Coordinated immune dysregulation in Juvenile Dermatomyositis revealed by single-cell genomics.

Juvenile Dermatomyositis (JDM) is one of several childhood-onset autoimmune disorders characterized by a type I interferon response and autoantibodies. Treatment options are limited due to incomplete understanding of how the disease emerges from dysregulated cell states across the immune system. We therefore investigated the blood of JDM patients at different stages of disease activity using single-cell transcriptomics paired with surface protein expression. By immunophenotyping peripheral blood mononuclear cells, we observed skewing of the B cell compartment towards an immature naive state as a hallmark of JDM at diagnosis. Furthermore, we find that these changes in B cells are paralleled by T cell signatures suggestive of Th2-mediated inflammation that persist despite disease quiescence. We applied network analysis to reveal that hyperactivation of the type I interferon response in all immune populations is coordinated with previously masked cell states including dysfunctional protein processing in CD4+ T cells and regulation of cell death programming in NK, CD8+ T cells and gdT cells. Together, these findings unveil the coordinated immune dysregulation underpinning JDM and provide insight into strategies for restoring balance in immune function.

Gene expression meta-analysis reveals aging and cellular senescence signatures in scleroderma-associated interstitial lung disease.

Aging and cellular senescence are increasingly recognized as key contributors to pulmonary fibrosis. However, our understanding in the context of scleroderma-associated interstitial lung disease (SSc-ILD) is limited. To investigate, we leveraged previously established lung aging- and cell-specific senescence signatures to determine their presence and potential relevance to SSc-ILD. We performed a gene expression meta-analysis of lung tissues from 38 SSc-ILD and 18 healthy controls and found that markers (GDF15, COMP, and CDKN2A) and pathways (p53) of senescence were significantly increased in SSc-ILD. When probing the established aging and cellular senescence signatures, we found that epithelial and fibroblast senescence signatures had a 3.6- and 3.7-fold enrichment, respectively, in the lung tissue of SSc-ILD and that lung aging genes (CDKN2A, FRZB, PDE1A, and NAPI12) were increased in SSc-ILD. These signatures were also enriched in SSc skin and associated with degree of skin involvement (limited vs. diffuse cutaneous). To further support these findings, we examined telomere length (TL), a surrogate for aging, in the lung tissue and found that, independent of age, SSc-ILD had significantly shorter telomeres than controls in type II alveolar cells in the lung. TL in SSc-ILD was comparable to idiopathic pulmonary fibrosis, a disease of known aberrant aging. Taken together, this study provides novel insight into the possible mechanistic effects of accelerated aging and aberrant cellular senescence in SSc-ILD pathogenesis.

Disease Course, Treatments, and Outcomes of Children With Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease.

OBJECTIVE: Systemic juvenile idiopathic arthritis-associated lung disease (SJIA-LD) is a life-threatening disease complication. Key questions remain regarding clinical course and optimal treatment approaches. The objectives of the study were to detail management strategies after SJIA-LD detection, characterize overall disease courses, and measure long-term outcomes. METHODS: This was a prospective cohort study. Clinical data were abstracted from the electronic medical record, including current clinical status and changes since diagnosis. Serum biomarkers were determined and correlated with presence of LD. RESULTS: We enrolled 41 patients with SJIA-LD, 85% with at least one episode of macrophage activation syndrome and 41% with adverse reactions to a biologic. Although 93% of patients were alive at last follow-up (median 2.9 years), 37% progressed to requiring chronic oxygen or other ventilator support, and 65% of patients had abnormal overnight oximetry studies, which changed over time. Eighty-four percent of patients carried the HLA-DRB1*15 haplotype, significantly more than patients without LD. Patients with SJIA-LD also showed markedly elevated serum interleukin-18 (IL-18), variable C-X-C motif chemokine ligand 9 (CXCL9), and significantly elevated matrix metalloproteinase 7. Treatment strategies showed variable use of anti-IL-1/6 biologics and addition of other immunomodulatory treatments and lung-directed therapies. We found a broad range of current clinical status independent of time from diagnosis or continued biologic treatment. Multidomain measures of change showed imaging features were the least likely to improve with time. CONCLUSION: Patients with SJIA-LD had highly varied courses, with lower mortality than previously reported but frequent hypoxia and requirement for respiratory support. Treatment strategies were highly varied, highlighting an urgent need for focused clinical trials.

