Pattern classification of interstitial lung diseases from computed tomography images using a ResNet-based network with a split-transform-merge strategy and split attention.

In patients with interstitial lung disease (ILD), accurate pattern assessment from their computed tomography (CT) images could help track lung abnormalities and evaluate treatment efficacy. Based on excellent image classification performance, convolutional neural networks (CNNs) have been massively investigated for classifying and labeling pathological patterns in the CT images of ILD patients. However, previous studies rarely considered the three-dimensional (3D) structure of the pathological patterns of ILD and used two-dimensional network input. In addition, ResNet-based networks such as SE-ResNet and ResNeXt with high classification performance have not been used for pattern classification of ILD. This study proposed a SE-ResNeXt-SA-18 for classifying pathological patterns of ILD. The SE-ResNeXt-SA-18 integrated the multipath design of the ResNeXt and the feature weighting of the squeeze-and-excitation network with split attention. The classification performance of the SE-ResNeXt-SA-18 was compared with the ResNet-18 and SE-ResNeXt-18. The influence of the input patch size on classification performance was also evaluated. Results show that the classification accuracy was increased with the increase of the patch size. With a 32 × 32 × 16 input, the SE-ResNeXt-SA-18 presented the highest performance with average accuracy, sensitivity, and specificity of 0.991, 0.979, and 0.994. High-weight regions in the class activation maps of the SE-ResNeXt-SA-18 also matched the specific pattern features. In comparison, the performance of the SE-ResNeXt-SA-18 is superior to the previously reported CNNs in classifying the ILD patterns. We concluded that the SE-ResNeXt-SA-18 could help track or monitor the progress of ILD through accuracy pattern classification.

Estimation of life expectancy and healthcare cost in rheumatoid arthritis patients with and without depression: a population-based retrospective cohort study.

Purpose: This study aimed to estimate the lifetime healthcare costs and loss of life expectancy (loss-of-LE) among patients with incident rheumatoid arthritis (RA) with and without depression. Methods: This 18 years longitudinal cohort study used data from Taiwan's National Health Insurance Research Database. In total, 43,311 patients with RA were included. Among them, 1,663 patients had depressive disorders in the year preceding the RA diagnosis. The survival function for patients with RA with or without depression was estimated and extrapolated over a lifetime using the rolling extrapolation algorithm. The loss-of-LE was calculated by comparing the sex, age, and calendar year-matched referents from vital statistics. The average monthly cost was calculated as the sum of the monthly costs for all patients divided by the number of surviving patients. Lifetime healthcare costs were estimated by multiplying the monthly average cost by the monthly survival probability. Results: The loss-of-LE for RA patients with and without depression was 5.60 years and 4.76 years, respectively. The lifetime costs of RA patients with and without depression were USD$ 90,346 and USD$ 92,239, respectively. However, the annual healthcare costs were USD$ 4,123 for RA patients with depression and USD$ 3,812 for RA patients without depression. Regardless of sex or age, RA patients with depression had higher annual healthcare costs than those without depression. Conclusion: Patients with RA and depression have a high loss-of-LE and high annual healthcare costs. Whether treating depression prolongs life expectancy and reduces healthcare costs warrants further investigation.

Application of impulse oscillometry to detect interstitial lung disease and airway disease in adults with rheumatoid arthritis.

BACKGROUND: We conducted a retrospective observational study to explore the potential application of impulse oscillometry (IOS) as an alternative to high-resolution computed tomography (HRCT) for detecting pulmonary involvement in patients with rheumatoid arthritis (RA) because clinically evident interstitial lung disease (ILD) and airway involvement are common in this population. METHODS: We enrolled 72 patients with RA who underwent pulmonary function tests (PFTs) and IOS between September 2021 and September 2022. We aimed to identify the PFT and IOS variables associated with lung diseases shown on HRCT images. RESULTS: In our cohort of 72 patients, 48 underwent HRCT; of these, 35 had airway disease or ILD and 13 showed no obvious abnormalities on HRCT. Abnormal IOS and PFT parameters were observed in 34 and 23 patients, respectively, with abnormal HRCT images. The predicted percentages for forced vital capacity, the ratio of forced expiratory volume in the first one second to forced vital capacity, and forced mid-expiratory flow value were significantly lower in patients with abnormal HRCT. Lung resistance at 5 Hz, difference in resistance between 5 and 20 Hz, resonant frequency (Fres), and reactance area were higher in these patients and reactance at 5 Hz was lower. Compared to other parameters, Fres > 14.14 was significantly associated with alterations in HRCT and may be used as an indicator for monitoring disease. CONCLUSION: Fres > 14.14 is significantly associated with lung involvement in RA patients. Performance of spirometry with IOS is more beneficial than spirometry alone for evaluating lung involvement in RA patients.

