Development Of Thyroid Dysfunction Research Articles

Combined use of tyrosine kinase inhibitors with PD-(L)1 blockade increased the risk of thyroid dysfunction in PD-(L)1 blockade: a prospective study

BackgroundAnti-programmed cell death-1 (ligand-1) antibody [PD-(L)1-Ab] can cause destructive thyroiditis and/or hypothyroidism. In addition, tyrosine kinase inhibitors (TKIs) frequently induce hypothyroidism. The aim of this prospective study is to examine the incidence and clinical characteristics of thyroid dysfunction induced by combination therapy of a PD-(L)1-Ab and TKI [PD-(L)1-Ab/TKI].MethodsA total of 757 patients treated with PD-(L)1-Ab or PD-(L)1-Ab/TKI were evaluated for anti-thyroid antibodies (ATAs) at baseline and for thyroid function for 48 weeks after treatment initiation and then observed until the last visit.ResultsThe cumulative incidences of destructive thyroiditis [4/23 (17.4%) vs. 45/734 (6.1%) patients, p < 0.001], isolated hypothyroidism [10/23 (43.5%) vs. 29/734 (4.0%) patients, p < 0.001], and all thyroid dysfunction [14/23 (60.9%) vs. 74/734 (10.1%) patients, p < 0.001] were significantly higher in the PD-(L)1-Ab/TKI group than PD-(L)1-Ab group, respectively. All patients positive for ATAs at baseline developed thyroid dysfunction after PD-(L)1-Ab/TKI treatment, a significantly higher incidence than that in those negative for ATAs at baseline [4/4 (100%) vs. 10/19 (52.6%) patients, p = 0.026].ConclusionsThe addition of TKIs increased the risk of thyroid dysfunction induced by PD-(L)1-Ab, with the risk being higher in patients positive for baseline ATAs.

Impact of obesity on immune-related adverse events and tyrosine kinase inhibitor side effects in patients with metastatic renal cell carcinoma (mRCC).

4560 Background: A pooled data analysis from clinical trials, including various cancer subtypes, showed that obesity is associated with a heightened incidence of immune-related adverse events (irAEs). However, the heterogeneous patient population across different demographics calls for further investigation into the correlation between obesity and adverse effects from immune checkpoint inhibitors (ICI) in mRCC. Additionally, there is limited available data regarding the association of obesity with tyrosine kinase inhibitors (TKIs) toxicities. We hypothesize that obesity may be linked to an increased rate of irAEs and TKIs toxicities in mRCC patients (pts). Methods: We conducted a retrospective analysis of pts diagnosed with mRCC using TriNetX Research Network (TriNetX LLC., Cambridge, Massachusetts, USA). We searched two cohorts (ICI and TKIs) and toxicities using the ICD-10-CM codes. Pts were categorized into two groups based on body mass index (BMI): obese (BMI ≥30) and non-obese (BMI &gt;19 - &lt; 30). Characteristics of the cohorts were balanced using propensity score matching. Results: A total of 4526 pts with mRCC receiving treatment met the inclusion criteria. 40% of pts were in ICI cohort (n=1811), and 60% (n=2715) in TKI cohort. In the ICI cohort 53% were obese (959/1811), and 47% non-obese (852/1811). Among both cohorts, 50% were male, 30% females, 20% unknown and the average age was 69-72. In TKI cohort, Obese group had 57% (1549/2715) pts while non-obese group included 43% (1166/2715) pts. In ICI cohort, there was no statistically significant difference in risk of developing thyroid dysfunction, liver toxicity, type 1 diabetes, adrenal insufficiency/hypophysitis, skin toxicity, pneumonitis, cardiomyopathy, colitis or myositis/arthropathy between obese and non-obese groups (p&gt;0.05). In TKI cohort, risk of thyroid dysfunction was higher among obese (0.177, n=187/1056) vs non-obese (0.131, n=102/781), p=0.007. Moreover, obese pts had a higher rate of diarrhea compared to non-obese (0.141 vs 0.109, p= 0.017). No significant difference was seen in the rate of developing other toxicities including liver dysfunction, mucositis, cardiovascular toxicities including hypertensive crisis or fatigue. (Table) Conclusions: The use of TKIs has shown an increased risk of developing thyroid dysfunction and diarrhea in obese pts. However, there is no difference in irAE with use of ICI between obese and non-obese pts. Further large studies are needed to support this observation and to study the mechanism by which obesity and metabolic syndromes influence the development of adverse effects. [Table: see text]

Ayurvedic Management of Hypomenorrhoea Associated with Thyroid Dysfunction

Women are more prone for developing thyroid dysfunction. And most common clinical presentations seen are irregular menstruation, weight gain, etc. So, there is a need for formulating a treatment protocol for the same. Aims: The present study is aimed to evaluate the effectiveness of Panchakarma along with internal medications in the management of hypomenorrhoea associated with thyroid dysfunction. Materials and methods: A female aged 38 years who was suffering from hypomenorrhoea in the last one year, associated with weight gain, and known case of hypothyroidism in the past 2 years, was enrolled for the study. She underwent Panchakarma therapy followed by internal medications for 3 months. And was followed up after the course of treatment. Results: There was significant relief in her symptoms and thyroid profile also came to normal. Conclusion: Ayurvedic management with Panchakarma therapy followed by internal medicine is having significant role in reversing the symptoms.

