RESUMEN
BACKGROUND: Anti-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]. METHODS: A 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. RESULTS: The 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]. CONCLUSIONS: The 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.
Asunto(s)
Antígeno B7-H1 , Inhibidores de Puntos de Control Inmunológico , Inhibidores de Proteínas Quinasas , Humanos , Masculino , Femenino , Estudios Prospectivos , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Anciano , Antígeno B7-H1/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Enfermedades de la Tiroides/inducido químicamente , Enfermedades de la Tiroides/epidemiología , Adulto , Incidencia , Neoplasias/tratamiento farmacológico , Anciano de 80 o más Años , Hipotiroidismo/inducido químicamente , Hipotiroidismo/epidemiologíaRESUMEN
Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs) in several organs including endocrine glands. Among endocrine irAEs, thyroid and pituitary irAEs are frequently observed, followed by primary adrenal insufficiency, insulin-dependent diabetes mellitus, and hypoparathyroidism. These conditions could lead to life-threatening consequences, such as adrenal crisis and diabetic ketoacidosis. On the other hand, several types of irAEs including thyroid and pituitary irAEs are reported to be associated with better overall survival. Therefore, it is important to understand and manage endocrine irAEs, which differ depending on the ICI regimen used. In this review, we describe the clinical features, potential biomarkers, management strategies, and possible mechanisms of thyroid and pituitary irAEs.
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Diabetes Mellitus Tipo 1 , Neoplasias , Enfermedades de la Hipófisis , Humanos , Glándula Tiroides , Hipófisis , BiomarcadoresRESUMEN
COVID-19 vaccines have resulted in a remarkable reduction in both the morbidity and mortality associated with COVID-19. However, there are reports of endocrine rare clinical conditions linked to COVID-19 vaccination. In this report, we present a case of hypophysitis following COVID-19 vaccination and review the literature on this condition. This case involved a 72-year-old male with type 1 diabetes who experienced symptoms such as vomiting, appetite loss, and headaches following his fifth COVID-19 vaccine dose. He was diagnosed with secondary adrenal insufficiency; subsequent assessment revealed an enlarged pituitary gland. Unlike previous cases, our patient has partial recovery from pituitary insufficiency, and his pituitary function gradually improved over time. Anti-pituitary antibodies (APAs) against corticotrophs, thyrotrophs, gonadotrophs, and folliculo stellate cells (FSCs) were detected in serum samples taken 3 months after onset. Hypophysitis after COVID-19 vaccination is a rare clinical condition, with only eight cases reported by the end of 2023, most occurring after the initial or second vaccination. Symptoms of hypophysitis after COVID-19 vaccination are similar to those of classic pituitary dysfunction. Pituitary insufficiency is persistent, with five of the above eight patients presenting posterior pituitary dysfunction and three patients presenting only anterior pituitary dysfunction. Two of those eight patients had autoimmune diseases. Our case suggests a potential link between acquired immunity, APA production, and pituitary damage. To elucidate the etiology of hypophysitis associated with COVID-19 vaccination, detailed investigation of patients with nonspecific symptoms after vaccination against COVID-19 is necessary.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Humanos , Masculino , Anciano , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/inmunología , COVID-19/complicaciones , COVID-19/prevención & control , COVID-19/inmunología , Hipófisis/inmunología , Hipófisis/patología , Autoanticuerpos/sangre , Hipofisitis/inducido químicamente , Hipofisitis/etiología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/complicaciones , Insuficiencia Suprarrenal/inducido químicamente , Insuficiencia Suprarrenal/etiología , SARS-CoV-2/inmunología , Vacunación/efectos adversosRESUMEN