Immune cell profiles of idiopathic inflammatory myopathy patients expressed anti-aminoacyl tRNA synthetase or anti-melanoma differentiation-associated gene 5 autoantibodies.

BACKGROUND: Patients with idiopathic inflammatory myopathy (IIM) often express a different type of myositis-specific autoantibodies (MSAs), each associated with different clinical symptoms. Understanding the immunopathogenesis of various IIM subgroups can help improve the diagnosis and prognosis of IIM patients with different MSAs. However, the immune cell profiles of these IIM patients with anti-aminoacyl tRNA synthetase (ARS) or anti-melanoma differentiation-associated gene 5 (MDA5) autoantibodies remain unclear. We focused on the immune cell profiles of IIM patients with anti-ARS or anti-MDA5 autoantibodies. RESULTS: The peripheral blood from IIM patients with anti-MDA5 autoantibody (MDA5 + group, n = 24) or one of the anti-ARS autoantibodies (ARS + group, n = 40) autoantibodies, and healthy controls (HC group, n = 60) were collected and examined. We found that IIM patients had a lower CD3 T cell population compared to the HC group. IIM patients showed a significantly lower TN cell population and a higher TEMRA cell population. Higher Th17 and Treg cell populations were found in these IIM patients than in the HC group. In these IIM patients, the MDA5 + group exhibited the higher percentages of Th17 and Treg cells than the ARS + group. It is noteworthy that the percentage of Th1 cells in the survival subgroup was higher than in the death subgroup in IIM patients with ARS + or MDA5 + . Furthermore, in the MDA5 + group, the percentage of Treg cells was higher in the survival subgroup compared to the death subgroup. CONCLUSIONS: Our study demonstrated that elevated Th1 may be a good prognostic indicator in IIM patients with ARS + or MDA5 + . Elevated Treg may also help predict a good prognosis in MDA5 + IIM patients. However, more large-scale studies and clinical samples are needed to verify the significance of Th1 and Treg cell subsets in clinical outcomes for these IIM patients with ARS + or MDA5 + . These data may help design a therapeutic approach that specifically targets the pathogenic immune molecular responsible for autoimmune attacks in IIM.

Elevated monocyte distribution width in patients with active adult-onset Still's disease: a novel activity indicator.

OBJECTIVES: Monocyte distribution width (MDW) correlates with volume modifications of circulating monocytes upon activation. Given the crucial role of monocyte activation in the pathogenesis of adult-onset Still's disease (AOSD), we aimed to examine the associations between MDW and disease activity or inflammatory parameters in this disease. METHODS: In 58 AOSD patients and 95 other patients with coronavirus disease 2019 (COVID-19) as disease control, MDW and complete blood count were determined using a UniCel DxH800 analyser. C-reactive protein (CRP) levels were measured by nephelometry, and ferritin levels by chemiluminescent immunoassay. AOSD activity was assessed using a modified Pouchot score. RESULTS: MDW was significantly higher in active AOSD patients (median 28.3, interquartile range [IQR] 23.3-32.1) compared with inactive AOSD (19.2, IQR 18.0-20.6, p<0.001) or non-severe COVID-19 patients (23.2, IQR 21.0-25.2, p<0.01). MDW was positively correlated with AOSD activity scores, CRP, and ferritin levels (all p<0.001). Longitudinal follow-up evaluation revealed that median MDW significantly declined (28.3 versus 18.5, p<0.001) along with disease activity, paralleling a decrease in CRP and ferritin levels. Severe COVID-19 and sepsis patients had elevated MDW, which were not different from active AOSD patients. Multivariate analysis revealed MDW as a significant predictor of active AOSD, and MDW threshold at 21.7 could predict an active status with a high sensitivity of 91.3% and specificity of 94.3%. CONCLUSIONS: Elevated MDW and its positive correlation with inflammatory parameters in AOSD patients indicate MDW as a novel activity indicator, with a high MDW value above 21.7 linked to a high probability of active AOSD.

Lifetime risk, life expectancy, loss-of-life expectancy, and lifetime healthcare expenditures for psoriasis in Taiwan: a nationwide cohort followed from 2000 to 2017.