Prevalence and Impact of Thyroid Dysfunction in Patients With Chronic Pulmonary Obstructive Pulmonary Disorder: A Systematic Review and Meta-Analysis.

Thyroid gland dysfunction (TGD) has been increasingly recognized as a potential comorbidity in patients with chronic obstructive pulmonary disease (COPD). This study was designed to determine the prevalence of TGD in COPD patients.This systematic review and meta-analysis was conducted according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).To comprehensively identify relevant studies, a systematic search was conducted in major electronic databases, including PubMed, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHIL).The search was limited to English-language studies published after 31December 2000. To determine the prevalence of TGDand assess the impacts, we compared forced vital capacity (FVC) (%), forced expiratory volume in one second (FEV1) (%), partial pressure of oxygen (PaO2) (mmHg), and partial pressure of carbon dioxide (PaCO2) (mmHg) between patients with and without TGD. A total of nine articles were included in this meta-analysis.The sample size of included studies ranged from 50 to 309.The pooled prevalence of TGD in patients with COPD was 45% (95% CI: 25% to 65%). The most common form of TGD was hypothyroidism. The study identified a lack of significant associations between TGD and COPD severity or various characteristics, highlighting the need for future prospective multi-center research, particularly with larger sample sizes to determine the clinical factors and biomarkers affecting the development of thyroid dysfunction in this population.

Endocrine Adverse Events Related To Immune Checkpoint Inhibitor Treatment: Relationship Between Antibodies and Severity of Thyroid Dysfunction.

The purpose of this study was to identify predictive and risk factors for the development of immune-related endocrinopathies and to analyze the incidence and characteristics of immune-related endocrinopathies in our population Design: A retrospective, single-centre cohort carried out at Gregorio Marañón Hospital between January 2018 -December 2019. A total of 163 patients were enrolled. In January 2018 and December 2019, we treated patients who underwent ICI treatment in the Medical Oncology Department of General University Hospital Gregorio Marañón, a tertiary care public hospital in Madrid, as part of an observational, retrospective, single-center cohort study. Endocrinopathies were diagnosed in 19.5% of the patients (n=32). The tumours with the highest incidence of endocrinopathies were non-small cell lung cancer (25,9%), kidney cell cancer (25%) and hepatocarcinoma (20%). Among the 32 patients who developed endocrinopathy, 18,8%, 19,13%, and 21,28% received anti-CTLA-4, anti-PD-1 and anti-PDL-1, respectively. Thyroid dysfunction was the most frequent endocrinopathy (12,8%). A higher percentage of patients with negative antiTPO and antiTG antibodies developed G1 hypothyroidism compared to patients with positive antibodies who developed a higher proportion of G2 hypothyroidism. The presence of an initial phase of thyrotoxicity was not related to greater severity. We observed longer progression-free survival in patients who developed thyroid dysfunction. Pre-existing antibodies were independently associated with endocrinopathies. Moreover, our study let us conclude that the presence of thyroid autoantibodies may be related to its severity. It is important to determine anti-thyroid antibodies prior to the start of immunotherapy as a risk factor for thyroid dysfunction, which in turn is a prognostic marker.

The Combined Effect of Immune Checkpoint Inhibitors and Tyrosine Kinase Inhibitors on Thyroid Function.

Background: Recent successes with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the treatment of solid malignancies have paved the way for a new era of combined therapy. A common side effect seen with each of these classes of treatment is thyroid dysfunction, with rates estimated at 30-40% for TKI and 10-20% for ICI. However, little is known about the effect of combined ICI+TKI therapy on thyroid function. Therefore, this study evaluated the incidence, clinical features, and risk factors for developing thyroid abnormalities during ICI+TKI therapy and the relationship to cancer outcomes. Methods: We conducted a retrospective cohort study of patients treated with combination ICI+TKI cancer therapy at City of Hope Comprehensive Cancer Center from 2017 to 2023 who had pretreatment normal thyrotropin (TSH) levels. Primary analyses assessed the frequency, timing, and severity of thyroid function test abnormalities during ICI+TKI cancer therapy, and the requirement for thyroid hormone replacement. Secondary analyses evaluated risk factors for the development of thyroid dysfunction, including sex and drug regimen, and the association with cancer progression-free survival or overall survival. Univariable and multivariable models were used. Results: There were 106 patients who received ICI+TKI therapy with a median age of 63.5 years and a median follow-up of 12.8 months (interquartile range [IQR] 5.9-20.9). Notably, 63.2% (67/106) developed thyroid function abnormalities during ICI+TKI therapy, including 11 (10.4%) with hyperthyroidism, 42 (39.6%) with subclinical hypothyroidism (SCHypo), and 14 (13.2%) with overt hypothyroidism. The onset of thyroid dysfunction occurred at a median of 7 weeks (IQR 3.1-9.0) after start of ICI+TKI treatment for hyperthyroidism, 8.0 weeks (IQR 3.0-19.0) for SCHypo, and 8.1 weeks (IQR 5.9-9.1) for overt or worsening hypothyroidism. Hyperthyroidism resolved to hypothyroidism or normal TSH without intervention in all subjects, suggesting thyroiditis, and hypothyroidism was readily treated with thyroid hormone replacement. Conclusions: Thyroid dysfunction is a frequent adverse event in individuals treated with combination ICI+TKI therapy, with our data suggesting a rapid onset and higher incidence than previously seen with ICI or TKI therapy alone. Therefore, close monitoring of thyroid function during initial therapy and multidisciplinary care with endocrinology are recommended to facilitate early detection and initiation of thyroid hormone replacement in these patients.

