Quantifying hospital-associated costs, and accompanying travel costs and productivity losses, before and after withdrawing tumour necrosis factor-alfa inhibitors in juvenile idiopathic arthritis.

OBJECTIVE: To quantify differences in hospital-associated costs, and accompanying travel costs and productivity losses, before and after withdrawing TNFi in JIA patients. METHODS: Retrospective analysis of prospectively collected data from electronic medical records of paediatric JIA patients treated with TNFi, which were either immediately discontinued, spaced (increased treatment interval) or tapered (reduced subsequent doses). Costs of hospital-associated resource use (consultations, medication, radiology procedures, laboratory testing, procedures under general anaesthesia, hospitalisation) and associated travel costs and productivity losses were quantified during clinically inactive disease until TNFi withdrawal (pre-withdrawal period) and compared with costs during the first and second year after withdrawal initiation (first and second year post-withdrawal). RESULTS: Fifty-six patients were included of whom 26 immediately discontinued TNFi, 30 spaced and zero tapered. Mean annual costs were €9,165/patient on active treatment (pre-withdrawal) and decreased significantly to €5,063/patient (-44.8%) and €6,569/patient (-28.3%) in the first and second year post-withdrawal, respectively (p< 0.05). Of these total annual costs, travel costs plus productivity losses were €834/patient, €1,180/patient, and €1,320/patient, in the three periods respectively. Medication comprised 80.7%, 61.5% and 72.4% of total annual costs in the pre-withdrawal, first, and second year post-withdrawal period, respectively. CONCLUSION: In the first two years after initiating withdrawal, the total annual costs are decreased compared with the pre-withdrawal period. However, cost reductions were lower in the second year compared with the first year post-withdrawal, primarily due to restarting or intensifying biologics. To support biologic withdraw decisions, future research should assess the full long-term societal cost impacts, and include all biologics.

Meningococcal ACWY conjugate vaccine immunogenicity in adolescents with primary or secondary immune deficiencies, a prospective observational cohort study.

BACKGROUND: Immunization with meningococcal ACWY conjugate vaccine induces protective antibodies against invasive meningococcal disease (IMD) caused by serogroups A, C, W and Y. We studied MenACWY-TT vaccine immunogenicity in adolescents with a heterogenous group of primary and secondary immune deficiency including patients with systemic lupus erythematosus, mixed connective tissue disease, vasculitis, uveitis, 22Q11 syndrome, sickle cell disease, and patients who underwent stem cell transplantation for bone marrow failure. FINDINGS: We enrolled 69 individuals aged 14-18 years diagnosed with a primary or secondary immune deficiency in a prospective observational cohort study. All patients received a single dose of MenACWY-TT vaccine during the catch-up campaign 2018-19 because of the IMD-W outbreak in the Netherlands. Capsular polysaccharide-specific (PS) IgG concentrations against MenACWY were measured before and 3-6, 12, and 24 months after vaccination. Overall, geometric mean concentrations (GMCs) of MenACWY-PS-specific IgG were lower in patients compared to data from healthy, aged-matched controls (n = 75) reaching significance at 12 months postvaccination for serogroup A and W (adjusted GMC ratios 0.26 [95% CI: 0.15-0.47] and 0.22 [95% CI: 0.10-0.49], respectively). No serious adverse events were reported by study participants. CONCLUSIONS: The MenACWY conjugate vaccine was less immunogenic in adolescent patients with primary or secondary immunodeficiency compared to healthy controls, urging the need for further surveillance of these patients and supporting considerations for booster MenACWY conjugate vaccinations in these patient groups.

Long-term immunoprotection after live attenuated measles-mumps-rubella booster vaccination in children with juvenile idiopathic arthritis.