Anti-thyroglobulin antibodies (TgAb) and/or anti-thyroid peroxidase antibodies (TPOAb) positivity at baseline is a risk marker for thyroid immune-related adverse events (thyroid-irAEs) in anti-programmed cell death-1 antibody (PD-1-Ab) treatment; however, it is unknown if TgAb and TPOAb titers are associated with clinical characteristics of thyroid-irAEs. Among 586 patients treated with PD-1-Ab at Nagoya University Hospital between 2 November 2015 and 30 September 2021, 57 patients developed thyroid-irAEs (thyrotoxicosis [n = 38]; hypothyroidism without prior thyrotoxicosis {isolated hypothyroidism} [n = 19]) in whom thyroid function, and TgAb and TPOAb titers were determined at baseline and at the onset. The changes in TgAb (median, 54.8 vs. 0.2 IU/mL; p = 0.002) and TPOAb titers (31.6 vs. 0 IU/mL; p = 0.032) from baseline to onset of developing thyroid-irAEs were greater in patients with thyrotoxicosis than patients with isolated hypothyroidism. Higher TgAb and TPOAb titers, and the TgAb titer at baseline were associated with an earlier onset of thyrotoxicosis and higher peak free thyroxine levels, respectively. Twenty-eight patients who developed hypothyroidism after thyrotoxicosis had higher TgAb (54.5 vs. 10.7 IU/mL; p = 0.011) and TPOAb titers at baseline (46.1 vs. 9.0 IU/mL; p < 0.001) and greater changes in TgAb (61.7 vs. 7.8 IU/mL; p = 0.025) and TPOAb titers (52.8 vs. -0.8 IU/mL; p < 0.001) than patients who did not develop hypothyroidism. The TgAb titer at baseline and changes in the TgAb and TPOAb titers were greater in patients with thyrotoxicosis than patients with isolated hypothyroidism, suggesting that the magnitude of the thyroid autoimmune response reflects the clinical types of thyroid-irAEs.
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Autoanticuerpos , Hipotiroidismo , Tirotoxicosis , Humanos , Tirotoxicosis/inducido químicamente , Tirotoxicosis/sangre , Tirotoxicosis/inmunología , Masculino , Femenino , Hipotiroidismo/inmunología , Hipotiroidismo/sangre , Hipotiroidismo/inducido químicamente , Autoanticuerpos/sangre , Persona de Mediana Edad , Anciano , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Adulto , Yoduro Peroxidasa/inmunologíaRESUMEN
The symptoms of diabetes insipidus may be masked by the concurrence of adrenal insufficiency and emerge after the administration of hydrocortisone, occasionally at high doses. To elucidate the mechanism underlying polyuria induced by the administration of high-dose corticosteroids in the deficiency of arginine vasopressin (AVP), we first examined the secretion of AVP in three patients in whom polyuria was observed only after the administration of high-dose corticosteroids. Next, we examined the effects of dexamethasone or aldosterone on water balance in wild-type and familial neurohypophyseal diabetes insipidus (FNDI) model mice. A hypertonic saline test showed that AVP secretion was partially impaired in all patients. In one patient, there were no apparent changes in AVP secretion before and after the administration of high-dose corticosteroids. In FNDI mice, unlike dexamethasone, the administration of aldosterone increased urine volumes and decreased urine osmolality. Immunohistochemical analyses showed that, after the administration of aldosterone in FNDI mice, aquaporin-2 expression was decreased in the apical membrane and increased in the basolateral membrane in the collecting duct. These changes were not observed in wild-type mice. The present data suggest that treatment with mineralocorticoids induces polyuria by reducing aquaporin-2 expression in the apical membrane of the kidney in partial AVP deficiency.
