Previous in vitro experiments have demonstrated that prostaglandin F2-alpha (PF
) reduced proliferation and adipogenesis in a murine cell line and human orbital fibroblasts derived from subjects with ...inactive Graves' orbitopathy (GO). The objective of this study was to determine if the PGF
analogue bimatoprost is effective at reducing proptosis in this population.
A randomized controlled double-masked crossover trial was conducted in a single tertiary care academic medical center. Patients with long-standing, inactive GO but persistent proptosis (>20 mm in at least one eye) were recruited. Allowing for a 15% dropout rate, 31 patients (26 females) were randomized in order to identify a treatment effect of 2.0 mm (p = 0.05; power 0.88). Following informed consent, participants were randomized to receive bimatoprost or placebo for three months, after which they underwent a two-month washout before switching to the opposite treatment. The primary outcome was the change in exophthalmometry readings over the two three-month treatment periods.
The mean exophthalmometer at baseline was 23.6 mm (range 20.0-30.5 mm), and the mean age of the patients was 55 years (range 28-74 years). The median duration of GO was 7.6 years (interquartile range 3.6-12.3 years). The majority were still suffering from diplopia (61.3%) with bilateral involvement (61.3%). Using multi-level modeling adjusted for baseline, period, and carry-over, bimatoprost resulted in a -0.17 mm (reduction) exophthalmometry change (confidence interval -0.67 to +0.32; p = 0.490). There was a mean change in intraocular pressure of -2.7 mmHg (confidence interval -4.0 to -1.4; p = 0.0070). One patient showed periorbital fat atrophy on treatment, which resolved on stopping treatment. Independent analysis of proptosis by photographic images (all subjects) and subgroup analysis on monocular disease (n = 12) did not show any apparent benefit.
In inactive GO, bimatoprost treatment over a three-month period does not result in an improvement in proptosis.
The Controlled Antenatal Thyroid Screening Study I (CATS-I) was a randomized controlled trial investigating the effects of levothyroxine therapy for suboptimal gestational thyroid function (SGTF), ...comparing outcomes in children of treated (SGTF-T) with untreated (SGTF-U) women during pregnancy. This follow-up study, CATS-II, reports the long-term effects on anthropometric, bone, and cardiometabolic outcomes in mothers and offspring and includes a group with normal gestational thyroid function (NGTF).
332 mothers (197 NGTF, 56 SGTF-U, 79 SGTF-T) aged 41.2±5.3 years (mean±SD) and 326 paired children assessed 9.3±1.0 years after birth for (i) body mass index (BMI); (ii) lean, fat, and bone mass by dual-energy X-ray absorptiometry; (iii) blood pressure, augmentation index, and aortic pulse-wave-velocity; and (iv) thyroid function, lipids, insulin, and adiponectin. The difference between group means was compared using linear regression.
Offspring's measurements were similar between groups. Although maternal BMI was similar between groups at CATS-I, after 9 years (at CATS-II) SGTF-U mothers showed higher BMI (median interquartile ratio 28.3 24.6-32.6 kg/m2) compared with NGTF (25.8 22.9-30.0 kg/m2; P = 0.029), driven by fat mass increase. At CATS-II SGTF-U mothers also had higher thyroid-stimulating hormone (TSH) values (2.45 1.43-3.50 mU/L) than NGTF (1.54 1.12-2.07 mU/L; P = 0.015), since 64% had never received levothyroxine. At CATS-II, SGTF-T mothers had BMI (25.8 23.1-29.8 kg/m2, P = 0.672) and TSH (1.68 0.89-2.96 mU/L; P = 0.474) values similar to NGTF mothers.
Levothyroxine supplementation of women with SGTF did not affect long-term offspring anthropometric, bone, and cardiometabolic measurements. However, absence of treatment was associated with sustained long-term increase in BMI and fat mass in women with SGTF.
Thyroid autoimmunity, especially Graves' disease or hypothyroidism with positive autoantibodies (TRAb) to the thyrotropin receptor (TSHR), occurs in 30-40% of patients with relapsing multiple ...sclerosis following treatment with alemtuzumab (ALTZ). ALTZ therapy therefore provides a unique opportunity to study the evolution of TRAb prior to clinical presentation. TRAb can stimulate (TSAb), block (TBAb), or not affect ("neutral") the TSHR function, causing hyperthyroidism, hypothyroidism, or euthyroidism, respectively.
A longitudinal retrospective analysis was conducted of TRAb bioactivity over a period of nine years in 45 multiple sclerosis patients receiving ALTZ using available stored serum. Of these 45 patients, 31 developed thyroid dysfunction (TD) and 14 remained euthyroid despite being followed for a minimum of five years (NO-TD). The presence of TRAb was evaluated at standardized time points: (i) before ALTZ, (ii) latest time available following ALTZ and before TD onset, and (iii) following ALTZ during/after TD onset. Serum TRAb were detected by published in-house assays (ihTRAb): flow cytometry detecting any TSHR-binding TRAb, and luciferase bioassays detecting TSAb/TBAb bioactivity. Purified immunoglobulin G was used to verify TSAb/TBAb in selected hypothyroid cases. Standard clinical automated measurements of TRAb, antithyroid peroxidase autoantibodies (TPOAb), thyrotropin, free thyroxine, and free triiodothyronine were also collected.
