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Deutsches Arzteblatt International Oct 2019Monoclonal antibodies (mAb) and fusion proteins (FP) are increasingly being used in children and adolescents. In this review, we analyze the evidence for their safety...
BACKGROUND
Monoclonal antibodies (mAb) and fusion proteins (FP) are increasingly being used in children and adolescents. In this review, we analyze the evidence for their safety and efficacy in the treatment of the most common chronic inflammatory diseases.
METHODS
We systematically searched PubMed, AWMF.org, and other databases for high-quality trials (i.e., randomized controlled trials with clinical primary endpoints) and guidelines published at any time up to 10 December 2018 that dealt with mAb and FP that are approved for pediatric use. The search term was "monoclonal anti- body/fusion protein [e. g. adalimumab] AND children."
RESULTS
The 620 hits included 25 high-quality trials (20 of them manufacturer- sponsored) on 9 mAb/FP (omalizumab, adalimumab, etanercept, ustekinumab, infliximab, golimumab, anakinra, canakinumab, tocilizumab, and abatacept), as well as 6 guidelines (3 each of levels S3 and S2k) on the treatment of bronchial asthma, psoriasis, juvenile idopathic arthritis, and chronic inflammatory bowel diseases. For none of these conditions are mAb and FP the drugs of first choice. Adverse drug effects are rare but sometimes severe (infection, immune dysregulation, tumors).
CONCLUSION
The retrieved trials have deficiencies that make it difficult to reliably evaluate the efficacy, safety, and utility of mAb/FP for children and adolescents with chronic inflammatory diseases. mAb/FP nonetheless represent a treatment option to be considered in case conventional immune-modulating drugs are ineffective. Researcher-initiated, high-quality trials and manufacturer-independent, systematic long-term evaluations of adverse effects (e.g., tumors) are sorely needed.
Topics: Adolescent; Antibodies, Monoclonal; Biological Products; Child; Humans; Proteins; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 31711560
DOI: 10.3238/arztebl.2019.0703 -
Journal of Clinical Medicine Apr 2023Biological disease-modifying anti-rheumatic drugs (bDMARDs) targeting interleukin (IL)-6 and IL-1β represent a steroid-sparing first-line therapy used in systemic-onset...
INTRODUCTION
Biological disease-modifying anti-rheumatic drugs (bDMARDs) targeting interleukin (IL)-6 and IL-1β represent a steroid-sparing first-line therapy used in systemic-onset juvenile idiopathic arthritis (sJIA). Recently, the occurrence of pulmonary alveolar proteinosis (PAP) in sJIA patients was reported with early-onset and exposure to bDMARDs as potential risk factors. We report on a new case with longitudinal immunomonitoring successfully treated by Janus Kinase inhibitors (JAKi) and review past clinical descriptions of this new entity.
METHODS
We report one case of pulmonary alveolar proteinosis and macrophage activation syndrome (PAP-MAS) with longitudinal immunomonitoring. We then conducted a review of the literature of seven publications reporting 107 cases of PAP-MAS sJIA, and included the main characteristics and evolution under treatment.
RESULTS
Of the seven articles analyzed, the incidence of PAP-MAS among sJIA patients varied from 1.28% to 12.9%. We report here a single case among a cohort of 537 sJIA patients followed in the pediatric department of the Hospices Civils de Lyon over the last 15 years. This child presented with all clinical and immunological characteristics of PAP-MAS. After several lines of treatment, he benefited from JAKi and improved with respect to both systemic symptoms and lung disease. In the literature, strategies with monoclonal antibodies targeting either INF-γ or IL-1β/IL-18 have been tested with variable results. Orally taken JAKi presents the advantage of targeting multiple cytokines and avoiding parenteral injections of monoclonal antibodies that may contribute to the pathogenesis.
CONCLUSIONS
JAKi represent a promising option in the treatment of lung disease associated with sJIA.
PubMed: 37048785
DOI: 10.3390/jcm12072702 -
Clinical and Experimental Immunology Feb 2021Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, hyperinflammatory disorder, characterized by multiorgan failure, fever and cytopenias. The diagnosis of... (Meta-Analysis)
Meta-Analysis
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, hyperinflammatory disorder, characterized by multiorgan failure, fever and cytopenias. The diagnosis of HLH and its subtype Macrophage Activation Syndrome (MAS) remains a challenge. Interleukin 18 (IL-18) is emerging as a potential biomarker for HLH/MAS but is currently not a part of diagnostic criteria. This systematic review aimed to assess the potential role of IL-18 in the diagnosis and monitoring of HLH and MAS, and was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed and Embase were searched on 30 January 2020. Studies included all subtypes of HLH and a range of underlying disorders in both children and adults. A total of 14 studies were included. Generally, serum IL-18 was elevated in both primary and secondary HLH (> 1000 pg/ml) compared with other inflammatory conditions and with healthy individuals; thus, serum IL-18 may be able to discriminate between HLH and other inflammatory conditions. Significantly increased IL-18 (> 10 000 pg/ml) was also consistently described in MAS compared with other subtypes of HLH. The ability of IL-18 to distinguish MAS from systemic juvenile idiopathic arthritis (JIA) is less unambiguous, as IL-18 levels > 100 000 pg/ml were described in sJIA patients both with and without MAS. IL-18 may help to differentiate between HLH subtypes and other inflammatory conditions. As HLH and MAS are rare disorders, only few and relatively small studies exist on the subject. Larger, prospective multi-center studies are called for to assess the diagnostic precision of IL-18 for HLH and MAS.