Coordinated immune dysregulation in Juvenile Dermatomyositis revealed by single-cell genomics.

Juvenile Dermatomyositis (JDM) is one of several childhood-onset autoimmune disorders characterized by a type I interferon response and autoantibodies. Treatment options are limited due to incomplete understanding of how the disease emerges from dysregulated cell states across the immune system. We therefore investigated the blood of JDM patients at different stages of disease activity using single-cell transcriptomics paired with surface protein expression. By immunophenotyping peripheral blood mononuclear cells, we observed skewing of the B cell compartment towards an immature naive state as a hallmark of JDM. Furthermore, we find that these changes in B cells are paralleled by signatures of Th2-mediated inflammation. Additionally, our work identified SIGLEC-1 expression in monocytes as a composite measure of heterogeneous type I interferon activity in disease. We applied network analysis to reveal that hyperactivation of the type I interferon response in all immune populations is coordinated with dysfunctional protein processing and regulation of cell death programming. This analysis separated the ubiquitously expressed type I interferon response into a central hub and revealed previously masked cell states. Together, these findings reveal the coordinated immune dysregulation underpinning JDM and provide novel insight into strategies for restoring balance in immune function.

Gene Expression Meta-Analysis Reveals Aging and Cellular Senescence Signatures in Scleroderma-associated Interstitial Lung Disease.

Aging and cellular senescence are increasingly recognized as key contributors to pulmonary fibrosis. However, our understanding in the context of scleroderma associated interstitial lung disease (SSc-ILD) is limited. To investigate, we leveraged previously established lung aging and cell-specific senescence signatures to determine their presence and potential relevance to SSc-ILD. We performed a gene expression meta-analysis of lung tissue from 38 SSc-ILD and 18 healthy controls and found markers (GDF15, COMP, CDKN2A) and pathways (p53) of senescence were significantly increased in SSc-ILD. When probing the established aging and cellular senescence signatures, we found epithelial and fibroblast senescence signatures had a 3.6-fold and 3.7-fold enrichment respectively in the lung tissue of SSc-ILD and that lung aging genes ( CDKN2A, FRZB, PDE1A, NAPI12) were increased in SSc-ILD. These signatures were also enriched in SSc skin and associated with degree of skin involvement (limited vs. diffuse cutaneous). To further support these findings, we examined telomere length (TL), a surrogate for aging, in lung tissue and found independent of age, SSc-ILD had significantly shorter telomeres than controls in type II alveolar cells in the lung. TL in SSc-ILD was comparable to idiopathic pulmonary fibrosis, a disease of known aberrant aging. Taken together, this study provides novel insight into the possible mechanistic effects of accelerated aging and aberrant cellular senescence in SSc-ILD pathogenesis.

Multi-Modal Single-Cell Sequencing Identifies Cellular Immunophenotypes Associated With Juvenile Dermatomyositis Disease Activity.

Juvenile dermatomyositis (JDM) is a rare autoimmune condition with insufficient biomarkers and treatments, in part, due to incomplete knowledge of the cell types mediating disease. We investigated immunophenotypes and cell-specific genes associated with disease activity using multiplexed RNA and protein single-cell sequencing applied to PBMCs from 4 treatment-naïve JDM (TN-JDM) subjects at baseline, 2, 4, and 6 months post-treatment and 4 subjects with inactive disease on treatment. Analysis of 55,564 cells revealed separate clustering of TN-JDM cells within monocyte, NK, CD8+ effector T and naïve B populations. The proportion of CD16+ monocytes was reduced in TN-JDM, and naïve B cells and CD4+ Tregs were expanded. Cell-type differential gene expression analysis and hierarchical clustering identified a pan-cell-type IFN gene signature over-expressed in TN-JDM in all cell types and correlated with disease activity most strongly in cytotoxic cell types. TN-JDM CD16+ monocytes expressed the highest IFN gene score and were highly skewed toward an inflammatory and antigen-presenting phenotype at both the transcriptomic and proteomic levels. A transitional B cell population with a distinct transcriptomic signature was expanded in TN-JDM and characterized by higher CD24 and CD5 proteins and less CD39, an immunoregulatory protein. This data provides new insights into JDM immune dysregulation at cellular resolution and serves as a novel resource for myositis investigators.