Before ALTZ, combined ihTRAb (positive with flow cytometry and/or luciferase bioassay) but not automated TRAb were present in 5/16 (31.2%) TD versus 0/14 (0%) NO-TD (p = 0.017). Detectable ihTRAb preceded TD development in 9/28 (32.1%) and by a median of 1.2 years (range 28 days-7.3 years). Combination testing of ihTRAb and TPOAb at baseline predicted 20% of subsequent cases of hyperthyroidism and 83% of hypothyroidism.
Evidence is presented that TRAb measured with custom-made assays can be detected prior to any change in thyroid function in up to a third of cases of ALTZ-related TD. Furthermore, the presence of ihTRAb prior to ALTZ treatment was strongly predictive of subsequent TD. The findings suggest that a period of affinity maturation of TRAb may precede clinical disease onset in some cases. Combined testing of TPOAb and ihTRAb may increase the ability to predict those who will develop TD following ALTZ.
An association between breast cancer (BC) and thyroid autoimmunity (TA) has been frequently observed and several small-scale studies correlated the presence of thyroid peroxidase (TPO) autoantibodies ...(TPOAb) with an improved BC outcome. The presence of an immune response to shared thyroid/breast antigens has been hypothesized: both tissues express the sodium iodide symporter (NIS) and have a peroxidase activity: TPO in thyroid and lactoperoxidase (LPO) in breast. I have identified 3 possibilities: i) BC patients with TPOAb may also have autoantibodies to NIS (NISAb) ii) BC may express TPO iii) TPOAb may cross-react with LPO in BC. This thesis aimed to identify the TA/BC shared antigen(s) and also investigated the prognostic role of TPOAb in a large cohort of BC patients. The presence of NISAb was investigated by flow cytometry using CHO cells stably transfected with human NIS. No positive response was obtained in 42 patients with BC and/or TA, therefore NIS is unlikely to be an antigen. TPO transcripts (RT-PCR, QPCR, LongRange PCR) and protein (western blot, immunohistochemistry, immunofluorescence) were detected in BC tissues but at levels 104 times less than in thyroid tissue. TPO was also expressed in adipose tissue and different cancers. Some potentially BC specific TPO isoforms were identified. The observational large-scale study conducted on 1974 women affected with BC did not reveal any evidence for a significant impact of TPOAb and/or thyroid function on BC prognosis. In conclusion, BC and thyroid tissues share similar properties and could be common targets of TA, with TPO being the most likely common antigen; further studies are needed to clarify the role of tissue-specific TPO isoforms. The roles of TPOAb and thyroid function on BC prognosis have to be reconsidered, maybe focusing on different TA aspects (e.g. goitre, different autoantibodies).
An association between breast cancer (BC) and thyroid autoimmunity (TA) has been frequently observed and several small-scale studies correlated the presence of thyroid peroxidase (TPO) autoantibodies ...(TPOAb) with an improved BC outcome. The presence of an immune response to shared thyroid/breast antigens has been hypothesized: both tissues express the sodium iodide symporter (NIS) and have a peroxidase activity: TPO in thyroid and lactoperoxidase (LPO) in breast. I have identified 3 possibilities: i) BC patients with TPOAb may also have autoantibodies to NIS (NISAb) ii) BC may express TPO iii) TPOAb may cross-react with LPO in BC. This thesis aimed to identify the TA/BC shared antigen(s) and also investigated the prognostic role of TPOAb in a large cohort of BC patients. The presence of NISAb was investigated by flow cytometry using CHO cells stably transfected with human NIS. No positive response was obtained in 42 patients with BC and/or TA, therefore NIS is unlikely to be an antigen. TPO transcripts (RT-PCR, QPCR, LongRange PCR) and protein (western blot, immunohistochemistry, immunofluorescence) were detected in BC tissues but at levels 104 times less than in thyroid tissue. TPO was also expressed in adipose tissue and different cancers. Some potentially BC specific TPO isoforms were identified. The observational large-scale study conducted on 1974 women affected with BC did not reveal any evidence for a significant impact of TPOAb and/or thyroid function on BC prognosis. In conclusion, BC and thyroid tissues share similar properties and could be common targets of TA, with TPO being the most likely common antigen; further studies are needed to clarify the role of tissue-specific TPO isoforms. The roles of TPOAb and thyroid function on BC prognosis have to be reconsidered, maybe focusing on different TA aspects (e.g. goitre, different autoantibodies).