INTRODUCTION: Vaccines, especially live attenuated vaccines, in children with JIA pose a great challenge due to both potential lower immunogenicity and safety as a result of immunosuppressive treatment. For many years, in the Netherlands, JIA patients receive a measles-mumps-rubella (MMR) booster vaccine at the age of nine years as part of the national immunization program. OBJECTIVES: To study long-term humoral immunoprotection in a large cohort of JIA patients who received the MMR booster vaccine while being treated with immunomodulatory therapies at the Wilhelmina Children's Hospital in Utrecht, the Netherlands. METHODS: MMR-specific IgG antibody concentrations in stored serum samples of vaccinated JIA patients were determined with chemiluminescent microparticle immunoassays (CMIA). Samples were analyzed five years after MMR booster vaccination and at last available follow-up visit using both crude and adjusted analyses. Additional clinical data were collected from electronic medical records. RESULTS: In total, 236 samples from 182 patients were analyzed, including 67 samples that were available five years post-vaccination, and an additional 169 samples available from last visits with a median duration after vaccination of 6.9 years (IQR: 2.8-8.8). Twenty-eight patients were using biologic disease-modifying antirheumatic drugs (bDMARDS) of whom 96% anti-TNF agents and 4% tocilizumab. Percentages of protective antibody levels against measles after five years were significantly lower for patients who used bDMARD therapy at vaccination compared to patients who did not: 60% versus 86% (P = 0.03). For mumps (80% versus 94%) and rubella (60% versus 83%) this difference did not reach statistical significance (P = 0.11 and P = 0.07, respectively). Antibody levels post-vaccination decreased over time, albeit not significantly different between bDMARD users and non-bDMARD users. CONCLUSION: The MMR booster vaccine demonstrated long-term immunogenicity in the majority of children with JIA from a large cohort, although lower percentages of protective measles antibody levels were observed in bDMARD users. Hence, it might be indicated to measure antibody levels at least five years after MMR booster vaccination in the latter group and advice an extra booster accordingly.

Juvenile idiopathic arthritis patients with positive family history of autoimmune thyroid disease might benefit from serological screening: analysis of the international Pharmachild registry.

BACKGROUND: Little is known about the association between juvenile idiopathic arthritis (JIA) and autoimmune thyroid disease (AITD) and therefore there are no indications for AITD screening in this population, which is possible using standard blood tests. The objective of this study is to determine the prevalence and predictors of symptomatic AITD in JIA patients from the international Pharmachild registry. METHODS: Occurrence of AITD was determined from adverse event forms and comorbidity reports. Associated factors and independent predictors for AITD were determined using univariable and multivariable logistic regression analyses. RESULTS: The prevalence of AITD after a median observation period of 5.5 years was 1.1% (96/8965 patients). Patients who developed AITD were more often female (83.3% vs. 68.0%), RF positive (10.0% vs. 4.3%) and ANA positive (55.7% vs. 41.5%) than patients who did not. AITD patients were furthermore older at JIA onset (median 7.8 years vs. 5.3 years) and had more often polyarthritis (40.6% vs. 30.4%) and a family history of AITD (27.5% vs. 4.8%) compared to non-AITD patients. A family history of AITD (OR = 6.8, 95% CI: 4.1 - 11.1), female sex (OR = 2.2, 95% CI: 1.3 - 4.3), ANA positivity (OR = 2.0, 95% CI: 1.3 - 3.2) and older age at JIA onset (OR = 1.1, 95% CI: 1.1 - 1.2) were independent predictors of AITD on multivariable analysis. Based on our data, 16 female ANA positive JIA patients with a family history of AITD would have to be screened during ±5.5 years using standard blood tests to detect one case of AITD. CONCLUSIONS: This is the first study to report independent predictor variables for symptomatic AITD in JIA. Female ANA positive JIA patients with positive family history are at increased risk of developing AITD and thus might benefit from yearly serological screening.

Identifying disrupted biological factors and patient-tailored interventions for chronic fatigue in adolescents and young adults with Q-Fever Fatigue Syndrome, Chronic Fatigue Syndrome and Juvenile Idiopathic Arthritis (QFS-study): study protocol for a randomized controlled trial with single-subject experimental case series design.

