Stan, Marius N

Background: Levothyroxine (LT4) is the mainstay of therapy for hypothyroidism. Yet, despite physician efforts at dose titration, some patients remain hypothyroid on LT4 doses in excess of weight-based calculations, a condition known as refractory hypothyroidism. The LT4 absorption test (LT4AT) has been proposed to have utility in these patients by enabling distinction of LT4 malabsorption from pseudomalabsorption, a condition of intentional nonadherence. Given its rare use in clinical practice, we reviewed our institution's experience with the LT4AT to assess its impact on management of refractory hypothyroidism. Methods: We reviewed the charts of 16 patients diagnosed with refractory hypothyroidism and who had completed the LT4AT between January 2015 to January 2019. The primary aim was to determine the utility of this test in distinguishing LT4 malabsorption from pseudomalabsorption. Secondary aims were to determine whether the results of this test impacted physicians' management decisions, as well as to report on clinical outcomes at follow-up. Our LT4AT is a six-hour test wherein patients receive a weight-based dose of LT4 followed by serial measurements of total thyroxine (TT4) and thyrotropin (TSH). Percentage absorption is calculated using the following formula, with normal absorption being ≥60%: Results: Percentage absorption was calculated in 13 of 16 patients due to lack of TT4 data for 3 patients. Absorption was impaired in one patient (% absorbed = 0), who had known causes of malabsorption. The remaining 12 patients had normal absorption by hour 4 of the test (% absorption 60–158) in conjunction with upward TT4 trends. Clinical follow-up ranged from 1 to 32 months (median 6.5 months), with 11 patients having follow-up data. Six of these had normal or suppressed TSH values at most recent follow-up, and four had improved but persistent TSH elevations. The one said patient with malabsorption improved with intravenous LT4. Conclusions: The LT4AT can provide valuable information for distinguishing malabsorption from pseudomalabsorption. Our findings support the combined use of calculated percentage absorptions with TT4 trends for at least a four-hour time frame when making determinations regarding absorption.

Abstract Context The CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves disease (GD) by promoting autoreactive B-cell activation. Objective Evaluate efficacy and safety of a human, blocking, nondepleting anti-CD40 monoclonal antibody, iscalimab, in hyperthyroid patients with GD. Design Open-label, phase II proof-of-concept study. Setting Multicenter. Patients Fifteen with GD. Intervention Patients received 5 doses of iscalimab at 10 mg/kg intravenously over 12 weeks. Main outcome measures Thyroid-related hormones and autoantibodies, plasma soluble CD40, free CD40 on B cells, soluble CXCL13, pharmacokinetics, and safety were assessed. Results The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks. A clinical response and biochemical euthyroidism was observed in 7 of 15 (47%) patients. Free and total triiodothyronine and thyroxine normalized in 7 patients who did not receive any rescue medication with antithyroid drugs (ATD), and 2/15 (13.3%) showed normal thyrotropin. Six (40%) patients required ATD. Four of 7 responders relapsed after treatment completion. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab) significantly declined in all patients (mean 15.3 IU/L vs 4.0 IU/L, 66% reduction; P < 0.001) and TSH-R-Ab levels normalized in 4 (27%). Thyroperoxidase and thyroglobulin autoantibodies significantly decreased in responders. Iscalimab rapidly reduced serum CXCL13 concentrations (P < 0.001). Twelve (80.0%) patients reported at least 1 adverse event (AE). All treatment-related AE were mild or moderate and resolved by end of the study. Conclusion Iscalimab was generally safe and clinically effective in a subgroup of hyperthyroid GD patients. The potential therapeutic benefit of iscalimab should be further tested.

Background: Severe pretibial myxedema (PTM) can be difficult to manage, highlighting the need to investigate newer therapies. Rituximab (RTX) and intravenous immunoglobulin (IVIg) have been tried in Graves' orbitopathy. Since PTM and orbitopathy share a similar underlying pathophysiology, this study aimed to explore these therapies for progressive PTM. Methods: The electronic database was screened for PTM patients evaluated at the Mayo Clinic, Rochester, from 2002 to 2016, and three patients who received IVIg and five who received RTX are reported. PTM pattern was classified as non-pitting edema, plaque and induration, nodular/nummular, and elephantiasis. PTM was confirmed by biopsy in six patients. Results: The patients' median age was 53.8 years, 75% were female, and all but one patient were either active or former smokers. All patients were euthyroid and had progressed despite various therapies prior to starting these agents. Six patients had a plaque and induration pattern, and two had a nodular pattern with elephantiasis. After therapy, six (75%) patients had PTM stability or improvement both subjectively and objectively (80% with RTX and 66% with IVIg). The three patients (one in the IVIg group and two in the RTX group) who had subjective improvement had a plaque pattern. One patient with elephantiasis had a transient response to IVIg and another had stability after RTX. Thyrotropin receptor antibody values and orbitopathy also improved in patients who demonstrated PTM improvement. No serious adverse events were reported, but one patient each had transient hypertension and injection-site thrombophlebitis after IVIg. Conclusions: Immunomodulation therapy was followed by PTM improvement or stability in most patients, with a slightly better response after RTX compared to IVIg. A validated response assessment instrument and larger series of patients are required to determine if the underlying disease process could be curtailed with these agents.

