Collaborative research in myositis-related disorders: MIHRA, a global shared community model.

Myositis International Health and Research Collaborative Alliance (MIHRA) is a newly formed purpose-built non-profit charitable research organization dedicated to accelerating international clinical trial readiness, global professional and lay education, career development and rare disease advocacy in IIM-related disorders. In its long form, the name expresses the community's scope of engagement and intent. In its abbreviation, MIHRA, conveys linguistic roots across many languages, that reflects the IIM community's spirit with meanings such as kindness, community, goodness, and peace. MIHRA unites the global multi-disciplinary community of adult and pediatric healthcare professionals, researchers, patient advisors and networks focused on conducting research in and providing care for pediatric and adult IIM-related disorders to ultimately find a cure. MIHRA serves as a resourced platform for collaborative efforts in investigator-initiated projects, consensus guidelines for IIM assessment and treatment, and IIM-specific career development through connecting research networks.MIHRA's infrastructure, mission, programming and operations are designed to address challenges unique to rare disease communities and aspires to contribute toward transformative models of rare disease research such as global expansion and inclusivity, utilization of community resources, streamlining ethics and data-sharing policies to facilitate collaborative research. Herein, summarises MIHRA operational cores, missions, vision, programming and provision of community resources to sustain, accelerate and grow global collaborative research in myositis-related disorders.

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.

Consensus-based recommendations for the management of juvenile localised scleroderma.

In 2012, a European initiative called Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile localised scleroderma (JLS) is a rare disease within the group of paediatric rheumatic diseases (PRD) and can lead to significant morbidity. Evidence-based guidelines are sparse and management is mostly based on physicians' experience. This study aims to provide recommendations for assessment and treatment of JLS. Recommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was formed, mainly from Europe, and consisted of 15 experienced paediatric rheumatologists and two young fellows. Recommendations derived from a validated systematic literature review were evaluated by an online survey and subsequently discussed at two consensus meetings using a nominal group technique. Recommendations were accepted if ≥80% agreement was reached. In total, 1 overarching principle, 10 recommendations on assessment and 6 recommendations on therapy were accepted with ≥80% agreement among experts. Topics covered include assessment of skin and extracutaneous involvement and suggested treatment pathways. The SHARE initiative aims to identify best practices for treatment of patients suffering from PRDs. Within this remit, recommendations for the assessment and treatment of JLS have been formulated by an evidence-informed consensus process to produce a standard of care for patients with JLS throughout Europe.

European consensus-based recommendations for diagnosis and treatment of immunoglobulin A vasculitis-the SHARE initiative.

OBJECTIVES: IgA vasculitis (IgAV, formerly known as Henoch-Schönlein purpura) is the most common cause of systemic vasculitis in childhood. To date, there are no internationally agreed, evidence-based guidelines concerning the appropriate diagnosis and treatment of IgAV in children. Accordingly, treatment regimens differ widely. The European initiative SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) aims to optimize care for children with rheumatic diseases. The aim therefore was to provide internationally agreed consensus recommendations for diagnosis and treatment for children with IgAV. METHODS: Recommendations were developed by a consensus process in accordance with the EULAR standard operating procedures. An extensive systematic literature review was performed, and evidence-based recommendations were extrapolated from the included papers. These were evaluated by a panel of 16 international experts via online surveys and subsequent consensus meeting, using nominal group technique. Recommendations were accepted when ⩾80% of experts agreed. RESULTS: In total, 7 recommendations for diagnosis and 19 for treatment of paediatric IgAV were accepted. Diagnostic recommendations included: appropriate use of skin and renal biopsy, renal work-up and imaging. Treatment recommendations included: the importance of appropriate analgesia and angiotensin-converting enzyme inhibitor use and non-renal indications for CS use, as well as a structured approach to treating IgAV nephritis, including appropriate use of CS and second-line agents in mild, moderate and severe disease along with use of angiotensin-converting enzyme inhibitors and maintenance therapy. CONCLUSION: The SHARE initiative provides international, evidence-based recommendations for the diagnosis and treatment of IgAV that will facilitate improvement and uniformity of care.

European consensus-based recommendations for the diagnosis and treatment of rare paediatric vasculitides - the SHARE initiative.

