Journal of clinical immunology · 2025
Цели иммунных неблагополучных событий в лечении рака иммунотерапией с помощью комбинированных контрольно-пропускных пунктов объединяют пациентов IPEX.
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Moraes-Fontes Maria Francisca, Demengeot Jocelyne, Coutinho António
Аннотация
ВВЕДЕНИЕ: Конкретные детерминанты ущерба, наносимого аутоиммунным болезням целевой организацией, являются сложными и многофакторными, а некоторые генетические и экологические факторы признаются, но в основном остаются неизвестными. Иммунотерапия с " ингибиторами контрольной точки " (ИПК) осложняется неблагоприятными иммунными явлениями (ИРАЭ), происходящими у значительной части пациентов, с воспалением иммунологической аэтологии по конкретным органам. Мы предположили, что такие IRAE связаны с регуляционной дисфункцией Т клеток (Treg). Для того чтобы начать проверку этой гипотезы, мы сейчас сравнили мишени органов IRAE, вызванные ИПЦ, с теми, которые описаны в IPEX (Immune dys Regulation Polyendocrinopathy enteropaticy X-связанных) пациентов, имеющих вредные мутации в гене Foxp3, что приводит к недостаткам/отсутствию treg. МЕТОД: Мы сравнили частоту аутоиммунных заболеваний (AID) в three группы условий: ИПЦ IRAE, пациенты IPEX и население в целом (GP) с помощью PubMed 01/01/1998 в адрес 31/05/2024. Для каждой группы и для каждой аутоиммунной болезни была выбрана самая высокая сообщенная частота, которая была указана по ИПЦ-ИРАЕ и классифицирована как самая высокая или самая низкая. Выявлены энтеропатия, сыпь (экзема или другой дерматит), Трансминит/гепатит, гипотироидизм, повышенная липаза/экзокринный панкреатит, архальгия/воспалительный артрит, гипофизит, адренальная недостаточность, тип 1 Болит диабет, гемолитическая анемия, синдром Шёгрена, полимиальгия ревматика, анкилосирующий спондилит, системная волчанка эритематоза, множественный склероз и системный склероз. РЕЗУЛЬТАТЫ: Хотя дерматит и заболевания щитовидной железы также являются наиболее частым заболеванием АИД в ГП, последние, наряду с энтеропатией, гепатитом и адренной недостаточностью, гораздо чаще встречаются в ИПЦ-ИРАЕ и IPEX. Следует отметить, что наиболее часто встречающаяся система АИД в ГП, такая, как синдром de novo Sjögren, полимиальгия реумеатика, анкилосирующий спондилит, системная волчанка эритематос, множественный склероз и системный склероз, крайне редко встречается в ИПЦ-ИРАЕ (отчёты о конкретных случаях) и не описывается в IPEX. ЗАКЛЮЧЕНИЕ: Наш вывод служит дополнительным доказательством возможности того, что функциональное ингибирование/активация "Трега" является надежным механизмом, способствующим физиопатологии ИПЦ-ИРАЕ.
Оригинал публикации
The Targets of Immune Adverse Events in Cancer Immunotherapy by Combined Check-point Inhibitors Resemble those Seen in IPEX Patients.
INTRODUCTION: Specific determinants of target-organ damage in autoimmune diseases are complex and multifactorial, several genetic and environmental factors are recognized but mostly remain unknown. Immunotherapy with "check-point inhibitors" (CPI) is complicated by immune related adverse events (IRAE), occurring in a large fraction of patients, with organ-specific inflammation of immunologic aetiology. We hypothesized that such IRAE are associated to regulatory T cell (Treg) dysfunction. To start testing this hypothesis, we have now compared organ targets of CPI-induced IRAE with those described in IPEX (Immune dysregulation polyendocrinopathy enteropathy X-linked) patients carriers of deleterious mutations in the Foxp3 gene leading to deficient/absent Treg. METHOD: We compared the frequency of autoimmune diseases (AID) in three groups of conditions: CPI-induced IRAE, IPEX patients, and the General Population (GP) through a PubMed search from 01/01/1998 to 31/05/2024. For each group, and each autoimmune disease, the highest reported frequency was selected, listed in reference to CPI-IRAE and classified from the highest to lowest prevalence. Identified were enteropathy, rash (eczema or other dermatitis), transaminitis/hepatitis, hypothyroidism, increased lipase/exocrine pancreatitis, arthralgia/inflammatory arthritis, hypophysitis, adrenal insufficiency, type 1 diabetes mellitus, haemolytic anaemia, Sjögren´s syndrome, polymyalgia rheumatica, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis and systemic sclerosis. RESULTS: While dermatitis and thyroid disease are also the most frequent AID in the GP, the latter, together with enteropathy, hepatitis, and adrenal insufficiency are much more frequent in CPI-IRAE and IPEX. Of note, the most frequent systemic AID in the GP such as de novo Sjögren´s syndrome, polymyalgia rheumatica, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis and systemic sclerosis are extremely rare in CPI-IRAE (few case reports) and not described in IPEX.