Baseline characteristics of children with juvenile dermatomyositis enrolled in the first year of the new Childhood Arthritis and Rheumatology Research Alliance registry.

BACKGROUND: To report baseline characteristics, patient reported outcomes and treatment of children with Juvenile Dermatomyositis (JDM) in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. METHODS: Children newly diagnosed with JDM were enrolled in the CARRA Registry from 41 pediatric rheumatology centers. Baseline patient demographics, disease characteristics, assessments, patient reported outcome and treatments were recorded. RESULTS: In the first year, 119 JDM participants were enrolled. Most were female (63.4%), and white (72.3%) with a median diagnosis age 8.0 years (IQR 4.0-11.5), and median age of disease onset 7.0 years (IQR 3.5-7.5). They had characteristic rashes (92.4%), elevated muscle enzymes (83.2%), physician global score 4.0 (IQR 2.5-5.0) and manual muscle testing score 63.5 (IQR 51.0-75.0). Calcinosis (3.4%) and interstitial lung disease (< 1%) were uncommon. Myositis specific antibodies were measured and reported in nearly half of participants enrolled where anti-MJ followed by Anti-p155/140 were most common (11/49 and 7/53 respectively). Childhood Health Assessment Questionnaire (CHAQ) results showed mild-moderate disability (median 0.750, IQR 0.030-1.875), as did patient/parent global assessments of disease activity (median 3, patient IQR: 1.75-5.25; parent IQR: 1-7). Patient Reported Outcomes Measurement Information System (PROMIS®) Pediatric Global Health 7 scores, Pain Interference, Physical Function scores for Mobility, and Upper Extremity Function were commonly worse than 95% of the general pediatric population. CONCLUSIONS: In its inaugural year, 119 JDM patients were successfully enrolled in participapte in the New CARRA Registy. This registry will provide the necessary foundation to advance clinical research to improve outcomes using traditional measures and patient reported outcomes. With the CARRA biorepository, this infrastructure will enable future translational research. Together, these efforts may aid in future clinical trials, including comparative effectiveness trials.

Cross-Tissue Transcriptomic Analysis Leveraging Machine Learning Approaches Identifies New Biomarkers for Rheumatoid Arthritis.

There is an urgent need to identify biomarkers for diagnosis and disease activity monitoring in rheumatoid arthritis (RA). We leveraged publicly available microarray gene expression data in the NCBI GEO database for whole blood (N=1,885) and synovial (N=284) tissues from RA patients and healthy controls. We developed a robust machine learning feature selection pipeline with validation on five independent datasets culminating in 13 genes: TNFAIP6, S100A8, TNFSF10, DRAM1, LY96, QPCT, KYNU, ENTPD1, CLIC1, ATP6V0E1, HSP90AB1, NCL and CIRBP which define the RA score and demonstrate its clinical utility: the score tracks the disease activity DAS28 (p = 7e-9), distinguishes osteoarthritis (OA) from RA (OR 0.57, p = 8e-10) and polyJIA from healthy controls (OR 1.15, p = 2e-4) and monitors treatment effect in RA (p = 2e-4). Finally, the immunoblotting analysis of six proteins on an independent cohort confirmed two proteins, TNFAIP6/TSG6 and HSP90AB1/HSP90.

Access to Care and Diagnostic Delays in Juvenile Dermatomyositis: Results From the Childhood Arthritis and Rheumatology Research Alliance Legacy Registry.

