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EBioMedicine Apr 2023The cytokine interleukin-2 (IL-2) can stimulate both effector immune cells and regulatory T (Treg) cells. The ability of selectively engaging either of these effects has...
BACKGROUND
The cytokine interleukin-2 (IL-2) can stimulate both effector immune cells and regulatory T (Treg) cells. The ability of selectively engaging either of these effects has spurred interest in using IL-2 for immunotherapy of cancer and autoimmune diseases. Thus, numerous IL-2-based biologic agents with improved bias or delivery towards effector immune cells or Treg cells have been developed. This study systematically reviews clinical results of improved IL-2-based compounds.
METHODS
We searched the ClinicalTrials.gov database for registered trials using improved IL-2-based agents and different databases for available results of these studies.
FINDINGS
From 576 registered clinical trials we extracted 36 studies on different improved IL-2-based compounds. Adding another nine agents reported in recent literature reviews and based on our knowledge totalled in 45 compounds. A secondary search for registered clinical trials of each of these 45 compounds resulted in 141 clinical trials included in this review, with 41 trials reporting results.
INTERPRETATION
So far, none of the improved IL-2-based compounds has gained regulatory approval for the treatment of cancer or autoimmune diseases. NKTR-214 is the only compound completing phase 3 studies. The PIVOT IO-001 trial testing the combination of NKTR-214 plus Pembrolizumab compared to Pembrolizumab monotherapy in metastatic melanoma missed its primary endpoints. Also the PIVOT-09 study, combining NKTR-214 with Nivolumab compared to Sunitinib or Cabozantinib in advanced renal cell carcinoma, missed its primary endpoint. Trials in autoimmune diseases are currently in early stages, thus not allowing definite conclusions on efficacy.
FUNDING
This work was supported by public funding agencies.
Topics: Humans; Antineoplastic Agents; Interleukin-2; Carcinoma, Renal Cell; Kidney Neoplasms; Immunotherapy; Autoimmune Diseases
PubMed: 37004361
DOI: 10.1016/j.ebiom.2023.104539 -
Fertility and Sterility Mar 2020To determine whether overt/subclinical hypothyroidism and/or thyroid autoimmunity is associated with recurrent pregnancy loss (RPL) and whether treatment improves... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To determine whether overt/subclinical hypothyroidism and/or thyroid autoimmunity is associated with recurrent pregnancy loss (RPL) and whether treatment improves outcomes.
DESIGN
Systematic review and meta-analysis.
SETTING
University obstetrics and gynecology departments.
PATIENT(S)
Women with RPL and overt/subclinical hypothyroidism, and/or thyroid autoimmunity.
INTERVENTION(S)
None.
MAIN OUTCOME MEASURE(S)
Associations between RPL and overt/subclinical hypothyroidism and/or thyroid autoimmunity and any effects of treatment.
RESULT(S)
After our review of articles from PubMed, EMBASE, Web of Science, and CENTRAL, we found two interventional studies in which levothyroxine did not improve the subsequent live-birth rate in women with subclinical hypothyroidism with or without thyroid antibodies. A meta-analysis of five studies revealed the prevalence of subclinical hypothyroidism in RPL to be 12.9% (95% confidence interval [CI], 0%-35.2%). A meta-analysis of 17 studies revealed a statistically significant association between RPL and thyroid autoimmunity (odds ratio 1.94; 95% CI, 1.43-2.64). However, a randomized study suggested that levothyroxine does not benefit euthyroid women with thyroid autoimmunity.
CONCLUSION(S)
Based on the limited observational studies available, no association exists between RPL and subclinical hypothyroidism, nor does levothyroxine improve subsequent pregnancy outcomes. An association exists between RPL and thyroid autoimmunity, but levothyroxine does not improve subsequent pregnancy outcomes. Women with RPL should be screened/treated for overt thyroid disease but not thyroid autoimmunity. Thyroid antibody screening is not supported by the published studies, and further randomized studies are needed. No recommendation regarding the treatment of subclinical hypothyroidism can be made at this time; prospective and randomized studies are urgently needed.
Topics: Abortion, Habitual; Asymptomatic Diseases; Female; Humans; Hypothyroidism; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prenatal Diagnosis; Risk Factors; Thyroid Function Tests; Thyroiditis, Autoimmune
PubMed: 32192591
DOI: 10.1016/j.fertnstert.2019.11.003 -
Frontiers in Endocrinology 2023Hashimoto's thyroiditis (HT) is the most common autoimmune disease. HT may be associated with nonthyroidal autoimmune diseases, including celiac disease (CD) or other... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Hashimoto's thyroiditis (HT) is the most common autoimmune disease. HT may be associated with nonthyroidal autoimmune diseases, including celiac disease (CD) or other gluten-related conditions (GRC). In the last years, interest about gluten-free diet (GFD) has increased for its supposed extraintestinal anti-inflammatory effect; thus, many patients with HT initiate GFD on their own.