CONCLUSION: Our finding provides further evidence for the possibility that the functional inhibition/inactivation of Treg is a plausible contributing mechanism in the physiopathology of CPI-IRAE.
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Introduction
"To The Editor"
Cancer immunotherapy with anti-CTLA-4 and anti-PD-1 monoclonal antibodies (check-point inhibitors, CPI) is increasingly successful in patients with an otherwise poor prognosis. The treatment is believed to remove inhibitory signals, either at the level of anti-tumour effector (cytotoxic) T cells or of their interaction with tumour targets [ 1 , 2 ].
Immunotherapy with combination CPI (anti-CTLA-4 and anti-PD-1) is complicated by immune related adverse events (IRAE), occurring in 86.8% of patients, with organ-specific inflammation of immunologic aetiology [ 3 ]. Unleashing ridding immunity in a non-specific manner expectedly results in tumour-unrelated tissue aggression, in so far as potentially aggressive auto-reactive T and B cells are present in all healthy individuals, the latter demonstrating that self-tolerance is maintained by regulatory T cells (Treg) [ 4 ].
Immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) is an inborn error of immunity caused by deleterious mutations in the Foxp3 gene. This transcription factor is required for the development and suppressor function of Treg. Although there are diverse immune-mediated manifestations, neonates and infants with IPEX and consequent Treg dysfunction usually present with a triad of organ-specific autoimmunity, most commonly enteropathy, dermatitis, and endocrinopathy, invariably lethal if left untreated [ 5 ].
Aside from rare monogenic disorders, key determinants of most individual organ-specific autoimmunity remain to be established. Here we present findings supporting the hypothesis that CPI contribute to IRAE due to Treg depletion/dysfunction and hope to provide insight into organ-specific auto-immune diseases.
Methods
We aimed to compare the frequency of Autoimmune Diseases (AID) between CPI-IRAE, IPEX patients, and the General Population (GP).
First, we reviewed PubMed registered highest reported frequency for each CPI-IRAE identified as autoimmune (including antagonists of both the CTLA-4 and PD-1 axis) from meta-analysis, systematic and focused reviews, and Phase III clinical trials. The following keywords were used: “immune mediated adverse events due to ipilimumab and nivolumab”. Studies were eligible for inclusion if they reported frequency ratios. The date of publication, bibliographic reference, number of patients and frequency of IRAE can be found in Supplementary Table 1 . Next, we again used PubMed to determine the highest reported prevalence for each corresponding condition as well as the most frequent autoimmune diseases in the adult general population. The strategy used the following keywords: “INFLAMMATORY BOWEL DISEASE” OR “CROHN´S DISEASE” OR “ULCERATIVE COLITIS”, “ECZEMA” OR “ATOPIC DERMATITIS” OR “ATOPIC ECZEMA” OR “DERMATITIS”, “THYROIDITIS” OR “HASHIMOTO´S THYROIDITIS” AND “HYPOTHYROIDISM”, “AUTOIMMUNE PANCREATITIS”, “AUTOIMMUNE HEPATITIS”, “HYPOPHYSITIS”, “RHEUMATOID ARTHRITIS”, “HAEMOLYTIC ANAEMIA”, “ADDISON´S DISEASE OR ADRENAL INSUFFICIENCY”, “TYPE 1 DIABETES MELLITUS”, “POLYMYALGIA RHEUMATICA”, “ANKYLOSING SPONDYLITIS”, “SYSTEMIC LUPUS ERYTHEMATOSUS”, “MULTIPLE SCLEROSIS”, “SJÖGREN´S SYNDROME” and “SYSTEMIC SCLEROSIS”. The search included the words AND “PREVALENCE” AND (“1998/01/01“[Date - Publication]: “2024/05/31“[Date - Publication]). The word “NATIONAL” was incorporated in the search for rheumatoid arthritis, type 1 diabetes mellitus, systemic lupus erythematosus, multiple sclerosis and systemic sclerosis. Studies were eligible for inclusion if they reported