OBJECTIVE: To determine factors associated with diagnostic delays and outcomes in juvenile dermatomyositis (JDM) in the Childhood Arthritis and Rheumatology Research Alliance Legacy Registry (CLR). METHODS: This was a cross-sectional study of subjects aged 0 to 17 years with JDM enrolled to the CLR from 2010 to 2015. Access to care was measured by calculating the distance from the subject zip code of residence to the treating pediatric rheumatology center and determining the state density of pediatric rheumatologists based on the 2015 American College of Rheumatology Workforce Study. Delay was categorized as early (<30 days), typical (1-3 months), moderate (3-12 months), and severe (>12 months). Ordered generalized additive models were used to determine the association between these measures and diagnostic delays. RESULTS: The median time to diagnosis was 3.1 months; 37.2% of patients experienced moderate delays, and 14.6% experienced severe delays. In a univariate analysis, younger age of disease onset and male sex were associated with delays. Using a generalized additive model accounting for age, sex, race, and ethnicity, increasing distance from treating pediatric rheumatologist and younger age at disease onset were associated with diagnostic delay. There was no association between the state density of rheumatologists and diagnostic delays in this model. CONCLUSION: In the CLR, we found moderate to severe diagnostic delays in the majority of subjects with JDM. Our data suggest that access to care, measured as the distance traveled to treating rheumatologist, is an important factor associated with delays in care but also highlight age as a contributing factor, suggesting that JDM may be less recognizable in young children.

Parent Perspectives on Addressing Emotional Health for Children and Young Adults With Juvenile Myositis.

OBJECTIVE: To assess parent perspectives regarding the emotional health impact of juvenile myositis (JM) on patients and families, and to assess preferences for emotional health screening and interventions. METHODS: Parents of children and young adults with JM were purposively sampled for participation in focus groups at the Cure JM Foundation National Family Conference in 2018. Groups were stratified by patient age group (6-12, 13-17, and 18-21 years), and conversations were audiorecorded, transcribed verbatim, and co-coded via content analysis, with subanalysis by age group. A brief survey assessed preferences for specific emotional health interventions. RESULTS: Forty-five parents participated in 6 focus groups. Themes emerged within 2 domains: emotional challenges, and screening and interventions. Themes for emotional challenges comprised the impact of JM on: 1) patient emotional health, particularly depression and anxiety; 2) parent emotional health characterized by sadness, grief, anger, guilt, and anxiety; and 3) family dynamics, including significant sibling distress. Subanalysis revealed similar themes across age groups, but the theme of resiliency emerged specifically for young adults. Themes for emotional health screening and interventions indicated potential issues with patient transparency, several barriers to resources, the facilitator role of rheumatology providers, and preferred intervention modalities of online and in-person resources, with survey responses most strongly supporting child/parent counseling and peer support groups. CONCLUSION: JM is associated with intense patient and family distress, although resiliency may emerge by young adulthood. Despite existing barriers, increasing access to counseling, peer support groups, and online resources with rheumatology facilitation may be effective intervention strategies.

Risk factors associated with Pneumocystis jirovecii pneumonia in juvenile myositis in North America.