The association of gluten-free diet with thyroid autoimmunity in patients with celiac disease: a meta-analysis.

Background: Thyroid autoimmunity is an immune response to thyroid antigens that causes varying degrees of thyroid dysfunction. The sole effective treatment for Celiac Disease (CD) is a gluten-free diet (GFD). However, the association between GFD and thyroid autoimmunity in patients with CD has not been confirmed. Methods: A comprehensive search of several databases, involving PubMed, Embase, Web of Science, Medline, and Cochrane databases, was conducted to identify studies that primarily addressed the effects of GFD on thyroid autoimmunity in CD subjects. The meta-analysis involved studies that compared the risk of ATPO and ATG antibody positivity in CD patients with GFD, the risk of developing AITD, and the risk of developing thyroid dysfunction. Fixed-effects models or random-effects models were used to calculate the odds ratios (ORs) and their 95% confidence intervals (95% CIs). Results: A total of 10 observational studies met the inclusion criteria and included 6423 subjects. The results indicated that GFD is positively associated with thyroid autoimmunity in the children subgroup of CD patients (OR = 1.61, 95%CI 1.06-2.43, P = 0.02). However, there was no significant difference in thyroid autoimmunity between the group adhering to GFD and the control group in the total CD population. Conclusion: The results seem to indicate that subjects with a more pronounced autoimmunity (such as to have an early onset of CD) appear to have a greater risk of thyroid autoimmunity.

Complex relationship between gut microbiota and thyroid dysfunction: a bidirectional two-sample Mendelian randomization study.

Many studies have reported the link between gut microbiota and thyroid dysfunction. However, the causal effect of gut microbiota on thyroid dysfunction and the changes in gut microbiota after the onset of thyroid dysfunction are not clear. A two-sample Mendelian randomization (MR) study was used to explore the complex relationship between gut microbiota and thyroid dysfunction. Data on 211 bacterial taxa were obtained from the MiBioGen consortium, and data on thyroid dysfunction, including hypothyroidism, thyroid-stimulating hormone alteration, thyroxine deficiency, and thyroid peroxidase antibodies positivity, were derived from several databases. Inverse variance weighting (IVW), weighted median, MR-Egger, weighted mode, and simple mode were applied to assess the causal effects of gut microbiota on thyroid dysfunction. Comprehensive sensitivity analyses were followed to validate the robustness of the results. Finally, a reverse MR study was conducted to explore the alteration of gut microbiota after hypothyroidism onset. Our bidirectional two-sample MR study revealed that the genera Intestinimonas, Eubacterium brachy group, Ruminiclostridium5, and Ruminococcaceae UCG004 were the risk factors for decreased thyroid function, whereas the genera Bifidobacterium and Lachnospiraceae UCG008 and phyla Actinobacteria and Verrucomicrobia were protective. The abundance of eight bacterial taxa varied after the onset of hypothyroidism. Sensitivity analysis showed that no heterogeneity or pleiotropy existed in the results of this study. This novel MR study systematically demonstrated the complex relationship between gut microbiota and thyroid dysfunction, which supports the selection of more targeted probiotics to maintain thyroid-gut axis homeostasis and thus to prevent, control, and reverse the development of thyroid dysfunction.

Genome-wide association study of amidoarone-induced hypothyroidism

Abstract Background Amiodarone is a commonly prescribed antiarrhythmic drug used to manage supraventricular and ventricular arrhythmias. The use of amiodarone is associated with a broad range of adverse effects across several organ systems. As many as 10-20% of all patients treated with amiodarone develop thyroid dysfunction, most commonly amiodarone induced hypothyroidism (AIH). (1) Purpose We examined if AIH may have a genetic predisposition. Methods We conducted the first genome-wide association study of AIH using data from a large biobank. Cases were defined as individuals who within one year of amiodarone initiation were given a diagnosis of hypothyroidism or treated with thyroid hormone replacement. Controls were defined as individuals who were continuously treated with amiodarone, without any history of hypothyroidism. Odds Ratios (ORs) and 95% confidence intervals (CIs) were computed using logistic mixed model regression. Results In total, we identified 339 cases of AIH and 2,296 amiodarone-treated controls (Table 1). We found two risk loci, residing at chromosome 9q22.33 and 20p11.21. The lead variant at the first locus, rs9696968-G, was an intron variant located in PTCSC2 (OR: 2.32; 95% CI 1.91 – 2.83, P = 8.17 × 10-18). The other lead variant, rs1543443-A, was located 82 kb upstream to FOXA2 and was at borderline genome-wide significance (OR 1.77, 95% CI 1.44 – 2.19, P = 5.19 × 10-8; Figure 1). The locus in PTCSC2 is a top hit in thyroid cancer (OR 1.69) and hypothyroidism (OR 1.3). (2) FOXA2, a critical transcription factor, is recognized in mice for its role during development, in regulation of mature tissues, and once mutated also involved in cancer. (3) Conclusions We found two risk loci located in PTCSC2 and FOXA2 that were significantly associated with AIH, but replication is needed in order to confirm these associations. Indeed, it seems that individuals with genetic susceptibility to hypothyroidism are more likely to develop AIH, hence the PTCSC2 locus is a known high impact rick locus for hypothyroidism. These findings add to the potentials of pharmacogenetics in cardiology. Cases are individuals with hypothyroidism within one year after initiation of amiodarone therapy. Controls are disease free individuals who are continuously taking amiodarone. The Y-axis is the negative log10 of the P-value for each single nucleotide polymorphism. The X-axis is the chromosome, with positions on each chromosome ranging from lower to higher (left to right). Each novel locus is presented in red color. The dotted line marks the threshold for genome-wide significance.Table 1.Characteristics of study group.Figure 1.Manhattan plot of amiodarone induced hypothyroidism.

