Translation and validation in Italian of the methotrexate intolerance severity score for children and adults with arthritis.

OBJECTIVES: Methotrexate (MTX) is the most used drug to treat children and adults with arthritis and its use is burdened by adverse effects. The MTX intolerance severity score (MISS) was developed in English to identify patients who are intolerant to MTX. The aim of this study was to translate and validate the MISS in Italian. METHODS: The Italian version of the MISS was developed following the "guidelines for process of cross-cultural adaptation of self-reported measures". The Italian version of the MISS was validated in 125 patients with juvenile idiopathic arthritis (JIA) followed at the Rheumatology Unit of Bambino Gesù Children Hospital. We assessed the construct validity and calculated the internal consistency of the Italian MISS. We performed ROC analysis to assess the overall performance of the Italian MISS. RESULTS: We translated and adapted the MISS to the Italian language. The Italian MISS showed a very good internal consistency as shown by a Cronbach α of 0.87 (95% CI, 0.84-0.90) and a composite reliability of 0.89 (95% CI, 0.83-0.91).The Cohen's κ was 0.81 (95% CI, 0.71-0.91), suggesting a very good construct validity. The ROC analysis showed an area under the curve (AUC) of 0.97 (95% CI, 0.93-0.99). A threshold of 6 to define intolerant patients, showed a sensitivity of 98.3% and specificity of 81.2%. CONCLUSIONS: We developed the Italian version of the MISS and showed its validity and reliability to identify patients intolerant to MTX in clinical practice and in a research setting.

Autologous CD19-Targeting CAR T Cells in a Patient With Refractory Juvenile Dermatomyositis.

OBJECTIVE: The aim of this study is to report the safety and efficacy of CD19-targeting chimeric antigen receptor (CAR) T cells in a child with refractory juvenile dermatomyositis (JDM). METHODS: We describe a 12-year-old White male with severe, chronically active JDM refractory to multiple immunosuppressive treatment lines, including B cell depletion with rituximab. The patient received a single infusion of fresh, autologous, second-generation anti-CD19 CAR T cell product (lentiviral vector) manufactured on the Prodigy device (1 × 106 CAR T cells/kg), after lymphodepletion with cyclophosphamide (1,000 mg/m2 over two days) and fludarabine (90 mg/m2 over three days). Immunosuppressive and glucocorticoid treatment were withdrawn before leukapheresis and CAR T cell infusion. RESULTS: Before anti-CD19 CAR T cell therapy, the patient had persistent severe skin and muscular disease activity. CAR T cells expanded significantly (peak at day 7, 32.69 cells/µL). Complete B cell depletion was documented on day 5 in the blood and at week 2 in the bone marrow. The patient presented with fever as part of mild cytokine release syndrome (grade 1), transient anemia (grade 2), and neutropenia (grade 4). Neither infection nor neurotoxicity were observed. Laboratory tests, magnetic resonance imaging, Physician Global Assessment of disease activity, Childhood Myositis Assessment Scale, and Cutaneous Assessment Tool for myositis were performed at baseline and follow-up to assess treatment response, showing remarkable progressive improvement that persists over time, even after B cell recovery. CONCLUSION: This patient with JDM with severe chronic disease, refractory to multiple treatments, achieved sustained B cell depletion and ongoing immunosuppressive drug-free clinical and radiologic improvement eight months after a single infusion of anti-CD19 CAR T cells.

Hyperactivation and altered selection of B cells in patients with paediatric Sjogren's syndrome.