BACKGROUND: Chronic fatigue with a debilitating effect on daily life is a frequently reported symptom among adolescents and young adults with a history of Q-fever infection (QFS). Persisting fatigue after infection may have a biological origin with psychological and social factors contributing to the disease phenotype. This is consistent with the biopsychosocial framework, which considers fatigue to be the result of a complex interaction between biological, psychological, and social factors. In line, similar manifestations of chronic fatigue are observed in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and juvenile idiopathic arthritis (JIA). Cognitive behavioral therapy is often recommended as treatment for chronic fatigue, considering its effectiveness on the group level. However, not everybody benefits on the individual level. More treatment success at the individual level might be achieved with patient-tailored treatments that incorporate the biopsychosocial framework. METHODS: In addition to biological assessments of blood, stool, saliva, and hair, the QFS-study consists of a randomized controlled trial (RCT) in which a single-subject experimental case series (N=1) design will be implemented using Experience Sampling Methodology in fatigued adolescents and young adults with QFS, CFS/ME, and JIA (aged 12-29). With the RCT design, the effectiveness of patient-tailored PROfeel lifestyle advices will be compared against generic dietary advices in reducing fatigue severity at the group level. Pre-post analyses will be conducted to determine relevance of intervention order. By means of the N=1 design, effectiveness of both advices will be measured at the individual level. DISCUSSION: The QFS-study is a comprehensive study exploring disrupted biological factors and patient-tailored lifestyle advices as intervention in adolescent and young adults with QFS and similar manifestations of chronic fatigue. Practical or operational issues are expected during the study, but can be overcome through innovative study design, statistical approaches, and recruitment strategies. Ultimately, the study aims to contribute to biological research and (personalized) treatment in QFS and similar manifestations of chronic fatigue. TRIAL REGISTRATION: Trial NL8789 . Registered July 21, 2020.

Preclinical Aortic Atherosclerosis in Adolescents With Chronic Disease.

Background Adolescents with chronic disease are often exposed to inflammatory, metabolic, and hemodynamic risk factors for early atherosclerosis. Since postmortem studies have shown that atherogenesis starts in the aorta, the CDACD (Cardiovascular Disease in Adolescents with Chronic Disease) study investigated preclinical aortic atherosclerosis in these adolescents. Methods and Results The cross-sectional CDACD study enrolled 114 adolescents 12 to 18 years old with chronic disorders including juvenile idiopathic arthritis, cystic fibrosis, obesity, corrected coarctation of the aorta, and healthy controls with a corrected atrial septal defect. Cardiovascular magnetic resonance was used to assess aortic pulse wave velocity and aortic wall thickness, as established aortic measures of preclinical atherosclerosis. Cardiovascular magnetic resonance showed a higher aortic pulse wave velocity, which reflects aortic stiffness, and higher aortic wall thickness in all adolescent chronic disease groups, compared with controls (P<0.05). Age (ß=0.253), heart rate (ß=0.236), systolic blood pressure (ß=-0.264), and diastolic blood pressure (ß=0.365) were identified as significant predictors for aortic pulse wave velocity, using multivariable linear regression analysis. Aortic wall thickness was predicted by body mass index (ß=0.248) and fasting glucose (ß=0.242), next to aortic lumen area (ß=0.340). Carotid intima-media thickness was assessed using ultrasonography, and was only higher in adolescents with coarctation of the aorta, compared with controls (P<0.001). Conclusions Adolescents with chronic disease showed enhanced aortic stiffness and wall thickness compared with controls. The enhanced aortic pulse wave velocity and aortic wall thickness in adolescents with chronic disease could indicate accelerated atherogenesis. Our findings underscore the importance of the aorta for assessment of early atherosclerosis, and the need for tailored cardiovascular follow-up of children with chronic disease.

Whole Transcriptome Analysis Reveals Heterogeneity in B Cell Memory Populations in Patients With Juvenile Idiopathic Arthritis-Associated Uveitis.

