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Objective: Systemic sclerosis (SSc) is a rare, chronic disease characterized by fibrosis, vascular alterations and digital ulcerations. Few drugs have shown efficacy to enhance wound healing of existing SSc-related ulcers. Local delivery of treprostinil, a prostacyclin analogue, may improve wound healing. The present work aimed first at developing a mouse model of SSc-related ulcerations and second at assessing the effect of iontophoresis of treprostinil on wound healing., Methods: We used two murine models of SSc: chemically induced with HOCl, and urokinase-type plasminogen activator receptor (uPAR)-deficient. Excisional wounding was performed on the dorsal midline with a biopsy punch. Animals were randomized into three groups: treated with electrostimulation alone, with treprostinil iontophoresis or untreated. We assessed wound healing over time, as well as skin microvascular reactivity, inflammation, microvessel density and collagen distribution, before wounding and after re-epithelialization., Results: uPAR-/- mice, but not HOCl-treated mice, showed impaired wound healing and decreased microvascular reactivity compared with their controls. Treprostinil iontophoresis improved wound healing and microvascular density and decreased inflammation in uPAR-/- mice, while electro-stimulation did not. However, treprostinil had no effect on microvascular reactivity and collagen distribution., Conclusion: This study suggests that excisional wounds in uPAR-/- mice are a relevant model of SSc-related ulcers. In addition, treprostinil iontophoresis enhances wound healing in this model. Further work in now needed to show whether this effect translates in humans., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To evaluate the safety and efficacy of abatacept treatment for refractory juvenile localized scleroderma (jLS) in a retrospective study., Methods: A multicentre cohort study was performed to evaluate jLS subjects treated with abatacept with follow-up for 12 months to maximum of 24 months. Assessments at 6-month intervals included skin activity measures and physician global assessment of activity (PGA-A). Descriptive statistical analysis was performed., Results: Eighteen subjects were studied with median age of 13.4 years, the majority had linear scleroderma subtype, and musculoskeletal involvement. All had previously failed MTX and/or mycophenolate mofetil treatment and glucocorticoids. Abatacept was added to the subject's maintenance DMARD treatment; 13 also received glucocorticoids at start of abatacept. No serious adverse events occurred. Skin activity and PGA-A scores declined in nearly all by 6 months and continued to improve from 6 to 12 months. At 12 months, 15 (83%) subjects were considered responders, two (11%) treatment failures, and one dropped out for adverse event. Response was sustained for 11 (61%) subjects to 18 months and eight (44%) to 24 months. Overall, four (22%) subjects were treatment failures and three (16.7%) discontinued abatacept for adverse event. Active musculoskeletal problems improved in most affected subjects. Ten subjects were able to discontinue initial glucocorticoid and six concomitant DMARD treatment., Conclusion: Abatacept was found to be safe and effective for jLS subjects refractory to standard of care treatment. Subjects experienced improvement in both skin and musculoskeletal activity. Prospective studies should be performed to more fully evaluate abatacept's efficacy., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Juvenile systemic sclerosis (JSSc) is a rare disease of childhood and currently no international consensus exists with regard to its assessment and treatment. This SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) initiative, based on expert opinion informed by the best available evidence, provides recommendations for the assessment and treatment of patients with JSSc with a view to improving their outcome. Experts focused attention not only on the skin assessment but also on the early signs of internal organ involvement whose proper treatment can significantly affect the long-term outcome. A score for disease severity is proposed in order to perform a structured assessment of outcome over time but a validation in a wider patient population is recommended. Finally, a stepwise treatment approach is proposed in order to unify the standard of care throughout Europe with the aim to reduce morbidity and mortality in this disease., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To investigate safety and efficacy of MMF in patients with severe or MTX-refractory juvenile localized scleroderma., Methods: Consecutive juvenile localized scleroderma patients undergoing systemic treatment were included in a retrospective longitudinal study. Patients treated with MMF because they were refractory or intolerant to MTX (MMF-group) were compared with responders to MTX (MTX-group). Disease activity was assessed by Localized Scleroderma Cutaneous Assessment Tool and thermography. Disease course was established on the number of relapses and treatment changes. Relapse-free survival was examined by Kaplan-Meier analysis., Results: MMF and MTX groups included 22 and 47 patients, respectively. No significant difference in demographics, follow-up duration and treatment before diagnosis was observed between groups. The most represented clinical subtypes in the MMF-group were pansclerotic morphea and mixed subtype (P = 0.008 and P = 0.029, respectively), and linear scleroderma of the face in the MTX-group (P = 0.048). MMF was started because of MTX resistance (18 patients), relapse during MTX tapering/withdrawal (3 patients) and anaphylaxis to MTX (1 patient). After mean 9.4 years of follow-up, 90.9% of patients on MMF and 100% of those on MTX had inactive