prevalence ratios, were national, regional or population-based, irrespective of the sampling procedure, as long as case ascertainment was clearly-defined by often combined criteria such as the International Classification of Diseases (ICD), validated codes, claims data, questionnaires and physician diagnosis. Included were national and global systematic reviews and meta-analysis. We excluded studies that did not report sufficient published data (including the year/period of study) or original data. Articles were included after title and abstract revision, excluded when title and/or abstract were not relevant, not available or not satisfying inclusion criteria. References can be found in Supplementary Table 2 . The number of abstracts screened for each condition, the exact dates explored and the number of references identified are recorded in Supplementary Table 3 . Collected in a Supplementary File for each reference were country/city, type of sampling, use of assigned disease defining codes, period and point prevalence, and PMID number. For each condition, the reference of the chosen prevalence was underlined and highlighted in bold. Finally, we registered the highest reported frequency of autoimmune conditions in patients with IPEX syndrome. These are remarkably similar amid the largest cohorts, as reported in the most comprehensive review to date [ 5 ]. The literature was selected by two independent authors (MFMF, JD). In case of disagreement, a consensus was reached. For each condition, the search was supplemented by a manual search. The searches were limited to the English language.
The frequency of autoimmune conditions was compared between CP-IRAE and the GP and CP-IRAE and IPEX by Pearson correlation (p value less than 0.05 considered to be statistically significant). No further statistical inferences were made based on the facts that a proper comparison of prevalence rates demands estimates of bias from confounding variables, which were unmatchable, and, most importantly, such an analysis would be prejudiced by the low base rate of organ-specific autoimmunity in the GP, as opposed to its high prevalence in the small sample of IPEX patients.
Results
While dermatitis and thyroid disease are also the most frequent AID in the GP, the latter, together with enteropathy, hepatitis, and adrenal insufficiency are much more frequent in CPI-IRAE and IPEX. Of note, the most frequent systemic AID in the GP such as de novo Sjögren´s syndrome, polymyalgia rheumatica, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis and systemic sclerosis are extremely rare in CPI (few case reports) and not described in IPEX (Table 1 ). Table 1 Frequency of Immune-Related Adverse Events (IRAE) found in cancer patients treated with check-point inhibitors (CPI) compared to the corresponding prevalence in the general population (GP) and patients with immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) Target organ/Auto immune disease CPI-IRAE (%) Order of f GP (%) Order of f IPEX (%) Order of f Gut (diarrhoea/colitis) 45 1 1.4 4 100 1 Skin (eczema/other dermatitis) 42 2 7.7 2 89 2 Liver (transaminitis/hepatitis) 20 3 0.07 7 20 6 Thyroid (hypothyroidism) 17 4 8.8 * 1 26 5 Exocrine pancreas (pancreatitis/↑ lipase) 16.8 5 0.01 ɫ 10 Rare/underestimated 9 Joints (arthralgia/inflammatory arthritis) 14 6 4.86 ‡ 3 9 7 Pituitary gland (hypophysitis) 8 7 0.88 † 5 Not described Adrenal gland (insufficiency) 4.2 8 0.02 § 8 1.5 8 Endocrine pancreas (type 1 diabetes mellitus) 2.6 9 0.5 6 49 3 Erythrocytes (haemolytic anaemia) 0.6 10 0.02 9 33 4 Salivary/lacrimal glands (Sjögren´s syndrome) N = 17 ɸ 1.06 Not described Musculokeletal (polymyalgia rheumatica) N = 84 ɸ 0.86 Not described Enthesis (ankylosing spondylitis) N = 3 ɸ 0.8 Not described