Background: Patients with psoriasis have a significant disease burden throughout the life course. Nevertheless, the lifetime risk and disease burden of psoriasis across the entire lifespan is rarely quantified in an easily understandable way. Objective: To estimate the cumulative incidence rate, life expectancy, loss-of-life expectancy, and lifetime healthcare expenditures for incident psoriasis. Design and methods: Using real-world nationwide data from the National Health Insurance Research Database of Taiwan for 2000-2017, along with the life tables of vital statistics, we estimated cumulative incidence rate, life expectancy, loss-of-life expectancy, and lifetime healthcare expenditures for those with psoriasis using a semi-parametric survival extrapolation method. Results: A total of 217,924 new psoriasis cases were identified. The lifetime risk of psoriasis in patients aged 18-80 for both sexes decreased in Taiwan with a cumulative incidence rate of 7.93% in 2000 to 3.25% in 2017. The mean (±standard error) life expectancy after diagnosis was 27.11 (± 1.15) and 27.14 (±1.17) years for patients with moderate-to-severe psoriasis and psoriatic arthritis, respectively. Patients with moderate-to-severe psoriasis and psoriatic arthritis had a mean (±standard error) loss-of-life expectancy of 6.41 (±1.16) and 6.48 (±1.17) due to psoriasis, respectively. Male patients have higher lifetime and annual lifetime healthcare expenditures than female. Mean life expectancy, loss-of-life expectancy, and lifetime cost were relatively higher for younger patients. Conclusion: Among psoriatic patients, patients with moderate-to-severe psoriasis and psoriatic arthritis had substantial years of life lost, particularly for younger patients. Our results provide a reliable estimation of lifetime disease burden, and these estimates will help health authorities in cost-effectiveness assessments of public health interventions and allocation of services resources to minimize loss-of-life expectancy, and lifetime healthcare expenditures in patients with psoriasis.

Mirabegron is better tolerated than solifenacin in Sjogren's syndrome patients with overactive bladder symptoms-A randomized controlled trial.

OBJECTIVES: This study investigates the efficacy and adverse events of beta-3 agonists and antimuscarinic agents for managing overactive bladder syndrome in Sjogren syndrome. METHODS: Sjogren's syndrome patients with an Overactive Bladder Symptom Score (OABSS) >5 were enrolled and were randomly assigned to mirabegron 50 mg/day or solifenacin 5 mg/day. Patients were evaluated on the recruitment day and reassessed at Week 1, 2, 4, and 12. The study's primary endpoint was to have a significant change in OABSS at Week 12. The secondary endpoint was the adverse event and crossover rate. RESULTS: A total of 41 patients were included in the final analysis, with 24 in the mirabegron group and 17 in the solifenacin group. The study's primary outcome was a change of the OABSS at Week 12. We found that both mirabegron and solifenacin significantly reduce patients' OABSS after 12 weeks of treatment. The evolution of the OABSS was -3.08 for mirabegron and -3.71 for solifenacin (p = .56). Six out of 17 patients from the solifenacin group crossed over to the mirabegron arm due to severe dry mouth or constipation, while none from the mirabegron arm crossed over to the solifenacin group. Sjogren's syndrome-related pain was also improved in the mirabegron group (4.96-1.67, p = .008) compared to the solifenacin group (4.39-3.4, p = .49). CONCLUSIONS: Our study showed that mirabegron is equally effective as solifenacin in treating Sjogren's syndrome patients with overactive bladder. Mirabegron is superior to solifenacin in terms of treatment-related adverse events.

The detectable anti-interferon-γ autoantibodies in COVID-19 patients may be associated with disease severity.

BACKGROUND: Neutralizing anti-interferon (IFN)-γ autoantibodies are linked to adult-onset immunodeficiency and opportunistic infections. METHODS: To explore whether anti-IFN-γ autoantibodies are associated with disease severity of coronavirus disease 2019 (COVID-19), we examined the titers and functional neutralization of anti-IFN-γ autoantibodies in COVID-19 patients. In 127 COVID-19 patients and 22 healthy controls, serum titers of anti-IFN-γ autoantibodies were quantified using enzyme-linked immunosorbent assay, and the presence of autoantibodies was verified with immunoblotting assay. The neutralizing capacity against IFN-γ was evaluated with flow cytometry analysis and immunoblotting, and serum cytokines levels were determined using the MULTIPLEX platform. RESULTS: A higher proportion of severe/critical COVID-19 patients had positivity for anti-IFN-γ autoantibodies (18.0%) compared with non-severe patients (3.4%, p < 0.01) or healthy control (HC) (0.0%, p < 0.05). Severe/critical COVID-19 patients also had higher median titers of anti-IFN-γ autoantibodies (5.01) compared with non-severe patients (1.33) or HC (0.44). The immunoblotting assay could verify the detectable anti-IFN-γ autoantibodies and revealed more effective inhibition of signal transducer and activator of transcription (STAT1) phosphorylation on THP-1 cells treated with serum samples from anti-IFN-γ autoantibodies-positive patients compared with those from HC (2.21 ± 0.33 versus 4.47 ± 1.64, p < 0.05). In flow-cytometry analysis, sera from autoantibodies-positive patients could also significantly more effectively suppress the STAT1 phosphorylation (median,67.28%, interquartile range [IQR] 55.2-78.0%) compared with serum from HC (median,106.7%, IQR 100.0-117.8%, p < 0.05) or autoantibodies-negative patients (median,105.9%, IQR 85.5-116.3%, p < 0.05). Multivariate analysis revealed that the positivity and titers of anti-IFN-γ autoantibodies were significant predictors of severe/critical COVID-19. Compared with non-severe COVID-19 patients, we reveal that a significantly higher proportion of severe/critical COVID-19 patients are positive for anti-IFN-γ autoantibodies with neutralizing capacity. CONCLUSION: Our results would add COVID-19 to the list of diseases with the presence of neutralizing anti-IFN-γ autoAbs. Anti-IFN-γ autoantibodies positivity is a potential predictor of severe/critical COVID-19.

