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Abstract Background Systemic juvenile idiopathic arthritis (sJIA) is a complex disease with an autoinflammatory component of unknown etiology related to the innate immune system. A major role in the pathogenesis has been ascribed to proinflammatory cytokines like interleukin-6 (IL-6), and effective drugs inhibiting their signaling are being developed. This study evaluates sJIA patients treated with the IL-6 inhibitor tocilizumab (TCZ) concerning clinical response rate, disease course and adverse effects in a real-life clinical setting. Methods In 2009 a clinical and research consortium was established, including an online registry for autoinflammatory diseases (AID) (https://aid-register.de). Data for this retrospective TCZ study were documented by 13 centers. Results From 7/2009 to 4/2014, 200 patients with sJIA were recorded in the AID-registry. Out of these, 46 (19 m, 27 f, age 1–18 years) received therapy with TCZ. Long term treatment (median 23 months) has been documented in 24/46 patients who were evaluated according to Wallace criteria (active disease 6/24, inactive disease 5/24, remission 13/24 cases). Under observation co-medication were used in 40/46 cases. Adverse events were reported in 11/46 patients. The clinical response rate (no clinical manifestation, no increased inflammation parameters) within the first 12 weeks of treatment was calculated to be 35%. Conclusion Out of 200 sJIA children reported in the German AID-registry, 46 were treated with TCZ, showing a clinical response rate of 35% during the first 12 weeks, and inactive disease and/or remission under medication in 75% after one year. Adverse events were seen in 24% and severe adverse events in 4%. Trial registration The AID-Registry is funded by the BMBF (01GM08104, 01GM1112D, 01GM1512D).

Hypogammaglobulinemia is a common symptom in different immunodeficiencies. It is, however, not usually associated with Epstein–Barr virus (EBV) infections. The X-linked lymphoproliferative disease (XLP) on the other hand shows immunological changes in response to the EBV. Here we report three previously healthy boys, all of which developed persistent hypogammaglobulinemia following severe acute infectious mononucleosis. All three patients revealed T-cell abnormalities including inverted CD4/CD8 and increased CD8+ T-cell numbers. The number of IFN-γ-producing T cells were markedly increased in the two patients studied so far. In addition, patient 2 showed mainly T cells, instead of B cells, to be infected with the EBV. Apart from an uncle of patient 3, who died of malignant lymphoma, family history was unremarkable in all cases. All three patients exhibited mutations in the SH2D1A gene, establishing the diagnosis of XLP. Protein expression was found on immunoblot analysis in one patient with a missense mutation. Development of persistent hypogammaglobulinemia after severe primary EBV infection seems to be a specific diagnostic sign for XLP even in males with unremarkable family history. [ABSTRACT FROM AUTHOR]

Background: Methotrexate (MTX) intolerance in juvenile idiopathic arthritis (JIA) frequently leads to discontinuation due to anticipatory and associative gastrointestinal symptoms. Eye Movement Desensitization and Reprocessing (EMDR) has successfully been used in MTX intolerance, with lasting effects but frequently diminishing efficacy over time. BLAST (bi-lateral alternating stimulation tactile) wristbands utilize a similar process to EMDR. The aim of this study was to determine if utilization of BLAST wristbands could improve and prolong the effect of EMDR on patients with MTX intolerance., Methods: Consecutive patients admitted to the German Center for Pediatric and Adolescent Rheumatology with JIA and signs of MTX intolerance from October 2016 until March 2024 were included in this study. Treatment was performed using an adapted 8 phase EMDR protocol implementing BAST wristbands. Initial patients were treated with EMDR, subsequent patients additionally with BLAST wristbands. Health-related quality of live was determined using the PedsQL. Measurements of MISS (Methotrexate Intolerance Severity Score) and PedsQL were taken at 4 time points: directly before and after (MISS only) treatment, as well as 4 and 12 months after treatment. Changes in MISS and PedsQL were compared using descriptive statistics and repeated measures ANOVA., Results: 87 patients with MTX intolerance were included, 53 in group 1 without BLAST wristbands and 34 in group 2 which were concurrently treated with BLAST wristbands. All patients reported marked improvement of MTX intolerance symptoms (mean MISS score group 1: 15.0 ± 5.5 before treatment, 1.3 ± 1.5 after treatment, group 2: 16.8 ± 5.6 and 2.5 ± 2.5, respectively). After 4 and 12 months, MISS in group 1 was 8.1 ± 7.1 and 8.7 ± 8.4, and in group 2: 7.1 ± 6.3 and 6.5 ± 5.7. A repeated measures ANOVA showed a significant difference between the MISS results over time (F(3,114) = 64.6, p < 0.001), and also demonstrated a significant difference of the PedsQL results between the two groups over time (F(2,64) = 8.9, p < 0.001)., Conclusion: Treatment with Eye Movement Desensitization and Reprocessing (EMDR) could present an effective treatment of MTX intolerance, and using BLAST wristbands, further potential improvement is possible., (© 2024. The Author(s).)

Objectives: Unlike in adult rheumatology, for most forms of juvenile idiopathic arthritis (JIA) no reliable biomarkers currently exist to assess joint and disease activity. However, electrophoresis is frequently found changed in active juvenile arthritis. The objective of this study was to evaluate the α2-fraction of serum electrophoresis and its main components as biomarkers for JIA, categories extended/persistent oligoarthritis and seronegative polyarthritis, in comparison with the conventionally used erythrocyte sedimentation rate and C-reactive protein., Methods: Serum samples and clinical data from 181 patients with JIA were collected. Serum electrophoresis and α2-fraction and its components were determined using standard methods. Relationship between calculated α2-fraction of serum electrophoresis (CA2F) and its components, acute-phase parameters and cJADAS27 was assessed using Pearson's correlation coefficient and linear regression modelling, adjusting for confounding effects. Results were confirmed in a second cohort with 223 serum samples from 37 patients, using a mixed model to account for repeated measures., Results: Compared to ESR and CRP, CA2F showed higher correlation to cJADAS27, in particular for persistent oligoarthritis. Of the three components of the α2-fraction, haptoglobin showed the highest correlation to cJADAS27. Regression analysis demonstrated higher ability to predict cJADAS27 for CA2F, and especially for haptoglobin as a component thereof, than for CRP and ESR., Conclusion: Compared to conventional methods, α2-fraction of serum electrophoresis and specifically, haptoglobin show higher correlations with disease activity in common subtypes of JIA, representing excellent candidates as biomarkers for disease activity. Further studies are necessary to determine diagnostic value and correlations in other subtypes., (© 2022. The Author(s).)