OBJECTIVES: The European initiative Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) aimed to optimize care for children with rheumatic diseases. Systemic vasculitides are very rare in children. Consequently, despite recent advances, paediatric-specific information is sparse. The lack of evidence-based recommendations is an important, unmet need. This study aimed to provide recommendations for diagnosing and treating children with rare forms of childhood systemic vasculitis. METHODS: Recommendations were developed by a consensus process in accordance with the European League Against Rheumatism standard operating procedures. A systematic literature review informed the recommendations, which were devised and evaluated by a panel of experts via an online survey, and two consensus meetings using nominal group technique. Recommendations were accepted when ⩾ 80% of experts agreed. RESULTS: Ninety-three relevant articles were found, and 78 recommendations were accepted in the two consensus meetings. General, cross-cutting recommendations and disease-specific statements regarding the diagnosis and treatment of childhood-onset PAN, granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and Takayasu arteritis are provided. CONCLUSION: These Single Hub and Access point for paediatric Rheumatology in Europe recommendations were formulated through an evidence-based consensus process to support uniform, high-quality standard of care for children with rare forms of paediatric systemic vasculitis.

Autologous stem cell transplantation aids autoimmune patients by functional renewal and TCR diversification of regulatory T cells.

Autologous hematopoietic stem cell transplantation (HSCT) is increasingly considered for patients with severe autoimmune diseases whose prognosis is poor with standard treatments. Regulatory T cells (Tregs) are thought to be important for disease remission after HSCT. However, eliciting the role of donor and host Tregs in autologous HSCT is not possible in humans due to the autologous nature of the intervention. Therefore, we investigated their role during immune reconstitution and re-establishment of immune tolerance and their therapeutic potential following congenic bone marrow transplantation (BMT) in a proteoglycan-induced arthritis (PGIA) mouse model. In addition, we determined Treg T-cell receptor (TCR) CDR3 diversity before and after HSCT in patients with juvenile idiopathic arthritis and juvenile dermatomyositis. In the PGIA BMT model, after an initial predominance of host Tregs, graft-derived Tregs started dominating and displayed a more stable phenotype with better suppressive capacity. Patient samples revealed a striking lack of diversity of the Treg repertoire before HSCT. This ameliorated after HSCT, confirming reset of the Treg compartment following HSCT. In the mouse model, a therapeutic approach was initiated by infusing extra Foxp3(GFP+) Tregs during BMT. Infusion of Foxp3(GFP+) Tregs did not elicit additional clinical improvement but conversely delayed reconstitution of the graft-derived T-cell compartment. These data indicate that HSCT-mediated amelioration of autoimmune disease involves renewal of the Treg pool. In addition, infusion of extra Tregs during BMT results in a delayed reconstitution of T-cell compartments. Therefore, Treg therapy may hamper development of long-term tolerance and should be approached with caution in the clinical autologous setting.

Periodic fever in MVK deficiency: a patient initially diagnosed with incomplete Kawasaki disease.

Mevalonate kinase deficiency (MKD) is a rare autosomal recessive disorder causing 1 of 2 phenotypes, hyperimmunoglobulin D syndrome and mevalonic aciduria, presenting with recurrent fever episodes, often starting in infancy, and sometimes evoked by stress or vaccinations. This autoinflammatory disease is caused by mutations encoding the mevalonate kinase (MVK) gene and is classified in the group of periodic fever syndromes. There is often a considerable delay in the diagnosis among pediatric patients with recurrent episodes of fever. We present a case of an 8-week-old girl with fever of unknown origin and a marked systemic inflammatory response. After excluding infections, a tentative diagnosis of incomplete Kawasaki syndrome was made, based on the finding of dilated coronary arteries on cardiac ultrasound and fever, and she was treated accordingly. However, the episodes of fever recurred, and alternative diagnoses were considered, which eventually led to the finding of increased excretion of mevalonic acid in urine. The diagnosis of MKD was confirmed by mutation analysis of the MVK gene. This case shows that the initial presentation of MKD can be indistinguishable from incomplete Kawasaki syndrome. When fever recurs in Kawasaki syndrome, other (auto-)inflammatory diseases must be ruled out to avoid inappropriate diagnostic procedures, ineffective interventions, and treatment delay.

Health related quality of life measure in systemic pediatric rheumatic diseases and its translation to different languages: an international collaboration.

