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International Journal of Molecular... Mar 2023With the aging of the population, malignancies are becoming common complications in patients with rheumatoid arthritis (RA), particularly in elderly patients. Such... (Review)
Review
With the aging of the population, malignancies are becoming common complications in patients with rheumatoid arthritis (RA), particularly in elderly patients. Such malignancies often interfere with RA treatment. Among several therapeutic agents, immune checkpoint inhibitors (ICIs) which antagonize immunological brakes on T lymphocytes have emerged as a promising treatment option for a variety of malignancies. In parallel, evidence has accumulated that ICIs are associated with numerous immune-related adverse events (irAEs), such as hypophysitis, myocarditis, pneumonitis, and colitis. Moreover, ICIs not only exacerbate pre-existing autoimmune diseases, but also cause de novo rheumatic disease-like symptoms, such as arthritis, myositis, and vasculitis, which are currently termed rheumatic irAEs. Rheumatic irAEs differ from classical rheumatic diseases in multiple aspects, and treatment should be individualized based on the severity. Close collaboration with oncologists is critical for preventing irreversible organ damage. This review summarizes the current evidence regarding the mechanisms and management of rheumatic irAEs with focus on arthritis, myositis, and vasculitis. Based on these findings, potential therapeutic strategies against rheumatic irAEs are discussed.
Topics: Humans; Aged; Immune Checkpoint Inhibitors; Rheumatic Diseases; Arthritis, Rheumatoid; Neoplasms; Myositis; Vasculitis
PubMed: 36982715
DOI: 10.3390/ijms24065643 -
Pituitary Feb 2022Immune checkpoint inhibitors can cause various immune-related adverse events including secondary hypophysitis. We compared clinical characteristics of...
OBJECTIVE
Immune checkpoint inhibitors can cause various immune-related adverse events including secondary hypophysitis. We compared clinical characteristics of immunotherapy-induced hypophysitis (IIH) and primary hypophysitis (PH) DESIGN: Retrospective multicenter cohort study including 56 patients with IIH and 60 patients with PH.
METHODS
All patients underwent extensive endocrine testing. Data on age, gender, symptoms, endocrine dysfunction, MRI, immunotherapeutic agents and autoimmune diseases were collected.
RESULTS
Median time of follow-up was 18 months in IIH and 69 months in PH. The median time from initiation of immunotherapy to IIH diagnosis was 3 months. IIH affected males more frequently than PH (p < 0.001) and led to more impaired pituitary axes in males (p < 0.001). The distribution of deficient adenohypophysial axes was comparable between both entities, however, central hypocortisolism was more frequent (p < 0.001) and diabetes insipidus considerably less frequent in IIH (p < 0.001). Symptoms were similar except that visual impairment occurred more rarely in IIH (p < 0.001). 20 % of IIH patients reported no symptoms at all. Regarding MRI, pituitary stalk thickening was less frequent in IIH (p = 0.009). Concomitant autoimmune diseases were more prevalent in PH patients before the diagnosis of hypophysitis (p = 0.003) and more frequent in IIH during follow-up (p = 0.002).
CONCLUSIONS
Clinically, IIH and PH present with similar symptoms. Diabetes insipidus very rarely occurs in IIH. Central hypocortisolism, in contrast, is a typical feature of IIH. Preexisting autoimmunity seems not to be indicative of developing IIH.
Topics: Cohort Studies; Humans; Hypophysitis; Immunotherapy; Ipilimumab; Male; Retrospective Studies
PubMed: 34518996
DOI: 10.1007/s11102-021-01182-z -
Endocrinology, Diabetes & Metabolism... 2016Puumala hantavirus (PUUV) infection causes nephropathia epidemica (NE), a relatively mild form of haemorrhagic fever with renal syndrome (HFRS). Hypophyseal haemorrhage...
UNLABELLED
Puumala hantavirus (PUUV) infection causes nephropathia epidemica (NE), a relatively mild form of haemorrhagic fever with renal syndrome (HFRS). Hypophyseal haemorrhage and hypopituitarism have been described in case reports on patients with acute NE. Chronic hypopituitarism diagnosed months or years after the acute illness has also been reported, without any signs of a haemorrhagic aetiology. The mechanisms leading to the late-onset hormonal defects remain unknown. Here, we present a case of NE-associated autoimmune polyendocrinopathy and hypopituitarism presumably due to autoimmune hypophysitis. Thyroid peroxidase antibody seroconversion occurred between 6 and 12 months, and ovarian as well as glutamate decarboxylase antibodies were found 18 months after acute NE. Brain MRI revealed an atrophic adenohypophysis with a heterogeneous, low signal intensity compatible with a sequela of hypophysitis. The patient developed central (or mixed central and peripheral) hypothyroidism, hypogonadism and diabetes insipidus, all requiring hormonal replacement therapy. This case report suggests that late-onset hormonal defects after PUUV infection may develop by an autoimmune mechanism. This hypothesis needs to be confirmed by prospective studies with sufficient numbers of patients.