A 20-year study of autoimmune polyendocrine syndrome type II and III in Taiwan.

Autoimmune polyendocrine syndrome (APS) is a rare immune-endocrinopathy characterized by the failure of at least two endocrine organs. Clinical characteristics have mainly been described in the Western population. This study comprehensively analyzed the demographic and clinical manifestations of APS II and APS III in Taiwan. Patients aged ≥20 years with a diagnosis of APS II or APS III in ten hospitals between 2001 and 2021 were enrolled. The clinical and serological characteristics of the patients were retrospectively reviewed. Among the 187 enrolled patients (45 men and 142 women); only seven (3.7%) had APS II, while the others had APS III. Fifty-five patients developed hyperthyroidism and 44 patients developed hypothyroidism. Men were diagnosed with APS at a younger age than women (16.8 vs 27.8 years old, P = 0.007). Most patients were initially diagnosed with type 1 diabetes mellitus. There was a positive correlation between age at diagnosis and the likelihood of developing thyroid dysfunction. For every year older patients were diagnosed with APS III, the risk of developing hyperthyroidism increased by 3.6% (P = 0.002), and the risk of developing hypothyroidism increased by 3.7% (P = 0.035). Positive anti-parietal cell antibodies (APCA) were associated with a higher risk of anemia in patients with APS III (P < 0.001). This study provides the most comprehensive analysis of APS II and APS III in Asia. The percentage of patients with APS II was significantly lower than in the Western population. A second autoimmune endocrinopathy may develop several years after the first one. APCA examination is valuable when evaluating anemia in patients with APS.

FRI539 Vitamin D and Endocrine Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitors

Abstract Disclosure: Z. He: None. A. Leiter: None. E. Carroll: None. G. Santiago Pichardo: None. I. Khanna: None. E. Gutowski: None. E.J. Gallagher: Research Investigator; Self; Novartis Pharmaceuticals, Flare Therapeutics, Seagen. Background: Low vitamin D levels have been previously associated with the development of thyroid dysfunction in non-cancer populations. Thyroid dysfunction is one of the most common immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs). Currently, the effect of vitamin D deficiency or vitamin D supplementation on the development of ICI-induced thyroid dysfunction is unknown. This study was design to examine the association between baseline vitamin D levels and vitamin D supplementation, and the development of ICI-induced thyroid dysfunction. Methods: In this IRB-approved, retrospective cohort study, we collected demographic and clinical characteristics in addition to TSH, free T4, and vitamin D levels from patients with melanoma, multiple myeloma (MM), and transitional cell carcinoma (TCC) treated with ICIs between 2011 and 2020, in a large urban hospital system. The primary outcome was the occurrence of thyroid dysfunction defined by abnormal TSH or free T4 level after ICI initiation. Vitamin D deficiency / insufficiency was defined as serum 25-hydroxy-vitamin D level &amp;lt;30ng/mL. Patients were followed until the first occurrence of the primary outcome or the date of the most recent normal TSH level. Descriptive data are presented as n(%) and median±SD. Univariate and multivariate analysis were performed to examine the association between the primary outcome and vitamin D deficiency/ insufficiency or supplementation. Results: 288 patients with melanoma (n=111), MM (n=86) or TCC (n=91) were identified, with a median age of 65±13 years, and 64% were male. 110 (38%) patients experienced thyroid dysfunction. Among the TCC subgroup, the mean baseline TSH levels for patients who experienced the outcome was significantly higher than that for patients who did not (p = 0.0066). No statistical significance was found for the melanoma (p=0.42) or MM subgroups (p=0.30). Amongst patients with baseline vitamin D levels measured, we found no statistically significant association between thyroid dysfunction and baseline vitamin D deficiency (OR = 0.62, p = 0.34). In the entire cohort, the 1-year outcome-free rates for patients taking and not taking vitamin D supplementation were 68% and 61%, respectively (p=0.07). Vitamin D supplementation was found to reduce the risk of ICI-induced thyroid abnormality by approximately 40% (RR = 0.606, p=0.03) in the multivariate analysis. No difference in mortality was found between those who developed thyroid dysfunction and those who did not. Conclusions: In individuals with melanoma, MM and TCC, vitamin D supplementation may have a protective effect against ICI-induced thyroid dysfunction. Whether vitamin D supplementation impacts cancer response to ICIs is unknown at this time. Presentation: Friday, June 16, 2023

SAT453 Endocrine Related Adverse Events Of Immune Checkpoint Inhibitors In Cancer Patients Visiting Tertiary Care Center In Saudi Arabia

