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European Journal of Case Reports in... 2024Autoimmune diseases are not contraindications for immune checkpoint inhibitors (ICI) therapy in patients with cancer. However, immune-related adverse events (irAEs) are...
BACKGROUND
Autoimmune diseases are not contraindications for immune checkpoint inhibitors (ICI) therapy in patients with cancer. However, immune-related adverse events (irAEs) are frequently observed in patients receiving ICIs including dermatitis, thyroiditis, colitis, and pneumonitis. Thrombocytopenic purpura, aplasia, and haemophagocytic lymphohistiocytosis (HLH) are rarely observed during ICIs.
CASE DESCRIPTION
We report the case of a male patient with pre-existing untreated HLA B27 and ankylosing spondylitis with gastric cancer and liver metastases. The 79-year-old man was treated with anti-HER2 trastuzumab and anti-PD-1 nivolumab. Seventeen days after the seventh cycle of treatment, he presented at the emergency department with acute fever, confusion, and hypotension. Laboratory results showed pancytopenia, and elevation of ferritin and triglyceride. No infections were detected. Although not seen in a bone marrow biopsy, clinical presentation, and absence of infection, together with an H-score of 263, indicated HLH. The patient was treated with dexamethasone for four days and discharged on a tapering dose of steroids. At the two-month follow-up, clinical presentation was normal and blood test almost normalised. At 8 months, no liver metastases were observed.
CONCLUSIONS
In a patient with a pre-existing autoimmune condition, immunotherapy led to the development of HLH, which was controlled by glucocorticoid. Absence of the feature of haemophagocytosis in the bone marrow biopsy did not exclude the diagnosis, as HLH can occur in the spleen or in the liver. Glucocorticoid therapy did not prevent the anti-cancer effect of ICIs, and liver metastases disappeared 8 months post-HLH. This case warrants further research on the interplay between autoimmunity and ICI response, as well as ICI-induced irAEs.
LEARNING POINTS
Haemophagocytic lymphohistiocytosis (HLH) post seventh cycle of trastuzumab (anti-HER2) and nivolumab (anti-PD-1) was controlled with glucocorticoid.Breach of tolerance was due to immunotherapy-induced HLH in a patient with pre-existing autoimmune condition (HLA B27- positive ankylosing spondylitis).There was a complete disappearance of liver metastases 8 months post-HLH.
PubMed: 38715877
DOI: 10.12890/2024_004370 -
General Hospital Psychiatry 2024To investigate whether the association between depression and inflammatory joint disease (IJD; rheumatoid arthritis [RA], psoriatic arthritis [PsA], ankylosing...
OBJECTIVE
To investigate whether the association between depression and inflammatory joint disease (IJD; rheumatoid arthritis [RA], psoriatic arthritis [PsA], ankylosing spondylitis/spondyloarthropathies [AS], and juvenile idiopathic arthritis [JIA]) is affected by the severity or treatment-resistance of depression.
METHOD
Parallel cohort studies and case-control studies among 600,404 patients with a depressive episode identified in Swedish nationwide administrative registers. Prospective and retrospective risk for IJD in patients with depression was compared to matched population comparators, and the same associations were investigated in severe or treatment-resistant depression. Analyses were adjusted for comorbidities and sociodemographic covariates.
RESULTS
Patients with depression had an increased risk for later IJD compared to population comparators (adjusted hazard ratio (aHR) for any IJD 1.34 [95% CI 1.30-1.39]; for RA 1.27 [1.15-1.41]; PsA 1.45 [1.29-1.63]; AS 1.32 [1.15-1.52]). In case-control studies, patients with depression more frequently had a history of IJD compared to population controls (adjusted odds ratio (aOR) for any IJD 1.43 [1.37-1.50]; RA 1.39 [1.29-1.49]; PsA 1.59 [1.46-1.73]; AS 1.49 [1.36-1.64]; JIA 1.52 [1.35-1.71]). These associations were not significantly different for severe depression or TRD.
CONCLUSION
IJD and depression are bidirectionally associated, but this association does not seem to be influenced by the severity or treatment resistance of depression.
Topics: Humans; Sweden; Female; Male; Case-Control Studies; Adult; Middle Aged; Depressive Disorder, Treatment-Resistant; Comorbidity; Arthritis, Rheumatoid; Arthritis, Psoriatic; Aged; Registries; Severity of Illness Index; Spondylitis, Ankylosing; Arthritis, Juvenile; Young Adult; Cohort Studies; Adolescent
PubMed: 38714100
DOI: 10.1016/j.genhosppsych.2024.04.007 -
Frontiers in Immunology 2024Previous research has partially revealed distinct gut microbiota in ankylosing spondylitis (AS). In this study, we performed non-targeted fecal metabolomics in AS in...
