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.

Abstract Context The CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves’ disease (GD) by promoting auto-reactive B cell activation. Objective Evaluate efficacy and safety of a human, blocking, non-depleting 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 five 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 seven of 15 (47%) patients. Free and total T3 and T4 normalized in seven patients who did not receive any rescue medication with anti-thyroid drugs (ATD), and 2/15 (13.3%) showed normal TSH. Six (40%) patients required ATD. Four of seven responders relapsed after treatment completion. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab) significantly declined in all patients (mean 15.3 IU/L versus 4.0 IU/L, 66% reduction, P<0.001) and TSH-R-Ab levels normalized in four (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 one 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.