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1.
Artigo em Inglês | MEDLINE | ID: mdl-31331873

RESUMO

The aims of treating juvenile idiopathic arthritis are to elicit treatment response toward remission, while preventing future flares. Understanding patient and disease characteristics that predispose young people with this condition to these outcomes would allow the forecasting of disease process and the tailoring of therapies. The strongest predictor of remission is disease category, particularly oligoarthritis, although a few additional clinical predictors of treatment response have been identified. Novel evidence using biomarkers, such as S100 proteins and novel single nucleotide polymorphism data, could add value to clinical models. The future aim of personalised medicine in the treatment of juvenile idiopathic arthritis will be aided with international collaborations, allowing for the analysis of larger datasets with novel biomarker data. Combined clinical and biomarker panels will probably be required for predicting outcomes in such a complex disease.

3.
Pediatr Rheumatol Online J ; 17(1): 30, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31215480

RESUMO

BACKGROUND: Juvenile Dermatomyositis is a rare, potentially life-threatening condition with no known cure. There is no published literature capturing how children and young people feel about their condition, from their perspective. This study was therefore unique in that it asked children and young people what is it like to live with Juvenile Dermatomyositis. METHODS: Data were obtained from fifteen young people with Juvenile Dermatomyositis, between eight and nineteen years of age from one Paediatric Rheumatology department using audio-recorded interpretive phenomenology interviews. Data were analyzed phenomenologically, using a process that derives narratives from transcripts resulting in a collective composite of participants shared experiences, called a 'phenomenon'. RESULTS: The overarching metaphor of a rollercoaster captures the phenomenon of living with Juvenile Dermatomyositis as a young person, with the ups and downs at different time points clearly described by those interviewed. The five themes plotted on the rollercoaster, began with confusion; followed by feeling different, being sick, steroidal and scared from the medications; uncertainty; and then ended with acceptance of the disease over time. CONCLUSION: Young people were able to talk about their experiences about having Juvenile Dermatomyositis. Our findings will aid clinicians in their practice by gaining a deeper understanding of what daily life is like and highlighting ways to enhance psychosocial functioning. Hopefully, this study and any further resulting studies, will raise understanding of Juvenile Dermatomyositis worldwide and will encourage health care professionals to better assess psychosocial needs in the future.

4.
Pediatr Rheumatol Online J ; 17(1): 23, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31113443

RESUMO

BACKGROUND: Young people (YP; 12-24 years old) with rheumatic diseases face many challenges associated with chronic illness in addition to the physiological and psychosocial changes of adolescence. Timely access to developmentally appropriate multidisciplinary care is key to successfully managing rheumatic diseases, but gaps in the care of this vulnerable age group still exist. This study aimed to develop a benchmarking toolkit to enable comparative evaluation of YP rheumatology services in order to promote best practice and reduce variations in service delivery. METHODS: A staged and consultative method was used across a broad group of stakeholders in the UK (YP, parents/other carers, and healthcare professionals, HCPs) to develop this toolkit, with reference to pre-existing standards of YP-friendly healthcare. Eighty-seven YP (median age 19 years, range 12-24 years) and 26 rheumatology HCPs with 1-34 years of experience caring for YP have participated. RESULTS: Thirty quality criteria were identified, which were grouped into four main domains: assessment and treatment, information and involvement, accessibility and environment, and continuity of care. Two toolkit versions, one to be completed by HCPs and one to be completed by patients, were developed. These were further refined by relevant groups and face validity was confirmed. CONCLUSIONS: A toolkit has been developed to systematically evaluate and benchmark YP rheumatology services, which is key in setting standards of care, identifying targets for improvement and facilitating research. Engagement from YP, clinical teams, and commissioners with this tool should facilitate investigation of variability in levels of care and drive quality improvement.

5.
Ann Rheum Dis ; 78(7): 996-1002, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31138531

RESUMO

OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies. METHODS: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups. RESULTS: We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10-5. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10-53 and HLA-DRB1*03:01, p=3.25×10-9), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10-26) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10-11). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10-13) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10-6). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10-64) and position 9 of HLA-B (p=7.03×10-11). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies. CONCLUSIONS: These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.