OBJECTIVE
Previous research has partially revealed distinct gut microbiota in ankylosing spondylitis (AS). In this study, we performed non-targeted fecal metabolomics in AS in order to discover the microbiome-metabolome interface in AS. Based on prospective cohort studies, we further explored the impact of the tumor necrosis factor inhibitor (TNFi) on the gut microbiota and metabolites in AS.
METHODS
To further understand the gut microbiota and metabolites in AS, along with the influence of TNFi, we initiated a prospective cohort study. Fecal samples were collected from 29 patients with AS before and after TNFi therapy and 31 healthy controls. Metagenomic and metabolomic experiments were performed on the fecal samples; moreover, validation experiments were conducted based on the association between the microbiota and metabolites.
RESULTS
A total of 7,703 species were annotated using the metagenomic sequencing system and by profiling the microbial community taxonomic composition, while 50,046 metabolites were identified using metabolite profiling. Differential microbials and metabolites were discovered between patients with AS and healthy controls. Moreover, TNFi was confirmed to partially restore the gut microbiota and the metabolites. Multi-omics analysis of the microbiota and metabolites was performed to determine the associations between the differential microbes and metabolites, identifying compounds such as oxypurinol and biotin, which were correlated with the inhibition of the pathogenic bacteria and the promotion of the probiotic bacteria . Through experimental studies, the relationship between microbes and metabolites was further confirmed, and the impact of these two types of microbes on the enterocytes and the inflammatory cytokine interleukin-18 (IL-18) was explored.
CONCLUSION
In summary, multi-omics exploration elucidated the impact of TNFi on the gut microbiota and metabolites and proposed a novel therapeutic perspective: supplementation of compounds to inhibit potential pathogenic bacteria and to promote potential probiotics, therefore controlling inflammation in AS.
Topics: Humans; Spondylitis, Ankylosing; Gastrointestinal Microbiome; Probiotics; Male; Female; Metabolome; Adult; Feces; Metagenomics; Middle Aged; Prospective Studies; Metabolomics; Bacteria; Tumor Necrosis Factor Inhibitors
PubMed: 38711505
DOI: 10.3389/fimmu.2024.1369116 -
Journal of Clinical Hypertension... May 2024Ankylosing spondylitis (AS) is a chronic inflammatory arthritis affecting the spine, presenting a considerable morbidity risk. Although evidence consistently indicates...
Ankylosing spondylitis (AS) is a chronic inflammatory arthritis affecting the spine, presenting a considerable morbidity risk. Although evidence consistently indicates an elevated risk of ischemic heart disease among AS patients, debates persist regarding the likelihood of these patients developing left ventricular dysfunction (LVD). Our investigation aimed to determine whether individuals with AS face a greater risk of LVD compared to the general population. To accomplish this, we identified studies exploring LVD in AS patients across five major databases and Google Scholar. Initially, 431 studies were identified, of which 30 met the inclusion criteria, collectively involving 2933 participants. Results show that AS patients had: (1) poorer Ejection Fraction (EF) [mean difference (MD): -0.92% (95% CI: -1.25 to -0.59)], (2) impaired Early (E) and Late (atrial-A) ventricular filling velocity (E/A) ratio [MD: -0.10 m/s (95% CI: -0.13 to -0.08)], (3) prolonged deceleration time (DT) [MD: 12.30 ms (95% CI: 9.23-15.36)] and, (4) a longer mean isovolumetric relaxation time (IVRT) [MD: 8.14 ms (95% CI: 6.58-9.70)] compared to controls. Though AS patients show increased risks of both systolic and diastolic LVD, we found no significant differences were observed in systolic blood pressure [MD: 0.32 mmHg (95% Confidence Interval (CI): -2.09 to 2.73)] or diastolic blood pressure [MD: 0.30 mmHg (95% CI: -0.40 to 1.01)] compared to the general population. This study reinforces AS patients' susceptibility to LVD without a notable difference in HTN risk.
PubMed: 38708932
DOI: 10.1111/jch.14827 -
Molecular Biology Reports May 2024Ankylosing spondylitis (AS) is often regarded as the prototypical manifestation of spondylo-arthropathies that prevalently involves the axial skeleton with the potential...