LEARNING POINTS
Pituitary haemorrhage resulting in hypopituitarism has been reported during acute HFRS caused by PUUV and other hantaviruses.Central and peripheral hormone deficiencies developing months or years after HFRS have also been found, with an incidence higher than that in the general population. The pathogenesis of these late-onset hormonal defects remains unknown.This case report suggests that the late-onset hypopituitarism and peripheral endocrine defects after HFRS could evolve via autoimmune mechanisms.The sensitivity of current anti-pituitary antibody (APA) tests is low. A characteristic clinical course, together with typical brain MRI and endocrine findings may be sufficient for a non-invasive diagnosis of autoimmune hypophysitis, despite negative APAs.
PubMed: 27857837
DOI: 10.1530/EDM-16-0084 -
Acta Neurochirurgica Aug 2022IgG4-related hypophysitis (IgG4-RH) is a rare chronic inflammatory condition of the pituitary gland. This study reports the presentation, management and outcomes for...
PURPOSE
IgG4-related hypophysitis (IgG4-RH) is a rare chronic inflammatory condition of the pituitary gland. This study reports the presentation, management and outcomes for patients with histologically proven IgG4-related hypophysitis.
METHODS
A prospectively maintained electronic database was searched over a 14-year period from 1 January 2007 to 31 December 2020 at a single academic centre to identify all patients with a histological diagnosis of IgG4-RH. A retrospective case note review from electronic health records was conducted for each case to extract data on their presentation, management and outcomes.
RESULTS
A total of 8 patients (5 male) with a median age of 51 years were identified. The most common presenting symptoms were headache (4/8; 50%), fatigue (3/8; 37.5%) and visual impairment (2/8; 25%). Three patients were initially treated with high-dose steroids aiming for reduction of the pituitary mass. However, ultimately all patients underwent transsphenoidal surgery. Post-operative changes included radiological reduction in pituitary mass in all patients that had imaging (7/7; 100%), improvement in vision (1/2; 50%), residual thick pituitary stalk (5/7; 71.4%), persistent anterior hypopituitarism (4/8; 50%) and panhypopopituitarism including diabetes insipidus (3/8; 37.5%).
CONCLUSIONS
IgG4-RH is an increasingly recognised entity presenting with a variety of symptoms and signs. Clinical presentation is similar to other forms of hypophysitis. It is therefore important to consider IgG4-RH as a differential and to have a low threshold for pituitary biopsy, the diagnostic gold standard. The diagnosis of IgG4-RH will guide decisions for additional workup for IgG4-related disease, multi-disciplinary team involvement and follow-up.
Topics: Autoimmune Hypophysitis; Humans; Immunoglobulin G; Male; Middle Aged; Pituitary Diseases; Pituitary Gland; Retrospective Studies
PubMed: 35532784
DOI: 10.1007/s00701-022-05231-9 -
Journal of Mid-life Health 2022Lymphocytic hypophysitis (LYH) is a rare inflammatory disease in which lymphoplasmacytic infiltration of the pituitary gland can potentially lead to panhypopituitarism....
Lymphocytic hypophysitis (LYH) is a rare inflammatory disease in which lymphoplasmacytic infiltration of the pituitary gland can potentially lead to panhypopituitarism. This entity was first recognized in 1962 by Goudie and Pinkerton. We report the case of a 36-year-old nonpregnant female operated for a presumed nonsecreting pituitary adenoma. On intraoperative squash cytology and histology of excision biopsy confirmed the diagnosis of LYH. Review of the literature shows that most reported cases have occurred in women during pregnancy or during postpartum period. Many were accurately diagnosed only after biopsy or at necropsy. It is suspected to be an autoimmune endocrinopathy as concomitant lymphocytic infiltration of the thyroid and pituitary glands has been noted and antipituitary antibodies have been found in some instances. Clinically and radiologically, LYH may mimic a nonsecretory pituitary adenoma. Intraoperative diagnosis may prevent unnecessary excision of potentially functioning pituitary.