Purpose: Patients with juvenile idiopathic arthritis (JIA) are prone to developing chronic anterior uveitis (JIA-U+). Although several risk factors for JIA-U+ have been identified, the underlying etiology is poorly understood. Histopathological studies demonstrate B cell infiltrates in eye tissues of patients with JIA-U+. Methods: We performed transcriptome profiling of peripheral blood CD19-positive B cells taken from 14 cases with JIA-U+, 13 JIA cases without uveitis (JIA-U-), and five healthy controls. Deconvolution-based estimation was used to determine the immune cell fractions for each sample. Results: Deconvolution results revealed that naive B cells made up on average 71% of the CD19-positive cell fractions analyzed. Differential expression analysis identified 614 differentially expressed genes (DEGs) between the groups at nominal significance and six genes at a false discovery rate of 5% (FDR < 0.05). Head-to-head comparison of all JIA-U- versus JIA-U+ revealed no DEGs in the CD19+ B cell pool (FDR < 0.05). However, principal component analysis based on a panel of key genes for B cell subsets revealed that JIA-U+ cases bifurcate into distinct clusters, characterized by markedly disparate expression for genes associated with specific memory B cell populations. CIBERSORT analysis of the overall transcriptome of the new uveitis cluster identified an increased proportion of memory B cells. Conclusion: These data show that JIA-U- and JIA-U+ have a globally similar transcriptome considering the global peripheral CD19-positive B cell pool. However, heterogeneity in B cell memory genes among cases with uveitis suggests a role for specific memory B cell subsets in the etiology of JIA-U+.

2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases.

To update the European League Against Rheumatism (EULAR) recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) published in 2011. Four systematic literature reviews were performed regarding the incidence/prevalence of vaccine-preventable infections among patients with AIIRD; efficacy, immunogenicity and safety of vaccines; effect of anti-rheumatic drugs on the response to vaccines; effect of vaccination of household of AIIRDs patients. Subsequently, recommendations were formulated based on the evidence and expert opinion. The updated recommendations comprise six overarching principles and nine recommendations. The former address the need for an annual vaccination status assessment, shared decision-making and timing of vaccination, favouring vaccination during quiescent disease, preferably prior to the initiation of immunosuppression. Non-live vaccines can be safely provided to AIIRD patients regardless of underlying therapy, whereas live-attenuated vaccines may be considered with caution. Influenza and pneumococcal vaccination should be strongly considered for the majority of patients with AIIRD. Tetanus toxoid and human papilloma virus vaccination should be provided to AIIRD patients as recommended for the general population. Hepatitis A, hepatitis B and herpes zoster vaccination should be administered to AIIRD patients at risk. Immunocompetent household members of patients with AIIRD should receive vaccines according to national guidelines, except for the oral poliomyelitis vaccine. Live-attenuated vaccines should be avoided during the first 6 months of life in newborns of mothers treated with biologics during the second half of pregnancy. These 2019 EULAR recommendations provide an up-to-date guidance on the management of vaccinations in patients with AIIRD.

Incidence and prevalence of vaccine preventable infections in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD): a systemic literature review informing the 2019 update of the EULAR recommendations for vaccination in adult patients with AIIRD.

Objectives: The aims of this study were to update the evidence on the incidence and prevalence rates of vaccine preventable infections (VPI) in patients with autoimmune inflammatory rheumatic diseases (AIIRD) and compare the data to the general population when available. Methods: A literature search was performed using Medline, Embase and Cochrane library (October 2009 to August 2018). The primary outcome was the incidence or prevalence of VPI in the adult AIIRD population. Meta-analysis was performed when appropriate. Results: Sixty-three publications out of 3876 identified records met the inclusion criteria: influenza (n=4), pneumococcal disease (n=7), hepatitis B (n=10), herpes zoster (HZ) (n=29), human papillomavirus (HPV) infection (n=13). An increased incidence of influenza and pneumococcal disease was reported in patients with AIIRD. HZ infection-pooled incidence rate ratio (IRR) was 2.9 (95% CI 2.4 to 3.3) in patients with AIIRD versus general population. Among AIIRD, inflammatory myositis conferred the highest incidence rate (IR) of HZ (pooled IRR 5.1, 95% CI 4.3 to 5.9), followed by systemic lupus erythematosus (SLE) (pooled IRR 4.0, 95% CI 2.3 to 5.7) and rheumatoid arthritis (pooled IRR 2.3, 95% CI 2.1 to 2.6). HPV infection-pooled prevalence ratio was 1.6, 95% CI 0.7 to 3.4 versus general population, based on studies mainly conducted in the SLE population in Latin America and Asia. Pooled prevalence of hepatitis B surface antigen and hepatitis B core antibody in patients with AIIRD was similar to the general population, 3%, 95% CI 1% to 5% and 15%, 95% CI 7% to 26%, respectively. Conclusion: Current evidence shows an increased risk of VPI in patients with AIIRD, emphasising that prevention of infections is essential in these patients.