Skin, joints, kidney, marrow and nervous system (systemic lupus erythematosus) N = 19 ɸ 0.52 Not described Brain (multiple sclerosis) N = 1 ɸ 0.38 Not described Skin, lung, heart, gut, kidneys (systemic sclerosis) N = 7 ɸ 0.06 Not described Legend: f stands for frequency; *no iodine deficiency in the population; ɫJapanese data mostly regarding IgG4-related disease; ‡reports to rheumatoid arthritis; †surgical archive from 1986 to 2004. It therefore may underestimate the true occurrence of IgG4 hypophysitis, first recognized as an entity in 2006; §excludes congenital adrenogenital disorders; ɸ% undisclosed
Table 1 Frequency of Immune-Related Adverse Events (IRAE) found in cancer patients treated with check-point inhibitors (CPI) compared to the corresponding prevalence in the general population (GP) and patients with immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) Target organ/Auto immune disease CPI-IRAE (%) Order of f GP (%) Order of f IPEX (%) Order of f Gut (diarrhoea/colitis) 45 1 1.4 4 100 1 Skin (eczema/other dermatitis) 42 2 7.7 2 89 2 Liver (transaminitis/hepatitis) 20 3 0.07 7 20 6 Thyroid (hypothyroidism) 17 4 8.8 * 1 26 5 Exocrine pancreas (pancreatitis/↑ lipase) 16.8 5 0.01 ɫ 10 Rare/underestimated 9 Joints (arthralgia/inflammatory arthritis) 14 6 4.86 ‡ 3 9 7 Pituitary gland (hypophysitis) 8 7 0.88 † 5 Not described Adrenal gland (insufficiency) 4.2 8 0.02 § 8 1.5 8 Endocrine pancreas (type 1 diabetes mellitus) 2.6 9 0.5 6 49 3 Erythrocytes (haemolytic anaemia) 0.6 10 0.02 9 33 4 Salivary/lacrimal glands (Sjögren´s syndrome) N = 17 ɸ 1.06 Not described Musculokeletal (polymyalgia rheumatica) N = 84 ɸ 0.86 Not described Enthesis (ankylosing spondylitis) N = 3 ɸ 0.8 Not described Skin, joints, kidney, marrow and nervous system (systemic lupus erythematosus) N = 19 ɸ 0.52 Not described Brain (multiple sclerosis) N = 1 ɸ 0.38 Not described Skin, lung, heart, gut, kidneys (systemic sclerosis) N = 7 ɸ 0.06 Not described Legend: f stands for frequency; *no iodine deficiency in the population; ɫJapanese data mostly regarding IgG4-related disease; ‡reports to rheumatoid arthritis; †surgical archive from 1986 to 2004. It therefore may underestimate the true occurrence of IgG4 hypophysitis, first recognized as an entity in 2006; §excludes congenital adrenogenital disorders; ɸ% undisclosed
Frequency of Immune-Related Adverse Events (IRAE) found in cancer patients treated with check-point inhibitors (CPI) compared to the corresponding prevalence in the general population (GP) and patients with immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX)
Legend: f stands for frequency; *no iodine deficiency in the population; ɫJapanese data mostly regarding IgG4-related disease; ‡reports to rheumatoid arthritis; †surgical archive from 1986 to 2004. It therefore may underestimate the true occurrence of IgG4 hypophysitis, first recognized as an entity in 2006; §excludes congenital adrenogenital disorders; ɸ% undisclosed
There are large differences between CPI-IRAE and the GP with respect to adrenal insufficiency, hepatitis and enteropathy, with striking similarities between IRAE and IPEX for the same pathologies. Pearson correlation revealed a statistically significant strong interaction between CP-IRAE and IPEX ( r = 0.78, p = 0.02) while between CP-IRAE and the GP it was moderate and not significant ( r = 0.42, p = 0.22).
Discussion and Conclusion
If CPI were to simply enhance autoimmunity, ensuing de novo autoimmune reactions would be expected to amplify or at least mimic the general prevalence of AID, respecting its distribution in the GP. However, the prevalence of tissue or organs affected by CPI-IRAE is very different from AID in the GP. Instead, there is a stronger resemblance between CPI-IRAE and IPEX patients.