6.
Arthritis Rheumatol ; 71(8): 1377-1390, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30861625

RESUMO

OBJECTIVE: Objective evaluation of disease activity is challenging in patients with juvenile dermatomyositis (DM) due to a lack of reliable biomarkers, but it is crucial to avoid both under- and overtreatment of patients. Recently, we identified 2 proteins, galectin-9 and CXCL10, whose levels are highly correlated with the extent of juvenile DM disease activity. This study was undertaken to validate galectin-9 and CXCL10 as biomarkers for disease activity in juvenile DM, and to assess their disease specificity and potency in predicting the occurrence of flares. METHODS: Levels of galectin-9 and CXCL10 were measured by multiplex immunoassay in serum samples from 125 unique patients with juvenile DM in 3 international cross-sectional cohorts and a local longitudinal cohort. The disease specificity of both proteins was examined in 50 adult patients with DM or nonspecific myositis (NSM) and 61 patients with other systemic autoimmune diseases. RESULTS: Both cross-sectionally and longitudinally, galectin-9 and CXCL10 outperformed the currently used laboratory marker, creatine kinase (CK), in distinguishing between juvenile DM patients with active disease and those in remission (area under the receiver operating characteristic curve [AUC] 0.86-0.90 for galectin-9 and CXCL10; AUC 0.66-0.68 for CK). The sensitivity and specificity for active disease in juvenile DM was 0.84 and 0.92, respectively, for galectin-9 and 0.87 and 1.00, respectively, for CXCL10. In 10 patients with juvenile DM who experienced a flare and were prospectively followed up, continuously elevated or rising biomarker levels suggested an imminent flare up to several months before the onset of symptoms, even in the absence of elevated CK levels. Galectin-9 and CXCL10 distinguished between active disease and remission in adult patients with DM or NSM (P = 0.0126 for galectin-9 and P < 0.0001 for CXCL10) and were suited for measurement in minimally invasive dried blood spots (healthy controls versus juvenile DM, P = 0.0040 for galectin-9 and P < 0.0001 for CXCL10). CONCLUSION: In this study, galectin-9 and CXCL10 were validated as sensitive and reliable biomarkers for disease activity in juvenile DM. Implementation of these biomarkers into clinical practice as tools to monitor disease activity and guide treatment might facilitate personalized treatment strategies.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30875458

RESUMO

OBJECTIVE: In paediatric research, investigators rely on proxy reports of outcome, such as the proxy-completed Childhood Health Assessment Questionnaire (P-CHAQ), to assess function in JIA. As children mature, they may self-complete the adult Health Assessment Questionnaire (HAQ) or the un-validated adolescent-specific CHAQ (A-CHAQ). It is unclear how these measures compare and whether they are directly interchangeable. METHODS: Adolescents aged 11 to 17 years participating in the Childhood Arthritis Prospective Study, a UK multicentre inception cohort, were included. In a CAPS sub-study, adolescents self-completed the A-CHAQ and HAQ and proxies simultaneously completed the P-CHAQ at baseline and one year. Correlation and agreement between scores were assessed at baseline. Agreement and ability to similarly classify clinically important changes over time were assessed at one year following initial presentation to rheumatology. RESULTS: 107 adolescents (A-CHAQ and HAQ) or their proxies (P-CHAQ) had completed all three measures at baseline. Median age at diagnosis was 13 years and 61% were female. Although the three scores demonstrated strong correlations (r>0.8), they were not completely interchangeable, with agreement ranging between 70 and 80%. There was similar agreement between the changes in scores between baseline and one year. Using P-CHAQ minimal clinically important cut-offs, the A-CHAQ and HAQ similarly classified 80 to 90% of adolescents as having improved or worsened. CONCLUSION: Whilst there is relatively high agreement and similar classification of change between HAQ and two CHAQ scores, these are not completely interchangeable. This impacts the comparison of function when measured in different ways over the lifespan. This article is protected by copyright. All rights reserved.