OBJECTIVES: Paediatric Sjögren's syndrome (pSS) is a rare chronic autoimmune disorder, characterised by inflammation of exocrine glands. B cell hyperactivation plays a central role in adult-onset Sjogren. This study was designed to analyse B cell and T cell phenotype, levels of BAFF, and selection of autoreactive B cells in patients with pSS. METHODS: A total of 17 patients diagnosed with pSS and 13 healthy donors (controls) comparable for age were enrolled in the study. B cell and T cell subsets and frequency of autoreactive B cells in peripheral blood were analysed by flow cytometry. Levels of BAFF were analysed by ELISA. RESULTS: The relative frequency of total B cells, transitional, naïve and switched memory B cells was similar between pSS patients and controls. In patients with pSS, we observed a reduction in the frequency of unswitched memory B cells, an increased frequency of atypical memory B cells and an expansion of PD1hi CXCR5- T peripheral helper cells. Levels of BAFF were higher in patients with pSS compared with controls and correlated with serum levels of total IgG and titres of anti-Ro antibodies. The frequency of autoreactive B cells in the transitional, unswitched memory and plasmablast compartment was significantly higher in pSS patients than in controls. CONCLUSIONS: Our results point to a hyperactivation of B cells in pSS. Current therapies do not seem to affect B cell abnormalities, suggesting that novel therapies targeting specifically B cell hyperactivation need to be implemented for paediatric patients.

Identification of biomarkers in patients with rheumatoid arthritis responsive to DMARDs but with progressive bone erosion.

Introduction: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that may cause joint destruction and disability. The pharmacological treatment of RA aims at obtaining disease remission by effectively ceasing joint inflammation and arresting progressive bone erosions. Some patients present bone lesions accrual even after controlling joint inflammation with current therapies. Our study aimed to analyze lymphocyte subsets and levels of circulating cytokines in patients with RA with progressive bone erosions. Methods: We enrolled 20 patients with a diagnosis of RA and 12 healthy donors (HD). Patients with RA were divided into patients with bone erosions (RA-BE+) and without bone erosions (RA-BE-). Lymphocyte subsets in peripheral blood were evaluated by flow cytometry. Circulating cytokines levels were evaluated by protein array. Results: The distribution of lymphocyte subsets was not able to separate HD from AR patients and RA-BE+ and RA-BE- in cluster analysis. We observed a significant expansion of CXCR5- PD1+ T peripheral helper cells (Tph cells) and a reduction in both total memory B cells and switched memory B cells in RA patients compared to HD. We observed an expansion in the frequency of total B cells in RA-BE+ patients compared to RA-BE- patients. Unsupervised hierarchical clustering analysis of 39 cytokines resulted in a fairly good separation of HD from RA patients but not of RA-BE+ patients from RA-BE- patients. RA-BE+ patients showed significantly higher levels of IL-11 and IL-17A than RA-BE- patients. Conclusion: We show that patients with progressive erosive disease are characterized by abnormalities in B cells and in cytokines with a proven role in bone reabsorption. Understanding the role played by B cells and the cytokine IL-11 and IL-17A in progressive erosive disease can help identify novel biomarkers of erosive disease and design treatment approaches aimed at halting joint damage in RA.

Persistently active interferon-γ pathway and expansion of T-bet+ B cells in a subset of patients with childhood-onset systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease causing significant morbidity and mortality, despite important improvements in its management in the last decades. The objective of this work is to investigate the role of IFN-γ in the pathogenesis of childhood-onset systemic lupus erythematosus (cSLE), evaluating the crosstalk between IFN-α and IFN-γ and the expression of T-bet, a transcription factor induced by IFN-γ, in B cells of patients with cSLE. Expression levels of both IFN-α and IFN-γ-induced genes were upregulated in patients with cSLE. We found increased serum levels of CXCL9 and CXCL10 in patients with cSLE. Type I IFN score decreased with initiation of immunosuppressive treatment; conversely, type II IFN score and levels of CXCL9 were not significantly affected by immunosuppressive treatment. Type II IFN score and CXCL9 were significantly higher in patients with lupus nephritis. We observed the expansion of a population of naïve B cells expressing T-bet in a cluster of patients with cSLE. IFN-γ, but not IFN-α, induced the expression of T-bet in B cells. Our data suggest that IFN-γ is hyperactive in cSLE, especially in patients with lupus nephritis, and it is not modulated by therapy. Our data reinforce the potential of IFN-γ as a therapeutic target in SLE.

Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestations.

Common variable immune deficiency (CVID) is a heterogeneous disorder characterized by recurrent infections, low levels of serum immunoglobulins, and impaired vaccine responses. Autoimmune manifestations are common, but B cell central and peripheral selection mechanisms in CVID are incompletely understood. Here, we find that receptor editing, a measure of central tolerance, is increased in transitional B cells from CVID patients and that these cells have a higher immunoglobulin κ:λ ratio in CVID patients with autoimmune manifestations than in those with infection only. Contrariwise, the selection pressure in the germinal center on CD27bright memory B cells is decreased in CVID patients with autoimmune manifestations. Finally, functionally, T cell-dependent activation showed that naive B cells in CVID patients are badly equipped for activation and induction of mismatch repair genes. We conclude that central tolerance is functional whereas peripheral selection is defective in CVID patients with autoimmune manifestations, which could underpin the development of autoimmunity.

An Italian Multicenter Study on Anti-NXP2 Antibodies: Clinical and Serological Associations.

The identification of anti-NXP2 antibodies is considered a serological marker of dermatomyositis (DM), with calcinosis, severe myositis and, in some reports, with cancer. Historically, these associations with anti-NXP2 antibodies have been detected by immunoprecipitation (IP), but in the last few years commercial immunoblotting assays have been released. The aim of this collaborative project was to analyse the clinical features associated to anti-NXP2 antibodies, both with commercial line blot (LB) and IP. Myositis-specific and myositis-associated autoantibodies were detected in single centres by commercial line blot (LB); available sera were evaluated in a single centre by protein and RNA immunoprecipitation (IP), and IP-Western blot. Sixty patients anti-NXP2+ (NXP2+) positive by LB were compared with 211 patients anti-NXP2 negative with idiopathic inflammatory myositis (IIM). NXP2+ showed a younger age at IIM onset (p = 0.0014), more frequent diagnosis of dermatomyositis (p = 0.026) and inclusion-body myositis (p = 0.009), and lower rate of anti-synthetase syndrome (p < 0.0001). As for clinical features, NXP2+ more frequently develop specific skin manifestations and less frequently features related with overlap myositis and anti-synthetase syndrome. IP confirmed NXP2 positivity in 31 of 52 available sera (62%). Most clinical associations were confirmed comparing NXP2 LB+/IP+ versus NXP2-negative myositis, with the following exceptions: inclusion-body myositis diagnosis was not detected, whilst dysphagia and myositis were found more frequently in NXP2 LB+/IP+ patients. The 21 LB+ /IP-myositis patients did not show differences in clinical features when compared with the NXP2-myositis patients and more frequently displayed multiple positivity at LB. Risk of developing cancer-associated myositis was similar between NXP2-positive and NXP2-negative myositis patients, either when detected by LB or IP. Protein-IP confirmed NXP2 antibodies in nearly 60% of sera positive for the same specificity with commercial assay. Double-positive cases rarely occurred in myositis patients with a clinical diagnosis other than dermatomyositis. Patients only positive by LB (LB+/IP-) did not display clinical features typical of NXP2. NXP2 positivity by LB should be confirmed by other methods in order to correctly diagnose and characterize patients affected by idiopathic inflammatory myositis.

Targeting interferon-γ in hyperinflammation: opportunities and challenges.

