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Pituitary Oct 2019Immune checkpoint inhibitors, single or in combination, have recently become a cornerstone for the treatment of many malignancies. Ipilimumab, a CTLA-4 inhibitor, was...
BACKGROUND
Immune checkpoint inhibitors, single or in combination, have recently become a cornerstone for the treatment of many malignancies. Ipilimumab, a CTLA-4 inhibitor, was initially FDA approved for treatment of unresectable or metastatic melanoma and subsequently in combination therapy for other cancers. Ipilimumab-induced hypophysitis (IH) risk of development varies in different studies between 0 and 17%. Furthermore, little is known on how to predict which patients will develop IH and its impact on efficacy of Ipilimumab and survival for these patients. Here we reviewed IH and its impact on progression-free survival (PFS) and overall survival (OS).
METHODS
Retrospective, IRB- approved review of consecutive 117 melanoma patients who received ipilimumab between 2011 and 2016 was undertaken. Demographic and clinical characteristics, treatment timing and doses, time to progression after therapy, and survival data were reviewed. Patients were predefined in two groups: patients with and without IH. Descriptive statistics were used to summarize the demographic and clinical characteristics of the study sample. All values are shown as means and standard deviation [mean (SD)] unless indicated otherwise. P < 0.05 was considered to be statistically significant.
RESULTS
Of the 117 patients, 15 (12.8%) with a median age of 62.1 years developed IH. In the IH cohort, 10 (66.7%) were male and were significantly older than females (median 67.7 vs. 50.8; P = 0.009). This difference was not seen in non-IH group. Male patients with IH were significantly older than males without IH (67.7 vs. 56.4 years, P = 0.020), however this difference was not observed in females. No patient who received prior cancer systemic therapy (0/30) developed IH vs. 17.2% (15/72) without prior therapy developed IH (OR 0.00; 95% CI 0.00 to 0.73, P = 0.011). Between IH and non-IH patients, there was no difference in gender, race, ethnicity, BMI, diabetes or autoimmune disease at baseline, number of administered ipilimumab cycles, presence of primary melanoma lesion, or BRAF status. IH and non-IH patients had a similar median PFS (8.1 vs. 6.8 months, HR = 0.51, 95% CI 0.24 to 1.05 P = 0.062) and OS (53.3 vs. 29.5 months; HR 0.66, 95% CI 0.30 to 1.46; P = 0.307).
CONCLUSION
In this study of melanoma patients treated with Ipilimumab, risk of developing IH was high (almost 13%). Older age in men and no prior cancer therapy were associated with IH higher risk. Development of IH was not associated with PFS or OS. Increased use of immune checkpoint inhibitors in the future will impact IH overall risk, thus awareness is needed. Given the lack of reliable identifiable risk factors, close monitoring of signs and symptoms after each therapy cycle is critical for early detection and treatment of hypophysitis.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Immunological; Female; Humans; Hypophysitis; Ipilimumab; Male; Melanoma; Middle Aged; Progression-Free Survival; Retrospective Studies; Risk Factors
PubMed: 31327112
DOI: 10.1007/s11102-019-00978-4 -
Expert Review of Clinical Immunology Nov 2021Hypophysitis is an inflammation of the pituitary gland and a rare case of hypopituitarism. Despite the expanding spectrum of histological variants and causative agents,... (Review)
Review
INTRODUCTION
Hypophysitis is an inflammation of the pituitary gland and a rare case of hypopituitarism. Despite the expanding spectrum of histological variants and causative agents, its pathogenesis is far to be fully understood. The present review is focused on recent evidence concerning the pathogenesis of autoimmune hypophysitis by searching through online databases like MEDLINE and Scopus up to May 2021.
AREAS COVERED
Hypophysitis frequently develops in the context of a strong autoimmune background, including a wide spectrum of subtypes ranging from the commonest form of lymphocytic hypophysitis to the newly described and less common IgG4-, anti-PIT-1, and ICI-induced forms. A peculiar combination of genetic predisposition, pituitary damage and immunological setting represents the pathogenetic basis of autoimmune hypophysitis, which is characterized by diffuse infiltration of the gland by lymphocytes and variable degrees of fibrosis followed by pituitary cell destruction. Anti-pituitary antibodies (APA) have been described in sera from patients suffering from autoimmune hypophysitis, though their pathophysiological significance remains largely unknown and their diagnostic value limited.