8.
Artigo em Inglês | MEDLINE | ID: mdl-30378704

RESUMO

AIM: Juvenile idiopathic inflammatory myopathies (IIM) have been recently reclassified into clinico-serological subgroups. Myopathological correlates of the subgroups are incompletely understood. METHODS: We studied muscle biopsies from 101 children with clinically and serologically-defined juvenile IIM from the UK JDM Cohort and Biomarker Study by applying the international JDM score tool, myopathological review, and C5b-9 complement analysis. RESULTS: Autoantibody data were available for 90/101 cases with 18/90 cases positive for anti-TIF1γ, 15/90 anti-NXP2, 11/90 anti-MDA5, 5/90 anti-Mi2, and 6/90 anti-PmScl. JDM biopsy severity scores were consistently low in the anti-MDA5 group, high in the anti-Mi2 group, and widely distributed in the other groups. Biopsies were classified histologically as perifascicular atrophy (22/101), macrophage-rich necrosis (6/101), scattered necrosis (2/101), clustered necrosis (2/101), inflammatory fibre invasion (2/101), chronic myopathic change (1/101), diffuse endomysial macrophage infiltrates (40/101), and minimal change (24/101). MDA5 cases segregated with the minimal change group and showed no capillary C5b-9-deposition. The Mi2 group displayed high severity scores and a tendency towards sarcolemmal complement deposition. NXP2 and TIF1γ groups showed a variety of pathologies with a high proportion of diffuse endomysial macrophage infiltrates and a high proportion of capillary C5b-9 deposition. CONCLUSION: We have shown that juvenile idiopathic inflammatory myopathies have a spectrum of histopathological phenotypes and show distinct complement attack complex deposition patterns. Both correlate in some cases with the serological subtypes. Most cases do not show typical histological features associated with dermatomyositis (e.g. perifascicular atrophy). In contrast, more than half show relatively mild histopathological changes. This article is protected by copyright. All rights reserved.

9.
Arthritis Rheumatol ; 2018 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-30350355

RESUMO

OBJECTIVE: Evidence suggests that aberrant function of innate lymphoid cells (ILC), whose functional and transcriptional profile overlap with T helper (Th) cell subsets, contribute to immune-mediated pathologies. To date, analysis of Juvenile Idiopathic Arthritis (JIA) immune-pathology has concentrated on the contribution of CD4+ T-cells; we have previously identified an expansion of Th17 cells within the synovial fluid (SF) of JIA patients. Here, we extend this analysis to investigate a role for ILC and other IL-17 producing T-cell subsets. METHODS: ILC and CD3+ T-cell subsets were defined in peripheral blood mononuclear cells (PBMC) (healthy adult, healthy child and JIA patients) and JIA SF mononuclear cells (SFMC) using flow cytometry. Defined subsets in SFMC were correlated with clinical measures including physician's visual analogue scale (VAS), active joint count and erythrocyte sedimentation rate (ESR). Transcription factor and cytokine profiles of sorted ILC were assessed by qPCR. RESULTS: Group 1 ILC (ILC1), NKp44-group 3 ILC (NCR-ILC3) and NKp44+group 3 ILC (NCR+ILC3) were enriched in the JIA-SFMC compared to PBMC, which corresponded with an increase in transcripts for TBX21, IFNG and IL17A. Of the ILC subsets, NCR-ILC3 frequency in JIA-SFMC displayed the strongest positive association with clinical measures which was mirrored by an expansion in IL-17A+CD4+, IL-17A+CD8+ and IL-17A+γδ T-cells. CONCLUSION: We demonstrate that the strength of the IL-17A signature in JIA-SFMC is determined by multiple lymphoid cell-types, including NCR-ILC3, IL-17A+CD4+, IL-17A+CD8+ and IL-17A+γδ T-cells. These observations may have important implications for the development of stratified therapeutics. This article is protected by copyright. All rights reserved.

10.
Curr Opin Rheumatol ; 30(6): 650-654, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30124602

RESUMO

PURPOSE OF REVIEW: The aim of this article is to provide a summary of the recent therapeutic advances and the latest research on outcome measures for juvenile dermatomyositis (JDM). RECENT FINDINGS: Several new international studies have developed consensus-based guidelines on diagnosis, outcome measures and treatment of JDM to standardize and improve patient care. Myositis-specific antibodies together with muscle biopsy histopathology may help the clinician to predict disease outcome. A newly developed MRI-based scoring system has been developed to standardize the use of MRI in assessing disease activity in JDM. New data regarding the efficacy and safety of rituximab, especially for skin disease, and cyclophosphamide in JDM support the use of these medications for severe refractory cases. SUMMARY: International network studies, new biomarkers and outcome measures have led to significant progress in understanding and managing the rare inflammatory myositis conditions such as JDM.