disease. No significant difference in relapse-free survival between the groups was found (P = 0.066, log-rank test), although MMF likely induced more persistent remission. MMF was well tolerated and combination of MMF and MTX did not increase its efficacy., Conclusion: The present study adds strong evidence on the efficacy and tolerance of MMF in severe and/or MTX-refractory juvenile localized scleroderma. Further controlled studies are needed to prove its efficacy as first line treatment., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To estimate the effect of disease activity, as measured by the European Scleroderma Research Group Activity Index (EScSG-AI), on the risk of subsequent organ damage in a large systemic sclerosis (SSc) cohort., Methods: Of 421 SSc patients from the Canadian Scleroderma Research Group database with disease duration of ⩽ 3 years, 197 who had no evidence of end-stage organ damage initially and available 3 year follow-up were included. Disease activity was assessed by the EScSG-AI with two variability measures: the adjusted mean EScSG-AI (the area under the curve of the EScSG-AI over the observation period) and persistently active disease/flare. Outcomes were based on the Medsger severity scale and included accrual of a new severity score (Δ ⩾ 1) overall and within organ systems or reaching a significant level of deterioration in health status., Results: After adjustment for covariates, the adjusted mean EScSG-AI was the most consistent predictor of risk across the study outcomes over 3 years in dcSSc: disease progression defined as Δ ⩾ 1 in any major internal organ, significant decline in forced vital capacity and diffusing capacity of carbon monoxide, severity of visceral disease and HAQ Disability Index worsening. In multivariate analysis, progression of lung disease was predicted solely by adjusted mean EScSG-AI, while the severity of lung disease was predicted the adjusted mean EScSG-AI, older age, modified Rodnan skin score (mRSS) and initial severity. The EScSG-AI was associated with patient- and physician-assessed measures of health status and overpowered the mRSS in predicting disease outcomes., Conclusion: Disease activity burden quantified with the adjusted mean EScSG-AI predicted the risk of deterioration in health status and severe organ involvement in dcSSc. The EScSG-AI is more responsive when done repeatedly and averaged., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Objectives: Juvenile localized scleroderma (JLS) is a rare condition that is often difficult to assess and for which a variety of monitoring tools have been described. We aimed to describe how monitoring tools are used and perceived by clinicians in the UK, to ascertain treatments used for JLS and to provide a description of transition arrangements to adult care., Methods: An e-survey of UK paediatric rheumatologists and dermatologists managing children and young people (CYP) with JLS was distributed using the national organisations representing these clinician groups. We asked respondents for their views and experience using 15 JLS monitoring tools, about transition services and about treatments used., Results: Thirty-five dermatologists and 13 paediatric rheumatologists responded. Paediatric rheumatologists managed more CYP with JLS than dermatologists (median 16-20 and 3, respectively). Transition arrangements were reported by 43% of dermatologists and 91% of paediatric rheumatologists. Medical photography was the most frequently regularly used monitoring tool (73% respondents). The modified Rodnan skin score was the skin score used most commonly: 33% of paediatric rheumatologists and 3% of dermatologists reported using this tool frequently. Topical treatments and ultraviolet light were used by 49-80% of dermatologists and 0-8% paediatric rheumatologists. Biologic drugs and CYC were used by 0-3% of dermatologists and 31-46% of paediatric rheumatologists., Conclusion: How monitoring tools are accessed, used and perceived by paediatric rheumatologists and dermatologists in the UK varies between and within clinician groups, as do treatment prescribing patterns and transition arrangements. These differences will impact on the feasibility of conducting multicentre clinical trials and on standardising clinical care., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To analyse therapeutic management of eosinophilic fasciitis (EF)., Methods: We reviewed 34 adult patients with biopsy-proven EF. Analyses focused on the therapeutic management, including treatment modalities, responses and associated or predictive factors., Results: Thirty-four patients were included with a diagnosis age of 53 (15) years. They were featured by cutaneous manifestations (88%) including morphoea (41%), myalgia (86%) and hypereosinophilia (85%). Thirty-two patients (94%) were eligible for treatment evaluation and all received CSs as a first-line therapy. Fifteen patients (47%) received methylprednisolone pulses (MPPs) at treatment initiation and 14 patients (44%) received an immunosuppressive drug (ISD), usually MTX (86%), as a second-line therapy. Complete remission was achieved for 69% of patients, remission with disability 19% and failure 12%. A poor outcome was associated with a diagnosis time delay of >6 months [odds ratio (OR) = 14.7] and the lack of MPPs (OR = 12.9)., Conclusion: Our study reports new insights into the therapeutic management of EF: (i) CS treatment remains the standard therapy for EF, taken alone or in association with an ISD; (ii) MPPs at initiation of treatment are associated with a better outcome and a lower need of ISD use; (iii) an ISD, usually MTX, might be useful as a second-line therapy, mainly in patients with morphoea-like lesions. Naturally, these practical conclusions should be confirmed by a prospective and multicentre study.