As the sole known defect in IPEX is the absence (in null mutations) or deficiency (in hypomorphic mutations) of Treg function, it is tempting to propose that functional inhibition/inactivation of Treg is a plausible contributing mechanism to the physiopathology of IRAE. CPI-IRAE and IPEX clinical phenotypes differ in the frequency of type 1 diabetes mellitus (T1DM), rarely reported as IRAE in CPI-treated patients. The fact that IPEX patients with hypomorphic Foxp3 mutations also remain unaffected by T1DM is suggestive that partial Treg function suffices to ensure pancreatic islet cell immune homeostasis (Supplementary Table 4 ). There are also remarkable similarities between animal studies and human disease both for PD-1 and CTLA-4 mutations, among others, but none are as severe as those that occur in scurfy mice or IPEX patients (Supplementary Table 5 ).
As limitations to the present report, we recognize that (i) we did not differentiate between milder from severe (≥ 3) adverse events graded by the National Cancer Institute Common Terminology Criteria for Adverse Events. All grade adverse events were included. However, we wish to point out that there is a very likely underestimation of the real frequency of bona fide autoimmune disease in patients under CPI. While enteropathy and hepatitis in the GP and IPEX patients are supported by histological features, most CPI treated patients with adverse events are not subjected to such diagnostic procedures; (ii) the accuracy of case definition for the identification of patients in our study relies on different set of diagnostic standards used for identifying patients (such as International Classification of Diseases – ICD codes, physician diagnosis, and global alliances of national societies diagnostic and classification criteria), as well as distinct sampling techniques (including administrative databases, dedicated registry data, hospital records, questionnaires, clinical examination, and combination of clinical examination and questionnaire), and this should be considered when comparing results across studies; (iii) evidence concerning autoimmune disease prevalence is generally scarce and non-existent in some populations; (iv) we are comparing the frequency of IRAE in adult cancer patients treated with CPI with the corresponding prevalence of diseases in the GP versus that of auto-immune disorders in IPEX, the latter described in paediatric patient cohorts. Once again, epidemiological methodology impacts the prevalence rates (point prevalence, cumulative prevalence, period prevalence) and the population ages studied (children only, adults only) from which we privileged studies encompassing all age groups.
Organ-specific autoimmune diseases develop when immune dysregulation causes tissue damage. Despite limitations due to the retrospective nature and heterogeneity of the included studies, the key strength of our study is the fact that cancer immunotherapy patients represent unique but unexplored human models for unravelling determinants of AID, a longstanding question in fundamental immunology. As cancer incidence continues to rise, millions of patients will be eligible for immunotherapy and we believe the time has come for questions on AID to be systematically addressed, namely by generating more complete immunological information in these patients. We would hope that this will be the case in a good fraction of the thousands of ongoing clinical trials with CPI therapy.
Supplementary Information
Below is the link to the electronic supplementary material. Supplementary Material 1 (DOCX 249 KB)
Supplementary Material 1 (DOCX 249 KB)
"To The Editor"
Cancer immunotherapy with anti-CTLA-4 and anti-PD-1 monoclonal antibodies (check-point inhibitors, CPI) is increasingly successful in patients with an otherwise poor prognosis. The treatment is believed to remove inhibitory signals, either at the level of anti-tumour effector (cytotoxic) T cells or of their interaction with tumour targets [ 1 , 2 ].
Immunotherapy with combination CPI (anti-CTLA-4 and anti-PD-1) is complicated by immune related adverse events (IRAE), occurring in 86.8% of patients, with organ-specific inflammation of immunologic aetiology [ 3 ]. Unleashing ridding immunity in a non-specific manner expectedly results in tumour-unrelated tissue aggression, in so far as potentially aggressive auto-reactive T and B cells are present in all healthy individuals, the latter demonstrating that self-tolerance is maintained by regulatory T cells (Treg) [ 4 ].
Immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) is an inborn error of immunity caused by deleterious mutations in the Foxp3 gene. This transcription factor is required for the development and suppressor function of Treg. Although there are diverse immune-mediated manifestations, neonates and infants with IPEX and consequent Treg dysfunction usually present with a triad of organ-specific autoimmunity, most commonly enteropathy, dermatitis, and endocrinopathy, invariably lethal if left untreated [ 5 ].
Aside from rare monogenic disorders, key determinants of most individual organ-specific autoimmunity remain to be established. Here we present findings supporting the hypothesis that CPI contribute to IRAE due to Treg depletion/dysfunction and hope to provide insight into organ-specific auto-immune diseases.
Methods
We aimed to compare the frequency of Autoimmune Diseases (AID) between CPI-IRAE, IPEX patients, and the General Population (GP).