Abstract
Background: In Spring 2020 the severe acute respiratory syndrome coronavirus 2 pandemic disease (Covid-19) badly affected Northern Italy. We have described for the first time the occurrence ...of thyrotoxicosis due to atypical subacute thyroiditis in 15% of patients hospitalised for Covid-19 pneumonia, compared with only 1% among patients hospitalised in the same wards during Spring 2019, thus before the Covid-19 pandemic. The whole group of Covid-19 patients also had median serum TSH concentrations significantly lower compared with the control group. The atypical thyroiditis induced by Covid-19 is not associated with neck pain, affects more men than women and especially those severely ill, thus coexists with non-thyroidal illness syndrome. Subacute thyroiditis is classically followed by subsequent occurrence of permanent thyroid dysfunction and autoimmunity, thus we have started a systematic follow-up program of these patients.
Methods: Longitudinal follow-up study of survived Covid-19 patients without previous known history of thyroid disorders and/or medications, assessing serum thyroid function and autoantibodies, C reactive protein (CRP), full blood count (FBC) and thyroid ultrasound (US) every 3 months. Patients showing baseline (at hospitalisation for Covid-19) thyroid dysfunction and/or focal hypoechoic areas suggestive for subacute thyroiditis at US performed 3 months post-infection, also underwent thyroid 99mTc or I123uptake.
Results: To date, 53 patients have been included in the follow-up study. At 3 months post-infection, all of them presented with increased median (IQR) serum TSH concentrations compared with baseline: 1.3 (0.9–2.0) mIU/L versus 0.9 (0.5–1.8) mIU/L (p=0.0001). Similarly, serum concentrations of free-thyroxine, free-triiodothyronine, CRP and FBC had normalised compared with baseline. All patients had negative autoantibodies to TSH receptor; autoantibodies to thyroglobulin and to thyroid peroxidase were positive in 6/53 (11%) and 5/53 (9%) of patients, respectively. The thyroid US showed the presence of focal hypoechoic areas of thyroiditis in 16/51 (32%) patients, with thyroid uptake normal in 6/16 (37%), focally reduced in 8/16 (50%) and diffusely reduced in 2/16 (12%).
Conclusions: At 3 months after Covid-19 disease all patients had a normalised thyroid function, however imaging findings suggestive for subacute thyroiditis were still present in about one third of cases. The thyroid dysfunction induced by Covid-19 seems not mediated by autoimmunity. It is important to continue to follow these patients since they might develop thyroid dysfunction during the following months.
Background
Alemtuzumab is an effective therapy for relapsing multiple sclerosis. Autoimmune thyroid events are a common adverse event.
Objective
Describe endocrine and multiple sclerosis outcomes ...over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients in the phase 3 CARE-MS I, II, and extension studies who experienced adverse thyroid events.
Methods
Endocrine and multiple sclerosis outcomes were evaluated over 6 years. Thyroid event cases, excluding those pre-existing or occurring after Year 6, were adjudicated retrospectively by expert endocrinologists independently of the sponsor and investigators.
Results
Thyroid events were reported for 378/811 (46.6%) alemtuzumab-treated patients. Following adjudication, endocrinologists reached consensus on 286 cases (75.7%). Of these, 39.5% were adjudicated to Graves’ disease, 2.5% Hashimoto's disease switching to hyperthyroidism, 15.4% Hashimoto's disease, 4.9% Graves’ disease switching to hypothyroidism, 10.1% transient thyroiditis, and 27.6% with uncertain diagnosis; inclusion of anti-thyroid antibody status reduced the number of uncertain diagnoses. Multiple sclerosis outcomes of those with and without thyroid events were similar.
Conclusion
Adjudicated thyroid events occurring over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients were primarily autoimmune. Thyroid events were considered manageable and did not affect disease course. Thyroid autoimmunity is a common but manageable adverse event in alemtuzumab-treated relapsing multiple sclerosis patients.
ClinicalTrials.gov Registration Numbers: CARE-MS I (NCT00530348); CARE-MS II (NCT00548405); CARE-MS Extension (NCT00930553)
Children whose mothers had low thyroid hormone levels during pregnancy have been reported to have decreased cognitive function. The reported research is part of the follow-on study of the Controlled ...Antenatal Thyroid Screening Study (CATS I), a randomised controlled trial which investigated the impact of treated vs. untreated low thyroid hormone level in women during pregnancy with the primary outcome being the child's IQ at age 3. No significant differences in IQ were found between the treated and untreated groups. These children are now aged between 7 and 10 years and aspects of their cognitive functioning including their IQ are being reassessed as part of CATS II.
Cognitive assessments generate an IQ score and further tests administered will investigate long term memory function and motor coordination. The aim is to complete the assessments with 40% of the children born to mothers either in the treated or untreated low thyroid hormone groups (n = 120 per group). Also children born to mothers who had normal thyroid functioning during CATS I are being assessed for the first time (n = 240) to provide a comparison. Assessments are conducted either in the research facility or the participant's home.
The study is designed to assess the cognitive functioning of children born to mothers with low thyroid hormone levels and normal thyroid functioning during pregnancy. This is the largest study of its type and also is distinguishable in its longitudinal design. The research has the potential to have a significant impact on public health policy in the UK; universal screening of thyroid hormone levels in pregnancy may be the recommendation.
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