EXPERT OPINION
In recent years hypophysitis has gained interest due to the increased number of new diagnoses and the recognition of novel subtypes. Further studies could lead to improvements in biochemical/immunological diagnosis and targeted treatments.
Topics: Autoimmune Hypophysitis; Humans; Hypophysitis; Immunoglobulin G; Pituitary Diseases; Pituitary Gland
PubMed: 34464545
DOI: 10.1080/1744666X.2021.1974297 -
Cancers Jan 2022Immune checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of metastatic melanoma. However, ICI are often associated with immune-related adverse...
Immune checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of metastatic melanoma. However, ICI are often associated with immune-related adverse events (IRAE) such as colitis, hepatitis, pancreatitis, hypophysitis, pneumonitis, thyroiditis, exanthema, nephritis, myositis, encephalitis, or myocarditis. Biomarkers associated with the occurrence of IRAE would be desirable. In the literature, there is only little data available and furthermore mostly speculative, especially in view of genetic alterations. Our major aim was to check for possible associations between NGS-based genetic alterations and IRAE. We therefore analyzed 95 melanoma patients with ICI and evaluated their NGS results. We checked the data in view of potential associations between copy number variations (CNVs), small variations (VARs), human leucocyte antigen (HLA), sex, blood count parameters, pre-existing autoimmune diseases and the occurrence of IRAE. We conducted a literature research on genetic alterations hypothesized to be associated with the occurrence of IRAE. In total, we identified 39 genes that have been discussed as hypothetical biomarkers. We compared the list of these 39 genes with the tumor panel that our patients had received and focused our study on those 16 genes that were also included in the tumor panel used for NGS. Therefore, we focused our analyses on the following genes: , , , , , , , , , , , , , , , . We obtained relevant results: female sex was significantly associated with the development of hepatitis, combined immunotherapy with colitis, increased total and relative monocytes at therapy initiation were significantly associated with the development of pancreatitis, the same, pre-existing autoimmune diseases. Further significant associations were as follows: HLA homozygosity (hepatitis), and VARs on (pancreatitis). Regarding CNVs, significant markers included deletions and (IRAE), duplications and (hepatitis), and (encephalitis), and , , , and (myositis). Myositis and encephalitis, both, were associated with alterations of and , which might explain their joined appearance in clinical practice. The association between HLA homozygosity and IRAE was clarified by finding HLA-A homozygosity as determining factor. We identified several genetic alterations hypothesized in the literature to be associated with the development of IRAE and found significant results concerning pre-existing autoimmune diseases and specific blood count parameters. Our findings can help to better understand the development of IRAE in melanoma patients. NGS might be a useful screening tool, however, our findings have yet to be confirmed in larger studies.
PubMed: 35053465
DOI: 10.3390/cancers14020302 -
Child Neurology Open 2022Lymphocytic hypophysitis (LH) is a rare autoimmune disorder involving the destruction of the anterior pituitary due to lymphocytic infiltration. The disease shows a...
Lymphocytic hypophysitis (LH) is a rare autoimmune disorder involving the destruction of the anterior pituitary due to lymphocytic infiltration. The disease shows a female predominance, commonly affecting women during late pregnancy into the postpartum period. The etiology of LH has not been well established and is presumed to be autoimmune based on the histopathological findings of lymphocytic infiltration and postpartum cases. Lymphocytic hypophysitis has yet to be studied in the context of a patient status post-recovery from COVID-19. Since the initial outbreak, additional information regarding the symptoms and outcomes has emerged on the virus's effects on the nervous system. We present a novel case of post-COVID lymphocytic hypophysitis in a pediatric patient at Dayton Children's Hospital. An 18-year-old previously healthy girl presented to the emergency department (ED) with acute onset headache and dizziness for 5 days. She had a history of symptomatic COVID-19 three weeks prior to the onset of current symptoms. Contrast enhanced magnetic resonance imaging (MRI) of the brain revealed diffuse thickening and enlargement of the infundibulum with homogenous contrast enhancement of the hypophyseal axis. Based on the suspicion for lymphocytic hypophysitis, she was started on Methylprednisolone 250 mg IV Q6hrs on day 1-3. Symptomatic clinical improvement was seen on day 3 with a significant decrease in the intensity of the headache. The case illustrates the varied presentation and neurological sequalae associated with the COVID-19 virus. The case described here is the first ever reported post-COVID manifestation of lymphocytic hypophysitis.