OBJECTIVES
The aim of this meta-analysis is to examine all available data in literature about the effect of a GFD on TgAb, TPOAb, TSH, FT4, and FT3 levels in patients with HT and no symptoms or histology of CD.
METHODS
The study was conducted according to MOOSE (Meta-analysis Of Observational Studies in Epidemiology). The search was performed on databases PubMed and Scopus. The last search was performed on 7 February 2023. Quality assessment was performed. Meta-analyses were performed using the random-effect model. Hedges' was used to measure the effect size (ES). Statistical analyses were performed using StataSE 17.
RESULTS
The online search retrieved 409 articles, and 4 studies with a total of 87 patients were finally included for quantitative analysis. The risk of bias was generally low. The mean period of GFD was almost 6 months. The meta-analyses showed reduction in antibody levels with ES: -0.39 for TgAb (95% CI: -0.81 to +0.02; = 0.06; ² = 46.98%) and -0.40 for TPOAb (95% CI: -0.82 to +0.03; = 0.07; ² = 47.58%). TSH showed a reduction with ES: -0.35 (95% CI: -0.64 to -0.05; = 0.02; ² = 0%) and FT4 showed an increase with ES: +0.35% (95% CI: 0.06 to 0.64; = 0.02; ² = 0%). FT3 did not display variations (ES: 0.05; 95% CI: -0.38 to +0.48; = 0.82; ² = 51%). The heterogeneity of TgAb, TPOAb, and FT3 data was solved performing sub-analyses between patients with or without GRC (TgAb = 0.02; TPOAb = 0.02; FT3 = 0.04) and only for FT3, performing a sub-analysis between patients taking and not taking LT4 ( = 0.03).
CONCLUSION
This is the first meta-analysis investigating the effect of GFD on HT. Our results seem to indicate a positive effect of the gluten deprivation on thyroid function and its inflammation, particularly in patients with HT and GRC. However, current lines of evidence are not yet sufficient to recommend this dietary approach to all patients with a diagnosis of HT.
Topics: Humans; Thyroiditis, Autoimmune; Diet, Gluten-Free; Celiac Disease; Autoantibodies; Hashimoto Disease; Thyrotropin
PubMed: 37554764
DOI: 10.3389/fendo.2023.1200372 -
Frontiers in Immunology 2019To help inform decision making in the clinical setting, we carried out a systematic review and meta-analysis to estimate the association of thyroid disease risks with... (Meta-Analysis)
Meta-Analysis
To help inform decision making in the clinical setting, we carried out a systematic review and meta-analysis to estimate the association of thyroid disease risks with obesity. Pubmed, Embase, Web of Science, Cochrane database and Google Scholar electronic databases were searched from inception to October 31, 2018 without language restrictions to explore the relationship between thyroid disorders and obesity. The relative risk (RR) or odds risk (OR) for thyroid disorders were pooled using the SPSS and STATA software. A total of 22 studies were included in the study. (1) Meta-analysis showed that obesity was significantly associated with an increased risk of hypothyroidism (RR = 1.86, 95% CI 1.63-2.11, < 0.001). Meta-analyses after stratification further showed that obese population had increased risks of overt hypothyroidism (RR = 3.21, 95% CI 2.12-4.86, < 0.001) and subclinical hypothyroidism (RR = 1.70, 95% CI 1.42-2.03, < 0.001). (2) Further meta-analysis also showed obesity was clearly associated with Hashimoto's thyroiditis (RR = 1.91, 95% CI 1.10-3.32, = 0.022), but not with Graves' disease. (3) In the meta-analysis of antibodies, obesity was correlated with positive thyroid peroxidase antibody (TPOAb) (RR = 1.93, 95% CI 1.31-2.85, = 0.001), but not with positive thyroglobulin antibody (TGAb). Obesity was significantly related to hypothyroidism, HT, and TPOAb, implying that prevention of obesity is crucial for thyroid disorders. PROSPERO: CRD42018096897.
Topics: Autoimmunity; Biomarkers; Disease Susceptibility; Humans; Obesity; Odds Ratio; Thyroid Diseases; Thyroid Function Tests; Thyroid Gland
PubMed: 31681268
DOI: 10.3389/fimmu.2019.02349 -
Translational Psychiatry Jan 2021Inflammation is increasingly recognized as a cause or consequence of common problems of humanity including obesity, stress, depression, pollution and disease states such...