OBJECTIVES: Pneumocystis jirovecii pneumonia (PJP) is associated with significant morbidity and mortality in adult myositis patients; however, there are few studies examining PJP in juvenile myositis [juvenile idiopathic inflammatory myopathy (JIIM)]. The purpose of this study was to determine the risk factors and clinical phenotypes associated with PJP in JIIM. METHODS: An research electronic data capture (REDCap) questionnaire regarding myositis features, disease course, medications and PJP infection characteristics was completed by treating physicians for 13 JIIM patients who developed PJP (PJP+) from the USA and Canada. Myositis features and medications were compared with 147 JIIM patients without PJP (PJP-) from similar geographic regions who enrolled in National Institutes of Health natural history studies. RESULTS: PJP+ patients were more often of Asian ancestry than PJP- patients [odds ratio (OR) 8.7; 95% CI 1.3, 57.9]. Anti- melanoma differentiation associated protein 5 (MDA5) autoantibodies (OR 12.5; 95% CI 3.0, 52.4), digital infarcts (OR 43.8; 95% CI 4.2, 460.2), skin ulcerations (OR 12.0; 95% CI 3.5, 41.2) and interstitial lung disease (OR 10.6; 95% CI 2.1, 53.9) were more frequent in PJP+ patients. Before PJP diagnosis, patients more frequently received pulse steroids, rituximab and more immunosuppressive therapy compared with PJP- patients. Seven PJP+ patients were admitted to the intensive care unit and four patients died due to PJP or its complications. CONCLUSIONS: PJP is a severe infection in JIIM that can be associated with mortality. Having PJP was associated with more immunosuppressive therapy, anti-MDA5 autoantibodies, Asian race and certain clinical features, including digital infarcts, cutaneous ulcerations and interstitial lung disease. Prophylaxis for PJP should be considered in juvenile myositis patients with these features.

Outcomes of Chronic Phase Chronic Myeloid Leukemia after Treatment with Multiple Tyrosine Kinase Inhibitors.

We sought to evaluate the outcomes of chronic phase (CP) chronic myeloid leukemia (CML) in an era where five tyrosine kinase inhibitors (TKIs) are commercially available for the treatment of CML. Records of patients diagnosed with CP CML, treated with TKIs and referred to our center were reviewed. Between January 2005 and April 2016, 206 patients were followed for a median of 48.8 (1.4-190.1) months. A total of 76 (37%) patients received one TKI, 73 (35%) received two TKIs and 57 (28%) were exposed to >3 TKIs (3 TKIs, n = 33; 4 TKIs, n = 17; 5 TKIs, n = 7). Nineteen (9.2%) patients progressed to advanced phases of CML (accelerated phase, n = 6; myeloid blastic phase, n = 4; lymphoid blastic phase, n = 9). One third (n = 69) achieved complete molecular response (CMR) at first-line treatment. An additional 55 patients achieved CMR after second-line treatment. Twenty-five patients (12.1%) attempted TKI discontinuation and 14 (6.8%) stopped TKIs for a median of 6.3 months (range 1-53.4). The 10-year progression-free survival and overall survival (OS) rates were 81% and 87%, respectively. OS after 10-years, based on TKI exposure, was 100% (1 TKI), 82% (2 TKIs), 87% (3 TKIs), 75% (4 TKIs) and 55% (5 TKIs). The best OS was observed in patients tolerating and responding to first line TKI, but multiple TKIs led patients to gain treatment-free remission.

Advances Toward Precision Medicine in Juvenile Dermatomyositis.

PURPOSE OF REVIEW: We seek to provide a summary of the recent advances in juvenile dermatomyositis (JDM) that are moving the field toward precision care and personalized medicine for this uncommon condition. RECENT FINDINGS: There has been a recent international focus on developing uniform classification, disease monitoring, and treatment for juvenile dermatomyositis. In addition, there has been a steady development of translational studies to determine the genetic determinants, transcriptomic profiles, and immune cell phenotypes in JDM. Recent work toward standardization of disease classification, monitoring, and assessments together with advances in science, technology, and computing will facilitate the advancement toward true precision and personalized medicine in juvenile dermatomyositis in the near future.

Gene Expression Meta-Analysis Reveals Concordance in Gene Activation, Pathway, and Cell-Type Enrichment in Dermatomyositis Target Tissues.