Topics: Animals; Diagnosis, Differential; Humans; Interleukin-18; Lymphohistiocytosis, Hemophagocytic; Macrophage Activation; Macrophage Activation Syndrome; Macrophages; Monitoring, Immunologic; Phenotype
PubMed: 33128796
DOI: 10.1111/cei.13543 -
Medicine Apr 2024The term "Rhupus" was employed to descriptively illustrate the overlap observed in some pediatric patients displaying features of both juvenile idiopathic arthritis...
INTRODUCTION
The term "Rhupus" was employed to descriptively illustrate the overlap observed in some pediatric patients displaying features of both juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE). Although "Rhupus" is traditionally used in adults, we applied it broadly to emphasize this clinical overlap.
METHODS
We sought to identify studies that registered signs, symptoms, imaging characteristics, and treatments given to patients with JIA and SLE. We searched four databases using a Boolean search string, resulting in 231 articles after duplicate removal. Title and abstract screening yielded 57 articles for full-text assessment. Full reviewed 13 extracted data regarding sex, age of onset, serologic and imaging findings, and management strategies. The NIH quality assessment tool was applied to ensure the internal validity of the articles.
RESULTS
From the 13 articles evaluated that meet inclusion criteria, none had standardized diagnostic algorithms. The total number of patients in those articles is 26, without discussing treatment guidelines.
DISCUSSION
Clinical presentation, diagnostic parameters, and treatment of pediatric Rhupus were synthesized in this review. Fundamental keys help distinguish the joint presentation when Juvenile Idiopathic Arthritis or Lupus is present, compared with the signs and symptoms when developing the overlapping syndrome. We highlight the importance of physicians knowing about this rare condition and call all specialists to report new cases of the disease so a consensus can be reached to establish standardized guidelines for diagnosing and treating Rhupus syndrome.
Topics: Adult; Humans; Child; Arthritis, Juvenile; Arthritis, Rheumatoid; Lupus Erythematosus, Systemic; Syndrome
PubMed: 38579098
DOI: 10.1097/MD.0000000000036451 -
Pediatric Research Mar 2020To develop a set of clinical criteria that identifies patients with a potential autoinflammatory IFNopathy. (Comparative Study)
Comparative Study
OBJECTIVE
To develop a set of clinical criteria that identifies patients with a potential autoinflammatory IFNopathy.
METHODS
Based on a literature review, a set of clinical criteria identifying genetically confirmed monogenic IFNopathies was selected. For validation, the clinical score was assessed in healthy controls (HCs) and 18 disease controls, including 2 known autoimmune IFNopathies, juvenile systemic lupus erythematosus (JSLE, n = 4) and dermatomyositis (JDM, n = 4); adenosine deaminase 2 deficiency (DADA2, n = 4); and oligoarticular juvenile idiopathic arthritis (oJIA, n = 6). We assessed an IFN score (IRG-S) in whole blood by NanoString using a previously published 28-gene-IRG-S and a reduced 6-gene-IRG-S.
RESULTS
The 12 patients with a possible IFNopathy had higher clinical scores (3-5) than the patients with sJLE, JDM, DADA2, and oJIA and in HCs. Both the 28-IRG-S and 6-IRG-S were significantly higher in the autoinflammatory IFNopathy patients compared to HCs and oJIA and DADA2 patients but not different from patients with JSLE and JDM. Subsequently, genetic analysis revealed mutations in genes previously reported in genes related to the IFN pathway in 9 of the 12 patients.
CONCLUSION
We developed a clinical score to identify patients with possible autoinflammatory IFNopathies. A clinical score was associated with a high IRG-S and may serve to identify patients with an autoinflammatory IFNopathy.
Topics: Age of Onset; Arthritis, Juvenile; Case-Control Studies; Child; Child, Preschool; Clinical Decision Rules; Clinical Decision-Making; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Humans; Infant; Interferon Type I; Lupus Erythematosus, Systemic; Male; Mutation; Phenotype; Predictive Value of Tests; Prognosis; Reproducibility of Results
PubMed: 31641281
DOI: 10.1038/s41390-019-0614-2 -
Arthritis Research & Therapy Dec 2019Adult-onset Still's disease (AOSD) is a rare inflammatory condition characterized by fever, rash, and arthritis. Because of its rarity, clinical trials are inherently...