Fatigue in childhood chronic disease.

BACKGROUND AND OBJECTIVES: Recently, in adults, the incidence and severity of fatigue was found to exist rather independently from the somatic diagnosis. Since fatigue is distressing when growing up with a chronic disease, we aim to investigate: (1) the prevalence and extent of fatigue among various paediatric chronic diseases and (2) the effect of fatigue on health-related quality of life (HRQoL). DESIGN AND SETTING: Cross-sectional study in two children's hospitals. PATIENTS: Children and adolescents 2-18 years of age with cystic fibrosis, an autoimmune disease or postcancer treatment visiting the outpatient clinic. OUTCOME MEASURES: Fatigue and HRQoL were assessed using the Pediatric Quality of Life Inventory (PedsQL) multidimensional fatigue scale (with lower scores indicating more fatigue) and PedsQL generic core scales, respectively. Linear regression analysis and analysis of covariance were used to compare fatigue scores across disease groups and against two control groups. The effect of fatigue on HRQoL was calculated. Data were adjusted for age, sex and reporting method. RESULTS: 481 children and adolescents were assessed (60% participation rate, mean age 10.7±4.9, 42% men). Children and adolescents with chronic disease reported more fatigue than the general population (mean difference -6.6, 95% CI -8.9 to -4.3 (range 0-100)), with a prevalence of severe fatigue of 21.2%. Fatigue scores did not differ significantly between disease groups on any fatigue domain. Fatigue was associated with lower HRQoL on all domains. CONCLUSIONS: Fatigue in childhood chronic disease is a common symptom that presents across disease, age and sex groups. Fatigue affects HRQoL. Our findings underscore the need to systematically assess fatigue. Future studies should determine possible biological and psychosocial treatment targets.

Bone-marrow derived mesenchymal stromal cells infusion in therapy refractory juvenile idiopathic arthritis patients.

OBJECTIVES: To compare the total number of adverse events (AEs) before and after mesenchymal stromal cell (MSC) infusion in refractory JIA and to evaluate its effectiveness. METHODS: Single-centre Proof of Mechanism Phase Ib, open label intervention study in JIA patients previously failing all biologicals registered for their diagnosis. Six patients received 2 million/kg intravenous infusions of allogeneic bone-marrow derived MSC. In case of ACR-Ped30-response but subsequent loss of response one and maximal two repeated infusions are allowed. RESULTS: Six JIA patients with 9.2 years median disease duration, still active arthritis and damage were included. All had failed methotrexate, corticosteroids and median five different biologicals. MSC were administered twice in three patients. No acute infusion reactions were observed and a lower post-treatment than pre-treatment incidence in AEs was found. The one systemic onset JIA (sJIA) patient had again an evolving macrophage activation syndrome, 9 weeks after tocilizumab discontinuation and 7 weeks post-MSC infusion. Statistically significant decreases were found 8 weeks after one MSC infusion in VAS well-being (75-56), the JADAS-71 (24.5-11.0) and the cJADAS10 (18.0-10.6). CONCLUSION: MSC infusions in six refractory JIA patients were safe, although in sJIA stopping the 'failing' biologic treatment carries a risk of a MAS flare, as the drug might still suppress the systemic features. TRIAL REGISTRATION: Trial register.nl, http://https://www.trialregister.nl, NTR4146.

Development and validation of a prognostic multivariable model to predict insufficient clinical response to methotrexate in rheumatoid arthritis.