Interferon-γ (IFNγ) is a pleiotropic cytokine with multiple effects on the inflammatory response and on innate and adaptive immunity. Overproduction of IFNγ underlies several, potentially fatal, hyperinflammatory or immune-mediated diseases. Several data from animal models and/or from translational research in patients point to a role of IFNγ in hyperinflammatory diseases, such as primary haemophagocytic lymphohistiocytosis, various forms of secondary haemophagocytic lymphohistiocytosis, including macrophage activation syndrome, and cytokine release syndrome, all of which are often managed by rheumatologists or in consultation with rheumatologists. Given the effects of IFNγ on B cells and T follicular helper cells, a role for IFNγ in systemic lupus erythematosus pathogenesis is emerging. To improve our understanding of the role of IFNγ in human disease, IFNγ-related biomarkers that are relevant for the management of hyperinflammatory diseases are progressively being identified and studied, especially because circulating levels of IFNγ do not always reflect its overproduction in tissue. These biomarkers include STAT1 (specifically the phosphorylated form), neopterin and the chemokine CXCL9. IFNγ-neutralizing agents have shown efficacy in the treatment of primary haemophagocytic lymphohistiocytosis in clinical trials and initial promising results have been obtained in various forms of secondary haemophagocytic lymphohistiocytosis, including macrophage activation syndrome. In clinical practice, there is a growing body of evidence supporting the usefulness of circulating CXCL9 levels as a biomarker reflecting IFNγ production.

The clinical phenotype of systemic sclerosis patients with anti-PM/Scl antibodies: results from the EUSTAR cohort.

OBJECTIVE: To evaluate clinical associations of anti-PM/Scl antibodies in patients with SSc in a multicentre international cohort, with particular focus on unresolved issues, including scleroderma renal crisis (RC), malignancies, and functional outcome of interstitial lung disease (ILD). METHODS: (1) Analysis of SSc patients from the EUSTAR database: 144 anti-PM/Scl+ without SSc-specific autoantibodies were compared with 7202 anti-PM/Scl-, and then to 155 anti-Pm/Scl+ with SSc-specific antibodies. (2) Case-control study: additional data were collected for 165 anti-PM/Scl+ SSc patients (85 from the EUSTAR registry) and compared with 257 anti-PM/Scl- SSc controls, matched for sex, cutaneous subset, disease duration and age at SSc onset. RESULTS: Patients with isolated anti-PM/Scl+, as compared with anti-Pm/Scl-, had higher frequency of muscle involvement, ILD, calcinosis and cutaneous signs of DM, but similar frequency of SRC and malignancies (either synchronous with SSc onset or not). The presence of muscle involvement was associated with a more severe disease phenotype. Although very frequent, ILD had a better functional outcome in cases than in controls. In patients with both anti-PM/Scl and SSc-specific antibodies, a higher frequency of typical SSc features than in those with isolated anti-PM/Scl was observed. CONCLUSION: The analysis of the largest series of anti-PM/Scl+ SSc patients so far reported helps to delineate a specific clinical subset with muscle involvement, cutaneous DM, calcinosis and ILD characterized by a good functional outcome. SRC and malignancies do not seem to be part of this syndrome.

Multidisciplinary Approach in the Early Detection of Undiagnosed Connective Tissue Diseases in Patients With Interstitial Lung Disease: A Retrospective Cohort Study.

Interstitial lung disease (ILD) encompasses a wide range of parenchymal lung pathologies with different clinical, histological, radiological, and serological features. Follow-up, treatment, and prognosis are strongly influenced by the underlying pathogenesis. Considering that an ILD may complicate the course of any connective tissue disease (CTD) and that CTD's signs are not always easily identifiable, it could be useful to screen every ILD patient for a possible CTD. The recent definition of interstitial pneumonia with autoimmune features is a further confirmation of the close relationship between CTD and ILD. In this context, the multidisciplinary approach is assuming a growing and accepted role in the correct diagnosis and follow-up, to as early as possible define the best therapeutic strategy. However, despite clinical advantages, until now, the pathways of the multidisciplinary approach in ILD patients are largely heterogeneous across different centers and the best strategy to apply is still to be established and validated. Aims of this article are to describe the organization of our multidisciplinary group for ILD, which is mainly focused on the early identification and management of CTD in patients with ILD and to show our results in a 1 year period of observation. We found that 15% of patients referred for ILD had an underlying CTD, 33% had interstitial pneumonia with autoimmune feature, and 52% had ILD without detectable CTD. Furthermore, we demonstrated that the adoption of a standardized strategy consisting of a screening questionnaire, specific laboratory tests, and nailfold videocapillaroscopy in all incident ILD proved useful in making the right diagnosis.