Mesenchymal stem cells suppressed skin and lung inflammation and fibrosis in topoisomerase I-induced systemic sclerosis associated with lung disease mouse model.

Systemic sclerosis associated with lung interstitial lung disease (SSc-ILD) is the most common cause of death among patients with SSc. Mesenchymal stem cell (MSCs) transplantations had been treated by SSc patients that showed in the previous case report. The therapeutic mechanisms and effects of MSCs on SSc-ILD are still obscure. In this study, we investigated the therapeutic effects and mechanisms of treatment of BM-MSC derived from C57BL/6 on the topoisomerase I (TOPO I) induced SSc-ILD-like mice model. The mice were immunized with a mixture of recombinant human TOPO I in PBS solution (500 U/mL) and completed Freund's adjuvant [CFA; 1:1 (volume/volume)] twice per week for 9 weeks. On week 10, the mice were sacrificed to analyze the related pathological parameters. Lung and skin pathologies were analyzed using histochemical staining. CD4 T-helper (TH) cell differentiation in lung and skin-draining lymph nodes was detected using flow cytometry. Our results revealed that allogeneic and syngeneic MSCs exhibited similar repressive effects on TOPO I-induced IgG1 and IgG2a in the SSc group. After intravascular (IV) treatment with syngeneic or allogeneic MSCs, the dermal thickness and fibrosis dramatically condensed and significantly reduced airway hyperresponsiveness. These findings showed that both allogeneic and syngeneic MSCs have therapeutic potential for SSc-ILD.

Screening and characterization of myositis-related autoantibodies in COVID-19 patients.

An efficient host immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) appears to be crucial for controlling and resolving this viral infection. However, many studies have reported autoimmune characteristics in severe COVID-19 patients. Moreover, clinical observations have revealed that COVID-19-associated acute distress respiratory syndrome shares many features in common with inflammatory myopathy including interstitial lung disease (ILD), most particularly rapidly progressive (RP)-ILD. This study explored this phenomenon by seeking to identify and characterize myositis-specific and related autoantibodies in 25 COVID-19 patients with mild or severe symptoms. Line blot analysis with the EUROLINE Myopathies Ag kit identified 9 (36%) patients with COVID-19 with one or more autoantibodies against several myositis-related antigens (Jo-1, Ku, Mi-2ß, PL-7, PL-12, PM-Scl 75, PM-Scl 100, Ro-52, and SRP); no anti-MDA5 antibodies were detected. As the presence of antibodies identified by line blots was unrelated to disease severity, we further characterized the autoantibodies by radioimmunoassay, in which [35 S]methionine-labeled K562 cellular antigens were precipitated and visualized by gel electrophoresis. This result was confirmed by an immunoprecipitation assay and immunoblotting; 2 patients exhibited anti-Ku70 and anti-Ku80 antibodies. Our data suggest that it is necessary to use more than one method to characterize and evaluate autoantibodies in people recovered from COVID-19, in order to avoid misinterpreting those autoantibodies as diagnostic markers for autoimmune diseases.

A Streamlined Diagnostic Process Improved the Outcomes of Patients with Adult-Onset Still's Disease: A Single-Center Retrospective Observational Study.