Objectives: Our aim was to describe clinical features and pattern of care in children with localized scleroderma presenting to secondary care during a 25-month incidence study., Methods: Eighty-seven patients were identified, and clinical features, serum autoantibodies, current treatment and outcome at 12 months were documented., Results: Fifty-eight (67%) had linear scleroderma, 25 (29%) non-linear morphoea and 4 (4%) a mixed pattern. Of the 58 patients with linear scleroderma, 29 (50%) presented with lesions of the trunk and/or limbs only, 26 (45%) with face-head localization only and 3 (5%) with both. Thirteen (15%) had extracutaneous features and 16 (43%) out of 37 were ANA positive. At 12 months, 59% were on MTX. At 12 months, 51 (65%) were improved/resolved, 14 (18%) were unchanged and 13 (17%) had deteriorated., Conclusion: Key findings included the high prevalence of face-head involvement in those with linear disease, and the high prevalence of extracutaneous disease and of ANA positivity. After 12 months, most patients improved according to clinician's opinion.

Objective: To evaluate the efficacy of mycophenolate mofetil (MMF) in the treatment of severe refractory juvenile localized scleroderma (JLS)., Methods: A retrospective chart review was performed in patients with JLS who had been treated with MMF after the failure of a combination of MTX and corticosteroids for at least 4 months, or whose JLS had concomitant severe extracutaneous manifestations. Outcome was assessed through clinical examination and thermography. Adverse events were recorded., Results: Ten patients (six females and four males) were enrolled in the study. JLS clinical subtypes were deep morphoea (two patients with disabling pansclerotic morphoea), generalized morphoea (three patients), linear scleroderma (five patients) affecting the limbs in two and face in three patients (en coup de sabre). The age at onset of disease was 8 (range 2-16) years, and the disease duration at the time of treatment with MMF was 18 (range 8-62) months. All MMF-treated patients experienced clinical improvement that allowed withdrawal or reduction of doses of corticosteroids and MTX. Over a follow-up of 27 (range 6-36) months, mild abdominal discomfort was reported in only one patient., Conclusions: MMF appears to be effective in arresting disease progression in severe or MTX-refractory JLS and is generally well tolerated. Further controlled studies are needed to confirm these data.

Objectives: To evaluate the effects of etanercept and thalidomide in the mouse model of bleomycin-induced scleroderma (BLM-IS)., Methods: This study involved four groups (n = 8 mice in each group). Dermal sclerosis was induced by repeated subcutaneous injections of BLM (10 microg) for 4 weeks in BALB/c mice. Control group received only phosphate-buffered saline. The second group received only BLM; the third and fourth groups were also given an intraperitoneal injection of 100 microg etanercept or 150 mg/kg thalidomide, respectively., Results: BLM increased serum TGF-beta1, tissue hydroxyproline levels and expression of alpha-smooth muscle actin (alpha-SMA), and dermal fibrosis was histopathologically prominent. Although thalidomide had no significant effect, etanercept caused decreases in levels of serum TGF-beta1, tissue hydroxyproline and number of alpha-SMA-positive cells., Conclusion: Inhibition of TNF-alpha with etanercept in BLM-IS was resulted in a significant reduction of the dermal sclerosis, collagen accumulation and the number of infiltrating myofibroblastic cells. TNF-alpha may play a key role in the progression of BLM-IS and TNF-alpha antagonists may be useful in the management of scleroderma.