Background: The plasticity of T helper-17 (Th17) and regulatory T (Treg) cells may be a clue to pathogenesis of Juvenile Idiopathic Arthritis (JIA). It is still unclear, whether targeted suppression of Interleukin (IL)-17 is able to influence regulatory function of Treg to control pro-inflammatory effectors in JIA. This study aimed to assess the effect of a Th17-stimulating cytokine environment and of IL-17A-inhibition on phenotype plasticity and suppressive function of Treg derived from JIA patients., Methods: Th17 and Treg characteristics of CD4 + helper T cells were investigated in blood samples of JIA patients with oligo- and polyarticular pattern and healthy controls (HC). Isolated CD4 + CD25 + CD127 - cells defined as Treg were cultivated with Th17-inducing cytokine environment as well as with IL-17A-inhibitors and analyzed for plasticity of phenotype by flow cytometry. Furthermore, inhibitory function of Treg on autologous effectors after cultivation with these stimuli was determined by suppression assays., Results: Our findings demonstrated significantly elevated proportions of Th17 and Th17-like Treg in JIA compared to HC. After incubation with Th17-inducing stimuli, increased FoxP3 expression in separated Treg in JIA and an impaired suppressive capacity in JIA and HC were found. Blockade of IL-17A resulted in adjustment of FoxP3-expression in JIA to proportions found in controls and in regular suppressive function., Conclusions: Our results demonstrate an induction of FoxP3 expressing Treg by Th17-inducing cytokines with concomitant mitigated suppressive function. In contrast, specific IL-17A blockade maintains suppressive Treg function and adjusted FoxP3-expression in JIA to levels found in controls. These findings may help to provide experimental evidence for the successful clinical use of IL-17A inhibition in JIA patients., (© 2022. The Author(s).)

Introduction: Due to potentially severe sequelae (impaired growth, condylar resorption, and ankylosis) early diagnosis of chronic rheumatic arthritis of the temporomandibular joint (TMJ) and timely onset of therapy are essential. Aim: Owing to very limited evidence the aim of the study was to identify and discuss controversial topics in the guideline development to promote further focused research. Methods: Through a systematic literature search, 394 out of 3771 publications were included in a German interdisciplinary guideline draft. Two workgroups (1: oral and maxillofacial surgery, 2: interdisciplinary) voted on 77 recommendations/statements, in 2 independent anonymized and blinded consensus phases (Delphi process). Results: The voting results were relatively homogenous, except for a greater proportion of abstentions amongst the interdisciplinary group (p < 0.001). Eighty-four percent of recommendations/statements were approved in the first round, 89% with strong consensus. Fourteen recommendations/statements (18.2%) required a prolonged consensus phase and further discussion. Discussion: Contrast-enhanced MRI was confirmed as the method of choice for the diagnosis of TMJ arthritis. Intraarticular corticosteroid injection is to be limited to therapy-refractory cases and single injection only. In adults, alloplastic joint replacement is preferable to autologous replacement. In children/adolescents, autologous reconstruction may be performed lacking viable alternatives. Alloplastic options are currently still considered experimental.

Background: Involvement of the temporomandibular joint can be shown in 40-90% of patients with rheumatoid arthritis and juvenile idiopathic arthritis (JIA), although it is often asymptomatic. Restricted jaw mobility and jaw pain can be found in approximately 20% of patients with JIA (prevalence: 70 per 100 000 persons). Early diagnosis and treatment of the underlying disease are essential for a good outcome, but uniform, consensus-based management is still lacking., Methods: The clinical practice guideline is based on the findings of a systematic literature review in multiple databases and a Delphi procedure to obtain consensus on the recommendations., Results: Most of the identified studies were retrospective. Patients with JIA should undergo clinical screening with a structured examination protocol once per year in childhood and adolescence, and thereafter as well if the temporomandibular joint is involved. The diagnosis of chronic rheumatoid arthritis of the temporomandibular joint is established with contrast-enhanced magnetic resonance imaging. Conservative treatment (antirheumatic basal therapy, local measures) is unsuccessful in less than 10% of patients. In such cases, arthroscopy and arthrocentesis can be used for temporary symptom relief and functional improvement. Intra-articular corticosteroid injections should be given only once, and only in otherwise intractable cases. In severe cases where all other options have been exhausted (<1%), open surgical treatment can be considered, including alloplastic joint replacement., Conclusion: Oligosymptomatic and asymptomatic cases are common even with radiologic evidence of marked joint damage. The possibility of rheumatic involvement of the temporomandibular joint must be kept in mind so that serious complications can be avoided. Regular clinical evaluation of the temporomandibular joint is recommended, particularly for patients with juvenile idiopathic arthritis.

Background: Flares of juvenile idiopathic arthritis (JIA) have been described in the context of various infections. Flares of rheumatic diseases in adults have been described following infection with SARS-CoV-2 in several cohorts. So far, the effect of infection with SARS-CoV-2 on the course of JIA is unknown., Methods: The database of the German Center for Pediatric and Adolescent Rheumatology was searched for patients with confirmed infection with SARS-CoV-2 and subsequent disease flare, admitted from July 2020 until June 2021. cJADAS-27, ESR and C-reactive protein, as well as uveitis activity, medication at the time of flare and treatment of flare was extracted. Patient cases were described individually., Results: Out of 988 patients admitted, five patients with remission off medication (n = 2) or inactive disease on medication (n = 3) were identified, with flare symptoms up to four weeks after infection with SARS-CoV-2., Conclusions: Flares can occur after infection with SARS-CoV-2 in patients with JIA in remission or inactive disease on medication. Treating physicians need to be aware of this fact, especially when counseling patients with rheumatic diseases about the respective dangers of COVID-19 and vaccination against SARS-CoV-2., (© 2021. The Author(s).)

