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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 For Immunotherapy of Cancer May 2021COVID-19, the syndrome caused by the infection with SARS-CoV-2 coronavirus, is characterized, in its severe form, by interstitial diffuse pneumonitis and acute...
COVID-19, the syndrome caused by the infection with SARS-CoV-2 coronavirus, is characterized, in its severe form, by interstitial diffuse pneumonitis and acute respiratory distress syndrome (ARDS). ARDS and systemic manifestations of COVID-19 are mainly due to an exaggerated immune response triggered by the viral infection. Cytokine release syndrome (CRS), an inflammatory syndrome characterized by elevated levels of circulating cytokines, and endothelial dysfunction are systemic manifestations of COVID-19. CRS is also an adverse event of immunotherapy (IMTX), the treatment of diseases using drugs, cells, and antibodies to stimulate or suppress the immune system. Graft-versus-host disease complications after an allogeneic stem cell transplant, toxicity after the infusion of chimeric antigen receptor-T cell therapy and monoclonal antibodies can all lead to CRS. It is hypothesized that anti-inflammatory drugs used for treatment of CRS in IMTX may be useful in reducing the mortality in COVID-19, whereas IMTX itself may help in ameliorating effects of SARS-CoV-2 infection. In this paper, we focused on the potential shared mechanisms and differences between COVID-19 and IMTX-related toxicities. We performed a systematic review of the clinical trials testing anti-inflammatory therapies and of the data published from prospective trials. Preliminary evidence suggests there might be a benefit in targeting the cytokines involved in the pathogenesis of COVID-19, especially by inhibiting the interleukin-6 pathway. Many other approaches based on novel drugs and cell therapies are currently under investigation and may lead to a reduction in hospitalization and mortality due to COVID-19.
Topics: Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; COVID-19; Cytokine Release Syndrome; Humans; Immunization, Passive; Immunotherapy; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Interleukin-6; Nitriles; Pyrazoles; Pyrimidines; SARS-CoV-2; Tumor Necrosis Factor-alpha; COVID-19 Serotherapy; COVID-19 Drug Treatment
PubMed: 33986127
DOI: 10.1136/jitc-2021-002392 -
Arthritis & Rheumatology (Hoboken, N.J.) Jul 2022The interleukin-1 (IL-1) mediated systemic autoinflammatory diseases, including the cryopyrin- associated periodic syndromes (CAPS), tumour necrosis factor...
The 2021 EULAR/American College of Rheumatology Points to Consider for Diagnosis, Management and Monitoring of the Interleukin-1 Mediated Autoinflammatory Diseases: Cryopyrin-Associated Periodic Syndromes, Tumour Necrosis Factor Receptor-Associated Periodic Syndrome, Mevalonate Kinase Deficiency,...
BACKGROUND
The interleukin-1 (IL-1) mediated systemic autoinflammatory diseases, including the cryopyrin- associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) and deficiency of the IL-1 receptor antagonist (DIRA), belong to a group of rare immunodysregulatory diseases that primarily present in early childhood with variable multiorgan involvement. When untreated, patients with severe clinical phenotypes have a poor prognosis, and diagnosis and management of these patients can be challenging. However, approved treatments targeting the proinflammatory cytokine IL-1 have been life changing and have significantly improved patient outcomes.
OBJECTIVE
To establish evidence-based recommendations for diagnosis, treatment and monitoring of patients with IL-1 mediated autoinflammatory diseases to standardise their management.
METHODS
A multinational, multidisciplinary task force consisting of physician experts, including rheumatologists, patients or caregivers and allied healthcare professionals, was established. Evidence synthesis, including systematic literature review and expert consensus (Delphi) via surveys, was conducted. Consensus methodology was used to formulate and vote on statements to guide optimal patient care.
RESULTS
The task force devised five overarching principles, 14 statements related to diagnosis, 10 on therapy, and nine focused on long-term monitoring that were evidence and/or consensus-based for patients with IL-1 mediated diseases. An outline was developed for disease-specific monitoring of inflammation-induced organ damage progression and reported treatments of CAPS, TRAPS, MKD and DIRA.
CONCLUSION
The 2021 EULAR/American College of Rheumatology points to consider represent state-of-the-art knowledge based on published data and expert opinion to guide diagnostic evaluation, treatment and monitoring of patients with CAPS, TRAPS, MKD and DIRA, and to standardise and improve care, quality of life and disease outcomes.