Objectives: The recently developed cold stimulus fingertip lacticemy test (CS-FTL) provides biochemical assessment of peripheral perfusion in patients with Raynaud's phenomenon (RP). We evaluated how the CS-FTL test can assess the acute effect of nifedipine in microvascular dynamics on primary RP and RP secondary to SSc., Methods: A double-blinded controlled trial with crossover design was performed in 20 primary RP and 20 SSc patients. Patients received one single sublingual placebo or 10 mg nifedipine capsule, with crossover after a 15-day washout period. FTL was determined in resting conditions (pre-CS-FTL) and 10 min after CS (post-CS-FTL), before and 1 h after drug administration. Percent variation in post- vs pre-CS-FTL was expressed as deltaCS-FTL., Results: Before intervention, CS induced FTL decrease in primary RP (deltaCS-FTL = -21.3 +/- 13.0%) and FTL increase in SSc patients (deltaCS-FTL = +24.5 +/- 21.2%). Placebo had no effect on pre-CS-FTL, post-CS-FTL and deltaCS-FTL in primary RP and SSc. Nifedipine induced a significant decrease in pre-CS-FTL (1.94 +/- 0.45 vs 1.57 +/- 0.41 mg/dl; P = 0.005) and post-CS-FTL (1.53 +/- 0.35 vs 1.32 +/- 0.37 mg/dl; P = 0.004) in primary RP and a significant decrease in post-CS-FTL (3.18 +/- 1.43 vs 2.56 +/- 1.30 mg/dl; P = 0.028) and deltaCS-FTL (+15.9 +/- 24.7% vs -12.9 +/- 16.6%; P = 0.001) in SSc., Conclusions: The CS-FTL test was able to demonstrate and quantify a dual effect of nifedipine on the biochemical dimension of peripheral perfusion in primary RP and in SSc patients in which there was a significant improvement in tissue perfusion in resting conditions and after exposure to a CS. The CS-FTL test will enrich the armamentarium for investigation and clinical evaluation of conditions associated with RP.

Objective: Juvenile localized scleroderma (JLS) includes a number of conditions often grouped together. With the long-term goal of developing uniform classification criteria, we studied the epidemiological, clinical and immunological features of children with JLS followed by paediatric rheumatology and dermatology centres., Methods: A large, multicentre, multinational study was conducted by collecting information on the demographics, family history, triggering environmental factors, clinical and laboratory features, and treatment of patients with JLS., Results: Seven hundred and fifty patients with JLS from 70 centres were enrolled into the study. The disease duration at diagnosis was 18 months. Linear scleroderma (LS) was the most frequent subtype (65%), followed by plaque morphea (PM) (26%), generalized morphea (GM) (7%) and deep morphea (DM) (2%). As many as 15% of patients had a mixed subtype. Ninety-one patients (12%) had a positive family history for rheumatic or autoimmune diseases; 100 (13.3%) reported environmental events as possible trigger. ANA was positive in 42.3% of the patients, with a higher prevalence in the LS-DM subtype than in the PM-GM subtype. Scl70 was detected in the sera of 3% of the patients, anticentromere antibody in 2%, anti-double-stranded DNA in 4%, anti-cardiolipin antibody in 13% and rheumatoid factor in 16%. Methotrexate was the drug most frequently used, especially during the last 5 yr., Conclusion: This study represents the largest collection of patients with JLS ever reported. The insidious onset of the disease, the delay in diagnosis, the recognition of mixed subtype and the better definition of the other subtypes should influence our efforts in educating trainees and practitioners and help in developing a comprehensive classification system for this syndrome.

Great strides have been made in identifying and managing the organ-based complications of systemic sclerosis (SSc). There is no room for the nihilism towards treating this disease that used to be so prevalent. However, there is still relatively little hard evidence on which to base treatment decisions. Previous trials have been constrained by the low disease prevalence and the difficulty in recruiting sufficient patients especially with disease of recent onset. The results of past trials have often been confounded by the failure to recognize the marked heterogeneity of SSc and the inclusion of patient subsets with widely varying disease expression, course and outcome. It is recognized that progress will only be made in this area with coordinated multicentre studies. As a result, national and international networks of clinicians with expertise in the management of SSc have been formed. In the UK, the Systemic Sclerosis Study Group has established a national scleroderma register and, together with the Scleroderma Special Interest Group of the British Society for Rheumatology (BSR), a multicentre base for therapeutic studies. As a result of developments in our understanding of the pathogenesis of scleroderma and our ability to subset patients more effectively, a number of rather more rational approaches to treating the disease and its complications are being tested. In parallel with this, considerable progress is being made in developing universally agreed measures of disease activity and severity and in identifying surrogate laboratory markers of disease activity that are relevant to therapeutic studies. These multicentre trials need substantial funding and often do not attract support from the pharmaceutical industry. It was because of the difficulty in financing long-term, multicentre studies in uncommon conditions that the ARC/BSR Clinical Trials Programme was established. The QUINS trial, which is funded by this Programme, is described here as an example of one of several therapeutic protocols being developed by the UK Systemic Sclerosis Study Group that are currently being tested in multicentre trials. Contact details are provided in the appendix for clinicians who are interested in registering patients on the UK Scleroderma Register or participating in this or in the other therapeutic studies.