11.
Arthritis Res Ther ; 20(1): 180, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30111380

RESUMO

BACKGROUND: It is currently impossible to predict the prognosis of patients with juvenile dermatomyositis (JDM). The aim of this study was to find clinical features most strongly associated with outcome variables in JDM as a first step towards tailor-made treatment. METHODS: In a large, prospectively followed, multicenter cohort study of 340 patients with JDM, each contributing multiple visits, a Bayesian model of disease activity was developed, using the four continuous outcome variables creatine kinase (CK), childhood myositis assessment score (CMAS), manual muscle testing of 8 muscle groups (MMT8) and the physician's global assessment of disease activity (PGA). Covariates were clinical signs and symptoms. Correlations among visits of the same patient were resolved by introducing subject-specific random effects. RESULTS: Myalgia and dysphonia were associated with worse disease activity according to all outcome variables. Periorbital rash, rash on the trunk, rash over large joints, nail fold changes and facial swelling were associated with higher PGA. Notably, periorbital rash was also associated with higher CK and lower CMAS and nail fold changes with lower CMAS. Contractures were associated with lower CMAS and MMT8 and higher PGA. Patients with higher CMAS exhibited a higher MMT8 as well. PGA had the highest probability among the four outcome variables of being abnormal even if the other three outcome variables were normal. CONCLUSIONS: The signs and symptoms associated with disease activity could be used to stratify patients and adapt treatment plans to disease activity. The correlation between CMAS and MMT8 and the unique information captured by PGA implied that PGA should be maintained as an outcome variable, whereas CMAS and MMT8 might be simplified.

12.
Front Immunol ; 9: 1372, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29988398

RESUMO

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.

13.
Pediatr Rheumatol Online J ; 16(1): 39, 2018 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-29925386

RESUMO

BACKGROUND: Inflammatory effector T cells trigger inflammation despite increased numbers of Treg cells in the synovial joint of patients suffering from juvenile idiopathic arthritis (JIA). The cAMP response element (CREM)α is known to play a major role in regulation of T cells in SLE, colitis, and EAE. However, its role in regulation of effector T cells within the inflammatory joint is unknown. METHODS: CREM expression was analyzed in synovial fluid cells from oligoarticular JIA patients by flow cytometry. Peripheral blood mononuclear cells were incubated with synovial fluid and analyzed in the presence and absence of CREM using siRNA experiments for T cell phenotypes. To validate the role of CREM in vivo, ovalbumin-induced T cell dependent arthritis experiments were performed. RESULTS: CREM is highly expressed in synovial fluid T cells and its expression can be induced by treating healthy control PBMCs with synovial fluid. Specifically, CREM is more abundant in CD161+ subsets, than CD161- subsets, of T cells and contributes to cytokine expression by these cells. Finally, development of ovalbumin-induced experimental arthritis is ameliorated in mice with adoptively transferred CREM-/- T cells. CONCLUSION: In conclusion, our study reveals that beyond its role in SLE T cells CREM also drives an inflammatory phenotype of T cells in JIA.


Assuntos
Artrite Juvenil/metabolismo , Modulador de Elemento de Resposta do AMP Cíclico/metabolismo , Líquido Sinovial/metabolismo , Linfócitos T/metabolismo , Animais , Técnicas de Cultura de Células , Citometria de Fluxo/métodos , Humanos , Articulações/patologia , Camundongos , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real
14.
Arthritis Rheumatol ; 70(9): 1519-1529, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29648683