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Diabetes Insípida Neurogénica , Diabetes Insípida , Ratones , Animales , Poliuria/genética , Acuaporina 2/genética , Mineralocorticoides , Aldosterona , Riñón/metabolismo , Arginina Vasopresina/genética , Arginina Vasopresina/metabolismo , Dexametasona/farmacologíaRESUMEN
AIMS/HYPOTHESIS: Patients with GAD antibodies (GADAb) showing clinical features of type 2 diabetes typically exhibit progression to an insulin-dependent state in several months or years. This condition is diagnosed as slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) or latent autoimmune diabetes in adults, a subtype of adult-onset autoimmune diabetes. However, some patients diagnosed with adult-onset autoimmune diabetes do not progress to an insulin-dependent state. We conducted a retrospective cohort study to identify patients with non-insulin-dependent diabetes among those diagnosed with adult-onset autoimmune diabetes using measurable indicators in routine clinical practice. METHODS: We surveyed data from the electronic medical records of all patients with GADAb from eight medical centres in Japan for selecting and analysing patients who matched the diagnostic criteria of SPIDDM. RESULTS: Overall, 345 patients were analysed; of these, 162 initiated insulin therapy (insulin therapy group), whereas 183 did not (non-insulin therapy group) during the follow-up period (median 3.0 years). Patients in the non-insulin therapy group were more likely to be male and presented a later diabetes onset, shorter duration of diabetes, higher BMI, higher blood pressure levels, lower HbA1c levels, lower GADAb levels and lesser antidiabetic agent use than those in the insulin therapy group when GADAb was first identified as positive. A Cox proportional hazards model showed that BMI, HbA1c levels and GADAb levels were independent factors for progression to insulin therapy. Kaplan-Meier analyses revealed that 86.0% of the patients with diabetes having GADAb who presented all three factors (BMI ≥ 22 kg/m2, HbA1c < 75 mmol/mol [9.0%] and GADAb <10.0 U/ml) did not require insulin therapy for 4 years. CONCLUSIONS/INTERPRETATION: Higher BMI (≥22 kg/m2), lower HbA1c (<75 mmol/mol [9.0%]) and lower GADAb levels (<10.0 U/ml) can predict a non-insulin-dependent state for at least several years in Japanese patients with diabetes having GADAb.
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Autoanticuerpos/sangre , Enfermedades Autoinmunes/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Glutamato Descarboxilasa/inmunología , Anciano , Enfermedades Autoinmunes/tratamiento farmacológico , Glucemia/metabolismo , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Seguimiento , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios RetrospectivosRESUMEN
We investigated whether peripheral combination treatment of a sodium-glucose cotransporter 2 (SGLT2) inhibitor and leptin improves glucose metabolism in insulin-dependent diabetes mellitus (IDDM) model mice. Twelve-week-old male C57BL6 mice were intraperitoneally administered a high dose of streptozotocin to produce IDDM. IDDM mice were then divided into five groups: SGLT2 inhibitor treatment alone, leptin treatment alone, leptin and SGLT2 inhibitor co-treatment, untreated IDDM mice, and healthy mice groups. The blood glucose (BG) level at the end of the dark cycle was measured, and a glucose tolerance test (GTT) was performed and compared between the five groups. Leptin was peripherally administered at 20 µg/day using an osmotic pump, and an SGLT2 inhibitor, ipragliflozin, was orally administered at 3 mg/kg/day. Monotherapy with SGLT2 inhibitor or leptin significantly improved glucose metabolism in mice as evaluated by BG and GTT compared with the untreated group, whereas the co-treatment group with SGLT2 inhibitor and leptin further improved glucose metabolism as compared with the monotherapy group. Notably, glucose metabolism in the co-treatment group improved to the same level as that in the healthy mice group. Thus, peripheral combination treatment with leptin and SGLT2 inhibitor improved glucose metabolism in IDDM mice without the use of insulin.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Glucosa/metabolismo , Glucósidos/administración & dosificación , Leptina/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Tiofenos/administración & dosificación , Administración Oral , Animales , Modelos Animales de Enfermedad , Quimioterapia Combinada , Infusiones Intravenosas , Masculino , Ratones Endogámicos C57BLRESUMEN
Wolfram syndrome (WS) is mainly caused by mutations in the WFS1 gene and characterized by diabetes mellitus, optic atrophy, hearing loss, and central diabetes insipidus (CDI). WFS1 is an endoplasmic reticulum (ER)-resident transmembrane protein, and Wfs1 knockout (Wfs1-/-) mice, which have been used as a mouse model for WS, reportedly manifested impairment of glucose tolerance due to pancreatic ß-cell loss. In the present study, we examined water balance, arginine vasopressin (AVP) secretion, and ER stress in AVP neurons of the hypothalamus in Wfs1-/- mice. There were no differences in urine volumes between Wfs1-/- and wild-type mice with free access to water. Conversely, when mice were subjected to intermittent water deprivation (WD) for 20 weeks, during which water was unavailable for 2 days a week, urine volumes were larger in Wfs1-/- mice, accompanied by lower urine AVP concentrations and urine osmolality, compared to wild-type mice. The mRNA expression of immunoglobulin heavy chain binding protein, a marker of ER stress, was significantly increased in the supraoptic nucleus and paraventricular nuclei in Wfs1-/- mice compared to wild-type mice after WD. Our results thus showed that Wfs1 knockout leads to a decrease in AVP secretion during dehydration, which could explain in part the mechanisms by which Wfs1 mutations cause CDI in humans.