First, we reviewed PubMed registered highest reported frequency for each CPI-IRAE identified as autoimmune (including antagonists of both the CTLA-4 and PD-1 axis) from meta-analysis, systematic and focused reviews, and Phase III clinical trials. The following keywords were used: “immune mediated adverse events due to ipilimumab and nivolumab”. Studies were eligible for inclusion if they reported frequency ratios. The date of publication, bibliographic reference, number of patients and frequency of IRAE can be found in Supplementary Table 1 . Next, we again used PubMed to determine the highest reported prevalence for each corresponding condition as well as the most frequent autoimmune diseases in the adult general population. The strategy used the following keywords: “INFLAMMATORY BOWEL DISEASE” OR “CROHN´S DISEASE” OR “ULCERATIVE COLITIS”, “ECZEMA” OR “ATOPIC DERMATITIS” OR “ATOPIC ECZEMA” OR “DERMATITIS”, “THYROIDITIS” OR “HASHIMOTO´S THYROIDITIS” AND “HYPOTHYROIDISM”, “AUTOIMMUNE PANCREATITIS”, “AUTOIMMUNE HEPATITIS”, “HYPOPHYSITIS”, “RHEUMATOID ARTHRITIS”, “HAEMOLYTIC ANAEMIA”, “ADDISON´S DISEASE OR ADRENAL INSUFFICIENCY”, “TYPE 1 DIABETES MELLITUS”, “POLYMYALGIA RHEUMATICA”, “ANKYLOSING SPONDYLITIS”, “SYSTEMIC LUPUS ERYTHEMATOSUS”, “MULTIPLE SCLEROSIS”, “SJÖGREN´S SYNDROME” and “SYSTEMIC SCLEROSIS”. The search included the words AND “PREVALENCE” AND (“1998/01/01“[Date - Publication]: “2024/05/31“[Date - Publication]). The word “NATIONAL” was incorporated in the search for rheumatoid arthritis, type 1 diabetes mellitus, systemic lupus erythematosus, multiple sclerosis and systemic sclerosis. Studies were eligible for inclusion if they reported prevalence ratios, were national, regional or population-based, irrespective of the sampling procedure, as long as case ascertainment was clearly-defined by often combined criteria such as the International Classification of Diseases (ICD), validated codes, claims data, questionnaires and physician diagnosis. Included were national and global systematic reviews and meta-analysis. We excluded studies that did not report sufficient published data (including the year/period of study) or original data. Articles were included after title and abstract revision, excluded when title and/or abstract were not relevant, not available or not satisfying inclusion criteria. References can be found in Supplementary Table 2 . The number of abstracts screened for each condition, the exact dates explored and the number of references identified are recorded in Supplementary Table 3 . Collected in a Supplementary File for each reference were country/city, type of sampling, use of assigned disease defining codes, period and point prevalence, and PMID number. For each condition, the reference of the chosen prevalence was underlined and highlighted in bold. Finally, we registered the highest reported frequency of autoimmune conditions in patients with IPEX syndrome. These are remarkably similar amid the largest cohorts, as reported in the most comprehensive review to date [ 5 ]. The literature was selected by two independent authors (MFMF, JD). In case of disagreement, a consensus was reached. For each condition, the search was supplemented by a manual search. The searches were limited to the English language.
The frequency of autoimmune conditions was compared between CP-IRAE and the GP and CP-IRAE and IPEX by Pearson correlation (p value less than 0.05 considered to be statistically significant). No further statistical inferences were made based on the facts that a proper comparison of prevalence rates demands estimates of bias from confounding variables, which were unmatchable, and, most importantly, such an analysis would be prejudiced by the low base rate of organ-specific autoimmunity in the GP, as opposed to its high prevalence in the small sample of IPEX patients.