RESUMO

OBJECTIVE: Potential targets for treat-to-target strategies in juvenile idiopathic arthritis are minimal disease activity (MDA) and clinically inactive disease (CID). We undertook this study to compare short- and long-term outcomes following achievement of MDA and CID on the 10-joint clinical Juvenile Arthritis Disease Activity Score (cJADAS10) and following achievement of CID on Wallace et al's preliminary criteria. METHODS: Children recruited to the Childhood Arthritis Prospective Study, a UK multicenter inception cohort, were selected if they were recruited prior to January 2011 and diagnosed as having oligoarthritis or rheumatoid factor-negative or -positive polyarthritis. One year following diagnosis, children were assessed for MDA on the cJADAS10 and for CID on both Wallace et al's preliminary criteria and the cJADAS10. Associations were tested between those disease states and functional ability, absence of joints with limited range of motion, psychosocial health, and pain at 1 year and annually to 5 years. RESULTS: Of 832 children, 70% were female and the majority had oligoarthritis (68%). At 1 year, 21% had achieved CID according to both definitions, 7% according to Wallace et al's preliminary criteria alone, and 16% according to the cJADAS10 alone; 56% had not achieved CID. Only 10% of children in the entire cohort achieved MDA without also achieving CID. Achieving either early CID state was associated with a greater absence of joints with limited range of motion. However, only CID according to the cJADAS10 was associated with improved functional ability and psychosocial health. Achieving CID was superior to achieving MDA in terms of short- and long-term pain and the absence of joints with limited range of motion. CONCLUSION: CID on the cJADAS10 may be preferable as a treatment target to CID on Wallace et al's preliminary criteria in terms of both feasibility of application and long-term outcomes.

15.
Rheumatology (Oxford) ; 57(8): 1381-1389, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29697850

RESUMO

Objectives: To determine if depressive symptoms assessed near diagnosis associate with future measures of pain, disability and disease for adolescent patients diagnosed with JIA. Methods: Data were analysed from JIA patients aged 11-16 years recruited to the Childhood Arthritis Prospective Study, a UK-based inception cohort of childhood-onset arthritis. Depressive symptoms (using the Mood and Feelings Questionnaire; MFQ), active and limited joint count, disability score (Childhood Health Assessment Questionnaire), pain visual analogue scale and patient's general evaluation visual analogue scale were collected. Associations between baseline measures (first visit to paediatric rheumatologist) were analysed using multiple linear regression. Linear mixed-effect models for change in the clinical measures of disease over 48 months were estimated including MFQ as an explanatory variable. Results: Data from 102 patients were analysed. At baseline, median (IQR) age was 13.2 years (11.9-14.2 years) and 14.7% scored over the MFQ cut-off for major depressive disorder. At baseline, depressive symptoms significantly associated with all clinical measures of disease (P ⩽ 0.01). High baseline depressive symptoms scores predicted worse pain (P ⩽ 0.005) and disability (P ⩽ 0.001) 12 months later but not active and limited joint counts. Conclusions: Adolescent patients with JIA and depressive symptoms had more active joints, pain and disability at the time of their first specialist appointment. The associations between baseline depression and both pain and disability continued for at least one year, however, this was not the case for active joint count.


Assuntos
Artrite Juvenil/complicações , Depressão/diagnóstico , Avaliação da Deficiência , Pessoas com Deficiência/reabilitação , Nível de Saúde , Qualidade de Vida , Adolescente , Artrite Juvenil/diagnóstico , Artrite Juvenil/reabilitação , Criança , Estudos Transversais , Depressão/etiologia , Depressão/reabilitação , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Índice de Gravidade de Doença , Inquéritos e Questionários , Fatores de Tempo
16.
Arthritis Rheumatol ; 70(8): 1319-1330, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29609200