Asunto(s)
Síndrome de Wolfram , Animales , Deshidratación , Diabetes Insípida Neurogénica , Retículo Endoplásmico , Estrés del Retículo Endoplásmico , Masculino , Proteínas de la Membrana , Ratones , Agua , Síndrome de Wolfram/genéticaRESUMEN
The programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis is vital for immune resistance during tumor development, while PD-L1 inhibitors can also inhibit the PD-L1/B7-1 (CD80) interaction, indicating one of the molecular differences between PD-1 and PD-L1 inhibitors. However, the clinical benefits of PD-L1 inhibitors in patients previously treated with PD-1 inhibitors remain unknown. In this study, we retrospectively analyzed the clinical data of eight patients with non-small cell lung cancer who received the PD-L1 inhibitor atezolizumab and previously treated with the PD-1 inhibitor nivolumab. The median progression-free survival was 2.1 months (1.8-18.7 months), and 4 of 8 patients achieved at least stable disease. In two of these patients, atezolizumab treatment resulted in longer progression-free survival (PFS) compared with that of nivolumab. Conversely, one patient exhibited grade 4 diabetic ketoacidosis (DKA) within 2 weeks after the initial administration of atezolizumab. Another patient had developed type 1 diabetes mellitus (T1DM) during the prior nivolumab treatment and then developed DKA due to an infection after the initiation of atezolizumab. Both of them had high-risk human leukocyte antigen-DR/DQ types relevant to T1DM. These results demonstrate the potential efficacy of PD-L1 inhibitors to some tumors that have acquired resistance to PD-1 inhibitors and suggest that appropriate managements are required for not only a newly onset of T1DM but also blood glucose control after the development of T1DM during a reiteration of the PD-1/PD-L1 blockade.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Nivolumab/uso terapéutico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Anti-programmed cell death-1 (PD-1) antibodies can cause thyroid dysfunction. However, no predictive biomarkers enabling stratification of thyroid dysfunction risk have been identified. METHODS: A total of 209 patients treated with an anti-PD-1 antibody were evaluated for anti-thyroid antibodies at baseline and prospectively for thyroid function every 6 weeks for 24 weeks after treatment initiation, and then observed until the visits stopped. Thyroid ultrasonography was performed if the patient was positive for anti-thyroid antibodies at baseline. RESULTS: Of the 209 patients, 19 (9.1%) developed thyroid dysfunction (destructive thyroiditis or hypothyroidism). The cumulative incidence of thyroid dysfunction was significantly higher in patients who were positive vs. negative for anti-thyroid antibodies (15/44 [34.1%] vs. 4/165 [2.4%], p < 0.001). Forty-two patients positive for anti-thyroid antibodies at baseline were divided into two groups according to the presence of an irregular echo pattern. The cumulative incidence of thyroid dysfunction was significantly higher in those with an irregular vs. a regular echo pattern (13/23 [56.5%] vs. 1/19 [5.3%], p = 0.001). None of the patients developed thyroid dysfunction after the initial 24-week period. CONCLUSIONS: The risk of thyroid dysfunction induced by anti-PD-1 antibodies can be predicted by evaluation of anti-thyroid antibodies and the thyroid echo pattern at baseline. TRIAL REGISTRATION: UMIN000019024.