PubMed: 35615060
DOI: 10.1177/2329048X221103051 -
International Journal of Molecular... Nov 2022Autoimmune hypophysitis (AH) is an autoimmune disease of the pituitary for which the pathogenesis is incompletely known. AH is often treated with corticosteroids;...
Autoimmune hypophysitis (AH) is an autoimmune disease of the pituitary for which the pathogenesis is incompletely known. AH is often treated with corticosteroids; however, steroids may lead to considerable side effects. Using a mouse model of AH (experimental autoimmune hypophysitis, EAH), we show that interleukin-1 receptor-associated kinase 1 (IRAK1) is upregulated in the pituitaries of mice that developed EAH. We identified rosoxacin as a specific inhibitor for IRAK1 and found it could treat EAH. Rosoxacin treatment at an early stage (day 0-13) slightly reduced disease severity, whereas treatment at a later stage (day 14-27) significantly suppressed EAH. Further investigation indicated rosoxacin reduced production of autoantigen-specific antibodies. Rosoxacin downregulated production of cytokines and chemokines that may dampen T cell differentiation or recruitment to the pituitary. Finally, rosoxacin downregulated class II major histocompatibility complex expression on antigen-presenting cells that may lead to impaired activation of autoantigen-specific T cells. These data suggest that IRAK1 may play a pathogenic role in AH and that rosoxacin may be an effective drug for AH and other inflammatory diseases involving IRAK1 dysregulation.
Topics: Autoantigens; Autoimmune Hypophysitis; Interleukin-1 Receptor-Associated Kinases; Animals; Mice
PubMed: 36499283
DOI: 10.3390/ijms232314958 -
Archivos de La Sociedad Espanola de... Apr 2024Cancer therapy relies on new antitumoral drugs called immune checkpoint inhibitors (ICI), which produce long-lasting anti-tumor responses and lengthen survival, but... (Review)
Review
Cancer therapy relies on new antitumoral drugs called immune checkpoint inhibitors (ICI), which produce long-lasting anti-tumor responses and lengthen survival, but cause autoimmune-type toxicity. The clinical characteristics induced by ICI are not well characterized to date and careful collection of clinical data is required to accurately define its safety profile. We conducted a literature search in the main clinical search engines to identify pharmacological ocular iatrogenic events of ICIs related to ocular motility. Four systematic reviews were found that included this type of ocular iatrogenesis as well as numerous isolated case reports. Reported adverse effects include: oculomotor paresis, optic neuropathy, optic atrophy, myastheniform syndromes, thyroid pseudo-orbitopathy, orbital apex syndrome, and hypophysitis. Most were managed without interruption or with partial interruption of cancer treatment. Aggressive systemic treatments were required for adequate management of ocular iatrogenic events. It is essential that the ophthalmologist become familiar with the new ICI oncological treatments, capable of causing severe and disabling motilidad ocular iatrogenesis for the patient. The communication of adverse effects and the report of the treatments used can help the most appropriate management of these patients. Research should be oriented towards complex differential diagnosis and to optimize decisions on cancer treatments.
Topics: Humans; Immune Checkpoint Inhibitors; Eye Movements; Eye; Optic Atrophy; Optic Nerve Diseases; Graves Ophthalmopathy
PubMed: 38013131
DOI: 10.1016/j.oftale.2023.11.011 -
Balkan Medical Journal Jul 2023
Topics: Humans; Autoimmune Hypophysitis; Hypopituitarism; Germinoma; Diagnostic Errors
PubMed: 37227236
DOI: 10.4274/balkanmedj.galenos.2023.2023-3-60 -
BMC Endocrine Disorders Jan 2022The differential diagnosis of IgG4-related hypophysitis and other inflammatory diseases or tumors involving sellar region is challenging even after sellar biopsy. Sellar...
BACKGROUND
The differential diagnosis of IgG4-related hypophysitis and other inflammatory diseases or tumors involving sellar region is challenging even after sellar biopsy. Sellar germinoma is usually infiltrated by lymphocytes or plasma cells, and may be confused with hypophysitis.
CASE PRESENTATION
A 36-year-old man with diabetes insipidus, elevated serum IgG4 level (336 mg/dl), and sellar mass was suspected to have IgG4-related hypophysitis, and no other lesion of IgG4-related disease was detected. After treated by prednisone and mycophenolate mofetil, the serum IgG4 decreased to 214 mg/dl. However, after withdrawal of the drugs, the IgG4 level increased to 308 mg/dl. Endocrine assessments revealed panhypopituitarism, and the sellar mass enlarged. Transsphenoidal sellar exploration and biopsy was conducted. Pathological examination showed that the lesion was germinoma with lymphocytes and plasma cells infiltration, and IgG4-staining was positive (70/HPF, IgG4/IgG ratio = 10%). The patient was then treated by cisplatin and etoposide. After four cycles of chemotherapy, the serum IgG4 was 201 mg/dl, and the sellar mass was invisible.