OBJECTIVE: The objective was to predict insufficient response to 3 months methotrexate (MTX) in DMARD naïve rheumatoid arthritis patients. METHODS: A Multivariable logistic regression model of rheumatoid arthritis patients starting MTX was developed in a derivation cohort with 285 patients starting MTX in a clinical multicentre, stratified single-blinded trial, performed in seven secondary care clinics and a tertiary care clinic. The model was validated in a validation cohort with 102 patients starting MTX at a tertiary care clinic. Outcome was insufficient response (disease activity score (DAS)28 >3.2) after 3 months of MTX treatment. Clinical characteristics, lifestyle variables, genetic and metabolic biomarkers were determined at baseline in both cohorts. These variables were dichotomized and used to construct a multivariable prediction model with backward logistic regression analysis. RESULTS: The prediction model for insufficient response in the derivation cohort, included: DAS28>5.1, Health Assessment Questionnaire>0.6, current smoking, BMI>25 kg/m2, ABCB1 rs1045642 genotype, ABCC3 rs4793665 genotype, and erythrocyte-folate<750 nmol/L. In the derivation cohort, AUC of ROC curve was 0.80 (95%CI: 0.73-0.86), and 0.80 (95%CI: 0.69-0.91) in the validation cohort. Betas of the prediction model were transformed into total risk score (range 0-8). At cutoff of ≥4, probability for insufficient response was 44%. Sensitivity was 71%, specificity 72%, with positive and negative predictive value of 72% and 71%. CONCLUSIONS: A prognostics prediction model for insufficient response to MTX in 2 prospective RA cohorts by combining genetic, metabolic, clinical and lifestyle variables was developed and validated. This model satisfactorily identified RA patients with high risk of insufficient response to MTX.

Consensus-based recommendations for the management of uveitis associated with juvenile idiopathic arthritis: the SHARE initiative.

BACKGROUND: In 2012, a European initiative called Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children and uveitis is possibly its most devastating extra-articular manifestation. Evidence-based guidelines are sparse and management is mostly based on physicians' experience. Consequently, treatment practices differ widely, within and between nations. OBJECTIVES: To provide recommendations for the diagnosis and treatment of JIA-associated uveitis. METHODS: Recommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was constituted, consisting of nine experienced paediatric rheumatologists and three experts in ophthalmology from Europe. Recommendations derived from a validated systematic literature review were evaluated by an Expert Committee and subsequently discussed at two consensus meetings using nominal group techniques. Recommendations were accepted if >80% agreement was reached (including all three ophthalmologists). RESULTS: In total, 22 recommendations were accepted (with >80% agreement among experts): 3 on diagnosis, 5 on disease activity measurements, 12 on treatment and 2 on future recommendations. CONCLUSIONS: The SHARE initiative aims to identify best practices for treatment of patients suffering from JIA-associated uveitis. Within this remit, recommendations for the diagnosis and treatment of JIA-associated uveitis have been formulated by an evidence-informed consensus process to suggest a standard of care for JIA-associated uveitis patients throughout Europe.

The safety of live-attenuated vaccines in patients using IL-1 or IL-6 blockade: an international survey.

BACKGROUND: Withholding live-attenuated vaccines in patients using interleukin (IL)-1 or IL-6 blocking agents is recommended by guidelines for both pediatric and adult rheumatic diseases, since there is a risk of infection in an immune suppressed host. However, this has never been studied. This retrospective, multicenter survey aimed to evaluate the safety of live-attenuated vaccines in patients using IL-1 or IL-6 blockade. METHODS: We contacted physicians involved in the treatment of autoinflammatory diseases to investigate potential cases. Patients were included if a live-attenuated vaccine had been administered while they were on IL-1 or IL-6 blockade. RESULTS: Seventeen patients were included in this survey (7 systemic juvenile idiopathic arthritis (sJIA), 5 cryopyrin associated periodic syndrome (CAPS), 4 mevalonate kinase deficiency (MKD) and 1 familial Mediterranean fever (FMF). Three patients experienced an adverse event, of which two were serious adverse events (a varicella zoster infection after varicella zoster booster vaccination, and a pneumonia after MMR booster). One additional patient had diarrhea after oral polio vaccine. Further, seven patients experienced a flare of their disease, which were generally mild. Eight patients did not experience an adverse event or a flare. CONCLUSION: We have described a case series of seventeen patients who received a live-attenuated vaccine while using IL-1 or IL-6 blocking medication. The findings of this survey are not a reason to adapt the existing guidelines. Prospective trials are needed in order to acquire more evidence about the safety and efficacy before considering adaptation of guidelines.

