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.

Withdrawing biologics in non-systemic JIA: what matters to pediatric rheumatologists?

OBJECTIVE: Approximately one third of children with JIA receive biologic therapy, but evidence on biologic therapy withdrawal is lacking. This study aims to increase our understanding of whether and when pediatric rheumatologists postpone a decision to withdraw biologic therapy in children with clinically inactive non-systemic JIA. METHODS: A survey containing questions about background characteristics, treatment patterns, minimum treatment time with biologic therapy, and 16 different patient vignettes, was distributed among 83 pediatric rheumatologists in Canada and the Netherlands. For each vignette, respondents were asked whether they would withdraw biologic therapy at their minimum treatment time, and if not, how long they would continue biologic therapy. Statistical analysis included descriptive statistics, logistic and interval regression analysis. RESULTS: Thirty-three pediatric rheumatologists completed the survey (40% response rate). Pediatric rheumatologists are most likely to postpone the decision to withdraw biologic therapy when the child and/or parents express a preference for continuation (OR 6.3; p < 0.001), in case of a flare in the current treatment period (OR 3.9; p = 0.001), and in case of uveitis in the current treatment period (OR 3.9; p < 0.001). On average, biologic therapy withdrawal is initiated 6.7 months later when the child or parent prefer to continue treatment. CONCLUSION: Patient's and parents' preferences were the strongest driver of a decision to postpone biologic therapy withdrawal in children with clinically inactive non-systemic JIA and prolongs treatment duration. These findings highlight the potential benefit of a tool to support pediatric rheumatologists, patients and parents in decision making, and can help inform its design.

Discontinuation of biologic DMARDs in non-systemic JIA patients: a scoping review of relapse rates and associated factors.

BACKGROUND: Biologic disease-modifying antirheumatic drugs (bDMARDs) have changed the treatment of juvenile idiopathic arthritis (JIA) patients notably, as bDMARDs enable substantially more patients to achieve remission. When sustained remission is achieved, tapering or even discontinuation of the bDMARD is advocated, to reduce side effects and costs. However, when and how to discontinue bDMARD therapy and what happens afterwards, is less known. OBJECTIVES: With this scoping review we aim to collect available data in current literature on relapse rate, time to relapse (TTR) and possible flare associated variables (such as time spent in remission and method of discontinuation) after discontinuing bDMARDs in non-systemic JIA patients. METHODS: We performed a literature search until July 2022 using the Pubmed database. All original studies reporting on bDMARD discontinuation in non-systemic JIA patients were eligible. Data on patient- and study characteristics, the applied discontinuation strategy, relapse rates and time to relapse were extracted in a standardized template. RESULTS: Of the 680 records screened, 28 articles were included in this review with 456 non-systemic JIA patients who tapered and/or stopped bDMARD therapy. Relapse rate after discontinuation of bDMARDs, either abruptly or following tapering, were 40-48%, 36.8-45.0% and 60-78% at 6, 8 and 12 months respectively. Total relapse rate ranged from 26.3% to 100%, with mean time to relapse (TTR) of 2 to 8.4 months, median TTR 3 to 10 months. All studies stated a good response after restart of therapy after flare. JIA subtype, type of bDMARD, concomitant methotrexate use, treatment duration, tapering method, age, sex, and time in remission could not conclusively be related to relapse rate or TTR. However, some studies reported a positive correlation between flare and antinuclear antibodies positivity, younger age at disease onset, male sex, disease duration and delayed remission, which were not confirmed in other studies. CONCLUSION: Flares seem to be common after bDMARD discontinuation, but little is known about which factors influence these flares in JIA patients. Follow up after discontinuation with careful registration of patient variables, information about tapering methods and flare rates are required to better guide tapering and/or stopping of bDMARDs in JIA patients in the future.

Trio-based whole exome sequencing in patients with suspected sporadic inborn errors of immunity: A retrospective cohort study.

