Autoimmune conditions and gastric cancer risk in a population-based study in the United Kingdom.

BACKGROUND: Although overall incidence of gastric cancer is decreasing, incidence has been increasing among young people in some Western countries. This trend may stem from the increase in autoimmune conditions. METHODS: A nested case-control study of gastric cancer in UK Clinical Practice Research Datalink. Up to ten cancer-free controls were matched to cases by age and sex. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for associations between analyzable autoimmune conditions (n = 34) and gastric cancer with Bonferroni correction. We evaluated associations between pernicious anaemia and other conditions. A meta-analysis of published prospective studies and ours was conducted. RESULTS: Among 6586 cases (1156 cardia, 1104 non-cardia, and 4334 overlapping/unspecified tumours) and 65,687 controls, any autoimmune condition was associated with gastric cancer (OR = 1.10; 95% CI: 1.01-1.20). Individuals with pernicious anaemia had higher gastric cancer risk than those without (OR = 2.75; 2.19-3.44). Among controls, pernicious anaemia was associated with seven other conditions (OR range: 2.21-29.80). The pooled estimate for any autoimmune condition and gastric cancer was 1.17 (1.14-1.21; n = 47,126 cases). CONCLUSION: Autoimmunity increases gastric cancer risk. Some autoimmune conditions may be indirectly associated with gastric cancer via pernicious anaemia. Pernicious anaemia could be considered for gastric cancer risk stratification and screening.

Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK.

BACKGROUND: A rise in the incidence of some autoimmune disorders has been described. However, contemporary estimates of the overall incidence of autoimmune diseases and trends over time are scarce and inconsistent. We aimed to investigate the incidence and prevalence of 19 of the most common autoimmune diseases in the UK, assess trends over time, and by sex, age, socioeconomic status, season, and region, and we examine rates of co-occurrence among autoimmune diseases. METHODS: In this UK population-based study, we used linked primary and secondary electronic health records from the Clinical Practice Research Datalink (CPRD), a cohort that is representative of the UK population in terms of age and sex and ethnicity. Eligible participants were men and women (no age restriction) with acceptable records, approved for Hospital Episodes Statistics and Office of National Statistics linkage, and registered with their general practice for at least 12 months during the study period. We calculated age and sex standardised incidence and prevalence of 19 autoimmune disorders from 2000 to 2019 and used negative binomial regression models to investigate temporal trends and variation by age, sex, socioeconomic status, season of onset, and geographical region in England. To characterise co-occurrence of autoimmune diseases, we calculated incidence rate ratios (IRRs), comparing incidence rates of comorbid autoimmune disease among individuals with a first (index) autoimmune disease with incidence rates in the general population, using negative binomial regression models, adjusted for age and sex. FINDINGS: Among the 22 009 375 individuals included in the study, 978 872 had a new diagnosis of at least one autoimmune disease between Jan 1, 2000, and June 30, 2019 (mean age 54·0 years [SD 21·4]). 625 879 (63·9%) of these diagnosed individuals were female and 352 993 (36·1%) were male. Over the study period, age and sex standardised incidence rates of any autoimmune diseases increased (IRR 2017-19 vs 2000-02 1·04 [95% CI 1·00-1·09]). The largest increases were seen in coeliac disease (2·19 [2·05-2·35]), Sjogren's syndrome (2·09 [1·84-2·37]), and Graves' disease (2·07 [1·92-2·22]); pernicious anaemia (0·79 [0·72-0·86]) and Hashimoto's thyroiditis (0·81 [0·75-0·86]) significantly decreased in incidence. Together, the 19 autoimmune disorders examined affected 10·2% of the population over the study period (1 912 200 [13·1%] women and 668 264 [7·4%] men). A socioeconomic gradient was evident across several diseases, including pernicious anaemia (most vs least deprived area IRR 1·72 [1·64-1·81]), rheumatoid arthritis (1·52 [1·45-1·59]), Graves' disease (1·36 [1·30-1·43]), and systemic lupus erythematosus (1·35 [1·25-1·46]). Seasonal variations were observed for childhood-onset type 1 diabetes (more commonly diagnosed in winter) and vitiligo (more commonly diagnosed in summer), and regional variations were observed for a range of conditions. Autoimmune disorders were commonly associated with each other, particularly Sjögren's syndrome, systemic lupus erythematosus, and systemic sclerosis. Individuals with childhood-onset type 1 diabetes also had significantly higher rates of Addison's disease (IRR 26·5 [95% CI 17·3-40·7]), coeliac disease (28·4 [25·2-32·0]), and thyroid disease (Hashimoto's thyroiditis 13·3 [11·8-14·9] and Graves' disease 6·7 [5·1-8·5]), and multiple sclerosis had a particularly low rate of co-occurrence with other autoimmune diseases. INTERPRETATION: Autoimmune diseases affect approximately one in ten individuals, and their burden continues to increase over time at varying rates across individual diseases. The socioeconomic, seasonal, and regional disparities observed among several autoimmune disorders in our study suggest environmental factors in disease pathogenesis. The inter-relations between autoimmune diseases are commensurate with shared pathogenetic mechanisms or predisposing factors, particularly among connective tissue diseases and among endocrine diseases. FUNDING: Research Foundation Flanders.