INTRODUCTION: The diagnosis of adult-onset Still's disease (AOSD) is often delayed due to its clinical heterogeneity and lack of pathognomic features. Hence, there is an unmet need for an efficient diagnostic process. The major aim of this study was to compare the differences in disease outcomes between two groups of AOSD patients with and without implementation of the streamlined diagnostic process (SDP). METHODS: Of 172 febrile patients with skin rash and/or arthralgia, 112 individuals had AOSD. The tentative diagnosis of AOSD or non-AOSD was made with or without the SDP implementation. The selection criteria for AOSD outcomes analysis were as follows: (1) age at study entry older than 20 years, (2) fulfillment of the Yamaguchi criteria for AOSD diagnosis, and (3) a follow-up period longer than 6 months after initiation of therapy. Three outcome parameters were evaluated, including diagnosis lag period, the proportion of "early diagnosis," and the proportion of achieving disease remission after a 6-month therapy. RESULTS: The SDP was implemented for expediting AOSD diagnosis in 41 (36%) enrolled patients (SDP-implemented group). The diagnosis lag period was significantly shorter in the SDP-implemented group (median 2.0 weeks, interquartile range [IQR] 1.0-2.5 weeks) than in the non-SDP-implemented group (4.0 weeks, IQR 2.0-6.0 weeks, p < 0.001). A significantly higher proportion of "early diagnosis" was also found in the SDP-implemented group (75.6%) compared with the non-SDP-implemented group (33.8%, p < 0.001). We revealed a significantly higher proportion of achieving remission in the SDP-implemented group (85.4%) compared with the non-SDP-implemented group (67.6%, p < 0.05). Logistic regression analysis revealed SDP implementation as a potential predictor of achieving disease remission. CONCLUSIONS: Implementing an SDP for expediting diagnosis could improve outcomes for AOSD patients. This diagnostic process increased the early diagnosis rate and led to a higher disease remission rate. However, the beneficial effects of SDP implementation need further external validation.

Assessing the Immune Cell Subset and Genetic Mutations in Patients With Palindromic Rheumatism Seronegative for Rheumatoid Factor and Anti-Cyclic Citrullinated Peptide.

OBJECTIVE: The etiology underlying cases of palindromic rheumatism (PR) not associated with other rheumatic diseases in patients who are seronegative for rheumatoid factor and anti-cyclic citrullinated peptide (seronegative PR) is unclear. We aimed to investigate the immune cells and genes involved. METHODS: This was a single-center comparative study of 48 patients with seronegative PR and 48 healthy controls. Mass cytometry and RNA sequencing were used to identify distinct immune cell subsets in blood. Among the 48 seronegative PR patients, plasma samples from 40 patients were evaluated by enzyme-linked immunosorbent assay for cytokine levels, and peripheral blood samples from 25 patients were evaluated by flow cytometry for mononuclear cell subsets. Plasma samples from 21 patients were evaluated by real-time polymerase chain reaction for differential gene and protein expression, and samples from 3 patients were analyzed with whole-exome sequencing for gene mutations. RESULTS: Immunophenotyping revealed a markedly increased frequency of CD14+CD11b+CD36+ and CD4+CD25-CD69+ cells in seronegative PR patients with active flares compared with healthy controls (P < 0.0001 for both cell subset comparisons). Gene enrichment analyses of RNA-sequencing data from sorted CD14+CD11b+CD36+ and CD4+CD25-CD69+ cells showed involvement of the inflammatory/stress response, phagocytosis, and regulation of apoptosis functional pathways. Up-regulated expression of CXCL16 and IL10RA was observed in monocytes from PR patients. Up-regulation of PFKFB3, DDIT4, and TGFB1, and down-regulation of PDIA6 were found in monocytes and lymphocytes from PR patients with active flares and PR patients in intercritical periods. Plasma levels of S100A8/A9 and interleukin-1ß were elevated in PR patients. Whole-exome sequencing revealed novel polygenic mutations in HACL1, KDM5A, RASAL1, HAVCR2, PRDM9, MBOAT4, and JRKL. CONCLUSION: In seronegative PR patients, we identified a distinct CD14+CD11b+CD36+ cell subset that can induce an inflammatory response under stress and exert antiinflammatory effects after phagocytosis of apoptotic cells, and a CD4+CD25-CD69+ T cell subset with pro- and antiinflammatory properties. Individuals with genetic mutations involving epigenetic modification, potentiation and resolution of stress-induced inflammation/apoptosis, and a dysregulated endoplasmic reticulum stress response could be predisposed to seronegative PR.

The Immunogenicity and Safety of Three Types of SARS-CoV-2 Vaccines in Adult Patients with Immune-Mediated Inflammatory Diseases: A Longitudinal Cohort Study.

