Anti-synthetase and myelodysplastic syndromes with deep morphea: an example of shared immunopathogenesis? A case-based review.

Anti-synthetase syndrome (AS) is a subset of idiopathic inflammatory myopathy (IIM) characterized by the presence of anti-aminoacyl-transfer RNA synthetase accompanied by myositis, interstitial lung disease and other clinical features. According to a recent multicentric study, 31% of AS patients present skin lesions compatible with dermatomyositis, but sclerodermiform features are rare. Therefore, we aimed to report the case of a patient with simultaneous diagnosis of AS, deep morphea, vasculitic neuropathy, and myelodysplastic syndrome and review the current literature regarding these uncommon associations. A 57 year old man with axial and symmetrical proximal muscle weakness, skin thickening and B symptoms, later diagnosed with PL7 + AS, deep morphea, myelodysplastic syndrome (MDS) and vasculitic neuropathy documented by histopathologic studies and immunologic assessments. Since both AS and deep morphea share the vasculopathic changes and type II interferon-induced inflammation, we hypothesize that they may share pathogenic mechanisms. The muscle biopsy of the patient was consistent with AS and showed focal neutrophil infiltration. The patient received intensive immunosuppressive therapy for AS and vasculitic neuropathy, with high dose steroids, intravenous immunoglobulin (IVIg) and rituximab. Nonetheless, he suffered an unfavorable evolution with a fatal outcome due to septic shock. Albeit sclerodermiform features are rare in patients with AS, we propose a pathogenic link among AS, deep morphea and the autoimmune/autoinflammatory signs of MDS. The vasculopathic changes along with the activation of the innate and adaptive immune system leading to the production of proinflammatory cytokines may have been one of the contributing factors for the coexisting diagnosis of the patient.

Novel multispectral imaging to predict disease progression in pediatric morphea.

BACKGROUND: Morphea, or localized scleroderma, is an inflammatory, fibrosing skin disorder that can be progressive and debilitating. Infrared thermography frequently has false positive results. The aim of this study was to assess the ability of multispectral imaging to predict disease progression in children with morphea. METHODS: Children with morphea were recruited between 2016 and 2022. Multispectral images of affected and matched contralateral unaffected sites were obtained using the Antera™ 3D camera. Clinical assessment was performed using the Localized Scleroderma Assessment Tool (LoSCAT). Children were followed up every 3 months for imaging and clinical review. The main outcome measurement was correlation of hemoglobin gradient between affected and matched contralateral unaffected tissue and progression. RESULTS: Of 17 children, the average age was 12 years (range 6-18 years); most were female (76.5%) and white (94.1%). Nearly two-thirds (64.7%) had linear morphea, 35.2% had plaque morphea; 58.8% had been treated with systemic agents. The average LoSCAT score was 20.6 (range 5-73). The average hemoglobin gradient between affected and matched contralateral unaffected skin was four times higher in those who had progression (average differential 0.3, range 0.1-0.4) compared to those who did not (average differential 0.08, range 0.02-0.15). Using a cut off of a 0.18 hemoglobin gradient between affected and unaffected skin, the sensitivity of multispectral imaging for detecting progression in pediatric morphea is 90% with specificity of 100%. CONCLUSIONS: Multispectral imaging is a novel assessment tool with promising accuracy in predicting progression as an adjunct to clinical assessment in pediatric morphea. Further research should examine its performance against thermography.

Study about evaluation of efficacy of methotrexate in localized scleroderma using ultrasonography.

BACKGROUND: The treatment and curative effect evaluation of localized scleroderma (LS) still perplexes many clinical workers. PURPOSE: To investigate the efficiacy of methotrexate in the treatment of LS by the evaluation of ultrasonography. METHODS: A prospective study enrolled 10 patients treated with MTX for at least 6 months was conducted. Treatment outcome was evaluated by a clinical score and 15-MHz ultrasonography. Safety assessment included the monitoring of adverse drug reactions and clinical laboratory examinations. RESULTS: Eight of the 10 patients achieved clinical remission only with MTX. One patient was relieved after MTX combined with corticosteroids, while another one does not improve after the treatment of mycophenolate mofetil and corticosteroids. The effective rate of MTX is 80%. Nine patients were significantly improved with a decrease of the Localized Scleroderma Cutaneous Assessment Tool (the mean score of the LoSCAT cutaneous activity dropped from 5.2 to 1.0, p < 0.001, the mean score of the LS cutaneous damage dropped from 4.3 to 2.3, p = 0.002). The average difference of thickness between skin lesions and normal skin evaluated by ultrasonography decreased from 0.13 cm to 0.04 cm (p = 0.009) in eight patients. No serious adverse reactions occurred. CONCLUSION: Methotrexate is a safe and effective treatment for patients with LS. Ultrasonography can be considered as an efficient assessment tool for evaluation LS.