Background: Systemic juvenile idiopathic arthritis (sJIA) is a complex disease with dysregulation of the innate immune system driven by cytokines. A major role is ascribed to interleukin-1β (IL-1β), supporting the autoinflammatory character of the disease and offering an effective blocking mechanism for treatment. Here we present clinical practice data from the German AID-registry for patients treated with IL-1 inhibition (IL-1i)., Methods: In 2009 a clinical and research consortium (AID-Net) was established, including an online AID-registry. Patients with documented sJIA diagnosis were identified. Data for this retrospective IL-1i study were recorded by 17 centers. Response to treatment was evaluated according to Wallace criteria and additionally by an own classifying clinical response system., Results: In 6 years, 202 patients with confirmed sJIA were recorded in the AID-registry. Out of these, 111 children received therapy with Anakinra (ANA) (n = 84, 39 f) and/or Canakinumab (CANA) (n = 27, 15 f) at a median age of 8.7 y (range 0.6-19.1). During the first 12 months 75/111 (ANA 55, CANA 20) patients were evaluated according to Wallace criteria (achievement of inactive disease 28/55 and 17/20, remission over 6 months under medication 13/55 and 7/20 cases). Over the whole period of time, clinical response was preserved in the majority of patients (ANA 54/80, CANA 20/27). Arthritis mostly persisted in polyarticular (PA) courses. During treatment with IL-1i concomitant medication could be tapered in about 15%. IL-1i was discontinued in 59/111 patients. 45 (15) adverse events (AE)s in ANA (CANA) treated patients (19.7 (26.6) AE/100 ANA (CANA) exposure years, 95%CI: 14.4-26.4 (14.9-43.9)) were reported., Conclusion: In a large cohort of sJIA patients from Germany, we can confirm an overall favorable clinical response to both available IL-1 blocking agents. IL-1i was well tolerated with acceptable safety and effectiveness in a real-life clinical setting.

Objective: Using data from the German Biologics JIA Registry (BIKER), long-term safety of biologics for systemic-onset JIA with regard to adverse events of special interest was assessed., Methods: Safety assessments were based on adverse event reports after first dose through 90 days after last dose. Rates of adverse event, serious adverse event and 25 predefined adverse events of special interest were analysed. Incidence rates were compared for each biologic against all other biologics combined applying a mixed-effect Poisson model., Results: Of 260 systemic-onset JIA patients in this analysis, 151 patients received etanercept, 109 tocilizumab, 71 anakinra and 51 canakinumab. Patients with etanercept had higher clinical Juvenile Arthritis Disease Activity Score 10 scores, active joint counts and steroid use at therapy start. Serious adverse events were reported with higher frequency in patients receiving canakinumab [20/100 patient years (PY)] and tocilizumab (21/100 PY). Cytopenia and hepatic events occurred with a higher frequency with tocilizumab and canakinumab. Medically important infections were seen more often in patients with IL-6 or IL-1 inhibition. Macrophage activation syndrome occurred in all cohorts with a higher frequency in patients with canakinumab (3.2/100 PY) and tocilizumab (2.5/100 PY) vs anakinra (0.83/100 PY) and etanercept (0.5/100 PY). After adjustment only an elevated risk for infections in anakinra-treated patients remained significant. Three definite malignancies were reported in patients ever exposed to biologics. Two deaths occurred in patients treated with etanercept., Conclusion: Surveillance of pharmacotherapy as provided by BIKER is an import approach especially for patients on long-term treatment. Overall, tolerance was acceptable. Differences between several biologics were noted and should be considered in daily patient care., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

MTX is the medication most commonly used for antirheumatic treatment in juvenile idiopathic arthritis. It has high efficacy, is usually well tolerated and has an excellent safety profile. However, frequently intolerance symptoms develop that manifest as nausea, feelings of disgust or abdominal complaints prior to or directly after administration of the medication. No obvious toxicity is causing these intolerance symptoms, but symptoms are strictly limited to MTX and not transferred to other medications. MTX intolerance causes a significant reduction of quality of life in affected patients, frequently puts the treating physician in difficult situations regarding treatment choice, and may lead to uncomfortable decisions whether or not to stop an otherwise effective drug. Conventional countermeasures such as antiemetics, change of route from subcutaneous to oral or vice versa, or taste masking usually have only a limited effect. In this review, we present the current knowledge on MTX intolerance, its clinical picture and commonly employed strategies. We also consider newer behavioural treatment strategies that may offer a more effective symptom control., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The MM5 trial aimed at demonstrating a progression-free survival (PFS) difference in continued vs. response-adapted (in case of complete response, CR) lenalidomide (LEN) maintenance therapy (MT) in newly diagnosed, transplant-eligible multiple myeloma (MM). Patients were equally randomized to receive induction therapy with PAd (bortezomib/doxorubicin/dexamethasone) or VCD (bortezomib/cyclophosphamide/dexamethasone), high-dose melphalan and autologous blood stem cell transplantation, and LEN consolidation, followed by either LEN MT for a fixed duration of 2 years (LEN-2Y) or until achievement of CR (LEN-CR, intention-to-treat population n = 502): arms A1:PAd + LEN-2Y (n = 125), B1:PAd + LEN-CR (n = 126), A2:VCD + LEN-2Y (n = 126), B2:VCD + LEN-CR (n = 125). In the LEN-CR group (B1 + B2), n = 88/17.5% patients did not start or discontinued LEN MT due to CR. There was no PFS (p = 0.60, primary endpoint) nor overall survival (OS) (p = 0.15) difference between the four study arms. On pooled LEN MT strategies, OS (hazard ratio, hazard ratio [HR] = 1.42, p = 0.03) but not PFS (HR = 1.15, p = 0.20) was shorter in LEN-CR (B1 + B2) vs. LEN-2Y (A1 + A2) groups. PFS was shortened on landmark analyses from the start of LEN MT in patients being in CR in the LEN-CR group (LEN-CR vs. LEN-2Y, HR = 1.84, p = 0.02). OS from first progression was shortened in the LEN-CR vs. LEN-2Y group (HR = 1.60, p = 0.01). LEN MT should be applied beyond CR for at least 2 years.

