Best clinical practice in the treatment of juvenile systemic sclerosis: expert panel guidance - the result of the International Hamburg Consensus Meeting December 2022.

INTRODUCTION: Juvenile systemic sclerosis (jSSc) is an orphan disease with a prevalence of 3 in 1,000,000 children. Currently there is only one consensus treatment guideline concerning skin, pulmonary and vascular involvement for jSSc, the jSSc SHARE (Single Hub and Access point for pediatric Rheumatology in Europe) initiative, which was based on data procured up to 2014. Therefore, an update of these guidelines, with a more recent literature and expert experience, and extension of the guidance to more aspects of the disease is needed. AREAS COVERED: Treatment options were reviewed, and opinions were provided for most facets of jSSc including general management, some of which differs from adult systemic sclerosis, such as the use of corticosteroids, and specific organ involvement, such as skin, musculoskeletal, pulmonary, and gastroenterology. EXPERT OPINION: We are suggesting the treat to target strategy to treat early to prevent cumulative disease damage in jSSc. Conclusions are derived from both expert opinion and available literature, which is mostly based on adult systemic sclerosis (aSSc), given shared pathophysiology, extrapolation of results from aSSc studies was judged reasonable.

A purple plaque in a patient with systemic sclerosis.

We present the case of a 43-year old woman with anti-U3 ribonucleoprotein antibody-positive systemic sclerosis presenting with an enlarging purple plaque on the left upper arm. The skin was not sclerotic; however, there had been a cluster of long-standing telangiectases preceding the plaque. Histology and immunohistochemistry confirmed an angiosarcoma. There are five reported cases in the literature about angiosarcoma arising in the skin of patients with systemic sclerosis; however, to our knowledge, this is the first to have arisen from non-sclerotic skin. We would urge clinicians to adopt a high index of suspicion for atypical vascular tumours presenting in patients with systemic sclerosis.

Skin biopsy analysis of concurrent keloidal morphoea and systemic sclerosis confirms overlapping pathogenic pathways.

OBJECTIVES: Although localised forms of scleroderma (morphoea) have very different clinical features and outcomes from systemic sclerosis the two conditions can occur together in some patients. In this study we have explored skin gene expression in a series of patients with keloidal morphoea, a distinct clinical variant, concurrently with systemic sclerosis. METHODS: We compared skin gene expression from the keloidal lesions with that from skin elsewhere. We also examined a series of patients with diffuse or limited cutaneous SSc without morphoea and some healthy control skin biopsies. RESULTS: Keloidal morphoea has a distinct gene expression signature that is mainly driven by differential expression of fibroblast-related genes compared with other cell types. Indeed, the signature reflects a profibrotic pattern seen in diffuse cutaneous SSc but is much more extreme. We propose that keloidal morphoea skin provides unique insight into the profibrotic population of cells driving dcSSc. CONCLUSIONS: Understanding the biology of keloidal morphoea may give valuable insight into the molecular and cellular pathology of systemic sclerosis. The discrete nature of keloidal lesions raises the possibility of haematogenous spread and we suggest that the driving cells could represent blood derived cells derived from circulating progenitors.

Scleroderma mimics - Clinical features and management.

Systemic sclerosis is a severe immune-mediated rheumatic disease by virtue of its clinical impact and mortality. There are a number of other sclerosing skin diseases that should be considered in the differential diagnosis and these are important because they may require specialist investigation and management. In addition, long-term follow up of the different conditions should reflect the risk of associated complications and anticipated duration of therapy. This article reviews the clinical features of potential mimics of scleroderma (systemic sclerosis) including localised forms of scleroderma (morphoea) and other conditions that lead to skin thickening and connective tissue fibrosis or scarring.

Fabry International Prognostic Index: a predictive severity score for Anderson-Fabry disease.