Presenting characteristics and progression of pediatric-onset morphea: Interim analysis of a prospective registry.

Morphea is a rare fibrosing disorder with a highly variable disease course, which can complicate management. Here, we present a prospective cohort study describing the current treatments used in the management of pediatric-onset morphea and assessing responses to systemic and topical therapies. Most patients demonstrated inactive disease by 1 year, regardless of treatment, though recurrences were common in our cohort overall (39%). Our results support the need for continuous monitoring of all children with morphea following the completion of treatment, including topical treatment, due to high rates of disease relapse.

Bilateral en coup de sabre morphea in a male child: A rare presentation.

En coup de sabre is a rare subtype of morphea. Only a few bilateral cases have been reported to date. We report a case of a 12-year-old male child with two linear brownish depressed asymptomatic lesions over the forehead with hair loss on the scalp. After thorough clinical, ultrasonography and brain imaging, a diagnosis of bilateral en coup de sabre morphea was made and the patient was treated with oral steroids and weekly methotrexate.

Morphea after initiation of dupilumab in two pediatric atopic dermatitis patients.

Morphea is a rare multifactorial autoimmune disorder characterized by a complex and dynamic interplay between Th1 and Th2 signaling. Active clinical trials are currently investigating the safety and efficacy of dupilumab for the treatment of primary morphea. Here, we present two cases of morphea that developed in pediatric atopic dermatitis patients treated with dupilumab. These findings may support a causal relationship between IL-4 receptor blockade and the development of the early inflammatory phase of morphea.

Adult-Onset Linear Morphea (en coupe de sabre) of the Face Successfully Treated with Photoactivated Low-Temperature Platelet-Rich Plasma: A Valid Therapeutic Option.

Localized scleroderma (also known as morphea) is a chronic autoimmune disorder characterized by depressed, fibrotic, and dyschromic cutaneous lesions. It has a significant impact on the patient's daily life due to the unaesthetic evolution of the cutaneous lesions. Morphea is clinically divided into linear, circumscribed (plaque), generalized, pansclerotic, and mixed forms. Linear morphea en coupe de sabre (LM) usually arises in childhood. However, in about 32% of cases, it may arise in adulthood, showing a more aggressive course with also an increased risk of systemic involvement. Methotrexate is the first-line treatment for LM, although systemic steroids, topical agents (corticosteroids and calcineurin inhibitors), hyaluronic acid injections, and hydroxychloroquine or mycophenolate mofetil are valid therapeutic options. In any case, these treatments are not always effective and sometimes can be associated with important side effects and/or not tolerated by the patients. In this spectrum, platelet-rich plasma (PRP) injection can be considered a valid and safe alternative since PRP injections in the skin induce the release of anti-inflammatory cytokines and growth factors, thus reducing inflammation and increasing collagen remodeling. Herein, we describe a successful treatment of an adult-onset LM en coupe de sabre with photoactivated low-temperature PRP (Meta Cell Technology Plasma) sessions, showing an important local improvement of the lesion and patient satisfaction.

BULGARIAN PATIENT WITH ATROPHODERMA OF PASINI AND PIERINI- DESCRIPTION OF A CASE AND SHORT UPDATE.