Causal inference between pernicious anemia and cancers: a bidirectional two-sample mendelian randomization analysis.

BACKGROUND: Observational study investigated the association between pernicious anemia (PA) and cancers. However, with the exception of gastric cancer, the results are mostly contradictory. The purpose of this study was to investigate the potential causal relationship between PA and cancers through bidirectional two-sample Mendelian randomized (MR) analysis. METHODS: The European sample FinnGen project provided the genetic summary data for PA and 20 site-specific cancers. This bidirectional two-sample MR design mainly used the inverse variance weighting (IVW) method to evaluate the causal relationship between PA and cancer risk. Benjamini-Hochberg correction was performed to reduce the bias caused by multiple tests. RESULTS: Our study shows that there was a causal relationship between PA and gastric cancer, prostate cancer, testicular cancer and malignant melanoma of skin, and there was a reverse causal relationship between prostate cancer or gastric cancer and PA (P < 0.05). After Benjamini-Hochberg correction test, there was still a causal correlation between PA and gastric or prostate cancer (P' < 0.05), while there was only an implied causal association between PA and testicular cancer and malignant melanoma of skin (P'> 0.05). There was still a reverse causal relationship between gastric cancer and PA (P'< 0.05), while prostate cancer shows an implied reverse causal relationship(P'> 0.05). In addition, MR-Egger and MR-PRESSO tests showed no significant horizontal pleiotropy. CONCLUSIONS: PA may be genetically associated with testicular cancer, prostate cancer, gastric cancer, and malignant melanoma of skin.

Incidence and Predictors of Gastric Neoplastic Lesions in Corpus-Restricted Atrophic Gastritis: A Single-Center Cohort Study.

INTRODUCTION: Corpus-restricted atrophic gastritis is a chronic inflammatory disorder leading to possible development of type 1 neuroendocrine tumors (T1gNET), intraepithelial neoplasia (IEN), and gastric cancer (GC). We aimed to assess occurrence and predictors of gastric neoplastic lesions in patients with corpus-restricted atrophic gastritis at long-term follow-up. METHODS: A prospective single-center cohort of patients with corpus-restricted atrophic gastritis adhering to endoscopic-histological surveillance was considered. Follow-up gastroscopies were scheduled according to the management of epithelial precancerous conditions and lesions of the stomach guidelines. In case of new/worsening of known symptoms, gastroscopy was anticipated. Cox regression analyses and Kaplan-Meier survival curves were obtained. RESULTS: Two hundred seventy-five patients with corpus-restricted atrophic gastritis (72.0% female, median age 61 [23-84] years) were included. At a median follow-up of 5 (1-17) years, the annual incidence rate person-year was 0.5%, 0.6%, 2.8%, and 3.9% for GC/high-grade IEN, low-grade IEN, T1gNET, and all gastric neoplastic lesions, respectively. All patients showed at baseline operative link for gastritis assessment (OLGA)-2, except 2 low-grade (LG) IEN patients and 1 T1gNET patient with OLGA-1. Age older than 60 years (hazard ratio [HR] 4.7), intestinal metaplasia without pseudopyloric metaplasia (HR 4.3), and pernicious anemia (HR 4.3) were associated with higher risk for GC/HG-IEN or LG-IEN development and shorter mean survival time for progression (13.4, 13.2, and 11.1, respectively, vs 14.7 years, P = 0.01). Pernicious anemia was an independent risk factor for T1gNET (HR 2.2) and associated with a shorter mean survival time for progression (11.7 vs 13.6 years, P = 0.04) as well as severe corpus atrophy (12.8 vs 13.6 years, P = 0.03). DISCUSSION: Patients with corpus-restricted atrophic gastritis are at increased risk for GC and T1gNET despite low-risk OLGA scores, and those aged older than 60 years with corpus intestinal metaplasia or pernicious anemia seem to display a high-risk scenario.