Patients with immune-mediated inflammatory diseases (IMID) were seldom enrolled in the studies of SARS-CoV-2 vaccines, and real-world data regarding the immunogenicity of different types of vaccines is limited. We aimed to assess the immunogenicity and safety of three types of vaccines (AZD1222, mRNA-1273, and BNT162b2) in 253 patients with IMID and 30 healthcare workers (HCWs). Plasma levels of IgG-antibody against SARS-CoV-2 targeting the receptor-binding domain of spike protein (anti-S/RBD-IgG) were determined by chemiluminescent immunoassay 3-4 weeks after the first-dose and second-dose vaccination. The positive rate and titers of anti-S/RBD-IgG were significantly higher in mRNA-1273 or BNT162b2 than in the AZD1222 vaccine. Immunogenicity was augmented after the second dose of any vaccine type in all IMID patients, suggesting that these patients should complete the vaccination series. Anti-S/RBD-IgG titers after first-dose vaccination were significantly lower in RA patients than pSS patients, but there was no significant difference after second-dose vaccination among five groups of IMID patients. The positive rate and titers of anti-S/RBD-IgG were significantly lower in patients receiving abatacept/rituximab therapy than in those receiving other DMARDs. All three SARS-CoV-2 vaccines showed acceptable safety profiles, and the common AEs were injection site reactions. We identified SLE as a significant predictor of increased autoimmunity and would like to promote awareness of the possibility of autoimmunity following vaccination.

Consensus recommendations on managing the selected comorbidities including cardiovascular disease, osteoporosis, and interstitial lung disease in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA)-related comorbidities, including cardiovascular disease (CVD), osteoporosis (OP), and interstitial lung disease (ILD), are sub-optimally managed. RA-related comorbidities affect disease control and lead to impairment in quality of life. We aimed to develop consensus recommendations for managing RA-related comorbidities. METHODS: The consensus statements were formulated based on emerging evidence during a face-to-face meeting of Taiwan rheumatology experts and modified through three-round Delphi exercises. The quality of evidence and strength of recommendation of each statement were graded after a literature review, followed by voting for agreement. Through a review of English-language literature, we focused on the existing evidence of management of RA-related comorbidities. RESULTS: Based on experts' consensus, eleven recommendations were developed. CVD risk should be assessed in patients at RA diagnosis, once every 5 years, and at changes in DMARDs therapy. Considering the detrimental effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids on CVD risks, we recommend using the lowest possible dose of corticosteroids and prescribing NSAIDs cautiously. The OP/fragility fracture risk assessment includes dual-energy X-ray absorptiometry and fracture risk assessment (FRAX) in RA. The FRAX-based approach with intervention threshold is a useful strategy for managing OP. RA-ILD assessment includes risk factors, pulmonary function tests, HRCT imaging and a multidisciplinary decision approach to determine RA-ILD severity. A treat-to-target strategy would limit RA-related comorbidities. CONCLUSIONS: These consensus statements emphasize that adequate control of disease activity and the risk factors are needed for managing RA-related comorbidities, and may provide useful recommendations for rheumatologists on managing RA-related comorbidities.

Genomic sequencing and functional analyses identify MAP4K3/GLK germline and somatic variants associated with systemic lupus erythematosus.

OBJECTIVES: MAP4K3 (GLK) overexpression in T cells induces interleukin (IL)-17A production and autoimmune responses. GLK overexpressing T-cell population is correlated with severity of human systemic lupus erythematosus (SLE); however, it is unclear how GLK is upregulated in patients with SLE. METHODS: We enrolled 181 patients with SLE and 250 individuals without SLE (93 healthy controls and 157 family members of patients with SLE) in two independent cohorts from different hospitals/cities. Genomic DNAs of peripheral blood mononuclear cells were subjected to next-generation sequencing to identify GLK gene variants. The functional consequences of the identified GLK germline or somatic variants were investigated using site-directed mutagenesis and cell transfection, followed by reporter assays, mass spectrometry, immunoblotting, coimmunoprecipitation, and in situ proximity ligation assays. RESULTS: We identified 58 patients with SLE from Cohort #1 and #2 with higher frequencies of a somatic variant (chr2:39 477 124 A>G) in GLK 3'-untranslated region (UTR); these patients with SLE showed increased serum anti-double-stranded DNA levels and decreased serum C3/C4 levels. This somatic variant in 3'-UTR enhanced GLK mRNA levels in T cells. In addition, we identified five patients with SLE with GLK (A410T) germline variant in Cohort #1 and #2, as well as two other patients with SLE with GLK (K650R) germline variant in Cohort #1. Another GLK germline variant, A579T, was also detected in one patient with SLE from Cohort #2. Both GLK (A410T) and GLK (K650R) mutants inhibited GLK ubiquitination induced by the novel E3 ligase makorin ring-finger protein 4 (MKRN4), leading to GLK protein stabilisation. CONCLUSIONS: Multiple GLK germline and somatic variants cause GLK induction by increasing mRNA or protein stability in patients with SLE.