Topics: Child, Preschool; Cryopyrin-Associated Periodic Syndromes; Fever; Hereditary Autoinflammatory Diseases; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Mevalonate Kinase Deficiency; Quality of Life; Receptors, Interleukin-1; Rheumatology; United States
PubMed: 35621220
DOI: 10.1002/art.42139 -
Journal of Cutaneous Medicine and... 2022There is currently at least 1 biologic (adalimumab) approved in North America for treatment of Hidradenitis Suppurativa in the pediatric population. However, no reviews...
BACKGROUND
There is currently at least 1 biologic (adalimumab) approved in North America for treatment of Hidradenitis Suppurativa in the pediatric population. However, no reviews or clinical trials have specifically analyzed the effectiveness and safety data of biologic use in this population. The objective of this systematic review is to identify and summarize the outcomes of biologic therapy in pediatric patients with HS.
METHODS
MEDLINE and EMBASE databases were used to conduct the search on Sept 18, 2020.
RESULTS
The 15 included studies consisted of 26 patients, with the mean age of 15 ± 2.3 years. Females accounted for 53.8% ( = 14/26) of cases. The mean duration of HS prior to biologic initiation was 3.5 ± 2.9 years, with the majority having Hurley Stage II. The 26 patients received 34 biologics in total: 85.3% treated with TNF alpha inhibitors (adalimumab = 17, infliximab = 10, etanercept = 1, unspecified = 1), 5.9% with IL-12/23 inhibitors (ustekinumab = 2), 5.9% with IL-1 inhibitors (i.e., anakinra = 2) and 2.9% received IL-23 inhibitors (i.e., guselkumab = 1) biologics. Of the 26 patients, 23.1% ( = 6/26) experienced complete resolution (CR), 73.1% ( = 19/26) experienced partial resolution (PR), and 3.8% ( = 1/26) had no resolution outcomes reported. The time to resolution of HS lesions after biologic initiation ranged from 10 days to 11.5 months (mean: 5.1 months). No adverse events were reported in the studies.
CONCLUSION
Although anti-TNF alpha were the most common biologics used for HS in pediatric cases, large-scale trials specific to pediatric patients with HS are needed to confirm these findings.
Topics: Adalimumab; Adolescent; Biological Products; Child; Female; Hidradenitis Suppurativa; Humans; Infliximab; Tumor Necrosis Factor Inhibitors
PubMed: 34587768
DOI: 10.1177/12034754211049711 -
PLoS Neglected Tropical Diseases Jan 2023Few data exist on the distinct cytokine profiles of individuals with malaria coinfections and other diseases. This study focuses on data collation of distinct cytokine...
BACKGROUND
Few data exist on the distinct cytokine profiles of individuals with malaria coinfections and other diseases. This study focuses on data collation of distinct cytokine profiles between individuals with malaria coinfections and monoinfections to provide evidence for further diagnostic or prognostic studies.
METHODS
We searched five medical databases, including Embase, MEDLINE, PubMed, Ovid, and Scopus, for articles on cytokines in malaria coinfections published from January 1, 1983 to May 3, 2022, after which the distinct cytokine patterns between malaria coinfection and monoinfection were illustrated in heat maps.
RESULTS
Preliminary searches identified 2127 articles, of which 34 were included in the systematic review. Distinct cytokine profiles in malaria coinfections with bacteremia; HIV; HBV; dengue; filariasis; intestinal parasites; and schistosomiasis were tumor necrosis factor (TNF), interferon (IFN)-γ, IFN-α, interleukin (IL)-1, IL-1 receptor antagonist (Ra), IL-4, IL-7, IL-12, IL-15, IL-17; TNF, IL-1Ra, IL-4, IL-10, IL-12, IL-18, CCL3, CCL5, CXCL8, CXCL9, CXCL11, granulocyte colony-stimulating factor (G-CSF); TNF, IFN-γ, IL-4, IL-6, IL-10, IL-12, CCL2; IFN-γ, IL-1, IL-4, IL-6, IL-10, IL-12, IL-13, IL-17, CCL2, CCL3, CCL4, G-CSF; IL-1Ra, IL-10, CXCL5, CXCL8, CXCL10; TNF, IL-2, IL-4, IL-6, IL-10; and TNF, IFN-γ, IL-4, IL-5, IL-10, transforming growth factor-β, CXCL8, respectively.
CONCLUSION
This systematic review provides information on distinct cytokine profiles of malaria coinfections and malaria monoinfections. Further studies should investigate whether specific cytokines for each coinfection type could serve as essential diagnostic or prognostic biomarkers for malaria coinfections.