Inflammation is increasingly recognized as a cause or consequence of common problems of humanity including obesity, stress, depression, pollution and disease states such as autoimmunity, asthma, and infection. Maternal immune activation (MIA), triggered by both acute and systemic chronic inflammation, is hypothesized to be one of the mechanisms implicated in the pathogenesis of neurodevelopmental disorders (NDD). Although there is substantial preclinical evidence to support the MIA hypothesis, the human evidence is disparate. We performed a systematic review on human studies examining associations between maternal inflammatory states and offspring NDDs (autism spectrum disorder- ASD, attention deficit hyperactivity disorder-ADHD, Tourette syndrome-TS). 32 meta-analyses and 26 additional individual studies were identified. Maternal states associated with ASD include obesity, gestational diabetes mellitus, pre-eclampsia, pollution, stress, depression, autoimmune diseases, and infection. Maternal states associated with ADHD include obesity, pre-eclampsia, smoking, low socioeconomic status (SES), stress, autoimmune disease, and asthma. Maternal states associated with TS include low SES, depression, and autoimmune diseases. Diverse maternal inflammatory states in pregnancy are associated with common offspring NDDs. Given the increased prevalence of NDDs, there is urgent need to explore relative and cumulative maternal risk factors and disease mechanisms. Defining preventable risk factors in high-risk pregnancies could mitigate the expression and severity of NDDs.
Topics: Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Female; Humans; Inflammation; Neurodevelopmental Disorders; Pregnancy; Prenatal Exposure Delayed Effects; Risk Factors
PubMed: 33479207
DOI: 10.1038/s41398-021-01198-w -
Frontiers in Immunology 2021Primary immune regulatory disorders (PIRD) are associated with autoimmunity, autoinflammation and/or dysregulation of lymphocyte homeostasis. Autoimmune... (Meta-Analysis)
Meta-Analysis
Primary immune regulatory disorders (PIRD) are associated with autoimmunity, autoinflammation and/or dysregulation of lymphocyte homeostasis. Autoimmune lymphoproliferative syndrome (ALPS) is a PIRD due to an apoptotic defect in Fas-FasL pathway and characterized by benign and chronic lymphoproliferation, autoimmunity and increased risk of lymphoma. Clinical manifestations and typical laboratory biomarkers of ALPS have also been found in patients with a gene defect out of the Fas-FasL pathway (ALPS-like disorders). Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), we identified more than 600 patients suffering from 24 distinct genetic defects described in the literature with an autoimmune lymphoproliferative phenotype (ALPS-like syndromes) corresponding to phenocopies of primary immunodeficiency (PID) (), susceptibility to EBV (), antibody deficiency ( gain of function (GOF) loss of function (LOF) GOF), regulatory T-cells defects ( GOF), combined immunodeficiencies (), defects in intrinsic and innate immunity and predisposition to infection ( GOF, ) and autoimmunity/autoinflammation (). CTLA4 and LRBA patients correspond around to 50% of total ALPS-like cases. However, only 100% of CTLA4, PRKCD, TET2 and NRAS/KRAS reported patients had an ALPS-like presentation, while the autoimmunity and lymphoproliferation combination resulted rare in other genetic defects. Recurrent infections, skin lesions, enteropathy and malignancy are the most common clinical manifestations. Some approaches available for the immunological study and identification of ALPS-like patients through flow cytometry and ALPS biomarkers are provided in this work. Protein expression assays for NKG2D, XIAP, SAP, CTLA4 and LRBA deficiencies and functional studies of AKT, STAT1 and STAT3 phosphorylation, are showed as useful tests. Patients suspected to suffer from one of these disorders require rapid and correct diagnosis allowing initiation of tailored specific therapeutic strategies and monitoring thereby improving the prognosis and their quality of life.
Topics: Autoimmune Lymphoproliferative Syndrome; Early Diagnosis; Humans; Primary Immunodeficiency Diseases
PubMed: 34447369
DOI: 10.3389/fimmu.2021.671755 -
JAMA Aug 2019Maternal hypothyroidism and hyperthyroidism are risk factors for preterm birth. Milder thyroid function test abnormalities and thyroid autoimmunity are more prevalent,... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Maternal hypothyroidism and hyperthyroidism are risk factors for preterm birth. Milder thyroid function test abnormalities and thyroid autoimmunity are more prevalent, but it remains controversial if these are associated with preterm birth.
OBJECTIVE
To study if maternal thyroid function test abnormalities and thyroid autoimmunity are risk factors for preterm birth.