Asunto(s)
Receptor de Muerte Celular Programada 1/metabolismo , Glándula Tiroides/fisiopatología , Tiroiditis/inducido químicamente , Ultrasonografía/métodos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de RiesgoRESUMEN
Autoimmunity contributes to the pathogenesis of hypophysitis, a chronic inflammatory disease in the pituitary gland. Although primary hypophysitis is rare, the number of pituitary dysfunction cases induced by immune checkpoint inhibitors (ICIs) is increasing. While it is difficult to prove the involvement of autoimmunity in the pituitary glands, circulating anti-pituitary antibodies (APAs) can be measured by indirect immunofluorescence and used as a surrogate marker of pituitary autoimmunity. APAs are present in several pituitary diseases, including lymphocytic adenohypophysitis, lymphocytic infundibulo-neurohypophysitis (LINH), IgG4-related hypophysitis, and pituitary dysfunction induced by ICIs. Mass spectrometry analysis of antigens targeted by APAs clarified rabphilin-3A as an autoantigen in LINH. This demonstrates that APAs can be applied as a probe to identify novel autoantigens in other pituitary autoimmune diseases, including pituitary dysfunction induced by ICIs, which can aid in biomarker discovery.
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Autoanticuerpos/sangre , Hipofisitis Autoinmune/sangre , Animales , Autoanticuerpos/inmunología , Hipofisitis Autoinmune/inducido químicamente , Hipofisitis Autoinmune/inmunología , Biomarcadores/sangre , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Enfermedad Relacionada con Inmunoglobulina G4/sangre , Enfermedad Relacionada con Inmunoglobulina G4/inmunología , Hipófisis/inmunologíaRESUMEN
Hypophysitis, which is often accompanied by pituitary dysfunction, is classified into several subtypes based on the cause, histology, and the location of inflammation in the pituitary gland. A definitive diagnosis requires pituitary biopsy, which is invasive, and the process is limited to specialized clinical settings. In this opinion paper, we review the literature associated with hypophysitis, and provide the guidelines of the Japan Endocrine Society for the diagnosis and treatment of autoimmune and IgG4-related hypophysitis.
Asunto(s)
Hipofisitis Autoinmune/diagnóstico , Glucocorticoides/uso terapéutico , Hipopituitarismo/tratamiento farmacológico , Procedimientos Neuroquirúrgicos/métodos , Hipofisitis Autoinmune/complicaciones , Hipofisitis Autoinmune/metabolismo , Hipofisitis Autoinmune/terapia , Descompresión Quirúrgica/métodos , Endocrinología , Cefalea/etiología , Terapia de Reemplazo de Hormonas/métodos , Humanos , Hipopituitarismo/etiología , Hipopituitarismo/metabolismo , Japón , Imagen por Resonancia Magnética , Sociedades Médicas , Trastornos de la Visión/etiología , Campos VisualesRESUMEN
Central diabetes insipidus (CDI) is characterized by polyuria and polydipsia caused by impairment of arginine vasopressin (AVP) secretion. In this study, we evaluated plasma AVP concentrations during a hypertonic saline infusion test using a new AVP radioimmunoassay (RIA) which is now available in Japan. Thirteen control subjects, mostly with hypothalamo-pituitary disease but without CDI, and 13 patients with CDI were enrolled in the study. Whether or not subjects had CDI was determined based on the totality of clinical data, which included urine volumes and osmolality. Regression analysis of plasma AVP and serum Na concentrations revealed that the gradient was significantly lower in the CDI group than in the control group. The area under the receiver-operating-characteristic (ROC) curve was 0.99, and the <0.1 gradient cut-off values for the simple regression line to distinguish CDI from control had a 100% sensitivity and a 77% specificity. The ROC analysis with estimated plasma AVP concentrations at a serum Na concentration of 149 mEq/L showed that the area under the ROC curve was 1.0 and the <1.0 pg/mL cut-off values of plasma AVP had a 99% sensitivity and a 95% specificity. We conclude that measurement of AVP by RIA during a hypertonic saline infusion test can differentiate patients with CDI from those without CDI with a high degree of accuracy. Further investigation is required to confirm whether the cut-off values shown in this study are also applicable to a diagnosis of partial CDI or a differential diagnosis between CDI and primary polydipsia.
