An externally validated clinical-laboratory nomogram for myocardial involvement in adult idiopathic-inflammatory-myopathy patients.

OBJECTIVES: This study aimed at identifying clinical and laboratory risk factors for myocardial involvement (MI) in idiopathic inflammatory myopathies (IIMs) patients as well as constructing a risk-predicted nomogram for prediction and early identification of MI. METHODS: An IIMs cohort in southeastern China was constructed, including 504 adult IIMs patients who met the inclusion and exclusion criteria, and were hospitalized at four divisions of the First Affiliated Hospital, Zhejiang University School of Medicine from January 1st 2018 to April 30st 2022. After dividing patients into the training cohort and the validation cohort, risk factors for MI were identified through least absolute shrinkage and selection operator regression and multivariate logistic regression. A risk-predicted nomogram was established and validated internally and externally for discrimination, calibration and practicability. RESULTS: In this cohort, 17.7% of patients developed MI and the survival was significantly inferior to that of IIMs patients without MI (P < 0.001). In the training cohort, age > 55 years old (P < 0.001), disease activity > 10 points (P < 0.001), interleukin-17A (IL-17A) > 7.5 pg/ml (P < 0.001), lactic dehydrogenase (LDH) > 425 U/L (P < 0.001), anti-mitochondrial antibodies (AMAs, P = 0.017), and anti-MDA5 antibody (P = 0.037) were significantly correlated with development of MI. A nomogram was established by including the above values to predict MI and was found efficient in discrimination, calibration, and practicability through internal and external validation. CONCLUSION: This study developed and validated a nomogram model to predict the risk of MI in adult IIMs patients, which can benefit the prediction and early identification of MI as well as timely intervention in these patients.

Efficacy and Safety of Tofacitinib in Patients with Polymyalgia Rheumatica (EAST PMR): An open-label randomized controlled trial.

BACKGROUND: Polymyalgia rheumatica (PMR) is a common inflammatory disease in elderly persons whose mechanism of pathogenesis has not been elucidated. Glucocorticoids are the main first-line treatments but result in numerous side effects. Therefore, there is a need to explore pathogenetic factors and identify possible glucocorticoid-sparing agents. We aimed to study the pathogenetic features of the disease and assess the efficacy and safety of Janus tyrosine kinase (JAK)-inhibitor tofacitinib in patients with PMR. METHODS AND FINDINGS: We recruited treatment-naïve PMR patients from the First Affiliated Hospital, Zhejiang University School of Medicine, between September 2020 and September 2022. In the first cohort, we found that the gene expression patterns of peripheral blood mononuclear cells (PBMCs) in 11 patients (10 female, 1 male, age 68.0 ± 8.3) with newly diagnosed PMR were significantly different from 20 healthy controls (17 female, 3 male, age 63.7 ± 9.8) by RNA sequencing. Inflammatory response and cytokine-cytokine receptor interaction were the most notable pathways affected. We observed marked increases in expression of IL6R, IL1B, IL1R1, JAK2, TLR2, TLR4, TLR8, CCR1, CR1, S100A8, S100A12, and IL17RA, which could trigger JAK signaling. Furthermore, tofacitinib suppressed the IL-6R and JAK2 expression of CD4+T cells from patients with PMR in vitro. In the second cohort, patients with PMR were randomized and treated with tofacitinib or glucocorticoids (1/1) for 24 weeks. All PMR patients underwent clinical and laboratory examinations at 0, 4, 8, 12, 16, 20, and 24 weeks, and PMR activity disease scores (PMR-AS) were calculated. The primary endpoint was the proportion of patients with PMR-AS ≤10 at weeks 12 and 24. Secondary endpoints: PMR-AS score, c-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) at weeks 12 and 24. Thirty-nine patients with newly diagnosed PMR received tofacitinib, and 37 patients received glucocorticoid. Thirty-five patients (29 female, 6 male, age 64.4 ± 8.4) and 32 patients (23 female, 9 male, age 65.3 ± 8.7) patients completed the 24-week intervention, respectively. There were no statistically significant differences in primary or secondary outcomes. At weeks 12 and 24, all patients in both groups had PMR-AS <10. PMR-AS, CRP, and ESR were all significantly decreased in both groups. No severe adverse events were observed in either group. Study limitations included the single-center study design with a short observation period. CONCLUSIONS: We found that JAK signaling was involved in the pathogenesis of PMR. Tofacitinib effectively treated patients with PMR as glucocorticoid does in this randomized, monocenter, open-label, controlled trial (ChiCTR2000038253). TRIAL REGISTRATION: This investigator-initiated clinical trial (IIT) had been registered on the website (http://www.chictr.org.cn/, ChiCTR2000038253).