A study of the association between single nucleotide polymorphisms of the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene and the risk of ankylosing spondylitis in Egyptians.
BACKGROUND
Ankylosing spondylitis (AS) is often regarded as the prototypical manifestation of spondylo-arthropathies that prevalently involves the axial skeleton with the potential attribution of ERAP2 polymorphisms to AS predisposition. The purpose of this study was to determine the genetic association between ERAP2 gene rs2910686, and rs2248374 single nucleotide polymorphisms (SNPs) and the risk of ankylosing spondylitis in the Egyptian population.
METHODS AND RESULTS
A cross-sectional work involved 200 individuals: 100 AS individuals diagnosed based on modified New York criteria in 1984 with 100 healthy controls matched in age and gender. The study included a comprehensive evaluation of historical data, clinical examinations, and evaluation of the activity of the disease using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). A comprehensive laboratory and radiological evaluation were conducted, accompanied by an assessment and genotyping of the ERAP2 gene variants rs2248374 and rs2910686. This genotyping was performed utilizing a real-time allelic discrimination methodology.Highly statistically substantial variations existed among the AS patients and the healthy control group regarding rs2910686 and rs2248374 alleles. There was a statistically significant difference between rs2910686 and rs2248374 regarding BASDAI, BASFI, mSASSS, ASQoL, V.A.S, E.S.R, and BASMI in the active AS group.
CONCLUSIONS
ERAP2 gene SNPs have been identified as valuable diagnostic biomarkers for AS patients in the Egyptian population being a sensitive and non-invasive approach for AS diagnosis especially rs2910686. Highly statistically significant variations existed among the AS patients and the healthy control group regarding rs2910686 alleles and genotypes.Further research is recommended to explore the potential therapeutic implications of these SNPs.
Topics: Adult; Female; Humans; Male; Middle Aged; Alleles; Aminopeptidases; Case-Control Studies; Cross-Sectional Studies; Egypt; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; North African People; Polymorphism, Single Nucleotide; Spondylitis, Ankylosing
PubMed: 38704785
DOI: 10.1007/s11033-024-09404-w -
Biomarker Research May 2024The human leukocyte antigen (HLA) genes, exhibiting significant genetic diversity, are associated with susceptibility to various clinical diseases and diverse in drug...
BACKGROUND
The human leukocyte antigen (HLA) genes, exhibiting significant genetic diversity, are associated with susceptibility to various clinical diseases and diverse in drug responses. High costs of HLA sequencing and the population-specific architecture of this genetic region necessitate the establishment of a population-specific HLA imputation reference panel. Moreover, there is a lack of understanding about the genetic and phenotypic landscape of HLA variations within the Taiwanese population.
METHODS
We created models for a Taiwanese-specific HLA imputation reference panel. These models were trained with the array genotype data and HLA sequencing data from 845 Taiwanese subjects. HLA imputation was applied for 59,448 Taiwanese subjects to characterize the HLA allele and haplotype frequencies. Additionally, a phenome-wide association study (PheWAS) was conducted to identify the phenotypes associated with HLA variations. The association of the biallelic HLA variants with the binary and quantitative traits were evaluated with additive logistic and linear regression models, respectively. Furthermore, an omnibus test with likelihood-ratio test was applied for each HLA amino acid position in the multiallelic HLA amino acid polymorphisms to compare the difference between a fitted model and a null model following a χ2 distribution of n-1 degree of freedom at a position with n residues. Finally, we estimated the prevalence of adverse drug reactions (ADR)-related HLA alleles in the Taiwanese population.
RESULTS
In this study, the reference panel models displayed remarkable accuracy, with averages of 99.3%, 98.9%, and 99.1% for 2-, 4-, 6-digit alleles of the eight classical HLA genes, respectively. For PheWAS, a total of 18,136 significant associations with HLA variants across 26 phenotypes are identified (p < 5×10), highlighting the pleiotropy feature of the HLA region. Among the independent signals, 15 are novel, including the association of HLA-B pos 138 variation with ankylosing spondylitis (AS), and rs9266290 and rs9266292 with allergy. Through an analysis spanning the entire HLA region, we identified clusters of phenotype correlations. Finally, the carriers of pharmacogenomic related HLA alleles, including HLA-C*01:02 (35.86%), HLA-B*58:01 (20.9%), and HLA-B*15:02 (8.38%), were characterized in the Taiwanese general population.