BACKGROUND
Adult-onset Still's disease (AOSD) is a rare inflammatory condition characterized by fever, rash, and arthritis. Because of its rarity, clinical trials are inherently small and often uncontrolled. Our objective was to develop recommendations for the use of interleukin (IL)-1 inhibitors in the management of patients with AOSD, based on the best evidence and expert opinion.
METHODS
A panel of 10 experts (9 rheumatologists and 1 pediatrician) was established. The first step was dedicated to a comprehensive literature review and development of statements. Two separate literature searches were performed on the MEDLINE (Pubmed), EMBASE, and BIOSIS databases through April 2018 to identify (1) differences and similarities between AOSD and pediatric Still's disease (systemic juvenile idiopathic arthritis [SJIA]) and (2) the efficacy and safety of IL-1 inhibitors in AOSD treatment. In the second step, the statements were submitted in a Delphi process to a panel of 67 rheumatologists. Consensus threshold was set at 66%: positive, > 66% of voters selected scores 3 to 5; negative, > 66% of voters selected scores 1 or 2. In the third step, the voting results were analyzed, and the statements were finalized.
RESULTS
Eleven statements were developed. Forty-six of 67 rheumatologists (72%) participated in the Delphi process. A positive consensus was reached after the first round of voting and was full (> 95%) on the majority of statements. A large consensus was achieved in considering AOSD and SJIA as the same disease. The use of anti-IL-1 therapies in refractory patients was considered quite safe and effective both as the first and as a subsequent line of biologic treatment, especially in systemic patients. Because of the lack of head-to-head comparisons, a different profile of efficacy among IL-1 inhibitors could not be established. There was a large consensus that failure of the first IL-1 inhibitor does not preclude response to another one. The lack of studies comparing early versus late treatment did not allow to draw conclusions; however, data from SJIA suggest a better response in early treatment.
CONCLUSIONS
The Delphi method was used to develop recommendations that we hope will help clinicians in the management of patients with AOSD refractory to conventional therapies.
Topics: Adult; Antirheumatic Agents; Consensus; Delphi Technique; Female; Humans; Interleukin-1; Male; Still's Disease, Adult-Onset
PubMed: 31829244
DOI: 10.1186/s13075-019-2021-9 -
Pancreas Feb 2022Although pain management is central to pediatric chronic pancreatitis (CP) care, no evidence-based guidelines exist. In this scoping systematic review, we sought...
OBJECTIVES
Although pain management is central to pediatric chronic pancreatitis (CP) care, no evidence-based guidelines exist. In this scoping systematic review, we sought promising strategies for CP pain treatment in children.
METHODS
We systematically reviewed literature on pain management in children and adults with CP, and 2 conditions with similar pain courses: juvenile idiopathic arthritis and sickle cell disease.
RESULTS
Of 8997 studies identified, 287 met inclusion criteria. There are no published studies of analgesic medications, antioxidants, dietary modification, integrative medicine, or regional nerve blocks in children with CP. In adults with CP, studies of nonopioid analgesics, pancreatic enzymes, and dietary interventions have mixed results. Retrospective studies suggest that endoscopic retrograde cholangiopancreatography and surgical procedures, most durably total pancreatectomy with islet autotransplant, improve pain for children with CP. Follow-up was short relative to a child's life. Large studies in adults also suggest benefit from endoscopic therapy and surgery, but lack conclusive evidence about optimal procedure or timing. Studies on other painful pediatric chronic illnesses revealed little generalizable to children with CP.
CONCLUSIONS
No therapy had sufficient high-quality studies to warrant untempered, evidence-based support for use in children with CP. Multicenter studies are needed to identify pain management "best practices."
Topics: Adult; Child; Humans; Outpatients; Pain; Pain Management; Pancreatectomy; Pancreatitis, Chronic; Retrospective Studies; Treatment Outcome
PubMed: 35404888
DOI: 10.1097/MPA.0000000000001973 -
Pediatric Rheumatology Online Journal Feb 2022Patients with juvenile chronic inflammatory systemic diseases (jCID) are vulnerable to many circumstances when transitioning to adult-centered healthcare; this increases... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Patients with juvenile chronic inflammatory systemic diseases (jCID) are vulnerable to many circumstances when transitioning to adult-centered healthcare; this increases the burden of disease and worsen their quality of life.
METHODS
MEDLINE, Embase, Web of Science and Scopus were searched from inception to March 16, 2021. We included observational, randomized controlled trials and quasi-experimental studies that evaluated a transitional care program for adolescents and young adults with jCIDs. We extracted information regarding health-related quality of life, disease activity, drop-out rates, clinical attendance rates, hospital admission rates, disease-related knowledge, surgeries performed, drug toxicity and satisfaction rates.