Abstract Disclosure: A.M. Alqahtani: None. A.S. Alghassab: None. L.A. Alghamdi: None. M. Almalki: None. Introduction: Immune checkpoint inhibitors (ICIs) have been approved for the treatment of a different types of cancers. Those agents may result in exaggerated immune response leading to numerous toxicities referred to as immune-related adverse events particularly endocrinopathies affecting most commonly the thyroid and pituitary glands. Methods: We carried out a retrospective analysis of endocrine dysfunction in cancer patients receiving immune checkpoint inhibitors therapy namely pembrolizumab, nivolumab and ipilimumab between July 2018 and July 2022. A total of 123 patients were included in this analysis. We reviewed pituitary-, thyroid-, and adrenal-related hormone test results, as well as the clinical perspective of patients, to identify and characterize cases of hypophysitis, hypothyroidism, thyroiditis, and adrenal dysfunction. Results: A total of 123 patients were included in our study. Among them, Female participants were 67 (54.5%) and males were 56 (45.5%) with mean age of 53.7 years. Majority of the included patients (91.1%) received single agent and only 8.9% received combination therapy. The most used ICI in our cohort was pembrolizumab 73.9% followed by nivolumab 17.8% and the combination of either one of them (beside ipilimumab) was used in 8.9% of the time. The most frequent indication for ICIs was breast cancer (27.6%) followed by lung cancer (19.5%) and metastatic renal cell carcinoma (8.9%). The average number of cycles was 12 cycles, and the average duration of treatment was 12 months. The total incidence of all endocrinopathies was 22.7%. Out of 123 patients, 24 patients developed thyroid dysfunction in term of thyroiditis (1), subclinical hypothyroidism (7) or overt hypothyroidism (16). Hypophysitis occurred in one patient only. There was no occurrence of new onset diabetes mellitus in all groups. Pembrolizumab is thought to be the culprit in 18 patients of thyroid dysfunction and the patient who developed hypophysitis. Nivolumab was responsible about 4 cases of thyroid dysfunction. The rest of the cases were attributed to the combination therapy. The mean TSH level at the time of hypothyroidism diagnosis (overt hypothyroidism and subclinical hypothyroidism) was 95.8 mIU/L. And the mean free thyroxine level in overt hypothyroidism group was 6.3 pmol/L. Conclusion: Our cohort demonstrated an increased risk of thyroid dysfunction among cancer patients who receive immune checkpoint inhibitors. Pituitary dysfunction is infrequent adverse effect of these agents. Endocrine assessment is recommended prior to initiation of therapy and periodically afterward. Special attention should be given to pituitary dysfunction as it might be overlooked due to non-specific symptoms. Presentation: Saturday, June 17, 2023

Thyroid dysfunction induced by anti-PD-1 therapy is associated with a better progression-free survival in patients with advanced carcinoma

PurposeThyroid dysfunction is the most common immune-related adverse event during anti-programmed cell death 1 (anti-PD-1) therapy. In this study, we monitored patients with advanced malignant tumors who received anti-PD-1 therapy to observe the characteristic of anti-PD-1 therapy-induced thyroid dysfunction and its correlation with prognosis.MethodsPatients with advanced carcinoma treated with anti-PD-1 therapy were evaluated for thyroid function at baseline and after treatment initiation from August 2020 to March 2022. Seventy-three patients were finally included in the study.ResultsAmong these patients, 19 (26.03%) developed thyroid dysfunction after receiving anti-PD-1 therapy. Primary hypothyroidism and thyrotoxicosis were the most common clinical manifestation. Anti-PD-1-induced thyroid dysfunction occurred 63 (26–131) days after administration; thyrotoxicosis appeared earlier than primary hypothyroidism. In Kaplan–Meier survival analysis, the progression-free survival (PFS) of the thyroid dysfunction group was better than that of the no thyroid dysfunction group (227 (95% confidence interval (CI) 50.85–403.15) days vs 164 (95% CI 77.76–250.24) days, p = 0.026). Male patients had better PFS than female patients (213 (95% CI 157.74–268.26) days vs 74 (95% CI 41.23–106.77) days, p = 0.031). In cox proportional hazards regression model, anti-PD-1-induced thyroid dysfunction remained an independent predictor of better PFS (hazard ratio (HR) = 0.339(0.136–0.848), p = 0.021).ConclusionThyroid dysfunction is a common immune-related adverse events in advanced cancer patients treated with anti-PD-1 therapy and predicts a better prognosis.Trial registrationThis study was retrospectively registered with Trial ClinicalTrials.gov (NCT05593744) on October 25, 2022.

Prevalence, Risk Factors, and Clinical and Biochemical Characteristics of Alemtuzumab-Induced Graves Disease.