CONCLUSIONS
We successfully delivered the HLA imputation for 59,448 Taiwanese subjects and characterized the genetic and phenotypic landscapes of the HLA variations. In addition, we quantified the estimated prevalence of the ADR-related HLA alleles in the Taiwanese population. The developed HLA imputation reference panel could be used for estimation of population HLA allele frequencies, which can facilitate further studies in the role of HLA variants in a wider range of phenotypes in the population.
PubMed: 38702819
DOI: 10.1186/s40364-024-00591-z -
BMC Medical Genomics May 2024Observational studies that reveal an association between periodontitis (PD) and ankylosing spondylitis (AS) exist. However, observational research is prone to reverse...
BACKGROUND
Observational studies that reveal an association between periodontitis (PD) and ankylosing spondylitis (AS) exist. However, observational research is prone to reverse causality and confounding factors, which make it challenging to infer cause-and-effect relationships. We conducted a two-sample Mendelian randomization (MR) study to examine the causal relationship between the genetic prediction of PD and AS.
METHODS
In our study, single-nucleotide polymorphisms (SNPs) were defined as instrumental variables (IVs). The genetic association with PD came from the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) consortium, wherein 17353 cases of European ancestry and 28210 controls of European ancestry were included in this study. The genetic association with AS from the Neale Laboratory Consortium included 337,159 individuals from the United Kingdom, with 968 cases and 336,191 controls. MR analysis was mainly performed using the inverse-variance weighted (IVW) method. In addition, the robustness of the study findings was assessed using sensitivity, pleiotropy, and heterogeneity analyses.
RESULTS
Eighteen independent SNPs with P-values significantly smaller than 1 × 10 were used as IV SNPs for PD, while 39 independent SNPs with P-values significantly smaller than 1 × 10 were used as IV SNPs for AS. The results of the IVW method revealed no causal association between PD and AS (odds ratio = 1.00, 95% confidence interval: 0.99953 to 1.00067, P = 0.72). The MR-Egger method did not support the causal association between PD and AS. It is unlikely that horizontal pleiotropy distorts causal estimates based on sensitivity analysis. No significant heterogeneity was observed in the Q test. The ''leave-one-out'' analysis demonstrated that the robustness of our results was unaffected by eliminating any of the IVs. Likewise, no significant causative effect for AS on PD was observed in the inverse MR analysis.
CONCLUSIONS
The study results do not support shared heritability or a causal association between PD and AS.
Topics: Spondylitis, Ankylosing; Mendelian Randomization Analysis; Humans; Polymorphism, Single Nucleotide; Periodontitis; Genetic Predisposition to Disease
PubMed: 38698441
DOI: 10.1186/s12920-024-01845-3 -
Rheumatology and Therapy Jun 2024In this commentary, we review clinical data which helps inform individualized benefit-risk assessment for tofacitinib in patients with psoriatic arthritis (PsA) and...
In this commentary, we review clinical data which helps inform individualized benefit-risk assessment for tofacitinib in patients with psoriatic arthritis (PsA) and ankylosing spondylitis (AS). ORAL Surveillance, a safety trial of patients ≥ 50 years of age with rheumatoid arthritis (RA) and cardiovascular risk factors, found increased rates of safety outcomes (including major adverse cardiovascular events [MACE], malignancies excluding non-melanoma skin cancer, and venous thromboembolism) with tofacitinib versus tumor necrosis factor inhibitors (TNFi). Post hoc analyses of ORAL Surveillance have identified subpopulations with different relative risk versus TNFi; higher risk with tofacitinib was confined to patients ≥ 65 years of age and/or long-time current/past smokers, and specifically for MACE, patients with a history of atherosclerotic cardiovascular disease (ASCVD). In patients without these risk factors, risk differences between tofacitinib and TNFi could not be detected. Given differences in demographics, pathophysiology, and comorbidities, we sought to examine whether the risk stratification observed in RA is also appropriate for PsA and AS. Data from the PsA tofacitinib development program show low absolute risk of safety outcomes in patients < 65 years of age and never smokers, and low MACE risk in patients with no history of ASCVD, consistent with results from ORAL Surveillance. No MACE, malignancies, or venous thromboembolism were reported in the tofacitinib AS development program. The mechanism of the ORAL Surveillance safety findings is unknown, and there are no similar prospective studies of sufficient size and duration. Accordingly, it is appropriate to use a precautionary approach and extrapolate differentiating risk factors identified from ORAL Surveillance (age ≥ 65 years, long-time current/past smoking, and history of ASCVD) to PsA and AS. We recommend an individualized approach to treatment decisions based on these readily identifiable risk factors, in line with updated labeling for Janus kinase inhibitors and international guidelines for the treatment of PsA and AS.Trial Registration: NCT02092467, NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661, NCT01877668, NCT01882439, NCT01976364, NCT00678210, NCT01710046, NCT01241591, NCT01186744, NCT01276639, NCT01309737, NCT01163253, NCT01786668, NCT03502616.