Objective: To analyze the reported association of IL1RN polymorphisms with response to interleukin-1 (IL-1) blockade in a German cohort of patients with systemic juvenile idiopathic arthritis (JIA), and to assess the impact of other factors on treatment response., Methods: Sixty-one patients with systemic JIA who had received IL-1 blockade were identified within the German Autoinflammatory Disease registry DNA biobank. Response to IL-1 blockade was assessed according to 1) the clinical response (initially at least a transient response or good response compared to a poor response), 2) switch (or no switch) to anti-IL-6 receptor therapy following IL-1 blockade, 3) achievement of clinically inactive disease within 6 months of IL-1 blockade, 4) improvement in disease activity measured using the modified Juvenile Arthritis Disease Activity Score, and 5) achievement of a glucocorticoid-free state. In addition, basic demographic data, key features of the disease course, laboratory data, and IL1RN single-nucleotide polymorphisms (SNPs) were assessed., Results: Six of 7 IL1RN SNPs reported to be associated with response to anakinra therapy were analyzed. These 6 IL1RN SNPs were inherited as haplotypes. An association of IL1RN haplotypes and SNPs with response to IL-1 blockade could not be confirmed in this cohort of patients with systemic JIA. Patients who received tocilizumab following IL-1 blockade had a longer duration from disease onset to diagnosis than those who did not receive tocilizumab (median 0.27 years versus 0.08 years)., Conclusion: The results of this study could not confirm an impact of IL1RN SNPs on response to IL-1 blockade therapy with either anakinra or canakinumab in a cohort of patients with systemic JIA. However, a longer time frame from disease onset to diagnosis was associated with poorer long-term treatment response, thereby supporting the "window of opportunity" hypothesis that suggests improved long-term treatment response with shorter time from disease onset to diagnosis (and treatment)., (© 2019 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Methotrexate (MTX) is the medication most commonly used for antirheumatic treatment in juvenile idiopathic arthritis. It has high efficacy, is usually well tolerated and has an excellent safety profile. However, intolerance symptoms frequently develop, which manifest as nausea, feelings of disgust, or abdominal complaints prior to or directly after application of the medication. A direct side effect can usually be easily excluded; however, the symptoms are limited to treatment with MTX. This MTX intolerance causes a significant reduction in the quality of life of affected patients, frequently puts the treating physician in an uncomfortable situation, and not uncommonly results in discontinuation of treatment. Conventional countermeasures such as antiemetics, change of route from subcutaneous to oral or vice versa, or, for example, taste masking, usually have only limited effect. Newer behavioral treatment strategies raise hopes of more effective symptom control.

B cell development is a highly regulated process involving multiple differentiation steps, yet many details regarding this pathway remain unknown. Sequencing of patients with B cell-restricted immunodeficiency reveals autosomal dominant mutations in TOP2B. TOP2B encodes a type II topoisomerase, an essential gene required to alleviate topological stress during DNA replication and gene transcription, with no previously known role in B cell development. We use Saccharomyces cerevisiae, and knockin and knockout murine models, to demonstrate that patient mutations in TOP2B have a dominant negative effect on enzyme function, resulting in defective proliferation, survival of B-2 cells, causing a block in B cell development, and impair humoral function in response to immunization.

Background: The term systemic juvenile idiopathic arthritis (sJIA) describes an autoinflammatory condition characterized by arthritis and severe systemic inflammation, which in later stages can transform into interleukin (IL)-17-driven autoimmune arthritis. IL-1 antagonists have been used with good efficacy in the early stages of sJIA., Methods: A whole transcriptome analysis of peripheral blood RNA samples was performed in six patients with sJIA and active systemic disease, before initiating treatment with the IL-1β receptor antagonist anakinra, and after induction of inactive disease, compared with a single-sample control cohort of 21 patients in several clinical stages of sJIA activity. Whole transcriptomes were compared longitudinally and interindividually including gene ontology and motif enrichment analysis of differentially expressed genes., Results: There were 741 transcripts were identified using a threshold with a p value <0.01 and a fold change > 2. HLADRB1 and CD74 were identified as the most strongly upregulated genes in inactive compared to active disease; CD177 expression was significantly enhanced in active disease compared to inactive disease. Motif enrichment analysis revealed STAT4, BCL6, and STAT3 as the most prominent transcription factors that were present during active disease. In addition, strong upregulation of the major histocompatability complex II (MHCII) ligand CD74 was found in both active and inactive sJIA compared to healthy controls., Conclusion: Using transcription factor motif enrichment, this study identifies novel putative pathways in sJIA (STAT4, BCL6) implicating B cell activation at an earlier stage than predicted in refractory disease. The implication of BCL-6 dependent pathways argues for occurrence of autoimmunity early within the process of sJIA chronification. Transcriptional regulation of HLA-DRB1, a recently described independent genetic risk factor, in combination with its cooperating partner CD74 in patients where sJIA is confirmed, supports pathogenic involvement in alterations in antigen presentation during sJIA.