RESUMO

OBJECTIVE: To determine whether systemic juvenile idiopathic arthritis (JIA) susceptibility loci that were identified by candidate gene studies demonstrate association with systemic JIA in the largest study population assembled to date. METHODS: Single-nucleotide polymorphisms (SNPs) from 11 previously reported systemic JIA risk loci were examined for association in 9 populations, including 770 patients with systemic JIA and 6,947 controls. The effect of systemic JIA-associated SNPs on gene expression was evaluated in silico in paired whole genome and RNA sequencing data from the lymphoblastoid cell lines (LCLs) of 373 European subjects from the 1000 Genomes Project. Responses of systemic JIA-associated SNPs to anakinra treatment were evaluated in 38 US patients for whom treatment response data were available. RESULTS: We found no association between the previously reported 26 SNPs and systemic JIA. Expanded analysis of the regions containing the 26 SNPs revealed only 1 significant association: the promoter region of IL1RN (P < 1 × 10-4 ). Systemic JIA-associated SNPs correlated with IL1RN expression in LCLs, with an inverse correlation between systemic JIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with a lack of response to anakinra therapy (odds ratio 28.7 [95% confidence interval 3.2-255.8]). CONCLUSION: In our study, IL1RN was the only candidate locus associated with systemic JIA. The implicated SNPs are among the strongest known determinants of IL1RN and interleukin-1 receptor antagonist levels, linking low expression with increased systemic JIA risk. Homozygous high expression alleles predicted nonresponsiveness to anakinra therapy, making them ideal candidate biomarkers to guide systemic JIA treatment. This study is an important first step toward the personalized treatment of systemic JIA.

17.
Blood Adv ; 2(7): 777-786, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29618462

RESUMO

Patients with juvenile idiopathic arthritis (JIA) can experience a severe disease course, with progressive destructive polyarthritis refractory to conventional therapy with disease-modifying antirheumatic drugs including biologics, as well as life-threatening complications including macrophage activation syndrome (MAS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative immunomodulatory strategy for patients with such refractory disease. We treated 16 patients in 5 transplant centers between 2007 and 2016: 11 children with systemic JIA and 5 with rheumatoid factor-negative polyarticular JIA; all were either refractory to standard therapy, had developed secondary hemophagocytic lymphohistiocytosis/MAS poorly responsive to treatment, or had failed autologous HSCT. All children received reduced toxicity fludarabine-based conditioning regimens and serotherapy with alemtuzumab. Fourteen of 16 patients are alive with a median follow-up of 29 months (range, 2.8-96 months). All patients had hematological recovery. Three patients had grade II-IV acute graft-versus-host disease. The incidence of viral infections after HSCT was high, likely due to the use of alemtuzumab in already heavily immunosuppressed patients. All patients had significant improvement of arthritis, resolution of MAS, and improved quality of life early following allo-HSCT; most importantly, 11 children achieved complete drug-free remission at the last follow-up. Allo-HSCT using alemtuzumab and reduced toxicity conditioning is a promising therapeutic option for patients with JIA refractory to conventional therapy and/or complicated by MAS. Long-term follow-up is required to ascertain whether disease control following HSCT continues indefinitely.

18.
Arthritis Rheumatol ; 70(6): 957-962, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29426059

RESUMO

OBJECTIVE: Juvenile idiopathic arthritis (JIA) comprises 7 heterogeneous categories of chronic childhood arthritides. Approximately 5% of children with JIA have rheumatoid factor (RF)-positive arthritis, which phenotypically resembles adult rheumatoid arthritis (RA). Our objective was to compare and contrast the genetics of RF-positive polyarticular JIA with those of RA and selected other JIA categories, to more fully understand the pathophysiologic relationships of inflammatory arthropathies. METHODS: Patients with RF-positive polyarticular JIA (n = 340) and controls (n = 14,412) were genotyped using the Immunochip array. Single-nucleotide polymorphisms were tested for association using a logistic regression model adjusting for admixture proportions. We calculated weighted genetic risk scores (wGRS) of reported RA and JIA risk loci, and we compared the ability of these wGRS to predict RF-positive polyarticular JIA. RESULTS: As expected, the HLA region was strongly associated with RF-positive polyarticular JIA (P = 5.51 × 10-31 ). Nineteen of 44 RA risk loci and 6 of 27 oligoarticular/RF-negative polyarticular JIA risk loci were associated with RF-positive polyarticular JIA (P < 0.05). The RA wGRS predicted RF-positive polyarticular JIA (area under the curve [AUC] 0.71) better than did the oligoarticular/RF-negative polyarticular JIA wGRS (AUC 0.59). The genetic profile of patients with RF-positive polyarticular JIA was more similar to that of RA patients with age at onset 16-29 years than to that of RA patients with age at onset ≥70 years. CONCLUSION: RF-positive polyarticular JIA is genetically more similar to adult RA than to the most common JIA categories and thus appears to be a childhood-onset presentation of autoantibody-positive RA. These findings suggest common disease mechanisms, which could lead to novel therapeutic targets and shared treatment strategies.

