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Systemic sclerosis is the rheumatic disease with the highest individual mortality. The severity of the disease is determined by the extent of fibrotic changes to cutaneous and internal organ tissues, the most life-threatening visceral manifestations being interstitial lung disease, SSc-associated-pulmonary arterial hypertension and myocardial involvement. The heterogeneity of the disease has initially hindered the design of successful clinical trials, but considerations on classification criteria have improved patient selection in trials, allowing the identification of more homogeneous groups of patients based on progressive visceral manifestations or the extent of skin involvement with a focus of patients with early disease. Two major subsets of systemic sclerosis are classically described: limited cutaneous systemic sclerosis characterized by distal skin fibrosis and the diffuse subset with distal and proximal skin thickening. Beyond this dichotomic subgrouping of systemic sclerosis, new phenotypic considerations based on antibody subtypes have provided a better understanding of the heterogeneity of the disease, anti-Scl70 antibodies being associated with progressive interstitial lung disease regardless of cutaneous involvement. Two targeted therapies, tocilizumab (a monoclonal antibody targeting interleukin-6 receptors (IL-6R)) and nintedanib (a tyrosine kinase inhibitor), have recently been approved by the American Food & Drug Administration to limit the decline of lung function in patients with SSc-associated interstitial lung disease, demonstrating that such better understanding of the disease pathogenesis with the identification of key targets can lead to therapeutic advances in the management of some visceral manifestations of the disease. This review will provide a brief overview of the pathogenesis of SSc and will present a selection of therapies recently approved or evaluated in this context. Therapies evaluated and approved in SSc-ILD will be emphasized and a review of recent phase II trials in diffuse cutaneous systemic sclerosis will be proposed. We will also discuss selected therapeutic pathways currently under investigation in systemic sclerosis that still lack clinical data in this context but that may show promising results in the future based on preclinical data.

Background Giant cell arteritis (GCA) is a large vessel vasculitis characterized by granulomatous inflammation classically affecting the carotid artery branches. GCA most often presents with one or more classic clinical features which include headache, jaw claudication, temporal scalp tenderness, and polymyalgia rheumatica. In a minority of cases, GCA can adopt an “occult” presentation (i.e., failure to thrive in the setting of unexplained inflammation) where vascular manifestations affect vascular beds, such as lingual ulceration, not amenable to biopsy. While the diagnosis of GCA is often supported by temporal artery biopsy or imaging studies, such as temporal artery ultrasound or magnetic resonance angiography, these techniques are known to have limited sensitivity. As a result, there is the potential for GCA to be misdiagnosed where it presents both in the absence of classic clinical manifestations and without clear diagnostic evidence by imaging or histopathology. Case presentation A 78-year-old male presented to rheumatology on the inpatient consult service with unexplained headaches, failure to thrive, and persisting elevated acute phase reactants. He was admitted for unexplained fevers three times in as many months, with an unrevealing infectious and malignancy workup. His past medical history was remarkable for a shallow right lateral tongue ulcer that was non-healing despite weeks of acyclovir treatment. Two bitemporal artery ultrasounds did not suggest features of GCA and subsequent temporal artery biopsies failed to show healing or active arteritis. The patient was started on empiric corticosteroids tapered to discontinue over six months in conjunction with tocilizumab. He had rapid normalization of inflammatory markers (prior to tocilizumab initiation), anemia of chronic inflammation, and correction of his serum Na + without need for ongoing fluid restriction. Clinically, his headaches and unexplained weight loss improved and his serial exams showed complete resolution of his tongue ulcer, suspected to be end-organ damage from GCA. Conclusions Although the hospitalist service suspected GCA in this elderly patient with headaches, failure to thrive, recurrent fever of unknown origin, and elevated inflammatory markers, they were deterred from this diagnosis by repeat negative bitemporal artery ultrasounds and negative biopsies. This case demonstrates the need to survey for atypical vascular beds of GCA involvement, even in the presence of negative imaging and biopsy results.

Background Early diffuse cutaneous systemic sclerosis (dcSSc) has the highest case fatality among rheumatic diseases. We report baseline characteristics, current immunosuppressive therapies, progression of skin and internal organ involvement, and mortality in a multicenter prospective cohort from the United States (US) of America. Methods We performed a longitudinal analysis of participants from 12 US centers, from April 2012 to July 2020. All participants had early dcSSc or were at-risk for dcSSc, with ≤2 years since the first non-Raynaud’s phenomenon (RP) symptom. Results Three hundred one patients were included with a baseline median disease duration of 1.2 years since RP and a mean modified skin score of 21.1 units. At baseline, 263 (87.3%) had definite dcSSc and 38 (12.7%) were classified as at-risk; 112 (49.6%) patients were positive for anti-RNA polymerase III antibodies. The median follow-up duration was 24.5 months (IQR = 10.3–40.7 months). One hundred ninety (63.1%) participants were treated with an immunosuppressive therapy, of which mycophenolate mofetil was most used at baseline and follow-up. Of 38 who were classified as at-risk at baseline, 27 (71%) went on to develop dcSSc; these patients were characterized by higher baseline mean HAQ-DI (0.8 versus 0.4, p = 0.05) and higher baseline mRSS (8.8 versus 4.4, p < 0.01) in comparison with those who remained as limited cutaneous SSc. In the overall cohort, 48 participants (21.1%) had clinically significant worsening of skin fibrosis, mainly occurring in the first year of follow-up; 41 (23.3%) had an absolute forced vital capacity decline of ≥10%. Twenty participants (6.6%) died, of which 18 died in the first 3 years of follow-up. Cardiac involvement (33.3%), gastrointestinal dysmotility (22.2%), and progressive interstitial lung disease (ILD) (16.7%) were the main causes of death. Conclusion This US cohort highlights the management of early SSc in the current era, demonstrating progression of skin and lung involvement despite immunosuppressive therapy and high mortality due to cardiac involvement.