Atopic dermatitis and risk of autoimmune conditions: Population-based cohort study.

BACKGROUND: Atopic dermatitis (AD) is associated with immune dysregulation, but epidemiologic data on the pattern of autoimmune comorbidity in people with AD are limited. OBJECTIVE: We sought to determine the risk of autoimmune conditions in people newly diagnosed with AD. METHODS: Retrospective cohort analysis (January 2009 to December 2018), using the UK-based Oxford-Royal College of General Practitioners Research and Surveillance Centre primary care database. We compared baseline prevalence and incidence after diagnosis of autoimmune conditions in 173,709 children and adults with new-onset AD and 694,836 age-, sex-, and general practitioner practice-matched controls. Outcomes were a composite of any autoimmune condition (Crohn disease, ulcerative colitis, celiac disease, pernicious anemia, type 1 diabetes, autoimmune hypothyroidism, Graves disease, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, Sjögren syndrome, vitiligo, alopecia areata, and multiple sclerosis) and each individual autoimmune condition. RESULTS: Preexisting autoimmune conditions were more common in people diagnosed with AD compared to controls (composite 5.8% vs 4.3%). Excluding people with preexisting autoimmune disease, there was an association between AD and incidence of new-onset autoimmune disease (composite adjusted hazard ratio [aHR] 1.28; 95% confidence interval [CI] 1.23-1.34). Risk was highest for more severe AD (aHR 1.99; 95% CI 1.77-2.23) than moderate AD (aHR 1.33; 95% CI 1.19-1.49) or mild AD (aHR 1.22; 95% CI 1.16-1.28). People with AD were at significantly increased risk of developing psoriatic arthritis, Sjögren syndrome, Crohn disease, vitiligo, alopecia areata, pernicious anemia, ulcerative colitis, rheumatoid arthritis, and hypothyroidism (aHR range 1.17-2.06), but not other autoimmune conditions. CONCLUSION: People with AD have an increased risk of multiple autoimmune conditions, especially those with more severe AD.

Associations Between Autoimmune Conditions and Gastric Cancer Risk Among Elderly Adults in the United States.

INTRODUCTION: Pernicious anemia (PA) is a risk factor for gastric cancer. Other autoimmune conditions may also contribute. METHODS: In a case-control study, we evaluated 47 autoimmune conditions among 39,125 gastric cancers and 200,000 cancer-free controls. RESULTS: Six conditions were associated with increased gastric cancer risk (range of adjusted odds ratios: 1.28-1.93, P < 0.05): PA, membranous nephropathy, primary biliary cirrhosis, pure red cell aplasia, primary sclerosing cholangitis, and Graves disease. PA was associated with 8 other autoimmune conditions (adjusted odds ratios: 1.57-4.54, P < 0.05). DISCUSSION: Autoimmune conditions associated with gastric cancer or PA may reflect effects of autoimmune gastritis or other carcinogenic pathways.

Cobalamin deficiency presenting with thrombotic microangiopathy (TMA) features: A systematic review.