Novel Effects of Combination Therapy Through Inhibition of Caspase-1/Gasdermin D Induced-Pyroptosis in Lupus Nephritis.

Objectives: Combination therapy with mycophenolate mofetil, tacrolimus and steroids are effective in achieving complete remission in lupus nephritis (LN). Combination therapy uniquely downregulated caspase-1 compared with monotherapies, which can cleave gasdermin D (GSDMD) and was recently identified as the pyroptosis executioner. We therefore investigated whether combination therapy enabled the suppression of caspase-1/GSDMD-mediated pyroptosis in LN. Methods: Expression and activation of GSDMD were detected in kidney specimens of the human and mouse with LN using immunohistochemical staining and immunoblotting. Primary podocytes isolated from MRL/lpr mice were incubated with LPS+ATP, and pretreated with monotherapy or combination therapy. Inhibition of caspase-1/GSDMD-induced pyroptosis by combination therapy were assessed in MRL/lpr mice and human specimens. Pyroptosis was examined using a FAM caspase-1 kit and flow cytometry. The correlation between pyroptosis in peripheral blood and the systemic lupus erythematosus disease activity index (SLEDAI) was analyzed. Results: Kidney tissue specimens from LN patients and mice exhibited greatly increased expression levels and cleavage of GSDMD. In cultured podocytes, combination treatment significantly suppressed the activation of NLRP3 and caspase-1 and reduced GSDMD N-terminal levels. Combination therapy repressed disease progression through inhibition of caspase-1/GSDMD-mediated pyroptosis in both humans and MRL/lpr mice. Caspase-1/PI positive cell numbers in peripheral blood were positively correlated with SLE-DAI. LN patients with complete remission and partial remission had remarkably reduced caspase-1/PI positive cell numbers compared to baseline. Ac-FLTD-CMK, a GSDMD-derived inhibitor, prevented the development of LN. Conclusion: Combination therapy suppressed caspase-1/GSDMD-mediated pyroptosis in vitro and in vivo and reduced disease progression.

Clinical Value of 18F-FDG PET/CT Scan and Cytokine Profiles in Secondary Hemophagocytic Lymphohistiocytosis in Idiopathic Inflammatory Myopathy Patients: A Pilot Study.

Background: Secondary hemophagocytic lymphohistiocytosis (sHLH) is a rare but fatal complication in idiopathic inflammatory myopathy (IIM) patients. The clinical value of radiological manifestations and serum cytokines remain unknown in this systemic crisis. This study aims to investigate the clinical value of PET/CT scan and cytokine profiles in predicting and understanding sHLH in IIM patients. Methods: Adult IIM patients who were admitted to the four divisions of the First Affiliated Hospital, Zhejiang University School of Medicine (FAHZJU) from January 1, 2017 to December 31, 2020 were reviewed. PET/CT scan, cytokine profiles, and other factors of patients who met the inclusion and exclusion criteria were collected and analyzed. Results: Sixty-nine out of 352 IIM patients were finally enrolled into the study. Ten patients developed sHLH and 70.0% of them died within 6 months. After false discovery rate (FDR) correction and multivariate logistic regression analysis, increased serum interferon (IFN)-γ level (p = 0.017), higher spleen mean standard uptake value (SUVmean, p = 0.035), and positivity of anti-MDA5 antibody (p = 0.049) were found to be significantly correlated with development of sHLH in IIM patients. The combination of serum IFN-γ, spleen SUVmean, and anti-MDA5 antibody found a balanced and satisfying predictor with a cutoff value of 0.047 and AUC of 0.946. A moderate correlation was identified between ferritin and spleen SUVmean (p = 0.001, r = 0.380) as well as serum IFN-γ(p = 0.001, r = 0.398). Before FDR correction, higher bilateral lung SUVmean (p = 0.034) and higher colon/rectum SUVmean (p = 0.013) were also observed in IIM patients who developed sHLH. By narrowing down to IIM patients with sHLH, anti-MDA5-antibody-positive DM patients tended to suffer from unfavorable outcome (p = 0.004) in Kaplan-Meier survival analysis. Conclusion: Increased serum level of IFN-γ, elevated splenic FDG uptake, and positivity of anti-MDA5 antibody were significantly correlated with development of sHLH in IIM patients. Lung and lower digestive tract might also be affected due to systemic immune activation in IIM patients with sHLH. In addition, splenic FDG uptake, in combination with serum IFN-γand anti-MDA5 antibody, was found valuable in predicting development of sHLH in IIM patients. Among IIM patients with sHLH, anti-MDA5-antibody-positive DM patients showed higher tendency for unfavorable outcome.