Asunto(s)
Arginina Vasopresina/sangre , Diabetes Insípida Neurogénica/diagnóstico , Sodio/sangre , Vasopresinas , Diabetes Insípida Neurogénica/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Poliuria/sangre , Poliuria/diagnóstico , Radioinmunoensayo , Solución Salina HipertónicaRESUMEN
Immune checkpoint inhibitors(ICIs)have been widely used in patients with advanced malignancies. However, these drugs can cause immune-related adverse events(irAEs)in several organs, including lung, skin, gastrointestinal tract, liver, nerve, muscle, and endocrine organs. Endocrine irAEs include hypopituitarism, primary adrenal insufficiency, thyroid dysfunction, hypoparathyroidism, and type 1 diabetes mellitus, which can result in life-threatening consequences, such as adrenal crisis, thyroid storm, severe hypocalcemia, and diabetic ketoacidosis. Therefore, it is important to understand the clinical features of each endocrine irAE and to manage them appropriately. Recently, we have reported that the presence ofanti -thyroid antibodies at baseline become a biomarker to find the high-risk patients for thyroid dysfunction induced by anti-PD-1 antibody, nivolumab.
Asunto(s)
Neoplasias , Humanos , NivolumabRESUMEN
Autoimmune hypophysitis (AH) is thought to be an autoimmune disease characterized by lymphocytic infiltration of the pituitary gland. Among AH pathologies, lymphocytic infundibulo-neurohypophysitis (LINH) involves infiltration of the neurohypophysis and/or the hypothalamic infundibulum, causing central diabetes insipidus resulting from insufficiency of arginine vasopressin secretion. The pathophysiological and pathogenetic mechanisms underlying LINH are largely unknown. Clinically, differentiating LINH from other pituitary diseases accompanied by mass lesions, including tumours, has often been difficult, because of similar clinical manifestations. We recently reported that rabphilin-3A is an autoantigen and that anti-rabphilin-3A antibodies constitute a possible diagnostic marker for LINH. However, the involvement of rabphilin-3A in the pathogenesis of LINH remains to be elucidated. This study was undertaken to explore the role of rabphilin-3A in lymphocytic neurohypophysitis and to investigate the mechanism. We found that immunization of mice with rabphilin-3A led to neurohypophysitis. Lymphocytic infiltration was observed in the neurohypophysis and supraoptic nucleus 1 month after the first immunization. Mice immunized with rabphilin-3A showed an increase in the volume of urine that was hypotonic as compared with control mice. Administration of a cocktail of monoclonal anti-rabphilin-3A antibodies did not induce neurohypophysitis. However, abatacept, which is a chimeric protein that suppresses T-cell activation, decreased the number of T cells specific for rabphilin-3A in peripheral blood mononuclear cells (PBMCs). It ameliorated lymphocytic infiltration of CD3+ T cells in the neurohypophysis of mice that had been immunized with rabphilin-3A. Additionally, there was a linear association between the number of T cells specific for rabphilin-3A in PBMCs and the number of CD3+ T cells infiltrating the neurohypophysis. In conclusion, we suggest that rabphilin-3A is a pathogenic antigen, and that T cells specific for rabphilin-3A are involved in the pathogenesis of neurohypophysitis in mice. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Hipofisitis Autoinmune/inducido químicamente , Autoinmunidad , Proteínas del Tejido Nervioso , Neurohipófisis/metabolismo , Proteínas de Transporte Vesicular , Abatacept/administración & dosificación , Animales , Anticuerpos Monoclonales/administración & dosificación , Hipofisitis Autoinmune/inmunología , Hipofisitis Autoinmune/metabolismo , Hipofisitis Autoinmune/prevención & control , Autoinmunidad/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Inmunosupresores/administración & dosificación , Ratones , Neurohipófisis/efectos de los fármacos , Neurohipófisis/inmunología , Neurohipófisis/patología , Núcleo Supraóptico/inmunología , Núcleo Supraóptico/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Micción , Rabfilina-3ARESUMEN