Background: De novo variants (DNVs) are currently not routinely evaluated as part of diagnostic whole exome sequencing (WES) analysis in patients with suspected inborn errors of immunity (IEI). Methods: This study explored the potential added value of systematic assessment of DNVs in a retrospective cohort of 123 patients with a suspected sporadic IEI that underwent patient-parent trio-based WES. Results: A (likely) molecular diagnosis for (part) of the immunological phenotype was achieved in 12 patients with the diagnostic in silico IEI WES gene panel. Systematic evaluation of rare, non-synonymous DNVs in coding or splice site regions led to the identification of 14 candidate DNVs in genes with an annotated immune function. DNVs were found in IEI genes (NLRP3 and RELA) and in potentially novel candidate genes, including PSMB10, DDX1, KMT2C, and FBXW11. The FBXW11 canonical splice site DNV was shown to lead to defective RNA splicing, increased NF-κB p65 signalling, and elevated IL-1ß production in primary immune cells extracted from the patient with autoinflammatory disease. Conclusions: Our findings in this retrospective cohort study advocate the implementation of trio-based sequencing in routine diagnostics of patients with sporadic IEI. Furthermore, we provide functional evidence supporting a causal role for FBXW11 loss-of-function mutations in autoinflammatory disease. Funding: This research was supported by grants from the European Union, ZonMW and the Radboud Institute for Molecular Life Sciences.

3D stereophotogrammetry in children and adolescents with Scleroderma En Coup De Sabre/Parry-Romberg Syndrome: Description of a novel method for monitoring disease progression.

Background: The diagnosis of Scleroderma En Coup de Sabre (ECDS)/Parry Romberg Syndrome (PRS) is mainly based on characteristic clinical findings. Methods to objectively monitor the course of the disease in a standardized way are lacking. Objectives: This descriptive, retrospective, single centre cohort study aims to describe the contribution of 3D photographs in the assessment of the degree of facial asymmetry changes over time in growing children and adolescents with ECDS and PRS. Methods: Six patients diagnosed with ECDS/PRS, with a follow-up period of at least 24 months and at least three 3D photographs were included. Mirroring these 3D photographs was automatically performed using surface-based matching to generate a colour-coded distance map, illustrating the inter-surface distance and thereby asymmetry between the original and mirrored 3D photographs. The percentage of absolute distances between the original and mirrored 3D photograph were calculated. Results: In two patients, impressive decreases in the percentages of absolute distance levels over time were found, whereas the other patients did not show progression of asymmetry over time. Conclusion: This study shows the potential of 3D stereophotogrammetry as an objective tool to measure disease activity over time in patients with ECDS/PRS.

Gene signature fingerprints stratify SLE patients in groups with similar biological disease profiles: a multicentre longitudinal study.

OBJECTIVES: Clinical phenotyping and predicting treatment responses in SLE patients is challenging. Extensive blood transcriptional profiling has identified various gene modules that are promising for stratification of SLE patients. We aimed to translate existing transcriptomic data into simpler gene signatures suitable for daily clinical practice. METHODS: Real-time PCR of multiple genes from the IFN M1.2, IFN M5.12, neutrophil (NPh) and plasma cell (PLC) modules, followed by a principle component analysis, was used to identify indicator genes per gene signature. Gene signatures were measured in longitudinal samples from two childhood-onset SLE cohorts (n = 101 and n = 34, respectively), and associations with clinical features were assessed. Disease activity was measured using Safety of Estrogen in Lupus National Assessment (SELENA)-SLEDAI. Cluster analysis subdivided patients into three mutually exclusive fingerprint-groups termed (1) all-signatures-low, (2) only IFN high (M1.2 and/or M5.12) and (3) high NPh and/or PLC. RESULTS: All gene signatures were significantly associated with disease activity in cross-sectionally collected samples. The PLC-signature showed the highest association with disease activity. Interestingly, in longitudinally collected samples, the PLC-signature was associated with disease activity and showed a decrease over time. When patients were divided into fingerprints, the highest disease activity was observed in the high NPh and/or PLC group. The lowest disease activity was observed in the all-signatures-low group. The same distribution was reproduced in samples from an independent SLE cohort. CONCLUSIONS: The identified gene signatures were associated with disease activity and were indicated to be suitable tools for stratifying SLE patients into groups with similar activated immune pathways that may guide future treatment choices.

