underlying vasculopathy plays an important role in the initiation and perpetuation of SSc. Vascular manifestations such as Raynaud's phenomenon and digital ulcers are prominent in early disease stages and might substantially contribute to the SSc related mortality in later disease stages when pulmonary arterial hypertension becomes clinically evident. Vascular damage is thought to start with endothelial cell injury and apoptosis resulting in tissue hypoxia. Hypoxia is considered a main stimulus for vascular regenerative processes. However, despite the significant deterioration in number and quality of microvessels, there is a lack of appropriate compensatory repair processes by angiogenesis and vasculogenesis. In this review, we will discuss recent data about the pathophysiology of peripheral (acral) microvascular damage in SSc, highlight novel aspects behind the defective repair mechanisms in the vascular system in SSc and focus on SSc animal models with peripheral vascular changes.