Atypical Graves disease (GD) is a common complication in multiple sclerosis (MS) patients treated with alemtuzumab. We present epidemiological, clinical, and biochemical characteristics of alemtuzumab-induced GD. Retrospective follow-up study of MS patients treated with alemtuzumab from 2014 to 2020, including clinical course of GD, pregnancy outcome, and thyroid eye disease (TED). We enrolled 183 of 203 patients (90%, 68% women) treated with alemtuzumab at 4 hospitals in Norway. Seventy-five (41%) developed thyroid dysfunction, of whom 58 (77%) had GD. Median time from the first dose of alemtuzumab to GD diagnosis was 25 months (range, 0-64). Twenty-four of 58 GD patients (41%) had alternating phases of hyper- and hypothyroidism. Thyrotropin receptor antibodies became undetectable in 23 of 58 (40%) and they could discontinue antithyroid drug treatment after a median of 22 (range, 2-58) months. Conversely, 26 (44%) had active disease during a median follow-up of 39 months (range, 11-72). Two patients (3%) received definitive treatment with radioiodine, 6 (10%) with thyroidectomy. Nine developed TED (16%), 7 had mild and 2 moderate to severe disease. Four patients completed pregnancy, all without maternal or fetal complications. Patients who developed GD had a lower frequency of new MS relapses and MRI lesions than those without. GD is a very common complication of alemtuzumab treatment and is characterized by alternating hyper- and hypothyroidism. Both remission rates and the prevalence of TED were lower than those reported for conventional GD. Pregnancies were uncomplicated and GD was associated with a lower risk of subsequent MS activity.

A Case-Control Study of the Relationship Between Genetic Polymorphism and Cretinism in Xinjiang.

Cretinism is a subtype of congenital hypothyroidism, an endocrine disorder resulting from inadequate thyroid hormone production or receptor deficiency. Genetic abnormalities play a major role in the development of thyroid dysfunction. We recruited 183 participants with cretinism and 119 healthy participants from the Xinjiang Uyghur Autonomous Region and randomly selected 29 tag single nucleotide polymorphisms (tSNPs) in TSHB, PAX8, TPO, NKX2-5, and TSHR in all participants. We compared genotype and allele frequencies between cases and controls utilizing the chi-squared test, logistic regression analysis, and haplotype analysis. Using the chi-squared test, a single SNP was found to be associated with cretinism (recessive model: rs3754363, OR = 0.46, 95% CI = 0.27-0.80, P = 0.00519; genotype model: P = 0.01677). We stratified neurological, myxedematous, and mixed type and determined that another SNP was associated with a higher risk when comparing myxedematous type to the neurological type (rs2277923). rs3754363 has a statistically significant protective effect on people with cretinism, while rs2277923 may play a greater role in promoting the development of neurocretinism.

ПОБІЧНА ДІЯ ТЕРАПІЇ ІНГІБІТОРАМИ ИМУННИХ КОНТРОЛЬНИХ ТОЧОК НА ЩИТОПОДІБНУ ЗАЛОЗУ

Introduction. Survival of patients with advanced-stage cancers remains poor despite significant successes in targeted and chemotherapy. Immunotherapy is a systemic method of treatment that has expanded the possibilities of drug therapy for malignant tumors. Immunotherapy's side effect significantly differs from chemotherapeutic drugs and targeted therapy.&#x0D; Research rationale. One of the most common side effects is a toxic effect on the endocrine system, particularly the thyroid gland.&#x0D; Aim of the research. Conduct a systematic analysis of scientific literature on the side effects of immune checkpoint inhibitors on the thyroid gland.&#x0D; Materials and methods. A scientific search was conducted in Pubmed, Scopus, and Web of Science databases. The following search terms were used: "immune checkpoint inhibitors," "immunotherapy," "thyroid gland," and "side effects."&#x0D; Research results and discussion. Both PD-1/PD-L1 inhibitors and CTLA-4 inhibitors can cause thyroid dysfunction (hyperthyroidism or hypothyroidism). One of the meta-analyses reported no difference in the incidence of thyrotoxicity between the two drug groups. However, other meta-analyses have shown that this phenomenon is more common in patients treated with PD-1/PD-L1 inhibitors than with CTLA-4 inhibitors. In addition, scientists proved that hypothyroidism occurred statistically more often (3.8% of patients) than hyperthyroidism (1.7%). Hypothyroidism was more common in PD-1 inhibitor users than hyperthyroidism (7.0% vs. 3.2%, respectively). Patients with a history of autoimmune thyroid disease have a high risk of disease exacerbation after initiating immune checkpoint inhibitor therapy. The side effect of immune checkpoint inhibitors is developed mainly in women. The first laboratory signs of hypothyroidism are observed after 2-4 courses of immunotherapy. In most cases, the disease is asymptomatic, but in rare cases, it turns into permanent hypothyroidism and even thyroid crisis. The leading causes of destruction of the thyroid gland due to immune checkpoint inhibitors are damaged by autoantibodies or the production of thyroid-stimulating antibodies.&#x0D; Levothyroxine is prescribed at 0.8–1.6 μg/kg/day for treating hypothyroidism with clinical symptoms. For elderly patients and patients with cardiac pathology, the initial dose of the drug should be no more than 25-50 μg. Treatment with immune checkpoint inhibitors is usually continued. Treatment of thyrotoxicosis depends on the pathological mechanism that caused it. Most often, beta-blockers (atenolol and propranolol) are used to eliminate the symptoms of thyrotoxicosis. A feature of thyroiditis is its ability to transition into hypothyroidism, which can become permanent.&#x0D; Conclusions. The development of thyroid dysfunction is the most common consequence of autoimmune damage. PD-1 inhibitors are the most common cause of this condition. Usually, the disorders are asymptomatic and have the first degree of severity. Timely appointment for hormone replacement therapy allows the effective continuation of immunotherapy. However, some conditions may be refractory to such treatment, requiring steroid therapy and discontinuation of immunotherapy.&#x0D;