INTRODUCTION: Cobalamin deficiency may result in hematologic characteristics similar to thrombotic microangiopathy (TMA). To facilitate diagnosis, we reviewed reported cases of acquired cobalamin deficiency presenting with TMA features (c.def-TMA). METHODS: A literature search identified reports of c.def-TMA. Deficiency was defined as B12 levels of <118 pmol/L. Corrected reticulocyte counts and reticulocyte production indexes were calculated. Clinical features were presented as proportion abnormal and results summarized as medians and interquartile ranges (IQR). RESULTS: Patient level data was extracted from 41 identified cases. Median age (years) was 43 (30-55) with 21/41 (51%) being female. Cobalamin deficiency was noted in 35/40 (87.5%) but fold increases in MMA and HC were 30 and 6, respectively. The etiology was pernicious anemia in 28/41 (68%) cases. Anemia was both universal and severe, with hemoglobin levels of 55 g/L (4.7-6.6). Hypersegmented neutrophils were noted in 23/37 (62%), schistocytes in 29/38 (76%) and median LDH levels 3981 U/L (2004-5467). The RPI was <3.0% in all patients. Thrombocytopenia occurred in 33/41 (80.5%) with a median platelet count of 91 × 109/L (42-112). Plasma infusion or exchange was initiated in 14/41 (34%) with associated complications in 2 cases. CONCLUSION: Reticulocytopenia (RPI of <3.0%) was a universal finding that aids in differentiating c.def-TMA from other causes of hemolysis. C.def-TMA was associated with severe anemia, generally mild-moderate thrombocytopenia, and significant elevations in LDH.

Polyglandular autoimmune syndrome type III with a prevalence of cutaneous features.

Polyglandular autoimmune syndrome (PAS) is the name given to a group of autoimmune disorders of the endocrine glands. PAS type III (PAS III) comprises several autoimmune diseases (autoimmune thyroiditis, immune-mediated diabetes mellitus, pernicious anaemia, vitiligo, alopecia areata and many others) and is subdivided into four subcategories. We report the case of a 52-year-old woman with autoimmune thyroiditis, vitiligo, alopecia areata, psoriasis and lichen sclerosus, suggesting a clinical diagnosis of PAS IIIC with a singular prevalence of cutaneous features.

Anemia and hematinic deficiencies in anti-gastric parietal cell antibody-positive and -negative recurrent aphthous stomatitis patients with anti-thyroid antibody positivity.

BACKGROUND/PURPOSE: Serum anti-gastric parietal cell (GPCA), anti-thyroglobulin (TGA), and anti-thyroid microsomal antibodies (TMA) can be found in some recurrent aphthous stomatitis (RAS) patients. This study mainly assessed whether serum GPCA, TGA, TMA and RAS itself played significant roles in causing anemia and hematinic deficiencies in TGA/TMA-positive RAS patients with GPCA positivity (GPCA+/TGA/TMA/RAS patients) or negativity (GPCA-/TGA/TMA/RAS patients). METHODS: The mean corpuscular volume (MCV) and mean blood hemoglobin (Hb), iron, vitamin B12, and folic acid levels were measured and compared between any two of the four groups of 15 GPCA+/TGA/TMA/RAS patients, 69 GPCA-/TGA/TMA/RAS patients, 240 all autoantibodies-negative RAS patients (Abs-/RAS patients), and 342 healthy control subjects. RESULTS: GPCA+/TGA/TMA/RAS patients had significantly lower mean Hb (for men only) and vitamin B12 levels as well as significantly greater frequencies of Hb, iron, and vitamin B12 deficiencies than healthy control subjects. GPCA+/TGA/TMA/RAS patients had lower serum vitamin B12 level and higher MCV as well as a significantly greater frequency of vitamin B12 deficiency than GPCA-/TGA/TMA/RAS patients. Furthermore, both GPCA-/TGA/TMA/RAS and Abs-/RAS patients did have significantly lower mean Hb, MCV, and iron levels as well as significantly greater frequencies of Hb, iron and vitamin B12 deficiencies than healthy control subjects. There were no significant differences in blood data between GPCA-/TGA/TMA/RAS and Abs-/RAS patients CONCLUSION: Both serum GPCA positivity and RAS itself are the contributing factors causing anemia and hematinic deficiencies in GPCA+/TGA/TMA/RAS patients. RAS itself but not TGA/TMA positivity plays a significant role in causing anemia and hematinic deficiencies in GPCA-/TGA/TMA/RAS patients.

Anemia and hematinic deficiencies in gastric parietal cell antibody-positive and antibody-negative erosive oral lichen planus patients with thyroid antibody positivity.