OBJECTIVE: We conducted a comprehensive gene expression meta-analysis in dermatomyositis (DM) muscle and skin tissues to identify shared disease-relevant genes and pathways across tissues. METHODS: Six publicly available data sets from DM muscle and two from skin were identified. Meta-analysis was performed by first processing data sets individually then cross-study normalization and merging creating tissue-specific gene expression matrices for subsequent analysis. Complementary single-gene and network analyses using Significance Analysis of Microarrays (SAM) and Weighted Gene Co-expression Network Analysis (WGCNA) were conducted to identify genes significantly associated with DM. Cell-type enrichment was performed using xCell. RESULTS: There were 544 differentially expressed genes (FC ≥ 1.3, q < 0.05) in muscle and 300 in skin. There were 94 shared upregulated genes across tissues enriched in type I and II interferon (IFN) signaling and major histocompatibility complex (MHC) class I antigen-processing pathways. In a network analysis, we identified eight significant gene modules in muscle and seven in skin. The most highly correlated modules were enriched in pathways consistent with the single-gene analysis. Additional pathways uncovered by WGCNA included T-cell activation and T-cell receptor signaling. In the cell-type enrichment analysis, both tissues were highly enriched in activated dendritic cells and M1 macrophages. CONCLUSION: There is striking similarity in gene expression across DM target tissues with enrichment of type I and II IFN pathways, MHC class I antigen-processing, T-cell activation, and antigen-presenting cells. These results suggest IFN-γ may contribute to the global IFN signature in DM, and altered auto-antigen presentation through the class I MHC pathway may be important in disease pathogenesis.

Autoimmune Cytopenias in Pediatric Hematopoietic Cell Transplant Patients.

Background: Autoimmune cytopenias (AICs) are potentially life-threatening complications following hematopoietic cell transplantation (HCT), yet little is understood about the mechanism by which they develop. We hypothesized that discordant B cell and T cell recovery is associated with AICs in transplant patients, and that this might differ based on transplant indication. Methods: In this case control study of children who underwent HCT at our institution, we evaluated the clinical and transplant characteristics of subjects who developed AICs compared to a control group matched by transplant indication and donor type. In cases, we analyzed the state of immune reconstitution, including B cell recovery, T cell recovery, and chimerism, immediately prior to AIC onset. Subjects were stratified by primary indication for transplant as malignancy (n = 7), primary immune deficiency (PID, n = 9) or other non-malignant disease (n = 4). We then described the treatment and outcomes for 20 subjects who developed AICs. Results: In our cohort, cases were older than controls, were more likely to receive a myeloablative conditioning regimen and had a significantly lower prevalence of chronic GVHD. There were distinct differences in the state of immune recovery based on transplant indication. None of the patients (0/7) transplanted for primary malignancy had T cell recovery at AIC onset compared to 71% (5/7) of patients with PID and 33% (1/3) of patients with non-malignant disease. The subset of patients with PID and non-malignant disease who achieved T cell reconstitution (6/6) prior to AIC onset, all demonstrated mixed or split chimerism. Subjects with AIHA or multi-lineage cytopenias had particularly refractory courses with poor treatment response to IVIG, steroids, and rituximab. Conclusions: These results highlight the heterogeneity of AICs in this population and suggest that multiple mechanisms may contribute to the development of post-transplant AICs. Patients with full donor chimerism may have early B cell recovery without proper T cell regulation, while patients with mixed or split donor chimerism may have residual host B or plasma cells making antibodies against donor blood cells. A prospective, multi-center trial is needed to develop personalized treatment approaches that target the immune dysregulation present and improve outcomes in patients with post-transplant AICs.

Association of Short-Term Ultraviolet Radiation Exposure and Disease Severity in Juvenile Dermatomyositis: Results From the Childhood Arthritis and Rheumatology Research Alliance Legacy Registry.

OBJECTIVE: Ultraviolet (UV) radiation is considered to be an important environmental factor in the clinical course of children with juvenile dermatomyositis (DM). We aimed to evaluate the association between UV radiation and severe disease outcomes in juvenile DM. METHODS: This is a cross-sectional study of patients with juvenile DM enrolled in the US multicenter Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry from 2010 to 2015. The mean UV index (UVI) in the calendar month prior to symptom onset in each subject's zip code was calculated from daily satellite solar noon measurements. Multivariable logistic regression was used to model the relationship between the mean UVI and calcinosis as well as other outcomes of severe disease. Covariates included sex, race, age, time to diagnosis, disease duration, and latitude. RESULTS: In a multivariable model, there was no association between the mean UVI and calcinosis. African American race was associated with a 3-fold greater odds of calcinosis. However, there was a significant statistical interaction between race and mean UVI. Accounting for this interaction, the odds of calcinosis markedly decreased in African American subjects and steadily increased in non-African American subjects over a range of increasing the mean UVI. Higher mean UVI was associated with decreased odds of using biologics or nonmethotrexate disease-modifying antirheumatic drugs and skin ulceration. CONCLUSION: We described a novel association between UV radiation, calcinosis, and race in a large cohort of patients with juvenile DM. This study furthers our knowledge of the role of UV radiation in the clinical course of juvenile DM and highlights the complex interplay between genes and environment in the clinical phenotypes and development of calcinosis in children with juvenile DM.