Topics: Humans; Interleukin-10; Interleukin-17; Coinfection; Interleukin-6; Interleukin 1 Receptor Antagonist Protein; Interleukin-4; Cytokines; Interleukin-12; Tumor Necrosis Factor-alpha; Interferon-gamma; Granulocyte Colony-Stimulating Factor; Malaria
PubMed: 36716305
DOI: 10.1371/journal.pntd.0011061 -
Annals of the Rheumatic Diseases Jun 2021To summarise the available information on efficacy and safety of immunomodulatory agents in SARS-CoV-2 infection.
OBJECTIVE
To summarise the available information on efficacy and safety of immunomodulatory agents in SARS-CoV-2 infection.
METHODS
As part of a European League Against Rheumatism (EULAR) taskforce, a systematic literature search was conducted from January 2019 to 11 December 2020. Two reviewers independently identified eligible studies according to the Population, Intervention, Comparator and Outcome framework and extracted data on efficacy and safety of immunomodulatory agents used therapeutically in SARS-CoV-2 infection at any stage. The risk of bias was assessed with validated tools.
RESULTS
Of the 60 372 records, 401 articles were eligible for inclusion. Studies were at variable risk of bias. Randomised controlled trials (RCTs) were available for the following drugs: hydroxychloroquine (n=12), glucocorticoids (n=6), tocilizumab (n=4), convalescent plasma (n=4), interferon beta (n=2), intravenous immunoglobulins (IVIg) (n=2) and n=1 each for anakinra, baricitinib, colchicine, leflunomide, ruxolitinib, interferon kappa and vilobelimab. Glucocorticoids were able to reduce mortality in specific subsets of patients, while conflicting data were available about tocilizumab. Hydroxychloroquine was not beneficial at any disease stage, one RCT with anakinra was negative, one RCT with baricitinib+remdesivir was positive, and individual trials on some other compounds provided interesting, although preliminary, results.
CONCLUSION
Although there is emerging evidence about immunomodulatory therapies for the management of COVID-19, conclusive data are scarce with some conflicting data. Since glucocorticoids seem to improve survival in some subsets of patients, RCTs comparing glucocorticoids alone versus glucocorticoids plus anticytokine/immunomodulatory treatment are warranted. This systematic literature review informed the initiative to formulate EULAR 'points to consider' on COVID-19 pathophysiology and immunomodulatory treatment from the rheumatology perspective.
Topics: COVID-19; Glucocorticoids; Humans; Hydroxychloroquine; Immunization, Passive; Interleukin 1 Receptor Antagonist Protein; Rheumatic Diseases; SARS-CoV-2; COVID-19 Drug Treatment; COVID-19 Serotherapy
PubMed: 33589438
DOI: 10.1136/annrheumdis-2020-219725 -
Medicine Jun 2021To evaluate the efficacy of fusion proteins biologics (Etanercept (ETN), Anakinra (ANA), and Abatacept) combinations in the treatment of rheumatoid arthritis (RA) using... (Meta-Analysis)
Meta-Analysis
BACKGROUND
To evaluate the efficacy of fusion proteins biologics (Etanercept (ETN), Anakinra (ANA), and Abatacept) combinations in the treatment of rheumatoid arthritis (RA) using network meta-analysis to rank those according to their performance medicines. The performance of these processes is ranked according to the results of the analysis and an explanatory study of the possible results is carried out.
METHODS
Multiple databases including PubMed, EMBASE, and Cochrane Library were used to identify applicable articles and collect relevant data to analyze using STATA (14.0) software. The literature included in this study was divided into a combination of a placebo, methotrexate (MTX), and an observation group (1 of the 3 drugs). The last search date was December 12, 2019.
RESULTS
A total of 19 eligible randomized controlled trials of fusion proteins biologics were identified, a total of 1109 papers were included, and the results showed that the ETN + MTX had the highest probability of being the most clinically efficacious intervention, with a surface under the cumulative ranking curve of 91.6, was significantly superior (P < .05). Patients who had received ETN or ETN + MTX or ANA had effective compared with patients who had received placebo (95% CI 1.28%-8.47%; 1.92%-19.18%; 1.06%-10.45%).
CONCLUSIONS
1. The combination of ETN and MTX had the highest probability of optimal treatment compared to other drugs and 2. ENT, ENT + MTX, and ANA were effective in the treatment of RA compared to placebo.
Topics: Abatacept; Antirheumatic Agents; Arthritis, Rheumatoid; Biological Factors; Drug Therapy, Combination; Etanercept; Humans; Interleukin 1 Receptor Antagonist Protein; Methotrexate; Network Meta-Analysis
PubMed: 34128886
DOI: 10.1097/MD.0000000000026350 -
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 -
Therapeutic Advances in Musculoskeletal... 2020Despite being burdened by significant adverse events, glucocorticoids (GCs) are frequently employed in managing adult onset Still's disease (AOSD), prompting the need...