HOW THYROID PROFILE IS AFFECTED BY DIABETIC MELLITUS: A CROSS SECTIONAL STUDY

Background: Diabetes mellitus and thyroid illnesses are the two endocrine conditions that are seen in clinical practice the most frequently. Patients frequently have a tendency to suffer from both diabetes mellitus and thyroid dysfunction at the same time. This article illustrates why it is important to recognize the interdependent relationship that exists between thyroid illness and diabetes. Method: Present study was conducted among 193 T2DM patients. Patients’ last three month glucose level was measured by HBA1c and thyroid dysfunction evaluated by thyroid profiling. Association and prediction of different variables for developing thyroid dysfunction among diabetic patients was calculated using chi-square, t test and ROC curve. Result: Out of 193, 47 patients had thyroid dysfunction, majority 22(11.4%) had subclinical hypothyroidism. 13(6.7%) had Hypothyroidism, 6(3.1%) had subclinical Hyperthyroidism, 3(1.5%) had Hyperthyroidism and 3(1.5%) patients were euthyroid. The prevalence of established thyroid disease was higher in females 32 (68.1%). Out of 47 patients with thyroid dysfunction, 39(82.9%) patients had HBA1C &gt;6.5%. Conclusion: Age &gt;50 years and female gender played as risk factor for developing thyroid dysfunction among patients with T2DM. HBA1C &gt;6.5% and TSH more than 3.65mIU/L was independent risk factor for predicting thyroid dysfunction in T2DM.

Antiseptic solutions for skin preparation during central catheter insertion in neonates.

Central venous catheters (CVC) are associated with potentially dangerous complications such as thromboses, pericardial effusions, extravasation, and infections in neonates. Indwelling catheters are amongst the main risk factors for nosocomial infections. The use of skin antiseptics during the preparation for central catheter insertion may prevent catheter-related bloodstream infections (CRBSI) and central line-associated bloodstream infections (CLABSI). However, it is still not clear which antiseptic solution is the best to prevent infection with minimal side effects. To systematically evaluate the safety and efficacy of different antiseptic solutions in preventing CRBSI and other related outcomes in neonates with CVC. We searched CENTRAL, MEDLINE, Embase, and trial registries up to 22 April 2022. We checked reference lists of included trials and systematic reviews that related to the intervention or population examined in this Cochrane Review. SELECTION CRITERIA: Randomised controlled trials (RCTs) or cluster-RCTs were eligible for inclusion in this review if they were performed in the neonatal intensive care unit (NICU), and were comparing any antiseptic solution (single or in combination) against any other type of antiseptic solution or no antiseptic solution or placebo in preparation for central catheter insertion. We excluded cross-over trials and quasi-RCTs. We used the standard methods from Cochrane Neonatal. We used the GRADE approach to assess the certainty of the evidence. We included three trials that had two different comparisons: 2% chlorhexidine in 70% isopropyl alcohol (CHG-IPA) versus 10% povidone-iodine (PI) (two trials); and CHG-IPA versus 2% chlorhexidine in aqueous solution (CHG-A) (one trial). A total of 466 neonates from level III NICUs were evaluated. All included trials were at high risk of bias. The certainty of the evidence for the primary and some important secondary outcomes ranged from very low to moderate. There were no included trials that compared antiseptic skin solutions with no antiseptic solution or placebo. CHG-IPA versus 10% PI Compared to PI, CHG-IPA may result in little to no difference in CRBSI (risk ratio (RR) 1.32, 95% confidence interval (CI) 0.53 to 3.25; risk difference (RD) 0.01, 95% CI -0.03 to 0.06; 352 infants, 2 trials, low-certainty evidence) and all-cause mortality (RR 0.88, 95% CI 0.46 to 1.68; RD -0.01, 95% CI -0.08 to 0.06; 304 infants, 1 trial, low-certainty evidence). The evidence is very uncertain about the effect of CHG-IPA on CLABSI (RR 1.00, 95% CI 0.07 to 15.08; RD 0.00, 95% CI -0.11 to 0.11; 48 infants, 1 trial; very low-certainty evidence) and chemical burns (RR 1.04, 95% CI 0.24 to 4.48; RD 0.00, 95% CI -0.03 to 0.03; 352 infants, 2 trials, very low-certainty evidence), compared to PI. Based on a single trial, infants receiving CHG-IPA appeared less likely to develop thyroid dysfunction compared to PI (RR 0.05, 95% CI 0.00 to 0.85; RD -0.06, 95% CI -0.10 to -0.02; number needed to treat for an additional harmful outcome (NNTH) 17, 95% CI 10 to 50; 304 infants). Neither of the two included trials assessed the outcome of premature central line removal or the proportion of infants or catheters with exit-site infection. CHG-IPA versus CHG-A The evidence suggests CHG-IPA may result in little to no difference in the rate of proven CRBSI when applied on the skin of neonates prior to central line insertion (RR 0.80, 95% CI 0.34 to 1.87; RD -0.05, 95% CI -0.22 to 0.13; 106 infants, 1 trial, low-certainty evidence) and CLABSI (RR 1.14, 95% CI 0.34 to 3.84; RD 0.02, 95% CI -0.12 to 0.15; 106 infants, 1 trial, low-certainty evidence), compared to CHG-A. Compared to CHG-A, CHG-IPA probably results in little to no difference in premature catheter removal (RR 0.91, 95% CI 0.26 to 3.19; RD -0.01, 95% CI -0.15 to 0.13; 106 infants, 1 trial, moderate-certainty evidence) and chemical burns (RR 0.98, 95% CI 0.47 to 2.03; RD -0.01, 95% CI -0.20 to 0.18; 114 infants, 1 trial, moderate-certainty evidence). No trial assessed the outcome of all-cause mortality and the proportion of infants or catheters with exit-site infection. Based on current evidence, compared to PI, CHG-IPA may result in little to no difference in CRBSI and mortality. The evidence is very uncertain about the effect of CHG-IPA on CLABSI and chemical burns. One trial showed a statistically significant increase in thyroid dysfunction with the use of PI compared to CHG-IPA. The evidence suggests CHG-IPA may result in little to no difference in the rate of proven CRBSI and CLABSI when applied on the skin of neonates prior to central line insertion. Compared to CHG-A, CHG-IPA probably results in little to no difference in chemical burns and premature catheter removal. Further trials that compare different antiseptic solutions are required, especially in low- and middle-income countries, before stronger conclusions can be made.