The Interplay between CD27dull and CD27bright B Cells Ensures the Flexibility, Stability, and Resilience of Human B Cell Memory.

Memory B cells (MBCs) epitomize the adaptation of the immune system to the environment. We identify two MBC subsets in peripheral blood, CD27dull and CD27bright MBCs, whose frequency changes with age. Heavy chain variable region (VH) usage, somatic mutation frequency replacement-to-silent ratio, and CDR3 property changes, reflecting consecutive selection of highly antigen-specific, low cross-reactive antibody variants, all demonstrate that CD27dull and CD27bright MBCs represent sequential MBC developmental stages, and stringent antigen-driven pressure selects CD27dull into the CD27bright MBC pool. Dynamics of human MBCs are exploited in pregnancy, when 50% of maternal MBCs are lost and CD27dull MBCs transit to the more differentiated CD27bright stage. In the postpartum period, the maternal MBC pool is replenished by the expansion of persistent CD27dull clones. Thus, the stability and flexibility of human B cell memory is ensured by CD27dull MBCs that expand and differentiate in response to change.

One year in review 2019: idiopathic inflammatory myopathies.

The idiopathic inflammatory myopathies (IIMs) are a rare group of immune, systemic diseases characterised by muscle inflammation and frequently by extramuscular involvement. IIMs are heterogeneous with generally a chronic or subacute onset, which vary from less severe to more serious manifestations, not always easy to diagnose and even less to manage. In the past year, many studies have been published in order to clarify disease pathogenesis and improve patient management and treatment.The purpose of this review article is to provide an overview of the new insights in pathogenesis, serological findings, clinical manifestations and treatment of IIMs, summarising the most relevant studies published over the last year.

Pulmonary emphysema not combined with lung fibrosis in systemic sclerosis.

Interstitial Lung Disease (ILD) is a common finding of Systemic Sclerosis (SSc) mainly presenting in the form of Nonspecific Interstitial Pneumonia (NSIP) and deeply affecting patients' prognosis. Beside NSIP, other types of ILD have been reported. The most recently described pattern is the so-called Combined-pulmonary emphysema and lung fibrosis, characterized by the coexistence of both upper lobes centrilobular and paraseptal emphysema and lower lobes ILD. We presented three cases of patients with SSc, in which High Resolution Computed Tomography examinations showed emphysema with atypical distribution and radiological presentation, without or with mild signs of fibrosing lung disease, that stabilized after immunosuppressive treatment.

An unusual presentation of purine nucleoside phosphorylase deficiency mimicking systemic juvenile idiopathic arthritis complicated by macrophage activation syndrome.

BACKGROUND: Systemic juvenile idiopathic arthritis (sJIA) is an inflammatory condition that presents with fever, rash and arthritis. At onset systemic features are predominant and the diagnosis may be a challenge. Secondary hemophagocytic lymphohistiocytosis (sHLH) forms may be associated with different disorders, including rheumatic diseases, and this form is called macrophage activation syndrome (MAS). CXCL9 levels, a chemokine induced by IFNγ, are significantly elevated in patients with sHLH or MAS and are correlated with laboratory features of disease activity. High levels of IL-18 have been reported in patients with MAS during sJIA, as well as in some patients with sHLH and IL-18 is indeed known to induce IFNγ production. FINDINGS: We report a patient with a clinical presentation highly suggestive for systemic juvenile idiopathic arthritis (sJIA) onset complicated by MAS, and was later diagnosed with purine nucleoside phosphorylase (PNP)-deficiency with HLH. Some unusual features appeared when HLH was controlled and further investigations provided the correct diagnosis. Serum CXCL9 and IL-18 levels were found markedly elevated at disease onset, during the active phase of MAS and decreased progressively during the course. CONCLUSION: The reported case underlines the potential difficulties in discriminating sJIA from other causes of systemic inflammation. Furthermore, this supports the notion that especially in young children with a sJIA-like disease other mimicking conditions should be actively sought for. CXCL9 and IL-18 levels suggested that patients with PNP-deficiency may have a subclinical activation of the IFNγ pathway and indeed they are predisposed to develop sHLH.

