A case of IgG4-related disease associated with ulcerative colitis that was successfully treated with a JAK inhibitor.

Glucocorticoids (GC) are the standard of care for the induction and maintenance of remission in immunoglobulin G4 (IgG4)-related diseases. However, IgG4-related diseases often relapse with GC dose reduction, not only making GC dose reduction difficult but also necessitating GC dose escalation in many cases. Therefore, other immunosuppressive drugs are required to maintain remission. Here, we report a 39-year-old man with ulcerative colitis and IgG4-related disease who experienced a relapse of both diseases despite treatment with tacrolimus and 6-mercaptopurine. Following the initiation of tofacitinib, a Janus-associated kinase inhibitor, it was possible to reduce the GC dose while maintaining remission of both diseases. This case highlights the potential utility of Janus-associated kinase inhibitors in managing complex cases of IgG4-related disease, especially those with concurrent conditions such as ulcerative colitis.

HLA-DRB1 Is Associated with Therapeutic Responsiveness in IgG4-related Disease.

Objective Glucocorticoids are key drugs used in remission induction therapy for IgG4-related disease (IgG4-RD). However, the therapeutic outcomes vary widely, with some patients requiring long-term maintenance therapy and others relapsing repeatedly, whereas still others can tolerate withdrawal. These variations underscore the need for personalized treatment strategies for IgG4-RD. We examined the relationship between human leukocyte antigen (HLA) genotypes and the response to glucocorticoid treatment in patients with IgG4-RD. Methods Eighteen IgG4-RD patients visiting our hospital were included in the study. Peripheral blood samples were collected, HLA genotypes were determined, and the response to glucocorticoid treatment (maintenance dose at the time of last observation, glucocorticoid dose when the serum IgG4 level was the lowest after remission induction therapy, and occurrence of relapse) was examined retrospectively. Results The DQB1*12:01 genotypes were associated with a prednisolone maintenance dose of <7 mg/day. A prednisolone dose ≥10 mg with a minimum serum IgG4 level was significantly more common in B*40:01 and DRB1-GB-7-Val (DRB1*04:01, *04:03, *04:05, *04:06, and *04:10) patients than other alleles. Relapse also tended to be more common in DRB1-GB-7-Val carriers than other alleles. Conclusion These data suggest that HLA-DRB1 is associated with glucocorticoid treatment responsiveness and is important for follow-up monitoring of serum IgG4 levels during glucocorticoid tapering. We believe that these data will contribute to the future development of personalized medicine for IgG4-RD.

Analysis of the saliva microbiome in patients with immunoglobulin G4-related disease.

OBJECTIVES: This article aims to investigate the saliva microbiome in patients with immunoglobulin G4-related disease (IgG4RD) compared with primary Sjögren's syndrome (SS). METHODS: Saliva samples were collected from 11 IgG4RD and 11 SS patients who visited IMSUT Hospital, The Institute of Medical Science, The University of Tokyo. Deoxyribonucleic acid (DNA) was extracted from the samples, and primers were used to amplify the V3-V4 regions of bacterial and archaeal 16S ribosomal RNA (rRNA) genes, which was then analysed by paired-end sequencing. Amplicon reads were processed using QIIME2 to generate representative sequences. The Greengenes database was used to identify the bacterial flora in each sample and compare them between groups. RESULTS: The IgG4RD and SS groups exhibited differences in bacterial diversity. Cluster analyses of attributed classification groups by species and disease showed that IgG4RD and SS cases formed individual clusters. Significant differences in relative abundance between IgG4RD and SS were observed for the following organisms: Mogibacterium (P = .0051), Solobacterium moorei (P = .0195), Slackia (P = .0356), and Moryella (P = .0455). CONCLUSIONS: Salivary microbiome analysis of IgG4RD and SS patients revealed significantly higher relative proportions of Mogibacterium, S. moorei, Slackia, and Moryella bacteria in IgG4RD compared with SS.

Extraction of characteristic serum microRNAs and prediction of target genes in IgG4-related dacryoadenitis and sialadenitis.

OBJECTIVES: To identify the specific microRNAs (miRNAs) in IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) and predict the targeted genes. METHODS: miRNAs in the serum of nine patients with IgG4-DS, three patients with primary Sjögren's syndrome, and three healthy controls were analysed using the human miRNA chip, and miRNAs that exhibited significant fluctuation in expression in IgG4-DS patients were extracted. The respective target genes were predicted using an existing database, and expression of the target genes was evaluated in actual submandibular gland tissues affected by IgG4-DS. RESULTS: Serum miR-125a-3p and miR-125b-1-3p levels were elevated in IgG4-DS. Six candidate target genes (glypican 4, forkhead box C1, protein tyrosine phosphatase non-receptor type 3, hydroxycarboxylic acid receptor 1, major facilitator superfamily domain containing 11, and tumour-associated calcium signal transducer 2) were downregulated in the affected submandibular gland tissue. CONCLUSION: Overexpression of miR-125a-3p and miR-125b-1-3p is a hallmark of IgG4-DS. These miRNAs appear to be involved in the pathogenesis of IgG4-DS.