BACKGROUND/PURPOSE: Serum gastric parietal cell antibody (GPCA), thyroglobulin antibody (TGA), and thyroid microsomal antibody (TMA) are found in some erosive oral lichen planus (EOLP) patients. This study assessed whether serum GPCA, TGA and TMA and EOLP itself played significant roles in causing anemia and hematinic deficiencies in TGA/TMA-positive EOLP patients with GPCA positivity (GPCA+/TGA/TMA/EOLP patients) or negativity (GPCA-/TGA/TMA/EOLP patients). METHODS: The mean corpuscular volume (MCV) and mean blood hemoglobin (Hb), iron, vitamin B12, and folic acid levels were measured and compared between any two of the four groups of 29 GPCA+/TGA/TMA/EOLP patients, 80 GPCA-/TGA/TMA/EOLP patients, 198 all antibodies-negative EOLP patients (Abs-/EOLP patients), and 218 healthy control individuals. RESULTS: GPCA+/TGA/TMA/EOLP patients had significantly lower mean Hb and vitamin B12 levels as well as significantly greater frequencies of Hb, iron, and vitamin B12 deficiencies than healthy controls. GPCA+/TGA/TMA/EOLP patients had significantly lower serum vitamin B12 level and higher MCV as well as a significantly greater frequency of vitamin B12 deficiency than GPCA-/TGA/TMA/EOLP patients. Furthermore, both GPCA-/TGA/TMA/EOLP and Abs-/EOLP patients did have significantly lower mean Hb, MCV, and iron (for women only) levels, as well as significantly greater frequencies of Hb and iron deficiencies than healthy controls. However, there were no significant differences in measured blood data between GPCA-/TGA/TMA/EOLP and Abs-/EOLP patients. CONCLUSION: We conclude that serum GPCA is the major factor causing vitamin B12 deficiency, macrocytosis and pernicious anemia in GPCA+/TGA/TMA/EOLP patients. ELOP itself but not TGA/TMA positivity plays a significant role in causing anemia and hematinic deficiencies in GPCA-/TGA/TMA/EOLP patients.

Pernicious Anaemia with Gastric Carcinoids.

We report the case of a 42 year male with history of chronic anaemia who was found to have pernicious anaemia with beta thalassemia trait and had on esophago-gastric-duodenoscopy, gastric carcinoids with gastric atrophy. Pernicious anaemia and gastric carcinoids occurring simultaneously in a single individual is rare. Our case emphasises the need for esophago-gastric-duodenoscopy in cases of pernicious anaemia.

Cancer Risk After Pernicious Anemia in the US Elderly Population.

BACKGROUND & AIMS: Pernicious anemia, a result of autoimmune gastritis, is the most common cause of vitamin B12 deficiency, affecting 2% to 5% of the elderly population. Treatment with vitamin B12 cures the anemia, but not the gastritis. Findings from small studies have indicated that patients with pernicious anemia could have an increased risk of cancer. METHODS: We performed a population-based, case-control study of individuals in the Surveillance, Epidemiology, and End Results-Medicare database, comparing 1,138,390 cancer cases (age, 66-99 y) with 100,000 matched individuals without cancer (controls). Individuals with pernicious anemia were identified based on their medical claims within the year before selection for the study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression, and models were adjusted for sex, age, and calendar year of diagnosis and selection. RESULTS: Compared with controls, we found individuals with pernicious anemia to be at increased risk for noncardia gastric adenocarcinoma (OR, 2.18; 95% CI, 1.94-2.45) and gastric carcinoid tumors (OR, 11.43; 95% CI, 8.90-14.69). In addition, people with pernicious anemia have an increased risk of developing tonsilar cancer (OR, 2.00; 95% CI, 1.40-2.85), hypopharyngeal cancer (OR, 1.92; 95% CI, 1.35-2.73), esophageal squamous cell carcinoma (OR, 2.12; 95% CI, 1.76-2.55), small intestinal cancer (OR, 1.63; 95% CI, 1.32-2.02), liver cancer (OR, 1.49; 95% CI, 1.28- 1.73), myeloma (OR, 1.55; 95% CI, 1.37-1.75), acute myeloid leukemia (OR, 1.68; 95% CI, 1.46-1.93), and myelodysplastic syndrome (OR, 2.87; 95% CI, 2.53-3.26). People with pernicious anemia have a lower risk of rectal cancer than the general population (OR, 0.82; 95% CI, 0.74- 0.92). CONCLUSIONS: In a population-based, case-control study of individuals in the Surveillance, Epidemiology, and End Results-Medicare database, we found individuals with pernicious anemia to have significantly increased risks of gastric carcinoid tumors, adenocarcinomas, and other cancers located throughout the body.