PubMed: 36950203
DOI: 10.4103/jmh.jmh_32_21 -
Archives of Pathology & Laboratory... Nov 2017IgG4-related disease (IgG4-RD) is a systemic autoimmune fibroinflammatory disease that produces sclerotic, tumefactive masses containing dense lymphoplasmacytic... (Review)
Review
IgG4-related disease (IgG4-RD) is a systemic autoimmune fibroinflammatory disease that produces sclerotic, tumefactive masses containing dense lymphoplasmacytic infiltrates rich in immunoglobulin (Ig) G4 plasma cells. Initially characterized as a form of autoimmune pancreatitis, the distinctive histopathology of IgG4-RD has now been described in almost every organ system. However, because the clinical manifestations of IgG4-RD are diverse and nonspecific, the disease may go unsuspected until a biopsy or resection specimen is obtained to diagnose a presumed malignancy. Pathologists thus play a key role in the diagnosis of IgG4-RD, and familiarity with its histopathologic features is essential to preventing the irreversible comorbidities associated with this treatable disease. This brief review outlines the epidemiology, clinical manifestations, and histopathology of IgG4-RD, with the aim of furthering pathologists' awareness of and ability to diagnose this disorder.
Topics: Autoimmune Diseases; Autoimmune Hypophysitis; Diagnosis, Differential; Fibrosis; Humans; Immunoglobulin G; Lymphocytes, Tumor-Infiltrating; Plasma Cells
PubMed: 29072949
DOI: 10.5858/arpa.2017-0257-RA -
Endocrine Journal Nov 2020Autoimmunity contributes to the pathogenesis of hypophysitis, a chronic inflammatory disease in the pituitary gland. Although primary hypophysitis is rare, the number of... (Review)
Review
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.
Topics: Animals; Autoantibodies; Autoimmune Hypophysitis; Biomarkers; Fluorescent Antibody Technique, Indirect; Humans; Immune Checkpoint Inhibitors; Immunoglobulin G4-Related Disease; Pituitary Gland
PubMed: 33055452
DOI: 10.1507/endocrj.EJ20-0436 -
The Oncologist Jul 2016: In recent years, immune checkpoint inhibitors have emerged as effective therapies for advanced neoplasias. As new checkpoint target blockers become available and... (Review)
Review
UNLABELLED
: In recent years, immune checkpoint inhibitors have emerged as effective therapies for advanced neoplasias. As new checkpoint target blockers become available and additional tumor locations tested, their use is expected to increase within a short time. Immune-related adverse events (irAEs) affecting the endocrine system are among the most frequent and complex toxicities. Some may be life-threatening if not recognized; hence, appropriate guidance for oncologists is needed. Despite their high incidence, endocrine irAEs have not been fully described for all immunotherapy agents available. This article is a narrative review of endocrinopathies associated with cytotoxic T lymphocyte-associated antigen-4, blockade of programmed death receptor 1 and its ligand inhibitors, and their combination. Thyroid dysfunction is the most frequent irAE reported, and hypophysitis is characteristic of ipilimumab. Incidence, timing patterns, and clinical presentation are discussed, and practical recommendations for clinical management are suggested. Heterogeneous terminology and lack of appropriate resolution criteria in clinical trials make adequate evaluation of endocrine AEs difficult. It is necessary to standardize definitions to contrast incidences and characterize toxicity patterns. To provide optimal care, a multidisciplinary team that includes endocrinology specialists is recommended.
IMPLICATIONS FOR PRACTICE
Immune checkpoint inhibitors are already part of oncologists' therapeutic arsenal as effective therapies for otherwise untreatable neoplasias, such as metastatic melanoma or lung cancer. Their use is expected to increase exponentially in the near future as additional agents become available and their approval is extended to different tumor types. Adverse events affecting the endocrine system are among the most frequent and complex toxicities oncologists may face, and some may be life-threatening if not recognized. This study reviews endocrinopathies associated to immune checkpoint inhibitors available to date. Incidence, timing patterns, and clinical presentation are discussed, and practical recommendations for management are proposed.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; CTLA-4 Antigen; Endocrine System Diseases; Humans; Hypophysitis; Ipilimumab; Nivolumab; Programmed Cell Death 1 Receptor; Thyroid Diseases
PubMed: 27306911
DOI: 10.1634/theoncologist.2015-0509 -
Surgical Neurology International 2022Immunoglobulin (Ig)G4-related disease is a systemic fibroinflammatory disease characterized by dense infiltration of IgG4-positive plasma cells in the affected tissue(s)...