The effectiveness of tocilizumab in treating refractory adult-onset Still's disease with dichotomous phenotypes: IL-18 is a potential predictor of therapeutic response.

OBJECTIVE: Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder with clinical heterogeneity. Although tocilizumab (TCZ), an interleukin (IL)-6 receptor inhibitor, is an effective treatment for AOSD, the evidence regarding its efficacy on systemic or articular subtypes is conflicting. Furthermore, the predictors of therapeutic response are still elusive and worthy of exploration. METHODS: This two-center retrospective study analyzed the effectiveness and safety profile of TCZ treatment in 28 patients with refractory AOSD. The 28-joint disease activity score (DAS28) and systemic activity score were assessed before and during TCZ treatment period at weeks 12, 24, 36, and 48. Plasma levels of proinflammatory cytokines at baseline were determined using ELISA method. RESULTS: Among the systemic subtype patients, 10 (58.8%), 13 (76.5%), 14 (82.4%), and 15 (88.2%) patients achieved complete remission at week 12, 24, 36, and 48, respectively, in comparison to 2 (22.2%), 5 (55.6%), 6 (66.7%), and 7 (77.8%) who achieved disease remission (DAS28 < 2.6) at weeks 12, 24, 36, and 48, respectively, among articular subtype patients. The systemic activity scores and inflammatory parameters were significantly decreased after 12-week TCZ therapy, and TCZ could significantly reduce corticosteroid dose in AOSD patients. Multivariate analysis reveals that baseline IL-18 level is a significant predictor of poor therapeutic response at week 24 (odds ratio 7.86, p < 0.05). CONCLUSION: AOSD patients refractory to high-dose corticosteroids and methotrexate may respond well to TCZ treatment with a steroid-sparing effect and an acceptable safety. A high baseline IL-18 level may be a predictor of poor therapeutic response. Key Points • Tocilizumab may be effective and well-tolerated in refractory AOSD patients regardless of disease subtypes. • High plasma levels of IL-18 may predict poor response to tocilizumab in AOSD patients.

The Impact of b/tsDMARD Dose Reduction on Chronic Hepatitis B in Rheumatoid Arthritis Patients: A Two-Center Long-Term Safety Analysis.

BACKGROUND: We aimed to investigate the change of hepatitis B virus (HBV) viral loads and HBV reactivation (HBVr) in rheumatoid arthritis (RA) patients after tapering the dose of biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). METHODS: This two-center analysis retrospectively investigated the virological and biochemical evidence of HBVr in RA patients who underwent b/tsDMARD dose reduction. Serum levels of viral loads were determined using real-time PCR. Serum levels of alanine transaminase (ALT) were determined using spectrophotometry. RESULTS: Among a total of 40 HBsAg+ RA patients who tapered b/tsDMARDs, 14 (35%) used tocilizumab; 12 (30%) used tumor necrosis factor (TNF)-α inhibitors; and the rest used either abatacept or tofacitinib. We found that patients who had detectable HBV DNA before tapering achieved a one-log reduction in HBV DNA levels, in contrast to the findings in the other 12 patients who did not taper b/tsDMARDs (no change in HBV DNA levels with time). The incidence of HBVr (increased viral loads with hepatitis) was 4.62 (95%CI: 2.08, 10.28) and 2.26 (95%CI: 0.56, 9.02) events per 100 person-years before and after b/tsDMARD tapering, respectively. CONCLUSIONS: The HBV viral load decreased after the tapering of b/tsDMARDs in RA patients with detectable HBV DNA. Dose reduction in b/tsDMARDs might be beneficial.

Evaluations and Mechanistic Interrogation of Natural Products Isolated From Paeonia suffruticosa for the Treatment of Inflammatory Bowel Disease.