RESULTS
Fifteen studies met our inclusion criteria. The implementation of transition programs showed a reduction on hospital admission rates for those with transition program (OR 0.28; 95% CI 0.13 to 0.61; I 2 = 0%; p = 0.97), rates of surgeries performed (OR 0.26; 95% CI 0.12 to 0.59; I 2 = 0%; p = 0.50) and drop-out rates from the adult clinic (OR 0.23; 95% CI 0.12 to 0.46; I 2 = 0%; p = 0.88). No differences were found in other outcomes.
CONCLUSION
The available body of evidence supports the implementation of transition programs as it could be a determining factor to prevent hospital admission rates, surgeries needed and adult clinic attendance rates.
Topics: Adolescent; Adult; Autoimmune Diseases; Child; Chronic Disease; Cost of Illness; Cystic Fibrosis; Diabetes Mellitus; Humans; Irritable Bowel Syndrome; Quality of Life; Rheumatic Diseases; Transitional Care; Young Adult
PubMed: 35177101
DOI: 10.1186/s12969-022-00670-1 -
Journal of Immunology Research 2021To evaluate the effectiveness of Janus kinase (JAK) inhibitors for the treatment of patients with autoimmune disease and associated inflammatory ocular diseases. (Meta-Analysis)
Meta-Analysis
PURPOSE
To evaluate the effectiveness of Janus kinase (JAK) inhibitors for the treatment of patients with autoimmune disease and associated inflammatory ocular diseases.
METHODS
We identified relevant literature by screening the MEDLINE, PubMed, and Cochrane databases for randomized controlled trials, cohort studies, case controls, and case reports.
RESULTS
Seven studies, including 11 patients, were included in the final systematic analysis. Of the 11 patients, there were 5 cases of juvenile idiopathic arthritis- (JIA-) associated uveitis, 1 case of rheumatoid arthritis- (RA-) associated keratitis, 1 case of RA-associated scleritis, 1 case of psoriasis-associated conjunctivitis, 2 cases of noninfectious scleritis, and 1 case of uveitis with suspected autoimmune disease. None of these 11 patients responded adequately to conventional treatments, including biological agents; these were all refractory cases and switched to JAK inhibitor therapy. Irrespective of whether they were suffering from uveitis, scleritis, or other types of ocular inflammation, all 11 patients showed an improvement to JAK inhibitors without significant side effects. Different types of JAK inhibitors might be associated with different responses when used to treat ocular inflammation.
CONCLUSIONS
JAK inhibitors may represent an alternative treatment option for patients with autoimmune ocular inflammation.
Topics: Animals; Autoimmune Diseases; Disease Management; Disease Susceptibility; Eye Diseases; Humans; Inflammation; Janus Kinase Inhibitors; Molecular Targeted Therapy; Treatment Outcome
PubMed: 34966823
DOI: 10.1155/2021/2324400 -
Rheumatology (Oxford, England) Mar 2024We aimed to comprehensively analyse the available literature to identify the unmet requirements in transitional programs tailored specifically for patients diagnosed...
OBJECTIVES
We aimed to comprehensively analyse the available literature to identify the unmet requirements in transitional programs tailored specifically for patients diagnosed with JIA.
METHODS
According to published guidance on narrative reviews, a systematic review of the literature on transitional care in rheumatology was conducted. Pertinent documents were collected from reputable databases, such as Web of Science, Scopus, and MEDLINE/PubMed. The search encompassed literature published from the inception of each database until January 2023.
RESULTS
In this study, a comprehensive analysis of the findings of 34 studies was conducted. Among these, 12 studies focused on assessing the readiness of adolescents and young adults diagnosed with JIA. Additionally, 18 studies examined the effectiveness of structured transition programs in terms of adherence and satisfaction. Finally, 4 studies investigated disease-related outcomes in this population.
CONCLUSION
The need for transitioning children with rheumatic diseases to adult rheumatology services for continued care is clearly evident. However, the absence of established best practice guidelines presents a challenge in facilitating this transition effectively. Although several scoring systems have been proposed to ensure organized and seamless transfers, a consensus has not yet been reached. Furthermore, the socio-economic and cultural variations across countries further complicate the development of universal guidelines for transitioning children with rheumatic diseases. To address these concerns, our objective in conducting this literature review was to emphasize the significance of this issue and identify the specific requirements based on the unmet needs in the transition process.
Topics: Adolescent; Child; Humans; Young Adult; Arthritis, Juvenile; Consensus; Databases, Factual; Rheumatic Diseases; Transitional Care
PubMed: 37774006
DOI: 10.1093/rheumatology/kead518