Background: Systemic juvenile idiopathic arthritis (sJIA) is a complex disease with an autoinflammatory component of unknown etiology related to the innate immune system. A major role in the pathogenesis has been ascribed to proinflammatory cytokines like interleukin-6 (IL-6), and effective drugs inhibiting their signaling are being developed. This study evaluates sJIA patients treated with the IL-6 inhibitor tocilizumab (TCZ) concerning clinical response rate, disease course and adverse effects in a real-life clinical setting., Methods: In 2009 a clinical and research consortium was established, including an online registry for autoinflammatory diseases (AID) ( https://aid-register.de ). Data for this retrospective TCZ study were documented by 13 centers., Results: From 7/2009 to 4/2014, 200 patients with sJIA were recorded in the AID-registry. Out of these, 46 (19 m, 27 f, age 1-18 years) received therapy with TCZ. Long term treatment (median 23 months) has been documented in 24/46 patients who were evaluated according to Wallace criteria (active disease 6/24, inactive disease 5/24, remission 13/24 cases). Under observation co-medication were used in 40/46 cases. Adverse events were reported in 11/46 patients. The clinical response rate (no clinical manifestation, no increased inflammation parameters) within the first 12 weeks of treatment was calculated to be 35%., Conclusion: Out of 200 sJIA children reported in the German AID-registry, 46 were treated with TCZ, showing a clinical response rate of 35% during the first 12 weeks, and inactive disease and/or remission under medication in 75% after one year. Adverse events were seen in 24% and severe adverse events in 4%., Trial Registration: The AID-Registry is funded by the BMBF (01GM08104, 01GM1112D, 01GM1512D).

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the German language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. The participating centres were asked to collect demographic and clinical data along the JAMAR questionnaire in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity). A total of 319 JIA patients (2.8% systemic, 36.7% oligoarticular, 23.5% RF negative polyarthritis, and 37% other categories) and 100 healthy children were enrolled in eight centres. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the German version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and in clinical research.

Background: Methotrexate (MTX), commonly used in juvenile idiopathic arthritis (JIA), frequently has to be discontinued due to intolerance with anticipatory and associative gastrointestinal adverse effects. Eye Movement Desensitization and Reprocessing (EMDR) is a psychological method where dysfunctional experiences and memories are reprocessed by recall combined with bilateral eye movements. The objective of this study was to assess efficacy of EMDR for treatment of MTX intolerance in JIA patients., Methods: We performed an open prospective study on consecutive JIA patients with MTX intolerance. Intolerance was determined using the Methotrexate Intolerance Severity Score (MISS) questionnaire prior to treatment, directly after treatment and after four months. Health-related quality of life was determined using the PedsQL prior to and four months after treatment. Patients were treated according to an institutional EMDR protocol with 8 sessions over two weeks. Changes in MISS and PedsQL were analyzed using non-parametric statistics., Results: Eighteen patients with MTX intolerance (median MISS at inclusion 16.5, IQR = 11.75-20.25) were included. Directly after treatment, MTX intolerance symptoms were significantly improved (median MISS 1 (IQR = 0-2). After four months, median MISS score was at 6.5 (IQR = 2.75-12.25, p = 0.001), with 9/18 patients showing MISS scores ≥6. Median PedsQL after 4 months improved significantly from 77.6% to 85.3% (p = 0.008)., Conclusion: MTX intolerance in children with JIA was effectively treated using an EMDR protocol, with lasting effect over a period of 4 months. EMDR treatment can potentially increase quality of life of affected patients and enable continued MTX treatment.

Objective: To describe characteristics of patients with juvenile idiopathic arthritis (JIA) presenting with isolated arthritis of the temporomandibular joints (TMJ)., Methods: Patients with JIA with isolated TMJ arthritis from 4 large tertiary pediatric rheumatology centers were included. Demographic and clinical data were analyzed using descriptive statistics., Results: Fifty-five patients were identified (65% bilateral presentation). Six patients developed arthritis in other joints (median time 6 mos); 4 patients developed uveitis, all prior to arthritis. At last followup, 9% were still taking antirheumatic medications., Conclusion: JIA TMJ arthritis can occur in isolation, and is probably underdiagnosed. Care providers including dentists and orthodontists should be aware of this presentation.

Objectives: A high proportion of children with JIA will develop intolerance to MTX with anticipatory and associative gastrointestinal adverse effects. Parents and physicians frequently try to alleviate these symptoms with a variety of countermeasures. The objective of this study was to investigate the course of MTX intolerance within a 6 month period, and the effects of countermeasures on MTX intolerance severity., Methods: We performed a prospective study of 196 consecutive JIA patients treated with MTX. Intolerance was determined using the Methotrexate Intolerance Severity Score (MISS) questionnaire. MISS and countermeasures instituted by parents or physicians were determined at four time points, each 2 months apart. Countermeasures, classified into four types (antiemetic drugs, covert dosing, taste masking and complementary medicine), were analysed using non-parametric statistics and mixed linear modelling, adjusted by propensity scoring for use of countermeasures., Results: Ninety patients (46%) showed MTX intolerance, with 58 (64%) using countermeasures at time of inclusion. Median MISS at inclusion was 11 (interquartile range = 8.0-14.25), and did not change significantly over time. No significant difference in MISS score was observed between patients receiving countermeasures and those who did not. For specific countermeasures, MISS did not change significantly after introduction. Sensitivity analysis adjusting for propensity score indicated no significant association of MISS severity on parents' decision to implement any countermeasures., Conclusion: MTX intolerance was present in many children with JIA and symptoms decreased little in the short term. Various modalities used as countermeasures against nausea by parents showed no discernible effect., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background: Although several studies show that JIA-patients have significantly lower employment rates than the general population, the research on educational and occupational attainments in patients with juvenile idiopathic arthritis (JIA) remain conflicting most likely due to small sample sizes. Therefore, aim of this study is to compare the educational achievements and employment status of 3698 JIA-patients with the German general population (GGP)., Methods: "SEPIA" was a large cross-sectional study on the current status of a historic cohort of JIA-patients treated in a single center between 1952 and 2010. For the analyses of education and employment a sub-cohort was extracted, including only adult cases with a confirmed diagnosis of JIA (N = 2696). Participants were asked to fill out a standardized written questionnaire on education and employment. Outcome measures (education/unemployment) were directly standardized to the GGP using data obtained from the National Educational Panel Study 2013 (N = 11,728) and the German Unemployment Statistics 2012 of the Federal Statistical Office (N = 42,791,000)., Results: After age- and sex-standardization, 3% (95% Confidence Interval 1.9 to 4.1%) more of the JIA-patients (26%) than of the GGP (23%) had only reached primary education. In contrast, parents of JIA-patients had similar levels of education as parents in the GGP. With a standardized difference of 0.2% (95% CI: 0.16 to 0.19%), the unemployment rate in JIA-patients was slightly, but not significantly higher than in the GGP. Stratifying for disease duration and the current treatment status, differences were confirmed for persons diagnosed before 2001, whilst for patients diagnosed after 2000, differences were found only in JIA-patients with ongoing disease. Medium and high educational achievements did not differ statistically significant between JIA patients and the GPP., Conclusion: Educational achievements in German JIA-patients are significantly lower than in the GGP. Furthermore we were able to identify a slightly higher level of unemployment, especially in those with still under treatment and longer disease duration. Better treatment options as well as further development of social support programs might help to overcome this lifelong secondary effect of JIA.