Siglec-1 expression on monocytes is associated with the interferon signature in juvenile dermatomyositis and can predict treatment response.

OBJECTIVE: JDM is a rare chronic immune-mediated inflammatory disease with a predominant role for type I IFN responses. We aimed to determine the potential of Siglec-1 expression on monocytes as a novel IFN-inducible biomarker for disease activity monitoring and prediction of treatment response in patients with JDM. METHODS: Siglec-1 was measured by flow cytometry on circulating monocytes of 21 newly diagnosed JDM patients before start of treatment and, for 10 of these, also during follow-up. The expression levels of five type I IFN-stimulated genes, MX1, IFI44, IFI44L, LY6E and IFIT3, were measured by RT-qPCR to determine the IFN signature and calculate an IFN score. IFN-inducible plasma proteins CXCL10 and galectin-9 were measured by multiplex immunoassay. RESULTS: Siglec-1 and IFN score were increased in JDM patients compared with controls and correlated with clinical disease activity. Stratification of patients by Siglec-1 expression at diagnosis identified those with high Siglec-1 expression as having a higher risk of requiring treatment intensification within the first 3 months after diagnosis (55% vs 0% of patients, P = 0.01). Siglec-1 expression strongly correlated with plasma levels of previously validated biomarkers CXCL10 (rs = 0.81, P < 0.0001) and galectin-9 (rs = 0.83, P < 0.0001), and was superior to the IFN score in predicting treatment response (area under the curve 0.87 vs 0.53, P = 0.01). CONCLUSION: Siglec-1 on monocytes is a novel IFN-inducible biomarker in JDM that correlates with clinical disease activity and identifies patients at risk for a suboptimal treatment response. Further studies are required to validate these findings and their clinical potential.

Dutch patients, caregivers and healthcare professionals generate first nationwide research agenda for juvenile idiopathic arthritis.

BACKGROUND: Involving the end-users of scientific research (patients, carers and clinicians) in setting research priorities is important to formulate research questions that truly make a difference and are in tune with the needs of patients. We therefore aimed to generate a national research agenda for Juvenile Idiopathic Arthritis (JIA) together with patients, their caregivers and healthcare professionals through conducting a nationwide survey among these stakeholders. METHODS: The James Lind Alliance method was used, tailored with additional focus groups held to involve younger patients. First, research questions were gathered through an online and hardcopy survey. The received questions that were in scope were summarised and a literature search was performed to verify that questions were unanswered. Questions were ranked in the interim survey, and the final top 10 was chosen during a prioritisation workshop. RESULTS: Two hundred and seventy-eight respondents submitted 604 questions, of which 519 were in scope. Of these 604 questions, 81 were generated in the focus groups with younger children. The questions were summarised into 53 summary questions. An evidence checking process verified that all questions were unanswered. A total of 303 respondents prioritised the questions in the interim survey. Focus groups with children generated a top 5 of their most important questions. Combining this top 5 with the top 10s of patients, carers, and clinicians led to a top 21. Out of these, the top 10 research priorities were chosen during a final workshop. Research into pain and fatigue, personalised treatment strategies and aetiology were ranked high in the Top 10. CONCLUSIONS: Through this study, the top 10 research priorities for JIA of patients, their caregivers and clinicians were identified to inform researchers and research funders of the research topics that matter most to them. The top priority involves the treatment and mechanisms behind persisting pain and fatigue when the disease is in remission.

Dutch juvenile idiopathic arthritis patients, carers and clinicians create a research agenda together following the James Lind Alliance method: a study protocol.