Primary sclerosing cholangitis (PSC) has been known as a cause of secondary osteoporosis, which often requires medication. Herein, we give the first report of a case of a 38-year-old man with fatigue and paralysis in both upper limbs who had been treated with denosumab for secondary osteoporosis associated with PSC. Since bisphosphonate (alendronate) was ineffective in our patient, the treatment was changed from alendronate to denosumab. Despite replacements with calcium and active vitamin D (alfacalcidol; 1-hydroxycholecalciferol), he developed severe hypocalcemia (albumin-adjusted serum calcium: 5.2 mg/dL) 2 weeks after the second administration of denosumab, which required immediate correction. After that, the corrected serum calcium levels were controlled within the normal range with 0.75 µg of eldecalcitol (1α,25-dihydroxy-2ß-(3-hydroxypropyloxy)vitamin D3) and increased doses of calcium (1,500 mg daily) and phosphate (900 mg daily) without denosumab. Even though denosumab treatment had been terminated, the T score of the lumbar spine improved from -4.4 to -2.6 by 1 year after the second administration, possibly due to the amelioration of osteomalacia through the treatment with eldecalcitol and the higher doses of calcium and phosphate. This report indicates that denosumab can cause severe hypocalcemia in patients with osteoporosis associated with chronic diseases of the hepatobiliary system including PSC, in turn suggesting that the possibility of vitamin D deficiency or osteomalacia should be considered before administering treatments and that serum calcium levels should be closely monitored to detect life-threatening hypocalcemia in patients who have high risk factors for hypocalcemia.
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Conservadores de la Densidad Ósea/efectos adversos , Colangitis Esclerosante/complicaciones , Denosumab/efectos adversos , Hipocalcemia/inducido químicamente , Osteoporosis/tratamiento farmacológico , Adulto , Conservadores de la Densidad Ósea/uso terapéutico , Calcio/sangre , Colangitis Esclerosante/sangre , Colangitis Esclerosante/tratamiento farmacológico , Denosumab/uso terapéutico , Glucocorticoides/efectos adversos , Glucocorticoides/uso terapéutico , Humanos , Hipocalcemia/sangre , Masculino , Osteoporosis/sangre , Osteoporosis/etiologíaRESUMEN
Immune checkpoint inhibitors (ICIs) have become a promising treatment for advanced malignancies. However, these drugs can induce immune-related adverse events (irAEs) in several organs, including skin, gastrointestinal tract, liver, muscle, nerve, and endocrine organs. Endocrine irAEs comprise hypopituitarism, primary adrenal insufficiency, thyroid dysfunction, hypoparathyroidism, and type 1 diabetes mellitus. These conditions have the potential to lead to life-threatening consequences, such as adrenal crisis, thyroid storm, severe hypocalcemia, and diabetic ketoacidosis. It is therefore important that both endocrinologists and oncologists understand the clinical features of each endocrine irAE to manage them appropriately. This opinion paper provides the guidelines of the Japan Endocrine Society and in part the Japan Diabetes Society for the management of endocrine irAEs induced by ICIs.