Background: Inflammatory bowel disease can develop in the context of some rheumatic diseases in childhood, including juvenile idiopathic arthritis (JIA). Inflammatory bowel disease (IBD) is frequently associated with other immune-mediated diseases; however, systemic onset JIA (sJIA) has not previously been connected to IBD. Treatment of sJIA has significantly changed in recent years, possibly causing changes in inflammatory patterns. Therefore, data from the German Center for Pediatric and Adolescent Rheumtology from 2010 until 2015 were analyzed by retrospective chart review., Findings: Eighty-two patients with confirmed diagosis of sJIA were found. Of these, three were identified with a diagnosis of IBD confirmed by colonoscopy (two cases of Crohn's disease, one case of ulcerative colitis) 0.8 - 4.3 years after diagnosis. All three were treated with IL-1 antagonists (anakinra in two cases, canakinumab in one case) and were well controlled for sJIA symptoms at time of diagnosis of IBD CONCLUSIONS: IBD seems to be a rare, but possible complication of sJIA. Treatment with IL-1 antagonists might be a relevant factor for a switch in the clinical phenotype of the underlying inflammatory process.

Objectives: In recent years, concern has been raised about Juvenile Idiopathic Arthritis (JIA) that it could be associated with an increased risk for malignancies. Therefore, the cancer incidence in the JIA patients was evaluated and compared to the cancer incidence in the German population., Methods: A retrospective single-center hospital-based cohort study was performed using data on the JIA patients treated between 1952 and 2010 at the German Center for Pediatric and Adolescent Rheumatology (GCPAR) (Garmisch-Partenkirchen, Germany). Self-administered standardized questionnaires were sent out in 2012. Standardized incidence ratios (SIRs) and their corresponding 95% confidence intervals (95%CIs) were calculated., Results: The study cohort consisted of 3691 JIA patients, and the response rate was 66%. Patients age ranged from 3 to 73 years of which 64% were female. Total follow-up time was 60,075 person-years; a history of malignancy was reported by 47 patients. Most common types of cancer were melanoma (n = 11), cervical cancer (n = 8) and breast cancer (n = 7). The overall SIR for women was 1.19 (95%CI: 0.77; 1.60) and for men was 0.67 (95%CI: 0.27; 1.07). The SIR for melanoma was 3.21 (95%CI: 1.60; 5.73) in women, whereas in men no melanoma cases were observed., Conclusion: Although no overall increased cancer risk was found, results suggest that the risk of melanoma might be increased in female JIA patients.

Our objective was to translate the Functional Disability Inventory (FDI) into German, to evaluate its validity and to assess functional limitation in a large cohort of children and adolescents with juvenile fibromyalgia syndrome (jFMS). We administered several questions (e.g., sociodemographics, school-related issues) and questionnaires to 329 patients and one parent. The questionnaires included, among others, a German version of the FDI, the CHAQ (parent report), KIDSCREEN, tender point score (TPS), Depression Inventory for Children and Adolescents (DIKJ) and others. Patients were asked about the severity of pain today (NRS = numerical rating scale) and other symptoms. Internal consistency was evaluated with Cronbach's alpha. Construct validity of the FDI was evaluated by correlating the FDI with the questionnaires as well as with the pain and other variables, e.g., days missed school. An exploratory factor analysis (EFA) was also performed. Mean age was 13.9 years (SD ±2.48). Means were for pain today 5.37 (±2.39) and for the TPS 39.71 (±21.56). Internal consistency was α = .90. Low-to-moderate correlations were obtained between the FDI and the CHAQ (ρ = .51**), KIDSCREEN (e.g., physical well-being ρ = -.62**; peers and social support ρ = -.28**) as well as the pain variables (NRS ρ = .24**; TPS ρ = .38**). Psychological variables were also correlated with the FDI (e.g., DIJK ρ = .28**). An EFA suggested a two-factor solution. The FDI is a valid instrument for measuring functional limitations in German children and adolescents with jFMS.

Objective: Aims of the study were to investigate health-related quality of life (HRQOL) in adult patients with former diagnosis of Juvenile Idiopathic Arthritis (JIA), to compare their HRQOL with the general population and to identify factors related to a poor outcome., Methods: In 2012, a cross-sectional survey was performed by mailing a questionnaire to a large cohort of former and current patients of the German Centre for Rheumatology in Children and Adolescents. Only adult patients (≥18 years) with a diagnosis compatible with JIA were included (n = 2592; response 66%). The questionnaire included information about HRQOL (EQ5D), disease-related questions and socio-demographics. Prevalence and 95% confidence intervals (CI) of problems with mobility, self-care, usual activities, pain and anxiety/depression were standardized to the German general population. Factors associated with low HRQOL in JIA patients were identified using logistic regression models., Results: Sixty-two percent of the study population was female; age range was 18-73 years. In all dimensions, JIA patients reported statistically significantly more problems than the general population with largest differences in the pain dimension (JIA patients 56%; 95%CI 55-58%; general population 28%; 26-29%) and the anxiety/depression dimension (28%; 27-29% vs. 4%; 4-5%). Lower HRQOL in JIA patients was associated with female sex, older age, lower level of education, still being under rheumatic treatment and disability., Conclusions: HRQOL in adult JIA patients is considerably lower than in the general population. As this cohort includes historic patients the new therapeutic schemes available today are expected to improve HRQOL in future.