BACKGROUND: Rheumatic diseases in children are associated with significant morbidity and poor health-related quality of life (HRQOL). There is no health-related quality of life (HRQOL) scale available specifically for children with less common rheumatic diseases. These diseases share several features with systemic lupus erythematosus (SLE) such as their chronic episodic nature, multi-systemic involvement, and the need for immunosuppressive medications. HRQOL scale developed for pediatric SLE will likely be applicable to children with systemic inflammatory diseases. FINDINGS: We adapted Simple Measure of Impact of Lupus Erythematosus in Youngsters (SMILEY©) to Simple Measure of Impact of Illness in Youngsters (SMILY©-Illness) and had it reviewed by pediatric rheumatologists for its appropriateness and cultural suitability. We tested SMILY©-Illness in patients with inflammatory rheumatic diseases and then translated it into 28 languages. Nineteen children (79% female, n=15) and 17 parents participated. The mean age was 12±4 years, with median disease duration of 21 months (1-172 months). We translated SMILY©-Illness into the following 28 languages: Danish, Dutch, French (France), English (UK), German (Germany), German (Austria), German (Switzerland), Hebrew, Italian, Portuguese (Brazil), Slovene, Spanish (USA and Puerto Rico), Spanish (Spain), Spanish (Argentina), Spanish (Mexico), Spanish (Venezuela), Turkish, Afrikaans, Arabic (Saudi Arabia), Arabic (Egypt), Czech, Greek, Hindi, Hungarian, Japanese, Romanian, Serbian and Xhosa. CONCLUSION: SMILY©-Illness is a brief, easy to administer and score HRQOL scale for children with systemic rheumatic diseases. It is suitable for use across different age groups and literacy levels. SMILY©-Illness with its available translations may be used as useful adjuncts to clinical practice and research.

Near-infrared spectroscopy during exercise and recovery in children with juvenile dermatomyositis.

INTRODUCTION: We hypothesized that microvascular disturbances in muscle tissue play a role in the reduced exercise capacity in juvenile dermatomyositis (JDM). METHODS: Children with JDM, children with juvenile idiopathic arthritis (clinical controls), and healthy children performed a maximal incremental cycloergometric test from which normalized concentration changes in oxygenated hemoglobin (Δ[O2 Hb]) and total hemoglobin (Δ[tHb]) as well as the half-recovery times of both signals were determined from the vastus medialis and vastus lateralis muscles using near-infrared spectroscopy. RESULTS: Children with JDM had lower Δ[tHb] values in the vastus medialis at work rates of 25%, 50%, 75%, and 100% of maximal compared with healthy children; the increase in Δ[tHb] with increasing intensity seen in healthy children was absent in children with JDM. Other outcome measures did not differ by group. CONCLUSIONS: The results suggest that children with JDM may experience difficulties in increasing muscle blood volume with more strenuous exercise.

Changing winds in refractory autoimmune disease in children: clearing the road for tolerance with cellular therapies.

PURPOSE OF REVIEW: To give an overview of the recent advances in cellular therapies in pediatric autoimmune diseases. RECENT FINDINGS: Since the 1990s, autologous hematopoietic stem cell transplantation (HSCT) has been applied in more than 800 patients with severe refractory autoimmune diseases. Despite obvious successes, it is clear that the autoimmune disease in many of these patients relapsed. Anecdotal reports of allogeneic HSCT seem promising. Furthermore, several trials exploring the use of mesenchymal stem or stromal cells (MSC) for therapy of refractory autoimmune diseases have been published. Mostly allogeneic MSC are used at a dose of 1 million/kg intravenously. SUMMARY: Even though promising new agents have become available for the treatment of autoimmune disease (AID), some arthritis patients fail to achieve even a modest improvement. Cellular therapies may be the answer in steering the immune system into a more tolerant path. Autologous HSCT after an immunoablative pretreatment allows rebuilding of a partially reset immune system. A small group of severely refractory pediatric patients is unlikely to benefit from immunosuppressive therapies alone. With allogeneic transplant becoming safer and overall mortality numbers much lower in pediatric transplantation, allogeneic HSCT might become the more sensible option for this small group of refractory patients. A promising new cellular therapy is the use of MSC. The working mechanism is immunomodulatory, through induction of Tregs. Although their place is still to be determined, they may provide a safer alternative to severely compromised children or as an adjuvant therapy earlier in the disease. We have implemented cellular therapy options for our refractory pediatric AID patients. We consider progressing to cellular therapies in severely affected individuals, to ultimately cure their disease. Our cellular therapy protocols are provided in this review.

[DIRA: life-threatening but treatable inherited inflammatory disease]. / DIRA: levensbedreigende, maar behandelbare aangeboren ontstekingsziekte.

Deficiency of interleukin(IL)-1 receptor antagonist (DIRA) is an autosomal recessive inherited inflammatory disease, characterised by pustular skin rash and characteristic osteolytic and hypertrophic bone lesions. If left untreated, the disease may progress to a fatal sepsis with multiple organ failure. The symptoms result from an uncontrolled activity of the pro-inflammatory cytokines IL-1 alpha and IL-1 beta, due to the genetic lacking of the natural antagonist, IL-1 receptor antagonist (IL-1RA). Suppletion of the deficient protein induces rapid complete remission. Two cases from one family, both female neonates, illustrate the fatal natural progression, as well as the course under suppletion of IL-1RA (anakinra). Early recognition of this rare disorder can be life saving.