Results
While dermatitis and thyroid disease are also the most frequent AID in the GP, the latter, together with enteropathy, hepatitis, and adrenal insufficiency are much more frequent in CPI-IRAE and IPEX. Of note, the most frequent systemic AID in the GP such as de novo Sjögren´s syndrome, polymyalgia rheumatica, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis and systemic sclerosis are extremely rare in CPI (few case reports) and not described in IPEX (Table 1 ). Table 1 Frequency of Immune-Related Adverse Events (IRAE) found in cancer patients treated with check-point inhibitors (CPI) compared to the corresponding prevalence in the general population (GP) and patients with immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) Target organ/Auto immune disease CPI-IRAE (%) Order of f GP (%) Order of f IPEX (%) Order of f Gut (diarrhoea/colitis) 45 1 1.4 4 100 1 Skin (eczema/other dermatitis) 42 2 7.7 2 89 2 Liver (transaminitis/hepatitis) 20 3 0.07 7 20 6 Thyroid (hypothyroidism) 17 4 8.8 * 1 26 5 Exocrine pancreas (pancreatitis/↑ lipase) 16.8 5 0.01 ɫ 10 Rare/underestimated 9 Joints (arthralgia/inflammatory arthritis) 14 6 4.86 ‡ 3 9 7 Pituitary gland (hypophysitis) 8 7 0.88 † 5 Not described Adrenal gland (insufficiency) 4.2 8 0.02 § 8 1.5 8 Endocrine pancreas (type 1 diabetes mellitus) 2.6 9 0.5 6 49 3 Erythrocytes (haemolytic anaemia) 0.6 10 0.02 9 33 4 Salivary/lacrimal glands (Sjögren´s syndrome) N = 17 ɸ 1.06 Not described Musculokeletal (polymyalgia rheumatica) N = 84 ɸ 0.86 Not described Enthesis (ankylosing spondylitis) N = 3 ɸ 0.8 Not described Skin, joints, kidney, marrow and nervous system (systemic lupus erythematosus) N = 19 ɸ 0.52 Not described Brain (multiple sclerosis) N = 1 ɸ 0.38 Not described Skin, lung, heart, gut, kidneys (systemic sclerosis) N = 7 ɸ 0.06 Not described Legend: f stands for frequency; *no iodine deficiency in the population; ɫJapanese data mostly regarding IgG4-related disease; ‡reports to rheumatoid arthritis; †surgical archive from 1986 to 2004. It therefore may underestimate the true occurrence of IgG4 hypophysitis, first recognized as an entity in 2006; §excludes congenital adrenogenital disorders; ɸ% undisclosed
Table 1 Frequency of Immune-Related Adverse Events (IRAE) found in cancer patients treated with check-point inhibitors (CPI) compared to the corresponding prevalence in the general population (GP) and patients with immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) Target organ/Auto immune disease CPI-IRAE (%) Order of f GP (%) Order of f IPEX (%) Order of f Gut (diarrhoea/colitis) 45 1 1.4 4 100 1 Skin (eczema/other dermatitis) 42 2 7.7 2 89 2 Liver (transaminitis/hepatitis) 20 3 0.07 7 20 6 Thyroid (hypothyroidism) 17 4 8.8 * 1 26 5 Exocrine pancreas (pancreatitis/↑ lipase) 16.8 5 0.01 ɫ 10 Rare/underestimated 9 Joints (arthralgia/inflammatory arthritis) 14 6 4.86 ‡ 3 9 7 Pituitary gland (hypophysitis) 8 7 0.88 † 5 Not described Adrenal gland (insufficiency) 4.2 8 0.02 § 8 1.5 8 Endocrine pancreas (type 1 diabetes mellitus) 2.6 9 0.5 6 49 3 Erythrocytes (haemolytic anaemia) 0.6 10 0.02 9 33 4 Salivary/lacrimal glands (Sjögren´s syndrome) N = 17 ɸ 1.06 Not described Musculokeletal (polymyalgia rheumatica) N = 84 ɸ 0.86 Not described Enthesis (ankylosing spondylitis) N = 3 ɸ 0.8 Not described Skin, joints, kidney, marrow and nervous system (systemic lupus erythematosus) N = 19 ɸ 0.52 Not described Brain (multiple sclerosis) N = 1 ɸ 0.38 Not described Skin, lung, heart, gut, kidneys (systemic sclerosis) N = 7 ɸ 0.06 Not described Legend: f stands for frequency; *no iodine deficiency in the population; ɫJapanese data mostly regarding IgG4-related disease; ‡reports to rheumatoid arthritis; †surgical archive from 1986 to 2004. It therefore may underestimate the true occurrence of IgG4 hypophysitis, first recognized as an entity in 2006; §excludes congenital adrenogenital disorders; ɸ% undisclosed
Frequency of Immune-Related Adverse Events (IRAE) found in cancer patients treated with check-point inhibitors (CPI) compared to the corresponding prevalence in the general population (GP) and patients with immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX)
Legend: f stands for frequency; *no iodine deficiency in the population; ɫJapanese data mostly regarding IgG4-related disease; ‡reports to rheumatoid arthritis; †surgical archive from 1986 to 2004. It therefore may underestimate the true occurrence of IgG4 hypophysitis, first recognized as an entity in 2006; §excludes congenital adrenogenital disorders; ɸ% undisclosed
There are large differences between CPI-IRAE and the GP with respect to adrenal insufficiency, hepatitis and enteropathy, with striking similarities between IRAE and IPEX for the same pathologies. Pearson correlation revealed a statistically significant strong interaction between CP-IRAE and IPEX ( r = 0.78, p = 0.02) while between CP-IRAE and the GP it was moderate and not significant ( r = 0.42, p = 0.22).