Loss of an IgG plasma cell checkpoint in patients with lupus.

BACKGROUND: IgG antinuclear antibodies (ANAs) are a feature of several autoimmune diseases. These antibodies arise through defects in central or peripheral tolerance checkpoints. The specific checkpoints breached in patients with autoimmune disease are not fully understood. OBJECTIVES: We sought to study whether autoreactive plasma cells in lupus models and patients with systemic lupus erythematosus (SLE) arise as a consequence of defective antigen-specific selection or a global enhancement of IgG plasma cell differentiation. METHODS: We optimized and validated a novel technique to detect naturally occurring ANA+ B cells and plasma cells. RESULTS: We observed a major checkpoint for generation of ANA+ IgG+ plasma cells in both nonautoimmune mice and healthy human subjects. Interestingly, we observed increased numbers of ANA+ IgG+ plasma cells despite normal tolerance checkpoints in immature and naive B cells of lupus-prone MRL/lpr and NZB/W mice, as well as patients with SLE. This increase was due to increased numbers of total IgG+ plasma cells rather than lack of selection against ANA+ plasma cells. CONCLUSION: Using a method that permits quick and accurate quantification of autoreactive B cells and plasma cells in vivo within a native B-cell repertoire in mice and human subjects, we demonstrate the importance of a checkpoint that restricts the generation of IgG plasma cells and protects against IgG ANAs. Our observations suggest a fundamentally revised understanding of SLE: that it is a disease of aberrant B-cell differentiation rather than a defect in antigen-specific B-cell tolerance.

Muscle Expression of Type I and Type II Interferons Is Increased in Juvenile Dermatomyositis and Related to Clinical and Histologic Features.

OBJECTIVE: To evaluate the expression of type I interferon (IFNα/ß)- and type II IFN (IFNγ)-inducible genes in muscle biopsy specimens from patients with juvenile dermatomyositis (DM) and to correlate their expression levels with histologic and clinical features. METHODS: Expression levels of IFN-inducible genes and proinflammatory cytokines were assessed by quantitative polymerase chain reaction in muscle biopsy specimens from patients with juvenile DM (n = 39), patients with Duchenne's muscular dystrophy (DMD), and healthy controls. Muscle biopsy sections were stained and scored for severity of histopathologic features. The charts of patients with juvenile DM were reviewed for clinical features at the time of sampling and long-term outcomes. RESULTS: Muscle expression levels of IFNα/ß-inducible genes (type I IFN score), IFNγ, IFNγ-inducible genes (type II IFN score), and tumor necrosis factor (TNF) were significantly higher in juvenile DM patients not receiving glucocorticoid therapy before muscle biopsy (n = 27) compared to DMD patients (n = 24) (type I IFN score, P < 0.0001; type II IFN score, P < 0.001; TNF, P < 0.05) and healthy controls (n = 4) (type I IFN score, P < 0.01; type II IFN score, P < 0.01; TNF, P < 0.05). Immunofluorescence staining of muscle biopsy sections from untreated juvenile DM patients showed increased immunoreactivity for IFNγ and HLA class II molecules compared to controls. Type I and type II IFN scores were correlated with typical histopathologic features of juvenile DM muscle biopsy samples, such as infiltration of endomysial CD3+ cells (type I IFN score, r = 0.68; type II IFN score, r = 0.63), perimysial CD3+ cells (type I IFN score, r = 0.59; type II IFN score, r = 0.66), CD68+ cells (type II IFN score, r = 0.46), and perifascicular atrophy (type I IFN score, r = 0.61; type II IFN score, r = 0.77). Juvenile DM patients with a high type I IFN score, a high type II IFN score, and high TNF expression levels showed more severe disease activity at biopsy (P < 0.05). In addition, juvenile DM patients with a high type II IFN score at biopsy reached clinically inactive disease significantly later than patients with low type II IFN score (log rank chi-square value 13.53, P < 0.001). CONCLUSION: The increased expression of IFN-inducible genes in the muscle in juvenile DM patients and their association with histologic and clinical features further support a pathogenic role for both type I and type II IFNs in juvenile DM.