Mu Dan Pi (MDP), a traditional Chinese medicine derived from the root bark of Paeonia suffruticosa Andrews, is used to treat autoimmune diseases due to its anti-inflammatory properties. However, the impact of MDP on inflammatory bowel disease (IBD) and its principal active compounds that contribute to the anti-inflammatory properties are uncertain. Thus, this study systemically evaluated the anti-inflammatory effects of fractionated MDP, which has therapeutic potential for IBD. MDP fractions were prepared by multistep fractionation, among which the ethyl acetate-fraction MDP5 exhibited the highest potency, with anti-inflammatory activity screened by the Toll-like receptor (TLR)-2 agonist, Pam3CSK4, in a cell-based model. MDP5 (at 50 µg/ml, p < 0.001) significantly inhibited nuclear factor kappa-B (NF-κB) reporters triggered by Pam3CSK4, without significant cell toxicity. Moreover, MDP5 (at 10 µg/ml) alleviated proinflammatory signaling triggered by Pam3CSK4 in a dose-dependent manner and reduced downstream IL-6 and TNF-α production (p < 0.001) in primary macrophages. MDP5 also mitigated weight loss, clinical inflammation, colonic infiltration of immune cells and cytokine production in a murine colitis model. Index compounds including paeoniflorin derivatives (ranging from 0.1 to 3.4%), gallic acid (1.8%), and 1,2,3,4,6-penta-O-galloyl-ß-D-glucose (1.1%) in MDP5 fractions were identified by LC-MS/MS and could be used as anti-inflammatory markers for MDP preparation. Collectively, these data suggest that MDP5 is a promising treatment for IBD patients.

Increased Lipid Peroxidation May Be Linked to Ferritin Levels Elevation in Adult-Onset Still's Disease.

Lipid peroxidation (LPO) and hyper-ferritinemia are involved in inflammatory responses. Although hyper-ferritinemia is a characteristic of AOSD, its link to LPO remains unclear. We investigated the association between LPO and ferritin expression, and evaluated the relationship between LPO-related metabolites and inflammatory parameters. Mean fluorescence intensity (MFI) of LPO (C11-Biodipy581/591)-expressing PBMCs/monocytes in AOSD patients and healthy control (HC) subjects was determined by flow-cytometry analysis. Expression of ferritin and cytokines on PBMCs/macrophages was examined by immunoblotting. Plasma levels of LPO-related metabolites and cytokines were determined by ELISA and the MULTIPLEX platform, respectively. LPO MFI on PBMCs/monocytes were significantly higher in patients (median 4456 and 9091, respectively) compared with HC (1900, p < 0.05, and 4551, p < 0.01, respectively). Patients had higher ferritin expression on PBMCs (mean fold, 1.02) than HC (0.55, p < 0.05). Their ferritin expression levels on PBMCs stimulated with LPO inducers erastin or RSL3 (2.47 or 1.61, respectively) were higher than HC (0.84, p < 0.05, or 0.74, p < 0.01). Ferritin expression on erastin-treated/IL-1ß-treated macrophages from patients were higher than those from HC (p < 0.001). The elevated levels of LPO-related metabolites, including malondialdehyde and 4-hydroxyalkenals, were positively correlated with disease activity scores, suggesting LPO involvement in AOSD pathogenesis. Increased ferritin expression on PBMCs/macrophages stimulated with LPO inducers indicates a link between LPO and elevated ferritin.

Herbal Formula SS-1 Increases Tear Secretion for Sjögren's Syndrome.

Background: Sjögren's syndrome (SS) is an autoimmune inflammatory disease that primarily affects the exocrine glands, leading to glandular dysfunction. The hallmark symptoms of SS are dry eyes and mouth, compromising the quality of life of patients and decreasing their capacity to perform their daily activities. Objective: This study aims to evaluate the efficacy of the herbal formula SS-1 for its potential therapeutic benefits for patients with Sjögren's syndrome. Materials and Methods: The bioactivity profile of SS-1 was determined using four different SS-1 concentrations across 12 human primary cell systems of the BioMAP profile. After that, a randomized, double-blind, crossover, placebo-controlled trial was performed including 57 patients treated with SS-1 for 28 weeks. Results: Biologically multiplexed activity profiling in cell-based models indicated that SS-1 exerted anti-proliferative activity in B cells and promoted anti-inflammatory and immunomodulatory activity. In the clinical trial, Schirmer's test results revealed significant improvements in both eyes, with increases of 3.42 mm (95% CI, 2.44-4.41 mm) and 3.45 mm (95% CI, 2.32-4.59 mm), respectively, and a significant reduction in artificial tear use, which was -1.38 times/day, 95% CI, -1.95 to -0.81 times/day. Moreover, the increases in B-cell activating factor (BAFF) and B-cell maturation antigen (BCMA) levels were dampened by 53.20% (295.29 versus 555.02 pg/ml) and 58.33% (99.16 versus 169.99 pg/ml), respectively. Conclusion: SS-1 treatment significantly inhibited B-cell maturation antigen. No serious drug-related adverse effects were observed. Oral SS-1 administration may be a complementary treatment for Sjögren's syndrome.