The reduction of concomitant glucocorticoids dosage following treatment with IL-1 receptor antagonist in adult onset Still's disease. A systematic review and meta-analysis of observational studies.
BACKGROUND
Despite being burdened by significant adverse events, glucocorticoids (GCs) are frequently employed in managing adult onset Still's disease (AOSD), prompting the need for GC-sparing agents. In this work, we performed a systematic review and meta-analysis to synthesize the evidence about the reduction of concomitant GCs dosage and the rate of GCs discontinuation in patients with AOSD who were treated with anakinra, a recombinant IL-1 receptor antagonist.
METHODS
A systematic review of the literature was completed to identify all available data concerning the reduction of concomitant GCs dosage following anakinra in AOSD and a meta-analysis was thus performed using a random-effects model.
RESULTS
A significant reduction of the GCs dosage was detected by pooled analysis with mean difference of -22.4 mg/day [95% confidence interval (CI): -28.8 to -16.1, < 0.0001] at the last follow-up; the heterogeneity was moderate (Q = 11.67 with df = 7.00, < 0.0001, = 40.01%). Furthermore, the pooled analysis under a random effects model showed an overall rate of GCs discontinuation of 0.35 (95% CI: 0.28-0.41, < 0.0001); the heterogeneity was low (Q = 5.99 with df = 6.00, < 0.0001, = 0.00%).
DISCUSSION
Taking together all these findings, the reduction of concomitant GCs dosage following anakinra could be suggested, leading to a further improvement of AOSD therapeutic strategy.
CONCLUSION
In conclusion, the present systematic review and meta-analysis suggests the reduction of concomitant GCs dosage following treatment with anakinra. A percentage of patients are no longer required to be treated with GCs, discontinuing these drugs without a flare of the disease.
PubMed: 32595777
DOI: 10.1177/1759720X20933133 -
BMJ (Clinical Research Ed.) Jul 2020To assess the comparative effectiveness of biological medicines in rheumatoid arthritis in sufficiently similar patient populations, based on the current definitions of... (Meta-Analysis)
Meta-Analysis
Comparative effectiveness of biological medicines in rheumatoid arthritis: systematic review and network meta-analysis including aggregate results from reanalysed individual patient data.
OBJECTIVE
To assess the comparative effectiveness of biological medicines in rheumatoid arthritis in sufficiently similar patient populations, based on the current definitions of key outcomes.
DESIGN
Systematic review and network meta-analysis including aggregate results from reanalysed individual patient data.
DATA SOURCES
Clinical study reports and aggregate results from reanalyses of individual patient data on key outcomes for rheumatoid arthritis provided by study sponsors for studies conducted up to 2017, and several databases and registries from inception up to February 2017.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Randomised controlled trials investigating patient relevant outcomes in adults with rheumatoid arthritis treated with biological medicines in combination with methotrexate after methotrexate failure for at least 24 weeks.
RESULTS
45 eligible trials were identified. Combining data from clinical study reports and aggregate results from reanalyses of individual patient data allowed extensive analyses yielding sufficiently similar populations and homogeneous study results for network meta-analyses, including up to 35 studies on eight biological medicines combined with methotrexate. These analyses showed few statistically significant differences between the combination treatments. For example, anakinra showed less benefit than almost all the other seven biological medicines regarding clinical remission or low disease activity (clinical disease activity index ≤2.8 or ≤10, respectively) and certolizumab pegol showed more harm than the other seven biological medicines regarding serious adverse events or infections. Some outcomes had very wide 95% confidence intervals, potentially implying unidentified differences between the eight biological medicines, but wide 95% confidence intervals were less prominent for low disease activity, serious adverse events, and infections. Owing to a lack of head-to-head trials, results were mainly based on indirect comparisons with a limited number of studies, and recently approved Janus kinase inhibitors could not be included.
CONCLUSIONS
For patients with rheumatoid arthritis after methotrexate failure, only minor differences in benefits and harms were seen between biological medicines in combination with methotrexate. However, the analysis was hampered by a lack of long term direct comparisons. The substantial information gain achieved by the reanalysis of individual patient data calls for the routine availability of individual patient data.
Topics: Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; Disease Progression; Drug Therapy, Combination; Equivalence Trials as Topic; Female; Humans; Male; Methotrexate; Middle Aged; Remission Induction; Treatment Failure
PubMed: 32636183
DOI: 10.1136/bmj.m2288