PubMed: 38696034
DOI: 10.1007/s40744-024-00662-5 -
Annals of Medicine and Surgery (2012) May 2024Interleukin-33 (IL-33), belonging to the interleukin-1 cytokine family, has a decoy receptor soluble ST2 (sST2). IL-33 is found in oligodendrocytes and astrocytes and is... (Review)
Review
Interleukin-33 (IL-33), belonging to the interleukin-1 cytokine family, has a decoy receptor soluble ST2 (sST2). IL-33 is found in oligodendrocytes and astrocytes and is involved in central nervous system healing and repair, whereas ST2 is found in microglia and astrocytes. Some studies have found a link between changes in the IL-33/ST2 pathway and neurodegenerative disorders. This review article investigates the relationship between the interleukin-33 (IL-33)/ST2 pathway and neurodegenerative disorders. It was discovered that soluble st2 levels were increased. Furthermore, IL-33 levels were found to be lower in many neurodegenerative diseases such as Alzheimer's and amyotrophic lateral sclerosis (ALS). The association with other disorders, such as ankylosing spondylitis, multiple sclerosis, and systemic lupus erythematosus (SLE), was also observed. Various studies suggest that ST2/IL-33 signalling may be pivotal in the disease modulation of neurodegenerative disorders. The serum sST2 level test can be useful in determining the inflammatory status and severity of illness in many neurodegenerative disorders. In this review, we will discuss recent findings concerning the interleukin-33 (IL-33)/ST2 pathway and its role in the diagnosis and treatment of diseases with neurodegeneration.
PubMed: 38694387
DOI: 10.1097/MS9.0000000000001939 -
Clinical Ophthalmology (Auckland, N.Z.) 2024To report the prevalences of other non-thyroid autoimmune diseases and identify factors associated with their presence in ocular myasthenia gravis (OMG) subjects.
PURPOSE
To report the prevalences of other non-thyroid autoimmune diseases and identify factors associated with their presence in ocular myasthenia gravis (OMG) subjects.
SUBJECTS AND METHODS
A total of 208 subjects with OMG diagnosis were included. Demographic data, clinical characteristics, the ice-pack test, the acetylcholine receptor (AChR) antibody test, electrophysiology tests (single-fiber electromyography and repetitive nerve stimulation), the presence of thymoma, generalized myasthenia gravis conversion, and the presence of other non-thyroid autoimmune diseases (defined as the presence of at least one other non-thyroid autoimmune disease) were retrospectively reviewed. Factors associated with the presence of other non-thyroid autoimmune diseases were analyzed by univariate and multivariate logistic regression.
RESULTS
Of the total 208 subjects, 21 (10.10%) exhibited the presence of other non-thyroid autoimmune diseases (19 subjects (9.14%) and 2 subjects (0.96%) had one and two other non-thyroid autoimmune diseases, respectively), and systemic lupus erythematosus (SLE) was diagnosed in 9 subjects, followed by Sjogren's syndrome (7 subjects), rheumatoid arthritis (6 subjects), and ankylosing spondylitis (1 subject). Therefore, the prevalences of SLE, Sjogren's syndrome, rheumatoid arthritis, and ankylosing spondylitis in OMG subjects were estimated to be 4.33% (95% confidence interval (CI): 2.29-8.02%), 3.37% (95% CI: 1.64-6.79%), 2.88% (95% CI: 1.33-6.14%), and 0.48% (95% CI: 0.08-2.67%), respectively. Positivity of the AChR antibody was the only significant factor associated with the presence of other non-thyroid autoimmune diseases (odds ratio 4.10, 95% CI: 1.11-15.21, = 0.035).
CONCLUSIONS
The presence of other non-thyroid autoimmune diseases was found in approximately 10% of OMG patients, with SLE displaying the highest prevalence. We recommend screening and monitoring for other non-thyroid autoimmune diseases in OMG patients, particularly those with positivity of the AChR antibody.
PubMed: 38686013
DOI: 10.2147/OPTH.S458979