Clinical Juvenile Arthritis Disease Activity Score proves to be a useful tool in treat-to-target therapy in juvenile idiopathic arthritis.

OBJECTIVES: To assess if the Juvenile Arthritis Disease Activity Score (JADAS71) could be used to correctly identify patients with juvenile idiopathic arthritis (JIA) in need of antitumour necrosis factor therapy (anti-TNF) therapy 3 and 6 months after start of methotrexate (MTX). METHODS: Monocentric retrospective cohort study from 2011 to 2015 analysing all patients with oligoarticular JIA (OJIA) (n=39) and polyarticular course JIA (PJIA) (n=74) first starting MTX. Three and 6 months after MTX start, clinical and laboratory features and the 2011 American College of Rheumatology (ACR) JIA treatment recommendations (ACR clinical practice guideline (ACR-CPG)) were compared between groups starting and not starting anti-TNF therapy. The sensitivity and specificity of the ACR-CPG, JADAS71 and the clinical JADAS to identify non-responders after 12 months were calculated. RESULTS: Physicians escalated patients with significantly higher physician global assessment, clinical JADAS (cJADAS) and patient Visual Analogue Scale (VAS). The decision not to escalate was correct in 70%-75% as shown by MTX response. The implementation of the ACR-CPG would increase the current anti-TNF use from 12% to 65%. The use of (c)JADAS in identifying patients in need of anti-TNF therapy outperformed the ACR-CPG with a much higher sensitivity, specificity and accuracy. The cJADAS threshold for treatment escalation at month 3 and 6 was >5 and >3 for OJIA and >7 and >4 for PJIA, respectively. The performance of the cJADAS decreased when the patient VAS contribution to the total score was restricted and overall did not improve by adding the erythrocyte sedimentation rate. CONCLUSIONS: The cJADAS identifies patients in need of anti-TNF and is a user-friendly tool ready to be used for treat to target in JIA. The patient VAS is a critical item in the cJADAS for the decision to escalate to anti-TNF.

Reticular dysgenesis: international survey on clinical presentation, transplantation, and outcome.

Reticular dysgenesis (RD) is a rare congenital disorder defined clinically by the combination of severe combined immunodeficiency (SCID), agranulocytosis, and sensorineural deafness. Mutations in the gene encoding adenylate kinase 2 were identified to cause the disorder. Hematopoietic stem cell transplantation (HSCT) is the only option to cure this otherwise fatal disease. Retrospective data on clinical presentation, genetics, and outcome of HSCT were collected from centers in Europe, Asia, and North America for a total of 32 patients born between 1982 and 2011. Age at presentation was <4 weeks in 30 of 32 patients (94%). Grafts originated from mismatched family donors in 17 patients (55%), from matched family donors in 6 patients (19%), and from unrelated marrow or umbilical cord blood donors in 8 patients (26%). Thirteen patients received secondary or tertiary transplants. After transplantation, 21 of 31 patients were reported alive at a mean follow-up of 7.9 years (range: 0.6-23.6 years). All patients who died beyond 6 months after HSCT had persistent or recurrent agranulocytosis due to failure of donor myeloid engraftment. In the absence of conditioning, HSCT was ineffective to overcome agranulocytosis, and inclusion of myeloablative components in the conditioning regimens was required to achieve stable lymphomyeloid engraftment. In comparison with other SCID entities, considerable differences were noted regarding age at presentation, onset, and type of infectious complications, as well as the requirement of conditioning prior to HSCT. Although long-term survival is possible in the presence of mixed chimerism, high-level donor myeloid engraftment should be targeted to avoid posttransplant neutropenia.

Haematopoietic stem cell transplantation for autoimmune diseases.