AbstractThe course and pathogenesis of Graves’ disease and Graves’ ophthalmopathy are interdependent, influencing each other’s therapeutic choices. Multiple factors including geographic location, access to medical services, patient and physician preferences influence the management of these conditions. Graves’ disease is classically managed with one of three treatment options – antithyroid drugs, radioactive iodine, and thyroidectomy. In recent years, there has been a shift towards antithyroid drugs, including long term therapy with these agents, given the advantage of avoiding hypothyroidism and the apparent safety of this approach. In addition, new therapies are (slowly) emerging, focusing on immunomodulation. Technological advances are opening doors to non-pharmaceutical interventions that aim to deal with both structural thyroid abnormalities as well as biochemical abnormalities of hyperthyroidism. Graves’ ophthalmopathy management is guided by its activity and severity status, with treatment options including smoking cessation, control of hyperthyroidism, local eye measures, glucocorticoids, selenium, orbital radiotherapy, and surgery. In addition to these established treatment choices, new immunotherapy-based approaches are being tested. Some of them (tocilizumab and teprotumumab) are very promising but further evaluation is needed before we can establish their role in clinical care. Agents identified as beneficial in Graves’ disease management will likely be tested in Graves’ ophthalmopathy as well. In the coming years, our main clinical responsibility will be to find the proper balance between the benefits and potential risks of these incoming therapies, and to identify the subgroups of patients where this ratio is most likely to favor a safe and successful therapeutic outcome.

Purpose: Thyroid autoimmunity affects approximately 5% of the population, and its investigation relies heavily on the use of autoantibodies. Thyroid stimulating hormone receptor (TSHR) autoantibodies (TRAb) play a central role in the evaluation of Graves disease (GD), Graves ophthalmopathy (GO) and pretibial myxedema (PTM). However, there is still controversy regarding overall TRAb assay diagnostic accuracy and their prognostic utility. Methods: We reviewed and analyzed the literature reporting TRAb assays and their clinical utility. Results: Current assays measure the overall TRAb titer in a competitive manner (TSH binding inhibiting immunoglobulin assay) or biologic activity of the stimulating TSHR autoantibodies (thyroid stimulating immunoglobulin assay). Both types of assays have improved over time with advances in sensitivity and specificity. TRAb are particularly relevant in hyperthyroidism cases where use of iodinated contrast is not an option (e.g., pregnancy or recent use of iodinated contrast) or in cases of euthyroid eye disease, suspicious for GO. Third generation TRAb assays are useful for therapy selection in GD, prognostic predictions in GO and risk prediction for fetal and neonatal thyrotoxicosis. Discussion: Given the pathogenic role of TRAb, we expect that the future will bring useful evidence regarding their predictive role with respect to efficacy of therapeutic modalities for GO and PTM. We also hope to better understand the role of blocking and neutral antibodies against TSHR, and harness that ability for modulation of thyroid function or therapy of differentiated thyroid carcinoma managed with TSH suppression. Conclusions: Thyroid autoimmune diseases have seen tremendous gains in understanding their pathophysiology, largely antibody mediated. Better TRAb testing is becoming a springboard for providing individualized patient care.

Background: Thyroid lymphoma is a relatively rare disease often posing a diagnostic challenge. Reaching the final diagnosis can be delayed if insufficient biopsy material is obtained for immunohistochemistry analysis. The aim of this study was to evaluate the clinical, biochemical, and radiological features of thyroid lymphoma. Methods: A retrospective analysis was conducted of all Mayo Clinic patients evaluated between 2000 and 2014 who had a tissue biopsy positive for thyroid lymphoma. Results: Seventy-five subjects had biopsy-proven thyroid lymphoma, and 62.7% were primary thyroid lymphomas. The median age at diagnosis was 67 years (range 20–90 years). A total of 50.7% were male, and 54.7% had a history of Hashimoto's thyroiditis. Presenting symptoms included neck mass (88%), dysphagia (45.3%), and hoarseness (37.3%). The typical ultrasound appearance consisted of a solid, hypoechoic mass with increased vascularity and variable edge characteristics. Fine-needle aspiration (FNA) biopsies were abnormal in 70.7% of cases, and 42% indicated a specific lymphoma subtype. The diagnosis was confirmed in 53.3% by core biopsy, in 21.3% by thyroidectomy (partial or total), in 12% through incisional biopsy, and in 12% by lymph node biopsy. Core biopsy had a higher sensitivity compared with FNA (93% vs. 71%, p = 0.006). Conclusion: A rapidly enlarging neck mass in the setting of Hashimoto's thyroiditis should raise suspicion for thyroid lymphoma. Radiologically, this usually presents as a large, unilateral, thyroid-centered mass, hypoechoic by ultrasound, and expanding into adjacent soft tissues. Core-needle biopsy should be the first diagnostic test to expedite reaching the final diagnosis and decrease patient burden of additional tests and interventions.