Atrophoderma of Pasini and Pierini is a rare, considered benign, skin disease characterized by single or multiple asymptomatic atrophic plaques. Lesions can occur everywhere on the body with the trunk being the most often reported affected site. It appears in the second or third decade of life and affects mostly the female population, with male to female ratio of 1:6, commonly of white European descent. Different risk factors were described in the literature - genetic predisposition, infections with Epstein-Barr virus, varicella zoster and Borrelia burgdorferi, vaccinations, local trauma and more. Since the pandemic with COVID-19, skin manifestations after the viral infection with COVID-19 were reported. After a thorough search of the existing medical literature, we believe, we present the first case of a rapid progression of Atrophoderma of Pasini and Pierini after COVID-19 infection. Due to its similarity to morphea in some aspects, the condition is often misdiagnosed, and the proper treatment is often delayed. Sometimes the dilemma "Is it atrophoderma Pasini-Pierini or is it in fact morphea?" stays, but the exact histopathological verification and the "diagnostic clues" which can be used during the examination stage, are usually enough to diagnose the condition. We present a 63-year-old female with a rapid progression of atrophoderma of Pasini and Pierini after a COVID-19 infection. The lesion that she presented with was single, asymptomatic, with central hypopigmentation and slight atrophy, with a smooth, shiny surface and ivory color, and peripheral hyperpigmentation, measured 18x5cm, without the presence of perilesional erythema. The patient was initially diagnosed clinically with localized scleroderma (morphea) and treated with hydroxychloroquine 200 mg once daily for a 5-year period without improvement. Years later two biopsies from different lesional sites were taken, resulting in absence of sclerosis and dermal atrophy, but - reduction in the thickness of the dermis with fragmentation and hyalinization of collagen fibers forming a parallel orientation, dilated vascular vessels of small caliber and reduced number of skin appendages, confirming the diagnosis of atrophoderma Pasini-Pierini. The patient's therapy was switched to methotrexate with good therapeutic response. Often, the two conditions - morphea and atrophoderma of Pasini and Pierini can be mistaken due to its clinical similarity and sometimes coexistence. Therefore, we will shortly review the existing literature with key points on the similarities and differences.

Treatment of juvenile localized scleroderma: current recommendations, response factors, and potential alternative treatments.

PURPOSE OF REVIEW: Juvenile localized scleroderma (jLS) is a chronic autoimmune and fibrosing disease associated with a high risk for functional impairment. Antifibrotic options are limited, so current treatment strategies are focused on disease activity control. Pediatric rheumatologists are in consensus on the need to treat with systemic immunosuppressants, in particular, methotrexate. However, more than 30% of patients fail initial methotrexate treatment. This review provides an update on current management and reviews reports on potential alternative treatments. RECENT FINDINGS: An overview of current treatment recommendations and its efficacy are discussed. Recent studies have identified several factors associated with likelihood of treatment response. These include time to initiation of treatment, certain subtypes, and extracutaneous involvement. Findings from recent reports of alternative systemic immunomodulators, including biologic medications, will be summarized. SUMMARY: Methotrexate treatment has greatly improved outcome for most jLS patients but a substantial portion have refractory cutaneous and/or extracutaneous disease. Treatment response factors are being identified, which could lead to improved management strategies. Recent studies provide further support on mycophenolate mofetil as an alternative treatment. Data on biologic therapies is encouraging, with data suggesting efficacy for many extracutaneous manifestations but more studies are needed to evaluate these and other options for jLS.

Iontophoresis of treprostinil promotes wound healing in a murine model of scleroderma-related ulcers.

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.

Emerging therapeutics in the management of connective tissue disease. Part II: Dermatomyositis and scleroderma.

The management of connective tissue diseases is dramatically evolving with the advent of biologics and novel oral systemic therapeutics. Despite involvement in the care of these complex patients, there is a knowledge gap in the field of dermatology regarding these emerging agents. The second article in this continuing medical education series discusses new and emerging therapeutics for dermatomyositis and scleroderma that target cells, intracellular signaling pathways, and cytokines.

Bullous lichen sclerosus-generalized morphea overlap syndrome improved by tofacitinib.

We here report a case of a middle-aged man with an unusual case of bullous lichen sclerosus complicated with generalized morphea. He showed initial recurrent flaccid bullae, followed by ivory-white sclerotic plaques and extensive skin sclerosis, with additional walking disorder caused by knee-joint contracture, and ulcers on the lower extremities and back. The patient had no visceral involvement. After oral hydroxychloroquine and oral corticosteroids failed, the patient was given tofacitinib, which resolved his ulcers after 4 weeks and ameliorated his knee-joint contracture and skin sclerosis within 4 months. Owing to the occurrence of diffuse large B-cell lymphoma, he stopped using tofacitinib, and the ulcer and walking disorder reappeared. This is rare case of bullous lichen sclerosus-generalized morphea overlap syndrome. The patient recovered well after treatment with tofacitinib. His symptoms recurred after discontinuation of tofacitinib.