Background: Methotrexate (MTX) intolerance is a frequent problem of long-term treatment in juvenile idiopathic arthritis (JIA). Mutations in the methylentetrahydrofolate reductase (MTHFR) gene may increase toxicity of MTX, potentially constituting an initial stimulus for this conditioned response. The objective of this study was to investigate the relationship of common MTHFR gene mutations and occurrence of MTX intolerance in pediatric patients with JIA treated with MTX., Methods: Consecutive JIA patients on at least 3 months of MTX treatment were included in this study. Intolerance to MTX was determined using the Methotrexate Intolerance Severity Score (MISS) questionnaire, and MTX intolerance was defined as MISS values of ≥ 6. Presence of the two most common mutations in the MTHFR gene (C677T and A1298C) was tested using a PCR assay. Results were analyzed using descriptive and non-parametric statistics., Results: 196 patients were included (73 % female). Of those, 93 (46 %) showed MTX intolerance. 168 patients were genotyped for C677T and A1298C. MTX intolerance was not found to be significantly more frequent among patients with hetero- and homozygous or homozygous mutations C677T or A1298C compared to wild type or heterozygous mutations. Analysis of the correlation between numbers of mutations in these two loci to the MISS score did not yield a statistically significant correlation., Conclusion: Mutations in the MTHFR gene were not found to be significantly more frequent in JIA patients intolerant to MTX. Toxicity associated with the MTHFR gene seems to result from mechanisms different to those involved in clinical MTX intolerance.

Background: Several medications for treatment of Juvenile Idiopathic Arthritis (JIA) are considered to be carcinogenic. Therefore, the aim was to assess whether there is an association between therapeutic interventions and malignancies in JIA patients., Findings: A nested case-control study was carried out within a retrospective cohort study of 3698 JIA patients diagnosed between 1952 and 2010. All 48 JIA patients with a diagnosis of a malignant tumour and up to four matched controls for each received a questionnaire about their use of medication. Subsequently treatment was compared between cases and controls and analyses performed for 37 cases and 125 controls (response 88.5 %). Treatment with DMARD (84 %) was most frequently used, followed by glucocorticoids (66 %) and immunosuppressives (65 %). Twenty percent reported to have ever been taking biologics. Medication use did not differ significantly between cases and controls., Conclusions: Our results did not show an association between medications used and malignancies in JIA patients.

Objectives: Methotrexate (MTX) is the cornerstone disease-modifying anti-rheumatic drug (DMARD) in juvenile idiopathic arthritis (JIA). In Dutch patients, MTX intolerance occurred frequently and was associated with subcutaneous (SC) administration. The aim of this study was to assess the prevalence of MTX intolerance and its association with the route of administration in a German cohort of JIA patients., Methods: A cross-sectional study of JIA patients on MTX was performed. Primary outcome was MTX intolerance, which was determined using the validated Methotrexate Intolerance Severity Score (MISS) questionnaire. The prevalence of gastrointestinal adverse effects and MTX intolerance was compared between patients on MTX SC and MTX administered orally (PO)., Results: Of 179 JIA patients on MTX, 73 (40.8%) were intolerant. The odds of MTX intolerance were higher in patients using MTX exclusively SC compared to exclusively PO (adjusted odds ratio 3.37 [95% confidence interval 1.19-10.0]). There was strong evidence that the former experienced more behavioural complaints (76.1% vs. 47.4%, p=0.001) and weak evidence that they experienced more abdominal pain after MTX intake (43.5% vs. 27.4%, p=0.056)., Conclusions: The prevalence of MTX intolerance was high and exclusively SC administration of MTX was associated with MTX intolerance and behavioural adverse effects. The prevalence of gastrointestinal adverse effects was at least as high as in patients on MTX PO. The frequently held assumption that SC causes fewer side effects than PO seems unwarranted. Definite answers about the differences between SC and PO administration with respect to safety and efficacy should be obtained by randomised trials.

Introduction: Juvenile idiopathic arthritis is the most frequent chronic rheumatic disease in childhood. Synthetic disease modifying drugs (DMARDs) have been used in its treatment since the 1980s and have led to substantial improvement of quality of life and disease outcome. Recent pharmacological research has focused on newer medications, especially biologic agents., Areas Covered: Synthetic DMARDS, especially methotrexate, rightfully remain the first-line treatment of most categories of juvenile arthritis, as attested by several international guidelines. A substantial body of evidence supports these medications, and recent research tries to clarify their optimal use in the clinical setting, both as monotherapy and in combination with biologics. In addition, new forms of synthetic DMARDs are in the research pipeline, or are already used for rheumatoid arthritis., Expert Opinion: Methotrexate remains the preferred first-line medication for polyarticular arthritis, with leflunomide as a viable alternative in case of intolerance or toxicity, despite lack of approval in Europe and the US. Sulfasalazine and hydroxychloroquine are used only rarely in clinical practice, considered in combination with methotrexate if biologics are not available. New synthetic DMARDS are in the research pipeline for JIA, in the form of small molecules.