CONCLUSION
Sellar germinoma can mimic the clinical characteristics of IgG4-related hypophysitis. Poor response to glucocorticoids can be used as an exclusion criterion in the clinical diagnosis of IgG4-related hypophysitis.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Autoimmune Hypophysitis; Brain Neoplasms; Cisplatin; Diagnosis, Differential; Etoposide; Germinoma; Humans; Immunoglobulin G; Male; Sella Turcica
PubMed: 35033046
DOI: 10.1186/s12902-021-00930-3 -
Journal of Medical Case Reports Dec 2021Autoimmune hypophysitis is a rare condition that often results in enlargement of the pituitary gland and hypopituitarism due to inflammatory infiltration. Management of...
BACKGROUND
Autoimmune hypophysitis is a rare condition that often results in enlargement of the pituitary gland and hypopituitarism due to inflammatory infiltration. Management of autoimmune hypophysitis can include long-term hormonal replacement and close control of the inflammatory pituitary mass. Mass-related symptoms in patients with autoimmune hypophysitis are treated with anti-inflammatory therapy, surgery, and/or radiotherapy.
CASE PRESENTATION
We present a 25-year-old White man with visual field defects of the right eye, headache, and weight loss. Magnetic resonance imaging showed a sellar mass, and the patient underwent transcranial surgery. Histopathology revealed autoimmune hypophysitis with predominantly CD20 positive B-cell infiltration. Progression of visual field defects necessitated postoperatively anti-inflammatory treatment with prednisolone. Azathioprine was initiated under gradual tapering of prednisolone with stable conditions at first, but relapse followed after dose reduction. Therefore, rituximab treatment was initiated, which resulted in regression of the pituitary mass. Rituximab treatment was discontinued after 25 months. The patient has continuously been in remission for 4 years after rituximab treatment was stopped.
CONCLUSION
This case illustrates that rituximab might be an effective alternative treatment in B-cell predominant autoimmune hypophysitis.
Topics: Adult; Anti-Inflammatory Agents; Autoimmune Hypophysitis; Humans; Magnetic Resonance Imaging; Male; Pituitary Diseases; Prednisolone; Recurrence; Rituximab
PubMed: 34906226
DOI: 10.1186/s13256-021-03146-0 -
Anti-cancer Drugs Jan 2022Pembrolizumab is a mAb against the programmed cell death protein-1 (PD-1). It has been approved for the treatment of advanced melanoma (unresectable or metastatic) in...
Pembrolizumab is a mAb against the programmed cell death protein-1 (PD-1). It has been approved for the treatment of advanced melanoma (unresectable or metastatic) in adults. Side effects associated with the use of anti-PD-1 are usually considered well tolerated; nevertheless, there are immune-related adverse events that may require treatment discontinuation. A 79-year-old man diagnosed with stage IV right scapular melanoma experienced unspecific symptoms and alterations of the hypothalamus-hypophysis axis after six cycles with pembrolizumab. The case was compatible with immune-related hypophysitis. Autoimmune thyroiditis and primary hypophysitis were excluded and toxicity due to pembrolizumab was considered the cause of hypophysitis. Pembrolizumab was discontinued and toxicity was managed with corticosteroids and hormonal replacement therapy (HRT). After 7 months of follow-up, symptoms were controlled with HRT but thyrotropin and corticotropin hormones had not recovered. It was decided not to reintroduce immunotherapy. Although endocrine disorders are common with the use of anti-PD-1, hypophysitis is very rare. However, clinical signs and symptoms can be nonspecific, therefore, it has probably been underdiagnosed. Monitoring hormones before and during the treatment is important for an early diagnosis and also to replace the alterations with HRT to control the symptoms. Hormonal function does not always recover, but it does not mean immunotherapy cannot be restarted and it should be evaluated in every case.
Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Humans; Hypophysitis; Male; Melanoma; Neoplasm Metastasis; Neoplasm Staging; Skin Neoplasms
PubMed: 34261922
DOI: 10.1097/CAD.0000000000001129