BACKGROUND: Research on Juvenile Idiopathic Arthritis (JIA) should support patients, caregivers/parents (carers) and clinicians to make important decisions in the consulting room and eventually to improve the lives of patients with JIA. Thus far these end-users of JIA-research have rarely been involved in the prioritisation of future research. MAIN BODY: Dutch organisations of patients, carers and clinicians will collaboratively develop a research agenda for JIA, following the James Lind Alliance (JLA) methodology. In a 'Priority Setting Partnership' (PSP), they will gradually establish a top 10 list of the most important unanswered research questions for JIA. In this process the input from clinicians, patients and their carers will be equally valued. Additionally, focus groups will be organised to involve young people with JIA. The involvement of all contributors will be monitored and evaluated. In this manner, the project will contribute to the growing body of literature on how to involve young people in agenda setting in a meaningful way. CONCLUSION: A JIA research agenda established through the JLA method and thus co-created by patients, carers and clinicians will inform researchers and research funders about the most important research questions for JIA. This will lead to research that really matters.

Primary immunodeficiency associated with chromosomal aberration - an ESID survey.

BACKGROUND: Patients with syndromic features frequently suffer from recurrent respiratory infections, but little is known about the spectrum of immunological abnormalities associated with their underlying chromosomal aberrations outside the well-known examples of Down and DiGeorge syndromes. Therefore, we performed this retrospective, observational survey study. METHODS: All members of the European Society for Immunodeficiencies (ESID) were invited to participate by reporting their patients with chromosomal aberration (excluding Down and DiGeorge syndromes) in combination with one or more identified immunological abnormalities potentially relating to primary immunodeficiency. An online questionnaire was used to collect the patient data. RESULTS: Forty-six patients were included from 16 centers (24 males, 22 females; median age 10.4 years [range 1.0-69.2 years]; 36 pediatric, 10 adult patients). A variety of chromosomal aberrations associated with immunological abnormalities potentially relating to primary immune deficiency was reported. The most important clinical presentation prompting the immunological evaluation was 'recurrent ear-nose-throat (ENT) and airway infections'. Immunoglobulin isotype and/or IgG-subclass deficiencies were the most prevalent immunological abnormalities reported. CONCLUSIONS: Our survey yielded a wide variety of chromosomal aberrations associated with immunological abnormalities potentially relating to primary immunodeficiency. Although respiratory tract infections can often also be ascribed to other causes (e.g. aspiration or structural abnormalities), we show that a significant proportion of patients also have an antibody deficiency requiring specific treatment (e.g. immunoglobulin replacement, antibiotic prophylaxis). Therefore, it is important to perform immunological investigations in patients with chromosomal aberrations and recurrent ENT or airway infections, to identify potential immunodeficiency that can be specifically treated.

The Challenge of Immunoglobulin-G Subclass Deficiency and Specific Polysaccharide Antibody Deficiency--a Dutch Pediatric Cohort Study.

PURPOSE: Immunoglobulin(Ig)G-subclass deficiency and specific polysaccharide antibody deficiency (SPAD) are among the most frequent causes of recurrent respiratory infections in children. Little is known about their prevalence, clinical presentation and prognosis. No study has been published in a Western-European nor in a mainly non-tertiary cohort until now. Therefore, we performed this observational cohort study in children recruited from secondary and tertiary pediatric practices all over The Netherlands. METHODS: Dutch pediatricians were monthly asked to report patients with IgG-subclass deficiency and/or SPAD. Demographic, clinical and laboratory characteristics were collected. Separate informed consent was asked from parents and children (≥ 12 years of age) for annual update of the medical status. RESULTS: 49 children with confirmed IgG-subclass deficiency and/or SPAD were included. The majority of children (69%) was reported by four (out of 12) secondary hospitals with a pediatric immunologist in the staff. 45 children had ≥ 1 low IgG-subclass level and 11 had SPAD. IgG2 deficiency was the most prevalent IgG-subclass deficiency (37/49;76%). 10% of these children already showed bronchiectasis. Two-thirds were male (33/49;67%, p = 0.015). From 10 years of age, only boys were left and only boys showed progressive immunodeficiency during follow-up (11/24; 46%). CONCLUSIONS: This is the first Western-European mainly non-tertiary cohort of children with IgG-subclass deficiency and/or SPAD. The disease course is not always benign, especially in boys. Most children were reported and managed in secondary hospitals with a pediatric immunologist in the staff. To identify more patients, the awareness of these diseases among general pediatricians should increase.