Dysregulated miR-155 and miR-125b Are Related to Impaired B-cell Responses in Down Syndrome.

Children with Down Syndrome (DS) suffer from immune deficiency with a severe reduction in switched memory B cells (MBCs) and poor response to vaccination. Chromosome 21 (HSA21) encodes two microRNAs (miRs), miR-125b, and miR-155, that regulate B-cell responses. We studied B- and T- cell subpopulations in tonsils of DS and age-matched healthy donors (HD) and found that the germinal center (GC) reaction was impaired in DS. GC size, numbers of GC B cells and Follicular Helper T cells (TFH) expressing BCL6 cells were severely reduced. The expression of miR-155 and miR-125b was increased in tonsillar memory B cells and miR-125b was also higher than expected in plasma cells (PCs). Activation-induced cytidine deaminase (AID) protein, a miR-155 target, was significantly reduced in MBCs of DS patients. Increased expression of miR-155 was also observed in vitro. MiR-155 was significantly overexpressed in PBMCs activated with CpG, whereas miR-125b was constitutively higher than normal. The increase of miR-155 and its functional consequences were blocked by antagomiRs in vitro. Our data show that the expression of HSA21-encoded miR-155 and miR-125b is altered in B cells of DS individuals both in vivo and in vitro. Because of HSA21-encoded miRs may play a role also in DS-associated dementia and leukemia, our study suggests that antagomiRs may represent pharmacological tools useful for the treatment of DS.

One year in review 2018: idiopathic inflammatory myopathies.

Idiopathic inflammatory myopathies (IIMs) are a group of chronic autoimmune systemic diseases affecting the skeletal muscle and other organs. IIMs are also a complex group of diseases, in some cases, difficult to manage. Literature on IIMs has been growing fairly rapidly and keeping up-to-date on such a topic is of utmost importance for any rheumatologist who looks after IIM patients. Thus, the aim of this review is to summarise the most relevant literature contributions published over the last year on the pathogenesis, serology, diagnosis and treatment of IIMs.

CD19+CD24hiCD38hi B Cells Are Expanded in Juvenile Dermatomyositis and Exhibit a Pro-Inflammatory Phenotype After Activation Through Toll-Like Receptor 7 and Interferon-α.

Juvenile dermatomyositis (JDM) is a rare form of childhood autoimmune myositis that presents with proximal muscle weakness and skin rash. B cells are strongly implicated in the pathogenesis of the disease, but the underlying mechanisms are unknown. Therefore, the main objective of our study was to investigate mechanisms driving B cell lymphocytosis and define pathological features of B cells in JDM patients. Patients were recruited through the UK JDM Cohort and Biomarker study. Peripheral blood B cell subpopulations were immunophenotyped by flow cytometry. The results identified that immature transitional B cells were significantly expanded in active JDM, actively dividing, and correlated positively with disease activity. Protein and RNAseq analysis revealed high interferon alpha (IFNα) and TLR7-pathway signatures pre-treatment. Stimulation of B cells through TLR7/8 promoted both IL-10 and IL-6 production in controls but failed to induce IL-10 in JDM patient cells. Interrogation of the CD40-CD40L pathway (known to induce B cell IL-10 and IL-6) revealed similar expression of IL-10 and IL-6 in B cells cultured with CD40L from both JDM patients and controls. In conclusion, JDM patients with active disease have a significantly expanded immature transitional B cell population which correlated with the type I IFN signature. Activation through TLR7 and IFNα may drive the expansion of immature transitional B cells in JDM and skew the cells toward a pro-inflammatory phenotype.