BACKGROUND
Immunoglobulin (Ig)G4-related disease is a systemic fibroinflammatory disease characterized by dense infiltration of IgG4-positive plasma cells in the affected tissue(s) with or without elevated plasma levels of IgG4. Hypophysitis itself is a very rare disease with reported prevalence in the operative specimens are around 0.2-0.88%. IgG4-related hypophysitis (IgG4-RH) may account for a substantial percentage of cases previously regarded as idiopathic hypophysitis.
METHODS
This study is a registry-based, retrospective, and cohort study from a tertiary care hospital in North India. The medical records and clinical data of biopsy-proven and suspected IgG4-RH patients registered were retrospectively analyzed. Treatment outcome of cases was also explored during this analysis.
RESULTS
Two thousand and six sellar area space-occupying lesions have been operated-on since 2006, among them only four patients had IgG4-RH on histopathological specimen. One case was diagnosed on clinical suspicion. Mean age of the patients was 31.8 ± 6.32 years. Most frequent presenting complaint was headaches. Extracranial manifestations were present in four patients. The most common pituitary dysfunction was cortisol deficiency. 18 F-fluorodeoxyglucose positron emission tomography (18F FDG PET) was helpful in three cases for diagnosis of hypophysitis and other organ involvement. Classical histological findings with storiform fibrosis, obliterative phlebitis seen in two cases, and IgG4-positive plasma cell infiltration were positive in four cases. Surgery was the primary modality of treatment in all four cases. Only one patient received steroids as a primary therapeutic modality.
CONCLUSION
IgG4-RH is rare. High index of suspicion is required to diagnosis the case precisely. FDG PET is helpful in diagnosing hypophysitis and extrapituitary lesions.
PubMed: 36600729
DOI: 10.25259/SNI_1013_2022 -
Endocrinology, Diabetes & Metabolism... Dec 2019Durvalumab is a programmed cell death ligand 1 inhibitor, which is now approved in Australia for use in non-small-cell lung and urothelial cancers. Autoimmune diabetes...
SUMMARY
Durvalumab is a programmed cell death ligand 1 inhibitor, which is now approved in Australia for use in non-small-cell lung and urothelial cancers. Autoimmune diabetes is a rare immune-related adverse effect associated with the use of immune checkpoint inhibitor therapy. It is now being increasingly described reflecting the wider use of immune checkpoint inhibitor therapy. We report the case of a 49-year-old female who presented with polyuria, polydipsia and weight loss, 3 months following the commencement of durvalumab. On admission, she was in severe diabetic ketoacidosis with venous glucose: 20.1 mmol/L, pH: 7.14, bicarbonate 11.2 mmol/L and serum beta hydroxybutyrate: >8.0 mmol/L. She had no personal or family history of diabetes or autoimmune disease. Her HbA1c was 7.8% and her glutamic acid decarboxylase (GAD) antibodies were mildly elevated at 2.2 mU/L (reference range: <2 mU/L) with negative zinc transporter 8 (ZnT8) and islet cell (ICA) antibodies. Her fasting C-peptide was low at 86 pmol/L (reference range: 200-1200) with a corresponding serum glucose of 21.9 mmol/L. She was promptly stabilised with an insulin infusion in intensive care and discharged on basal bolus insulin. Durvalumab was recommenced once her glycaemic control had stabilised. Thyroid function tests at the time of admission were within normal limits with negative thyroid autoantibodies. Four weeks post discharge, repeat thyroid function tests revealed hypothyroidism, with an elevated thyroid-stimulating hormone (TSH) at 6.39 mIU/L (reference range: 0.40-4.80) and low free T4: 5.9 pmol/L (reference range: 8.0-16.0). These findings persisted with repeat testing despite an absence of clinical symptoms. Treatment with levothyroxine was commenced after excluding adrenal insufficiency (early morning cortisol: 339 nmol/L) and hypophysitis (normal pituitary on MRI).
LEARNING POINTS
Durvalumab use is rarely associated with fulminant autoimmune diabetes, presenting with severe DKA. Multiple endocrinopathies can co-exist with the use of a single immune checkpoint inhibitors; thus, patients should be regularly monitored. Regular blood glucose levels should be performed on routine pathology on all patients on immune checkpoint inhibitor. Clinician awareness of immunotherapy-related diabetes needs to increase in an attempt to detect hyperglycaemia early and prevent DKA.
PubMed: 31829972
DOI: 10.1530/EDM-19-0098