DATA SOURCES AND STUDY SELECTION
Studies were identified through a search of the Ovid MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar databases from inception to March 18, 2018, and by publishing open invitations in relevant journals. Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4] concentrations) or thyroid peroxidase (TPO) antibody measurements and gestational age at birth were screened for eligibility by 2 independent reviewers. Studies in which participants received treatment based on abnormal thyroid function tests were excluded.
DATA EXTRACTION AND SYNTHESIS
The primary authors provided individual participant data that were analyzed using mixed-effects models.
MAIN OUTCOMES AND MEASURES
The primary outcome was preterm birth (<37 weeks' gestational age).
RESULTS
From 2526 published reports, 35 cohorts were invited to participate. After the addition of 5 unpublished data sets, a total of 19 cohorts were included. The study population included 47 045 pregnant women (mean age, 29 years; median gestational age at blood sampling, 12.9 weeks), of whom 1234 (3.1%) had subclinical hypothyroidism (increased thyrotropin concentration with normal FT4 concentration), 904 (2.2%) had isolated hypothyroxinemia (decreased FT4 concentration with normal thyrotropin concentration), and 3043 (7.5%) were TPO antibody positive; 2357 (5.0%) had a preterm birth. The risk of preterm birth was higher for women with subclinical hypothyroidism than euthyroid women (6.1% vs 5.0%, respectively; absolute risk difference, 1.4% [95% CI, 0%-3.2%]; odds ratio [OR], 1.29 [95% CI, 1.01-1.64]). Among women with isolated hypothyroxinemia, the risk of preterm birth was 7.1% vs 5.0% in euthyroid women (absolute risk difference, 2.3% [95% CI, 0.6%-4.5%]; OR, 1.46 [95% CI, 1.12-1.90]). In continuous analyses, each 1-SD higher maternal thyrotropin concentration was associated with a higher risk of preterm birth (absolute risk difference, 0.2% [95% CI, 0%-0.4%] per 1 SD; OR, 1.04 [95% CI, 1.00-1.09] per 1 SD). Thyroid peroxidase antibody-positive women had a higher risk of preterm birth vs TPO antibody-negative women (6.6% vs 4.9%, respectively; absolute risk difference, 1.6% [95% CI, 0.7%-2.8%]; OR, 1.33 [95% CI, 1.15-1.56]).
CONCLUSIONS AND RELEVANCE
Among pregnant women without overt thyroid disease, subclinical hypothyroidism, isolated hypothyroxinemia, and TPO antibody positivity were significantly associated with higher risk of preterm birth. These results provide insights toward optimizing clinical decision-making strategies that should consider the potential harms and benefits of screening programs and levothyroxine treatment during pregnancy.
Topics: Adult; Autoantibodies; Autoimmune Diseases; Female; Gestational Age; Humans; Hypothyroidism; Infant, Newborn; Iodide Peroxidase; Pregnancy; Pregnancy Complications; Premature Birth; Thyroid Diseases; Thyroid Function Tests; Thyrotropin; Thyroxine
PubMed: 31429897
DOI: 10.1001/jama.2019.10931 -
Annals of the Rheumatic Diseases Jan 2023Recent insights supporting the safety of live-attenuated vaccines and novel studies on the immunogenicity of vaccinations in the era of biological disease-modifying...
OBJECTIVES
Recent insights supporting the safety of live-attenuated vaccines and novel studies on the immunogenicity of vaccinations in the era of biological disease-modifying antirheumatic drugs in paediatric patients with autoimmune/inflammatory rheumatic diseases (pedAIIRD) necessitated updating the EULAR recommendations.
METHODS
Recommendations were developed using the EULAR standard operating procedures. Two international expert committees were formed to update the vaccination recommendations for both paediatric and adult patients with AIIRD. After a systematic literature review, separate recommendations were formulated for paediatric and adult patients. For pedAIIRD, six overarching principles and seven recommendations were formulated and provided with the level of evidence, strength of recommendation and Task Force level of agreement.
RESULTS
In general, the National Immunisation Programmes (NIP) should be followed and assessed yearly by the treating specialist. If possible, vaccinations should be administered prior to immunosuppressive drugs, but necessary treatment should never be postponed. Non-live vaccines can be safely given to immunosuppressed pedAIIRD patients. Mainly, seroprotection is preserved in patients receiving vaccinations on immunosuppression, except for high-dose glucocorticoids and B-cell depleting therapies. Live-attenuated vaccines should be avoided in immunosuppressed patients. However, it is safe to administer the measles-mumps-rubella booster and varicella zoster virus vaccine to immunosuppressed patients under specific conditions. In addition to the NIP, the non-live seasonal influenza vaccination should be strongly considered for immunosuppressed pedAIIRD patients.