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Enfermedades del Sistema Endocrino/inducido químicamente , Enfermedades del Sistema Endocrino/terapia , Enfermedades del Sistema Inmune/inducido químicamente , Enfermedades del Sistema Inmune/terapia , Factores Inmunológicos/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Enfermedades de las Glándulas Suprarrenales/inducido químicamente , Enfermedades de las Glándulas Suprarrenales/terapia , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/inmunología , Diabetes Mellitus/inducido químicamente , Diabetes Mellitus/inmunología , Diabetes Mellitus/terapia , Enfermedades del Sistema Endocrino/diagnóstico , Humanos , Enfermedades del Sistema Inmune/diagnóstico , Factores Inmunológicos/uso terapéutico , Japón , Enfermedades de las Paratiroides/inducido químicamente , Enfermedades de las Paratiroides/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Sociedades Médicas/organización & administración , Sociedades Médicas/normas , Enfermedades de la Tiroides/inducido químicamente , Enfermedades de la Tiroides/terapiaRESUMEN
Thyroid dysfunction (TD) induced by immune checkpoint inhibitors is not sufficiently understood. The purpose of this retrospective observational study was to identify risk factors and the clinical course of TD induced by nivolumab. Patients with advanced solid tumors who were treated with nivolumab from March 2009 through to March 2016 at the National Cancer Center Hospital (Tokyo, Japan) were included. Thyroid function and antithyroid Abs from serum samples among all patients were evaluated at baseline and during nivolumab treatment. Overt hypothyroidism was defined as low serum-free T4 together with elevated thyroid-stimulating hormone (TSH) >10 µIU/mL. Thyrotoxicosis was defined as low TSH with elevated free T4 and/or free T3. We defined thyroid autoimmunity as the presence of antithyroid Abs at baseline, including antithyroid peroxidase Abs and antithyroglobulin Abs (TgAb). Twenty-three (14%) of a total of 168 patients developed TD, including 17 cases of hypothyroidism and 20 of thyrotoxicosis. Thyrotoxicosis followed by hypothyroidism occurred in 14 cases. Fourteen of 35 patients (40%) with thyroid autoimmunity developed TD vs 9 of 133 (7%) without (odds ratio 9.19; 95% confidence interval [CI], 3.53-23.9). In multivariate analysis, elevated TSH and TgAb at baseline were significantly associated with the development of TD, with odds ratio of 7.36 (95% CI, 1.66-32.7) and 26.5 (95% CI, 8.18-85.8), respectively. Association between TD and elevated antithyroid peroxidase Abs at baseline was not significant. These results suggest that patients with pre-existing TgAb and elevated TSH at baseline are at high risk of TD.
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Anticuerpos Monoclonales/efectos adversos , Autoanticuerpos/metabolismo , Enfermedades de la Tiroides/epidemiología , Glándula Tiroides/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Hipotiroidismo/inducido químicamente , Hipotiroidismo/epidemiología , Hipotiroidismo/inmunología , Japón/epidemiología , Masculino , Persona de Mediana Edad , Nivolumab , Oportunidad Relativa , Estudios Retrospectivos , Enfermedades de la Tiroides/inducido químicamente , Enfermedades de la Tiroides/inmunología , Glándula Tiroides/metabolismo , Tirotoxicosis/inducido químicamente , Tirotoxicosis/epidemiología , Tirotoxicosis/inmunología , Tirotropina/metabolismo , Adulto JovenRESUMEN
The molecular mechanism involved in the exocytosis of arginine vasopressin (AVP) is not fully known. Rabphilin-3A has been suggested as a novel autoantigen in infundibulo-neurohypophysitis (LINH), which leads to central diabetes insipidus through insufficient secretion of AVP. However, the role of rabphilin-3A in the pathogenesis of LINH remains unclear. Thus, the aim of the present study was to identify proteins binding rabphilin-3A in the posterior pituitary. Using glutathione S-transferase (GST)-pulldown assays and proteomic analyses, cullin-associated NEDD8-dissociated protein 1 (CAND1) was identified as a rabphilin-3A-binding protein in the posterior pituitary. Co-immunoprecipitation assays indicated that CAND1 interacted endogenously with rabphilin-3A. In addition, immunohistochemistry experiments showed that CAND1 immunoreactivity was detected mainly in the posterior pituitary, intermediate lobe, and the supraoptic nucleus in the hypothalamus, and less in the anterior lobe, partially co-localizing with rabphilin-3A. Overexpression of CAND1 resulted in deubiquitylation of rabphilin-3A in PC12 cells. Moreover, overexpression of CAND1 in PC12 cells co-transfected with AVP enhanced both basal and KCl-stimulated AVP secretion. The findings indicate that CAND1 inhibits the ubiquitylation of rabphilin-3A and positively regulates AVP secretion. These data shed light on a novel potential mechanism involving rabphilin-3A in AVP secretion, and suggest a new role of CAND1 as a regulator of hormone or neurotransmitter secretion.