Autoimmune haemolytic anaemia and autoimmune thrombocytopenia in childhood-onset systemic lupus erythematosus: updates on pathogenesis and treatment.

PURPOSE OF REVIEW: Autoimmune haemolytic anaemia (AIHA) and autoimmune thrombocytopenia are common complications of childhood-onset lupus, which may be life-threatening. A greater understanding of the pathogenesis of these haematologic manifestations will enhance our understanding of the biology of systemic lupus erythematosus (SLE) and inform the identification of novel treatments. RECENT FINDINGS: The mechanisms underlying AIHA and autoimmune thrombocytopenia are incompletely understood and likely multifactorial. Although the development of auto-antibodies is central to the disease process, recent studies have demonstrated the importance of cytokines in the underlying pathologic process. In-vitro and in-vivo evidence points to a role for IL17 in the pathogenesis of AIHA, which involves loss of tolerance to red cell auto-antigens and the development of autoantibodies. Sirolimus, an mTor inhibitor, has benefited patients with primary autoimmune cytopenias, possibly by stimulating T regulatory cells, and may also have efficacy for SLE-associated cytopenias. Similarly, low-dose recombinant human IL-2 therapy has shown promising results for improving platelet counts in patients with autoimmune thrombocytopenia, possibly by restoring the balance between T regulatory, T helper and Th17 cells. SUMMARY: The emergence of new agents directed at restoring immune dysregulation hold promise for the treatment of AIHA and autoimmune thrombocytopenia and should provide better tolerated alternatives to high-dose corticosteroids.

Gene therapy for haemophilia.

BACKGROUND: Haemophilia is a genetic disorder which is characterized by spontaneous or provoked, often uncontrolled, bleeding into joints, muscles and other soft tissues. Current methods of treatment are expensive, challenging and involve regular administration of clotting factors. Gene therapy has recently been prompted as a curative treatment modality. OBJECTIVES: To evaluate the safety and efficacy of gene therapy for treating people with haemophilia A or B. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis & Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.Date of last search: 06 November 2014. SELECTION CRITERIA: Eligible trials included randomised or quasi-randomised clinical trials, including controlled clinical trials comparing gene therapy (with or without standard treatment) with standard treatment (factor replacement) or other 'curative' treatment such as stem cell transplantation individuals with haemophilia A or B of all ages who do not have inhibitors to factor VIII or IX. DATA COLLECTION AND ANALYSIS: No trials of gene therapy for haemophilia were found. MAIN RESULTS: No trials of gene therapy for haemophilia were identified. AUTHORS' CONCLUSIONS: No randomised or quasi-randomised clinical trials of gene therapy for haemophilia were identified. Thus, we are unable to determine the effects of gene therapy for haemophilia. Gene therapy for haemophilia is still in its nascent stages and there is a need for well-designed clinical trials to assess the long-term feasibility, success and risks of gene therapy for people with haemophilia.

ITP in children: pathophysiology and current treatment approaches.

Primary immune thrombocytopenia (ITP) is one of the most common bleeding disorders of childhood. In most cases, it presents with sudden widespread bruising and petechiae in an otherwise well child. Thought to be mainly a disorder of antibody-mediated platelet destruction, ITP can be self-limited or develop into a chronic condition. In this review, we discuss current concepts of the pathophysiology and treatment approaches to pediatric ITP.