Discussion and Conclusion
If CPI were to simply enhance autoimmunity, ensuing de novo autoimmune reactions would be expected to amplify or at least mimic the general prevalence of AID, respecting its distribution in the GP. However, the prevalence of tissue or organs affected by CPI-IRAE is very different from AID in the GP. Instead, there is a stronger resemblance between CPI-IRAE and IPEX patients.
As the sole known defect in IPEX is the absence (in null mutations) or deficiency (in hypomorphic mutations) of Treg function, it is tempting to propose that functional inhibition/inactivation of Treg is a plausible contributing mechanism to the physiopathology of IRAE. CPI-IRAE and IPEX clinical phenotypes differ in the frequency of type 1 diabetes mellitus (T1DM), rarely reported as IRAE in CPI-treated patients. The fact that IPEX patients with hypomorphic Foxp3 mutations also remain unaffected by T1DM is suggestive that partial Treg function suffices to ensure pancreatic islet cell immune homeostasis (Supplementary Table 4 ). There are also remarkable similarities between animal studies and human disease both for PD-1 and CTLA-4 mutations, among others, but none are as severe as those that occur in scurfy mice or IPEX patients (Supplementary Table 5 ).
As limitations to the present report, we recognize that (i) we did not differentiate between milder from severe (≥ 3) adverse events graded by the National Cancer Institute Common Terminology Criteria for Adverse Events. All grade adverse events were included. However, we wish to point out that there is a very likely underestimation of the real frequency of bona fide autoimmune disease in patients under CPI. While enteropathy and hepatitis in the GP and IPEX patients are supported by histological features, most CPI treated patients with adverse events are not subjected to such diagnostic procedures; (ii) the accuracy of case definition for the identification of patients in our study relies on different set of diagnostic standards used for identifying patients (such as International Classification of Diseases – ICD codes, physician diagnosis, and global alliances of national societies diagnostic and classification criteria), as well as distinct sampling techniques (including administrative databases, dedicated registry data, hospital records, questionnaires, clinical examination, and combination of clinical examination and questionnaire), and this should be considered when comparing results across studies; (iii) evidence concerning autoimmune disease prevalence is generally scarce and non-existent in some populations; (iv) we are comparing the frequency of IRAE in adult cancer patients treated with CPI with the corresponding prevalence of diseases in the GP versus that of auto-immune disorders in IPEX, the latter described in paediatric patient cohorts. Once again, epidemiological methodology impacts the prevalence rates (point prevalence, cumulative prevalence, period prevalence) and the population ages studied (children only, adults only) from which we privileged studies encompassing all age groups.
Organ-specific autoimmune diseases develop when immune dysregulation causes tissue damage. Despite limitations due to the retrospective nature and heterogeneity of the included studies, the key strength of our study is the fact that cancer immunotherapy patients represent unique but unexplored human models for unravelling determinants of AID, a longstanding question in fundamental immunology. As cancer incidence continues to rise, millions of patients will be eligible for immunotherapy and we believe the time has come for questions on AID to be systematically addressed, namely by generating more complete immunological information in these patients. We would hope that this will be the case in a good fraction of the thousands of ongoing clinical trials with CPI therapy.
Supplementary Information
Below is the link to the electronic supplementary material. Supplementary Material 1 (DOCX 249 KB)
Supplementary Material 1 (DOCX 249 KB)