Autologous haematopoietic stem cell transplantation (HSCT) is the only treatment that is able to induce long-term, drug-free and symptom-free remission in several refractory autoimmune rheumatic diseases. Over 3,000 HSCT procedures for rheumatic and nonrheumatic severe autoimmune diseases have been performed worldwide. Specific conditioning regimens are currently used to eradicate the autoreactive immunological memory of patients. Although in vivo immune cell depletion with antithymocyte globulin or anti-CD52 is the norm for many regimens, ex vivo selection of CD34+ stem cells from the graft is controversial. Following the extensive immune depletion associated with serotherapy and chemotherapy, HSCT effectively resets the immune system by renewing the CD4+ T cell compartment, especially the regulatory T cell population. The risk of transplant-related mortality (TRM) within the first 100 days should be weighed against the risk of disease-related mortality, and the careful selection and screening of patients before transplantation is essential. Systemic sclerosis is the first autoimmune disease for which HSCT has been shown, in a randomized, controlled trial, to be associated with increased TRM in the first year but a significant long-term, event-free survival benefit afterwards. In this Review, we discuss the immunological mechanisms of HSCT in various autoimmune diseases and current HSCT regimens. After carefully taking into consideration the risks and benefits of HSCT and alternative therapies, we also discuss the efficacy, complications and proposed indications of this procedure.

Evolution, trends, outcomes, and economics of hematopoietic stem cell transplantation in severe autoimmune diseases.

Hematopoietic stem cell transplantation (HSCT) has evolved for >20 years as a specific treatment of patients with autoimmune disease (AD). Using European Society for Blood and Marrow Transplantation registry data, we summarized trends and identified factors influencing activity and outcomes in patients with AD undergoing first autologous HSCT (n = 1951; median age, 37 years [3-76]) and allogeneic HSCT (n = 105; median age, 12 years [<1-62]) in 247 centers in 40 countries from 1994 to 2015. Predominant countries of activity were Italy, Germany, Sweden, the United Kingdom, The Netherlands, Spain, France, and Australia. National activity correlated with the Human Development Index (P = .006). For autologous HSCT, outcomes varied significantly between diseases. There was chronological improvement in progression-free survival (PFS, P < 10-5), relapse/progression (P < 10-5), and nonrelapse mortality (P = .01). Health care expenditure was associated with improved outcomes in systemic sclerosis and multiple sclerosis (MS). On multivariate analysis selecting adults for MS, systemic sclerosis, and Crohn disease, better PFS was associated with experience (≥23 transplants for AD, P = .001), learning (time from first HSCT for AD ≥6 years, P = .01), and Joint Accreditation Committee of the International Society for Cellular Therapy and European Society for Blood and Marrow Transplantation accreditation status (P = .02). Despite improved survival over time (P = .02), allogeneic HSCT use remained low and largely restricted to pediatric practice. Autologous HSCT has evolved into a treatment modality to be considered alongside other modern therapies in severe AD. Center experience, accreditation, interspecialty networking, and national socioeconomic factors are relevant for health service delivery of HSCT in AD.

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

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

Recommendations for the management of autoinflammatory diseases.

: Autoinflammatory diseases are characterised by fever and systemic inflammation, with potentially serious complications. Owing to the rarity of these diseases, evidence-based guidelines are lacking. In 2012, the European project Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate regimens for the management of children and young adults with rheumatic diseases, facilitating the clinical practice of paediatricians and (paediatric) rheumatologists. One of the aims of SHARE was to provide evidence-based recommendations for the management of the autoinflammatory diseases cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD). These recommendations were developed using the European League Against Rheumatism standard operating procedure. An expert committee of paediatric and adult rheumatologists was convened. Recommendations derived from the systematic literature review were evaluated by an online survey and subsequently discussed at a consensus meeting using Nominal Group Technique. Recommendations were accepted if more than 80% agreement was reached. In total, four overarching principles, 20 recommendations on therapy and 14 recommendations on monitoring were accepted with ≥80% agreement among the experts. Topics included (but were not limited to) validated disease activity scores, therapy and items to assess in monitoring of a patient. By developing these recommendations, we aim to optimise the management of patients with CAPS, TRAPS and MKD.