The Spectrum of Thyroid Function Tests and Autoantibodies During Hospitalization and After Six Months of Discharge in COVID-19 Patients: Does COVID-19 Trigger Autoimmunity?

ABSTRACT Objective The aim of the study was to investigate thyroid function test (TFT) results and anti-thyroid antibody titers in acutely infected COVID-19 patients, as well as the changes in TFT and autoantibody results during the 6-months recovery period among survivors. Patients and Design A total of 163 adult COVID-19 patients and 124 COVID-19 survivors were evaluated in terms of TFT (thyroid stimulating hormone [TSH], free triiodothyronine [fT3], and free thyroxine [fT4]) and anti-thyroid antibodies (anti-thyroglobulin [anti-Tg] and anti-thyroid peroxidase [anti-TPO]). Results Thyroid dysfunction was noted in 56.4% of patients on admission, including the non-thyroidal illness syndrome (NTIS) in most cases. Presence vs. absence of thyroid dysfunction on admission was associated with significantly higher rate of severe disease (p < 0.001), while severe vs. mild-to-moderate disease was associated with significantly lower serum fT3 levels (p = 0.001). Overall, 94.4% of survivors were euthyroid at the time of 6 months post-discharge, while in some patients, the post-COVID-19 recovery period was also associated with significantly increased anti-TPO titers and the presence of new-onset or persistent subclinical hypothyroidism. Conclusion This is one of the few studies to evaluate TFT and autoantibodies over a 6-month period after recovery from COVID-19. The presence of emergent or persistent subclinical hypothyroidism and the significantly increased anti-TPO titers in some patients during the convalescence period suggest the need for follow-up for development of thyroid dysfunction and autoimmunity among COVID-19 survivors.

Thyroid dysfunction after immune checkpoint inhibitor treatment in a single-center Chinese cohort: a retrospective study.

Thyroid dysfunction is a common adverse event after immune checkpoint inhibitor (ICI) therapy. The clinical manifestations of thyroid immune-related adverse events (irAEs) are variable and the underlying mechanisms remain unclear. To identify the clinical and biochemical characteristics of Chinese patients with ICI-related thyroid dysfunction. We retrospectively reviewed patients with carcinoma who received ICI therapy and underwent evaluation of thyroid function during hospitalization at Peking Union Medical College Hospital between January 1, 2017 and December 31, 2020. Clinical and biochemical features were analyzed in patients who developed ICI-related thyroid dysfunction. Survival analyses were performed to determine the effect of thyroid autoantibodies on thyroid abnormalities and the impact of thyroid irAEs on clinical outcomes. The cohort included 270 patients with a median follow-up of 17.7 months; 120 (44%) of these patients developed thyroid dysfunction on immunotherapy. The most common thyroid irAE was overt hypothyroidism (with/without transient thyrotoxicosis), which occurred in 38% of patients (n = 45), followed by subclinical thyrotoxicosis (n = 42), subclinical hypothyroidism (n = 27), and isolated overt thyrotoxicosis (n = 6). The median time to first clinical presentation was 49 days (interquartile range 23, 93) for thyrotoxicosis and 98 days (interquartile range 51, 172) for hypothyroidism. In patients treated with PD-1 inhibitors, hypothyroidism was strongly associated with younger age (odds ratio [OR] 0.44, 95% confidence interval [CI] 0.29-0.67; P < 0.001), previous thyroid disease (OR 4.30, 95% CI 1.54-11.99; P = 0.005), and a higher baseline thyroid-stimulating hormone level (OR 2.76, 95% CI 1.80-4.23; P < 0.001). Thyrotoxicosis was only associated with the baseline thyroid-stimulating hormone (TSH) level (OR 0.59, 95% CI 0.37-0.94; P = 0.025). Thyroid dysfunction after initiation of ICI therapy was associated with better progression-free survival (hazard ratio [HR] 0.61, 95% CI 0.44-0.86; P = 0.005) and overall survival (hazard ratio 0.67, 95% CI 0.45-0.99; P = 0.046). Anti-thyroglobulin antibody positivity increased the risk of thyroid irAEs. The occurrence of thyroid irAEs with diverse phenotypes is common. Distinct clinical and biochemical characteristics suggest heterogeneity among different subgroups of thyroid dysfunction, which requires further research to explore the under mechanism.