Janus kinase inhibitors for treatment of morphea and systemic sclerosis: A literature review.

Morphea and systemic sclerosis (SSc) are rare disorders of connective tissue characterized by increased skin thickness and fibrosis, with current treatment options having variable efficacies, many with limited therapeutic benefit. Janus kinase (JAK) inhibitors have been shown in preclinical studies to inhibit the fibrotic pathway in murine models of systemic sclerosis, by blocking TGF-beta mediated pathway of STAT protein activation. Additionally, case reports of the treatment of morphea and SSc with tofacitinib, a JAK 1/3 inhibitor, have shown improvement in skin sclerosis. Several JAK inhibitors have been developed and utilized in dermatologic and rheumatologic diseases. To date, tofacitinib has been by far the most commonly trialed JAK inhibitor in patients with SSc and morphea. Herein we review the preclinical studies reported in the literature supporting the use and efficacy of JAK inhibitors for the treatment of morphea and the cutaneous manifestations of SSc, as well as discuss the clinical cases published to date illustrating the benefits of JAK inhibitors in disease management. The pathogenesis and mechanism of action will be reviewed as it relates to the process of skin fibrosis in morphea and SSc, along with the murine models illustrating efficacy of JAK inhibitors in fibrotic disease. Based on available preclinical and clinical data as well as consideration of the mechanism of action of JAK inhibitors on the pathway for cutaneous fibrosis, there is promising evidence to support the use and further study of JAK inhibitors in the management of morphea and cutaneous fibrosis in SSc.

Rapid response to abatacept in treatment-resistant pansclerotic morphoea.

Morphoea is a spectrum of disorders characterized by inflammation and sclerosis of the skin and potentially underlying tissues. There are no specific licensed treatments for morphoea and prospective studies on commonly used therapies are lacking. We describe a case of progressive, recalcitrant pansclerotic morphoea with a rapid response to abatacept.

Consensus-based recommendations for the management of juvenile systemic sclerosis.

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.

Mycophenolate mofetil for methotrexate-resistant juvenile localized scleroderma.

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.

Preliminary evidence on abatacept safety and efficacy in refractory juvenile localized scleroderma.

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.

Diagnosis and management of morphoea in children: an overview.

Paediatric morphoea (localized scleroderma) is an inflammatory sclerosing disorder of the skin and subcutis associated with tissue atrophy. It is thought that the disease develops on the background of genetic predisposition (e.g. mosaicism for the common linear variant) initiated by various trigger factors, and that detected autoantibodies and inflammatory cytokines represent secondary epiphenomena. In contrast to the common belief that morphoea is a benign self-limiting disorder, long-term data indicate that its chronicity, relapsing nature and extracutaneous complications lead to significant morbidity, particularly when the disease starts in early childhood. Early recognition may be challenging, and the most important clinical clues are band-like distribution, atrophy of underlying tissue, skin sclerosis, and localized loss of body/scalp hair, eyelashes or eyebrows. Extracutaneous manifestations occur in up to 20% of patients, with arthritis/arthralgia and neurological symptoms being most frequently observed, followed by ophthalmological complications such as uveitis. Corticosteroids and methotrexate are highly effective as first-line therapy in morphoea, leading to partial reversal of skin manifestations. However, the development of atrophy is not sufficiently prevented by standard therapy. There is a relapse rate of 25%-48% within the first years after stopping treatment, thus long-term follow-up is warranted. Mycophenolate mofetil seems to be a beneficial second-line therapy, and a new drug, abatacept, also seems to be a promising and well-tolerated second-line treatment option. Additionally, autologous fat injections are beneficial and may be used as an adjunct to ongoing therapy.

Reversible alopecia in En Coup de Sabre morphea.

En coup de sabre form of morphea often affects the scalp with thickening, sclerosis, dyspigmentation, and scarring alopecia. Traditionally, it has been thought that the alopecia is not responsive to treatment and permanent. This report presents two cases with extensive, apparent scarring alopecia that improved with medical treatment.