IntroductionLimited cutaneous systemic sclerosis (lcSSc) is the most frequent subset of systemic sclerosis. Despite this, lcSSc is not the major focus of clinical studies. The lack of interventional studies in lcSSc is due, in part, to a paucity of relevant outcome measures to effectively evaluate this subset. A combined response index dedicated to lcSSc would facilitate development of well-designed trials and approval of new drugs. The objective of this scoping review is to perform a broad and comprehensive identification of the outcome measures (core set items) within relevant domains, which have been used so far to assess lcSSc.Methods and analysisThe planned scoping review will be based on the approach proposed by Arksey et al and further developed by Levac et al. Development and reporting will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses—Extension for Scoping Reviews checklist and guidelines. The development of the search strategy was guided by the concepts of domains and outcomes based on the Outcome Measures in Rheumatology approach and by the different names and definitions of SSc, with a specific emphasis on their occurrence in clinical trial studies. Two databases will be searched: MEDLINE and Embase. Studies in English, published from the year 1988 onwards, will be included, since 1988 corresponds to the publication of LeRoy’s first consensus definition of lcSSc. Data will be extracted and analysed using a standardised charting tool.Ethics and disseminationNo ethical approval is required for this study. The results will be submitted to an international peer-reviewed journal and scientific conferences, informing the discussion on which items should be included in a combined response index dedicated to lcSSc (the CRISTAL project: Combined Response Index for Scleroderma Trial Assessing lcSSc).

Previous MRI studies of healthy children have reported age-related white matter (WM) changes in language and motor areas of the brain. The authors investigated WM development in healthy adolescent males through age-associated changes in fractional anisotropy (FA), radial (λ⊥) and axial (λ||) diffusivity. Twenty-four healthy adolescent males (mean age=16.6, SD=2.5 years) were divided into two groups with an age split of 16.9 years and underwent a whole-brain voxelwise analysis. At a threshold of p<0.001 and extent threshold of 100 contiguous voxels, several clusters with increased FA and axial diffusivity and no differences in radial diffusivity were observed in older adolescents compared to the younger adolescents in the left arcuate fasciculus, bilateral posterior internal capsule/thalamic radiation, bilateral prefrontal gyrus, right superior temporal gyrus, and posterior corpus callosum. Increased FA and λ|| of several clusters along the arcuate fasciculus significantly correlated with a test of language and semantic memory. These results suggest ongoing maturational changes especially in the arcuate fasiculus during late adolescence. Increased FA and λ|| with no changes in radial diffusivity may reflect a developmental pattern of reduced tortuousity toward more straightened fibers and/or increased axonal fiber organization during late adolescence.

The past three decades have witnessed an explosion in human genetics research, particularly research designed to identify genetic variants causing or increasing risk for disease. These efforts began spectacularly with early successes identifying relatively infrequent diseases following classical Mendelian patterns of inheritance. Now more common diseases with complex modes of inheritance are being addressed. Schizophrenia, with an estimated heritability factor of approximately 70 percent, belongs to this category. As with other genetically complex disorders, gene-mapping efforts have achieved mixed success for schizophrenia. Research has proceeded from classical family-based linkage analyses, indicating specific regions of the genome possibly harboring susceptibility genes, to genetic association designs. The latest series of investigations involves dense sets of common polymorphisms across the entire genome comparing cases and controls. These genome-wide association studies (GWAS) have revealed several plausible risk variants, most notably in the Human Leukocyte Antigen region. Still, the identified risk variants do not fully account for estimated heritability. Thus, much of the inherited risk for schizophrenia remains undetected. The reasons for our inability to solve the so-called missing heritability problem are discussed and designs for future studies are suggested.

Previous research has focused on the beneficial effects of soy and its active ingredients, isoflavones. For instance, soy consumption has been associated with lower cardiovascular and breast cancer risks. However, the number of reports demonstrating adverse effects of isoflavones due to their estrogenlike properties has increased. We present the case of a 19-y-old type 1 diabetic but otherwise healthy man with sudden onset of loss of libido and erectile dysfunction after the ingestion of large quantities of soy-based products in a vegan-style diet. Blood levels of free and total testosterone and dehydroepiandrosterone (DHEA) were taken at the initial presentation for examination and continuously monitored up to 2 y after discontinuation of the vegan diet. Blood concentrations of free and total testosterone were initially decreased, whereas DHEA was increased. These parameters normalized within 1 y after cessation of the vegan diet. Normalization of testosterone and DHEA levels was paralleled by a constant improvement of symptoms; full sexual function was regained 1 y after cessation of the vegan diet. This case indicates that soy product consumption is related to hypogonadism and erectile dysfunction. To the best of our knowledge, this is the first report of a combination of decreased free testosterone and increased DHEA blood concentrations after consuming a soy-rich diet. Hence, this case emphasizes the impact of isoflavones in the regulation of sex hormones and associated physical alterations.