19.
Arthritis Rheumatol ; 70(5): 785-793, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29342499

RESUMO

OBJECTIVE: In patients with severe or refractory juvenile dermatomyositis (DM), second-line treatments may be required. Cyclophosphamide (CYC) is used to treat some connective tissue diseases, but evidence of its efficacy in juvenile DM is limited. This study was undertaken to describe clinical improvement in juvenile DM patients treated with CYC and model the efficacy of CYC treatment compared to no CYC treatment. METHODS: Clinical data on skin, global, and muscle disease for patients recruited to the Juvenile DM Cohort and Biomarker Study were analyzed. Clinical improvement following CYC treatment was described using unadjusted analysis. Marginal structural models (MSMs) were used to model treatment efficacy and adjust for confounding by indication. RESULTS: Compared to the start of CYC treatment, there were reductions at 6, 12, and 24 months in skin disease (P = 1.3 × 10-10 ), global disease (P = 2.4 × 10-8 ), and muscle disease (P = 8.0 × 10-10 ) for 56 patients treated with CYC in unadjusted analysis. Limited evidence suggested a reduction in glucocorticoid dose (P = 0.047) in patients treated with CYC. MSM analysis showed reduced global disease and skin disease in patients who started an ~6-month course of CYC treatment >12 months ago compared to patients never or not yet treated with CYC. In the treated patients, the modified skin Disease Activity Score for juvenile DM was 1.19 units lower (P = 0.0085) and the physician's global assessment was 0.66 units lower (P = 0.027). Minor adverse events were reported in 3 patients within 1 year of stopping CYC. CONCLUSION: Our findings indicate that CYC is efficacious with no short-term side effects. Improvements in skin, global, and muscle disease were observed. Further studies are required to evaluate longer-term side effects.

20.
J Rheumatol ; 45(4): 547-554, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29335345

RESUMO

OBJECTIVE: Around one-third of patients with juvenile idiopathic arthritis (JIA) fail to respond to first-line methotrexate (MTX) or anti-tumor necrosis factor (TNF) therapy, with even fewer achieving ≥ American College of Rheumatology Pediatric 70% criteria for response (ACRpedi70), though individual responses cannot yet be accurately predicted. Because change in serum S100-protein myeloid-related protein complex 8/14 (MRP8/14) is associated with therapeutic response, we tested granulocyte-specific S100-protein S100A12 as a potential biomarker for treatment response. METHODS: S100A12 serum concentration was determined by ELISA in patients treated with MTX (n = 75) and anti-TNF (n = 88) at baseline and followup. Treatment response (≥ ACRpedi50 score), achievement of inactive disease, and improvement in Juvenile Arthritis Disease Activity Score (JADAS)-10 score were recorded. RESULTS: Baseline S100A12 concentration was measured in patients treated with anti-TNF [etanercept n = 81, adalimumab n = 7; median 200, interquartile range (IQR) 133-440 ng/ml] and MTX (median 220, IQR 100-440 ng/ml). Of the patients in the anti-TNF therapy group, 74 (84%) were also receiving MTX. Responders to MTX (n = 57/75) and anti-TNF (n = 66/88) therapy had higher baseline S100A12 concentration compared to nonresponders: median 240 (IQR 125-615) ng/ml versus 150 (IQR 87-233) ng/ml, p = 0.021 for MTX, and median 308 (IQR 150-624) ng/ml versus 151 (IQR 83-201) ng/ml, p = 0.002, for anti-TNF therapy. Followup S100A12 could be measured in 44/75 MTX-treated patients (34/44 responders) and 39/88 anti-TNF-treated patients (26/39 responders). Responders had significantly reduced S100A12 concentration (MTX: p = 0.031, anti-TNF: p < 0.001) at followup versus baseline. Baseline serum S100A12 in both univariate and multivariate regression models for anti-TNF therapy and univariate analysis alone for MTX therapy was significantly associated with change in JADAS-10. CONCLUSION: Responders to MTX or anti-TNF treatment can be identified by higher pretreatment S100A12 serum concentration levels.

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