Objectives: Chronic anterior uveitis is a serious complication of juvenile idiopathic arthritis (JIA); disease flares are highly associated with loss of vision. Leflunomide (LEF) is used successfully for JIA joint disease but its effectiveness in uveitis has not been determined. The aim of this study was to determine whether LEF improves flare rates of uveitis in JIA patients compared to preceding methotrexate (MTX) therapy., Method: A single-centre retrospective study of consecutive children with JIA and chronic anterior uveitis was performed. All children initially received MTX and were then switched to LEF. Demographic, clinical, and laboratory data, dose and duration of MTX and LEF therapy, concomitant medications and rate of anterior uveitis flares, as determined by an expert ophthalmologist, were obtained. Flare rates were compared using a generalized linear mixed model with a negative binomial distribution., Results: A total of 15 children were included (80% females, all antinuclear antibody positive). The median duration of MTX therapy was 51 (range 26-167) months; LEF was given for a median of 12 (range 4-47) months. Anti-tumour necrosis factor (anti-TNF-α) co-medication was given to four children while on MTX. By contrast, LEF was combined with anti-TNF-α treatment in six children. On MTX, JIA patients showed a uveitis flare rate of 0.0247 flares/month, while LEF treatment was associated with a significantly higher flare rate of 0.0607 flares/month (p = 0.008)., Conclusions: Children with JIA had significantly more uveitis flares on LEF compared to MTX despite receiving anti-TNF-α co-medication more frequently. Therefore, LEF may need to be considered less effective in controlling chronic anterior uveitis.

Background: Systemic juvenile idiopathic arthritis (sJIA) is commonly considered an autoinflammatory disease. However, sJIA patients may develop aggressive arthritis without systemic inflammation later in the disease, resembling an autoimmune phenotype similar to other subtypes of JIA. The objective of this study was to determine whether antinuclear antibodies (ANA) and rheumatoid factor (RF) will develop in patients with sJIA over the course of the disease., Findings: A single center sample of sJIA patients with follow-up of more than one year was obtained. A retrospective chart survey was used to extract demographic and clinical data as well as presence and titers of ANA and RF at diagnosis and during follow-up. 32 patients were included in the study, with a median age of 4.2 years and median follow-up of 6.0 years. 8/32 patients had ANA titers ≥ 1:80 at diagnosis, with 22/32 patients showing rising ANA titers with titers ≥ 1:80 at last follow-up (p =0.001). 10/32 patients had a positive RF at least once during follow-up, compared to 0/32 at diagnosis (p = 0.001). In 5/10 patients, positive RF was documented at least twice, more than twelve weeks apart. Patients treated with TNF antagonists were not significantly more likely to develop positive ANA titers (p = 0.425) or positive RF (p = 0.703)., Conclusions: Patients with sJIA developed increased ANA titers and positive RF over the course of the disease, independent of treatment with TNF antagonists. This might point towards an autoimmune, rather than an autoinflammatory phenotype later in the course of sJIA.

Plasminogen (plg), the circulating proenzyme of plasmin in blood, is a polymorphic protein and most of these natural variants have been identified using isoelectric focusing (IEF) gel electrophoresis. Here, we show that a rare plg gene polymorphism 504R/W is associated with IEF phenotype A3 on the protein level. One healthy individual with homozygous plg gene polymorphism 504W studied so far exhibited low normal plg antigen and slightly decreased plg activity, suggesting that this polymorphism is associated with (mild) hypoplasminogenemia. In addition, we present the findings of IEF phenotyping of plg mutants of 26 patients with severe hypoplasminogenemia, showing one of the following four IEF patterns: A3-like, A3A-like, B-like and AB-like. In the plasma of most compound heterozygous patients, only one of the two plg mutants was detectable by IEF electrophoresis, probably due to undetectable plasma concentration of the 2nd plg mutant. In almost all cases, pI of plg mutants and variants predicted by computer modeling were in good agreement with the observed IEF band pattern. plg phenotyping by IEF in combination with molecular genetic analysis of the plg gene is a useful approach to characterize plg mutants and variants further.

Hypogammaglobulinemia or agammaglobulinemia are major features of specific syndromes, including X-linked agammaglobulinemia and common variable immunodeficiency. However, the combination of hypogammaglobulinemia with specific dysmorphic features is less common, with only a few reported cases. One such report was a sporadic case of humoral immunodeficiency, facial dysmorphism, and limb anomalies in a young girl, later referred to as Hoffman syndrome. We report on a 7-year-old girl with almost complete loss of B cells, facial dysmorphism, and malformation of the limbs and genitalia, whose mother shows similar dysmorphic features with an attenuated version of the B-cell deficiency. We believe that all three cases described above represent the same condition. The features of the three affected individuals with Hoffman syndrome are reviewed. Further investigations in this recently recognized B-cell immunodeficiency syndrome are warranted., (Copyright © 2010 Wiley-Liss, Inc.)

Plasminogen (plg) deficiency has been classified as (i) hypoplasminogenemia or 'true' type I plg deficiency, and (ii) dysplasminogenemia, also called type II plg deficiency. Both forms, severe hypoplasminogenemia and dysplasminogenemia, are not causally linked to venous thrombosis. Dysplasminogenemia does not lead to a specific clinical manifestation and probably represents only a polymorphic variation in the general population, mainly in Asian countries. Severe hypoplasminogenemia is associated with compromised extracellular fibrin clearance during wound healing, leading to pseudomembraneous (ligneous) lesions on affected mucous membranes (eye, middle ear, mouth, pharynx, duodenum, upper and lower respiratory tract and female genital tract). Ligneous conjunctivitis is by far the most common clinical manifestation. More than 12% of patients with severe hypoplasminogenemia exhibit congenital occlusive hydrocephalus. In milder cases of ligneous conjunctivitis, topical application of plg-containing eye drops, fresh frozen plasma, heparin, corticosteroids or certain immunosuppressive agents (such as azathioprine) may be more or less effective. Oral treatment with sex hormones was successful in two female patients with ligneous conjunctivitis. In severe cases with possibly life-threatening multi-organ involvement, true therapeutic options are not available at present. The plg-knockout mouse is a useful tool to study the many different properties of plg in a variety of settings, such as wound healing, tissue repair and tissue remodeling, virulence and invasiveness of certain bacteria in the human host, tumor growth and dissemination, as well as arteriosclerosis.