IgG4-related Disease Emerging after COVID-19 mRNA Vaccination.

A 78-year-old Japanese woman with no history of rheumatic disease received 2 doses of the BNT162b2 COVID-19 mRNA vaccine. Two weeks later, she noticed bilateral swelling in the submandibular region. Blood tests showed hyper-immunoglobulin (Ig)G4emia, and 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) revealed the strong accumulation of FDG in the enlarged pancreas. She was diagnosed with IgG4-related disease (IgG4-RD) according to the American College of Rheumatology (ACR)/the European League Against Rheumatism (EULAR) classification criteria. Treatment was started with prednisolone at 30 mg/day, and the organ enlargement improved. We herein report a case of IgG4-RD that may have been associated with an mRNA vaccine.

Positive antiphospholipid antibodies and pulmonary embolism in a patient with adalimumab-induced lupus.

It is known that administration of tumor necrotic factor (TNF) inhibitors induces lupus. The case of a Crohn's disease patient who had been treated with adalimumab (ADA) and showed positive anti-DNA and antiphospholipid antibodies and developed pulmonary embolism is presented. Fortunately, early diagnosis and intervention helped her survive. Although ADA was withdrawn, the Crohn's disease did not recur, and the autoantibodies became negative without any steroid therapy. It is important to recognise that administration of TNF inhibitors may be associated with antiphospholipid syndrome. It is necessary to perform therapeutic interventions such as TNF inhibitor withdrawal and prompt anticoagulant therapy when such pathology is suspected.

The differential diagnosis of IgG4-related disease based on machine learning.

INTRODUCTION: To eliminate the disparity and maldistribution of physicians and medical specialty services, the development of diagnostic support for rare diseases using artificial intelligence is being promoted. Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a rare disorder often requiring special knowledge and experience to diagnose. In this study, we investigated the possibility of differential diagnosis of IgG4-RD based on basic patient characteristics and blood test findings using machine learning. METHODS: Six hundred and two patients with IgG4-RD and 204 patients with non-IgG4-RD that needed to be differentiated who visited the participating institutions were included in the study. Ten percent of the subjects were randomly excluded as a validation sample. Among the remaining cases, 80% were used as training samples, and the remaining 20% were used as test samples. Finally, validation was performed on the validation sample. The analysis was performed using a decision tree and a random forest model. Furthermore, a comparison was made between conditions with and without the serum IgG4 concentration. Accuracy was evaluated using the area under the receiver-operating characteristic (AUROC) curve. RESULTS: In diagnosing IgG4-RD, the AUROC curve values of the decision tree and the random forest method were 0.906 and 0.974, respectively, when serum IgG4 levels were included in the analysis. Excluding serum IgG4 levels, the AUROC curve value of the analysis by the random forest method was 0.925. CONCLUSION: Based on machine learning in a multicenter collaboration, with or without serum IgG4 data, basic patient characteristics and blood test findings alone were sufficient to differentiate IgG4-RD from non-IgG4-RD.

COVID-19 with essential thrombocythemia treated with apixaban for antithrombotic prophylaxis.

A 40-year-old man was admitted to our hospital for COVID-19. He had been treated for essential thrombocythemia (ET). He was diagnosed severe illness of COVID-19, oxygen therapy and dexamethasone were administered. There was a possibility of thromboembolic events in this case, apixaban for prophylaxis was added. With these treatments, the patient has made a good recovery, and he was discharged on hospital day 11. There is no standard strategy for prophylaxis of thrombosis in patients with ET, and apixaban could be a clinical benefit for these patients.

Interleukin 5-producing ST2+ memory Th2 cells in IgG4-related dacryoadenitis and sialadenitis.

Objectives: Immunoglobulin (Ig) G4-related disease (IgG4-RD) is often complicated by allergic disorders. This study was conducted to investigate the mechanism of type 2 helper T-inflammation (Th2-inflammation) in IgG4-related dacryoadenitis and sialadenitis (IgG4-DS). Methods: We separated and analyzed the proportion of growth stimulation expressed gene 2 (ST2)+ memory Th2 cells among the peripheral blood mononuclear cells by flow cytometry in cases with IgG4-DS and healthy individuals. Finally, we identified the role of ST2+ memory Th2 cells in the involved tissues. Results: The proportion of circulating ST2+ memory Th2 cells was much higher in the patients with IgG4-DS than in the healthy controls. Abundant infiltration of ST2+ memory Th2 cells was detected in the involved salivary glands and lymph nodes, and these cells produced interleukin-5. Conclusion: We demonstrated that there is an increase of interleukin-5 producing ST2+ memory Th2 cells in the involved tissues in IgG4-DS. This subset of cells is considered to be an important player in inducing the inflammatory Th2 environment characteristic of IgG4-DS.