CONCLUSIONS
These recommendations are intended for paediatricians, paediatric rheumatologists, national immunisation agencies, general practitioners, patients and national rheumatology societies to attain safe and effective vaccination and optimal infection prevention in immunocompromised pedAIIRD patients.
Topics: Adult; Humans; Child; Vaccines, Attenuated; Rheumatic Diseases; Vaccination; Immunosuppressive Agents; Antirheumatic Agents; Autoimmune Diseases
PubMed: 35725297
DOI: 10.1136/annrheumdis-2022-222574 -
Journal of Autoimmunity Apr 2024Among the over 80 different autoimmune diseases, psoriasis (PsO), rheumatoid arthritis (RA), and ankylosing spondylitis (AS) are common representatives. Previous studies... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Among the over 80 different autoimmune diseases, psoriasis (PsO), rheumatoid arthritis (RA), and ankylosing spondylitis (AS) are common representatives. Previous studies indicated a potential link with cancer risk, but suffered often from low statistical power. Thus, we aimed to synthesize the evidence and quantify the association to different female-specific cancer sites.
METHODS
The systematic review was performed according to PRISMA guidelines. A search string was developed for the databases PubMed, Web of Science, Cochrane Library and Embase. Results were screened independently by two investigators and the risk of bias was assessed using the ROBINS-E tool. Meta-analyses were performed using inverse variance weighted random-effects models. Statistical between-study heterogeneity was quantified by calculating Cochran's Q, τ, and Higgins' I statistics. Sources of heterogeneity were analyzed and adjusted for within an intensive bias assessment in the form of meta-regression, outlier, influential, and subgroup analyses. A range of methods were used to test and adjust for publication bias.
RESULTS
Of 10,096 records that were originally identified by the search strategy, 45 were included in the meta-analyses. RA was inversely associated with both breast and uterine cancer occurrence, while PsO was associated with a higher breast cancer risk. Outlier-adjusted estimates confirmed these findings. Bias assessment revealed differences in geographic regions, particularly in RA patients, with higher estimates among Asian studies. An additional analysis revealed no association between psoriatic arthritis and breast cancer.
CONCLUSIONS
RA seems to reduce the risk of breast and uterine cancers, while PsO appears to increase breast cancer risk. Further large studies are required to investigate potential therapy-effects and detailed biological mechanisms.
Topics: Humans; Female; Autoimmune Diseases; Arthritis, Rheumatoid; Arthritis, Psoriatic; Psoriasis; Breast Neoplasms
PubMed: 38428110
DOI: 10.1016/j.jaut.2024.103187 -
The Journal of International Medical... Dec 2021To perform a meta-analysis of randomized controlled trials to evaluate the efficacy of vitamin D supplementation on thyroid autoimmunity markers in Hashimoto's... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To perform a meta-analysis of randomized controlled trials to evaluate the efficacy of vitamin D supplementation on thyroid autoimmunity markers in Hashimoto's thyroiditis (HT).
METHODS
This meta-analysis included randomized controlled clinical trials identified by a systematic search of electronic databases (PubMed®, MEDLINE®, EMBASE, The Cochrane Library, China National Knowledge Infrastructure) from inception to August 2020. All studies included patients with HT that received vitamin D supplementation irrespective of the doses administered or the duration of treatment. The primary and secondary outcome measures were thyroid peroxidase antibody (TPOAb) and/or thyroglobulin antibody (TGAb) titres.
RESULTS
Eight studies ( = 652) were included. There was significant heterogeneity between the studies. Using a random-effect model, vitamin D supplementation reduced TPOAb titre (standardized mean difference [SMD]: -1.11; 95% confidence interval [CI]: 1-1.92, -0.29) and TGAb titre (SMD: -1.12; 95% CI: -1.96, -0.28). A subgroup analysis demonstrated that vitamin D supplementation for >3 months resulted in a decrease in TPOAb titre (SMD: -1.66, 95% CI: -2.91, -0.41) but treatment ≤3 months was ineffective. Treatment with vitamin D decreased TPOAb titre (SMD: -1.48; 95% CI: -2.53, -0.42) whereas vitamin D did not.
CONCLUSION
These data suggest that vitamin D reduces autoantibody titre in patients with HT.
Topics: Autoimmunity; Dietary Supplements; Hashimoto Disease; Humans; Vitamin D
PubMed: 34871506
DOI: 10.1177/03000605211060675