[Borrelial lymphocytoma]. / Borrelia-lymfocytoom.

BACKGROUND: Borrelial lymphocytoma is a relatively rare but typical presentation of Lyme disease. Predilection sites are the ears in children and chest/nipples in adults. It is treated like an erythema migrans and has a good prognosis. CASE DESCRIPTION: A 16-year-old boy presented with a swollen, red and painful right nipple since several months. An ultrasound showed normal breast tissue. The patient was referred to the pediatric surgeon who performed an incision biopsy. Histopathological examination revealed follicular hyperplasia without signs of malignancy. An infectious cause, most likely Lyme disease, was suspected. Serological analysis and PCR of the tissue confirmed the diagnosis of a borrelial lymphocytoma, and the patient was treated with doxycycline with good result. CONCLUSION: Early recognition of the characteristic clinical presentation of borrelial lymphocytoma, supported by positive results from serologic testing for Lyme disease, avoids the need for additional and invasive diagnostic tests.

A girl with autoimmune cytopenias, nonmalignant lymphadenopathy, and recurrent infections.

We describe a girl, now 9 years of age, with chronic idiopathic thrombocytopenic purpura, persistent nonmalignant lymphadenopathy, splenomegaly, recurrent infections, and autoimmune hemolytic anemia. Her symptoms partly fit the definitions of both autoimmune lymphoproliferative syndrome (ALPS) and common variable immunodeficiency disorders (CVIDs). Genetic analysis showed no abnormalities in the ALPS-genes FAS, FASLG, and CASP10. The CVID-associated TACI gene showed a homozygous polymorphism (Pro251Leu), which is found also in healthy controls.

B-lymphocyte reconstitution after repeated rituximab treatment in a child with steroid-dependent autoimmune hemolytic anemia.

We report the detailed long-term reconstitution of B-lymphocyte subpopulations, immunoglobulins, and specific antibody production after two courses of rituximab in a young, previously healthy girl with steroid-dependent autoimmune hemolytic anemia. B-lymphocyte subpopulations were surprisingly normal directly after reconstitution. However, there was a slower reconstitution after the second rituximab course, especially of non-switched and switched memory B-lymphocytes, and a temporary decline in IgM below age-matched reference values.

Transient hypertransaminasemia in paediatric patients with Crohn disease undergoing initial treatment with enteral nutrition.

OBJECTIVES: Total enteral nutrition (TEN) is frequently used as monotherapy in children with Crohn disease to prevent steroid toxicity. Liver disease is a known complication in inflammatory bowel disease, and liver enzymes are regularly obtained in these patients. PATIENTS AND METHODS: Prospective follow-up of liver enzymes was performed in 11 new consecutive patients ages 7.6 to 17.1 years who were primarily treated with TEN for 6 weeks. Liver enzymes were measured before starting TEN and after 3, 6, and 12 weeks. RESULTS: At the beginning of TEN, the mean aspartate aminotransferase (ASAT) was 18.4 U/L and the mean alanine aminotransferase (ALAT) 17.1 U/L. The mean ASAT and ALAT were 202.0 U/L and 269.0 U/L after 3 weeks and 109.6 U/L and 180.9 U/L at 6 weeks. After 12 weeks values decreased to 22.8 U/L (ASAT) and 20.9 U/L (ALAT). Overall, 9 of 11 patients had transient elevated ASAT and 10 patients showed elevated ALAT. Gamma-glutamyl transpeptidase was slightly elevated in 3 patients during therapy, but alkaline phosphatase and bilirubin showed no changes. None of the patients developed liver disease during follow-up, and prolonged clinical remission was achieved in 9 patients. CONCLUSIONS: This study shows that TEN can be associated with transient hypertransaminasemia without evidence of liver disease. We hypothesise that insulin resistance in patients with Crohn disease in combination with standard TEN formulae can result in transient hepatic steatosis causing the hypertransaminasemia. For the clinician it is important to be aware of this benign TEN-associated condition to prevent unnecessary investigations.