BACKGROUND: Anderson-Fabry disease (AFD) is a disorder of glycosphingolipid metabolism resulting from deficiency of α-galactosidase A and accumulation of globotriaosylceramide. Presentation is heterogeneous and, despite guidelines for initiation of therapy, there is no basis for defining subgroups that will progress more rapidly, whether treated or not. The authors of this study used clinical and pathological data recorded on 1483 patients in the Fabry Outcome Survey, a large international registry, to develop a prognostic severity score. METHODS: Parameters relevant to disease progression or outcome were initially selected, using variables that are readily available in clinical practice. Individual end points for renal, cardiac, neurological disease, and death were selected, and a composite end point developed. Potential prognostic variables were correlated with each end point, before multivariate analysis. Variables retaining significance were then used to construct organ specific and composite prognostic scores. Kaplan-Meier (KM) analysis, according to score, was performed for each end point. RESULTS: Analysis demonstrated that it is possible to differentiate groups of patients with different outcome probabilities. Cardiac, renal and neurological end points could each be categorised into three separate groups. The 80% event-free survival for these groups differed by approximately 10 years. The overall composite score, the Fabry International Prognostic Index (FIPI), distinguished two distinct groups where the 50% event-free survival differed by 10 years. CONCLUSIONS: A prognostic scoring system for AFD has been developed and retrospective validation performed. The FIPI should prove to be a valuable tool in the counselling and management of AFD patients, and in comparative analyses of outcome using different therapies.

A deficiency in the in vivo clearance of apoptotic cells is a feature of the NOD mouse.

Deficiencies in apoptotic cell clearance have been linked to autoimmunity. Here we examined the time-course of peritoneal macrophage phagocytosis of dying cells following the direct injection of apoptotic thymocytes into the peritoneum of NOD mice and BALB/c controls. Macrophages from NOD mice demonstrated a profound defect in the phagocytosis of apoptotic thymocytes as compared to control macrophages. Nonobese diabetic mice also demonstrated a decrease in the clearance of apoptotic cell loads following an apoptotic stimulus to thymocytes (dexamethasone) when compared to BALB/c or NOR controls. Further, NOD mice demonstrated an increase in apoptotic cell load following an apoptotic stimulus to keratinocytes (ultraviolet light, UVB) when compared to control strains. Animals deficient in macrophage phagocytosis of apoptotic debris often manifest an autoimmune phenotype characterized by the production of antinuclear autoantibodies (ANA). We determined whether increased apoptotic cell loads (through repeated exposure to UVB irradiation) could accelerate such autoimmune phenomena in young NOD mice. Following repeated UVB irradiation, NOD mice, but not BALB/c or NOR controls, developed ANA. We propose that abnormalities in apoptotic cell clearance by macrophages predispose NOD mice to autoimmunity.

Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo.

The extent of human memory T cell proliferation, differentiation, and telomere erosion that occurs after a single episode of immune challenge in vivo is unclear. To investigate this, we injected tuberculin purified protein derivative (PPD) into the skin of immune individuals and isolated responsive T cells from the site of antigenic challenge at different times. PPD-specific CD4+ T cells proliferated and differentiated extensively in the skin during this secondary response. Furthermore, significant telomere erosion occurred in specific T cells that respond in the skin, but not in those that are found in the blood from the same individuals. Tissue fluid obtained from the site of PPD challenge in the skin inhibited the induction of the enzyme telomerase in T cells in vitro. Antibody inhibition studies indicated that type I interferon (IFN), which was identified at high levels in the tissue fluid and by immunohistology, was responsible in part for the telomerase inhibition. Furthermore, the addition of IFN-alpha to PPD-stimulated CD4+ T cells directly inhibited telomerase activity in vitro. Therefore, these results suggest that the rate of telomere erosion in proliferating, antigen-specific CD4+ T cells may be accelerated by type I IFN during a secondary response in vivo.

Optimization of epicutaneous immunization for the induction of CTL.

The immune system of the skin has recently been exploited for the development of non-invasive vaccine technologies. However, one of the limitations of current vaccine protocols is the inefficient priming of cytotoxic T lymphocytes (CTL). In this study, we report that the application of either an immunodominant class I MHC restricted ovalbumin peptide or whole ovalbumin protein, to tape-stripped skin together with the co-application of the bacterial enterotoxin cholera toxin (CT) induces antigen-specific CTL. Tape-stripping (TS) was found to enhance the magnitude of antibody responses to co-administered protein and to promote the generation of antigen-specific IgG(2a) responses. As well, both cholera toxin and tape-stripping enhanced epidermal dendritic cell (DC) immigration into draining lymph nodes. The adjuvant effect of co-administered cholera toxin and tape-stripping in promoting CTL priming was not dependent on IL-12. Epicutaneous immunization has previously been shown to induce robust antibody responses to administered protein antigen. We now demonstrate the induction of robust and persistent CTL responses to epicutaneously administered protein antigen. Epicutaneous immunization is cheap, simple and effective. These findings suggest the potential use of the skin for the generation of protective immune responses to both viral and tumor challenge.