Radiological Characteristics of Patients With Anti-MDA5-Antibody-Positive Dermatomyositis in 18F-FDG PET/CT: A Pilot Study.

Objective: To elucidate the 18F-fluorodeoxyglucose (FDG) PET/CT characteristics and its prognostic value in the patients with anti-melanoma differentiation associated protein 5 antibody positive (anti-MDA5+) dermatomyositis (DM). Methods: This retrospective cross-sectional study included 26 patients with anti-MDA5+ DM and 43 patients with anti-MDA5 negative (anti-MDA5-) idiopathic inflammatory myopathy (IIM) who were examined by 18F-FDG PET/CT from January 1, 2017 to December 31, 2020. The maximum standardized uptake value (SUVmax) of multiple organs and other clinical characteristics of the patients were measured and analyzed. Results: Compared with the anti-MDA5- group, the patients in the anti-MDA5+ group showed higher bilateral lung SUVmax (p = 0.029), higher SUVmax of spleen (p = 0.011), and bone marrow (p = 0.048). Significant correlations between the spleen SUVmax and serum ferritin levels (r = 0.398, p < 0.001), erythrocyte sedimentation rate (ESR) (r = 0.274, p = 0.023), platelet count (r = -0.265, p= 0.028), myositis disease activity assessment score (r = 0.332, p = 0.005), bone marrow SUVmax (r = 0.564, p < 0.001), and bilateral lung SUVmax (r = 0.393, p < 0.001) were observed. Conclusion: 18F-FDG PET/CT was found valuable in quantifying the pulmonary focal inflammation and potentially unveil the distinctive characteristics and pathophysiological mechanisms in the patients with anti-MDA5+ DM.

Lupus gut microbiota transplants cause autoimmunity and inflammation.

BACKGROUND: The etiology of systemic lupus erythematosus (SLE) is multifactorial. Recently, growing evidence suggests that the microbiota plays a role in SLE, yet whether gut microbiota participates in the development of SLE remains largely unknown. To investigate this issue, we carried out 16 s rDNA sequencing analyses in a cohort of 18 female un-treated active SLE patients and 7 female healthy controls, and performed fecal microbiota transplantation from patients and healthy controls to germ-free (GF) mice. RESULTS: Compared to the healthy controls, we found no significant different microbial diversity but some significantly different species in SLE patients including Turicibacter genus and other 5 species. Fecal transfer from SLE patients to GF mice caused GF mice to develop a series of lupus-like phenotypic features, including increased serum autoimmune antibodies, imbalanced cytokines, altered distribution of immune cells in mucosal and peripheral immune response, and upregulated expression of genes related to SLE in recipient mice that received SLE fecal microbiota transplantation (FMT). Moreover, the metabolism of histidine was significantly altered in GF mice treated with SLE patient feces, as compared to those which received healthy fecal transplants. CONCLUSIONS: Overall, our results describe a causal role of aberrant gut microbiota in contributing to the pathogenesis of SLE. The interplay of gut microbial and histidine metabolism may be one of the mechanisms intertwined with autoimmune activation in SLE.

The lungs were on fire: a pilot study of 18F-FDG PET/CT in idiopathic-inflammatory-myopathy-related interstitial lung disease.

BACKGROUND: Interstitial lung disease (ILD) and its rapid progression (RP) are the main contributors to unfavourable outcomes of patients with idiopathic inflammatory myopathy (IIM). This study aimed to identify the clinical value of PET/CT scans in IIM-ILD patients and to construct a predictive model for RP-ILD. METHODS: Adult IIM-ILD patients who were hospitalized at four divisions of the First Affiliated Hospital, Zhejiang University School of Medicine (FAHZJU), from 1 January 2017 to 31 December 2020 were reviewed. PET/CT scans and other characteristics of patients who met the inclusion and exclusion criteria were collected and analysed. RESULTS: A total of 61 IIM-ILD patients were enrolled in this study. Twenty-one patients (34.4%) developed RP-ILD, and 24 patients (39.3%) died during follow-up. After false discovery rate (FDR) correction, the percent-predicted diffusing capacity of the lung for carbon monoxide (DLCO%, P = 0.014), bilateral lung mean standard uptake value (SUVmean, P = 0.014) and abnormal mediastinal lymph node (P = 0.045) were significantly different between the RP-ILD and non-RP-ILD groups. The subsequent univariate and multivariate logistic regression analyses verified our findings. A "DLM" model was established by including the above three values to predict RP-ILD with a cut-off value of ≥ 2 and an area under the curve (AUC) of 0.905. Higher bilateral lung SUVmean (P = 0.019) and spleen SUVmean (P = 0.011) were observed in IIM-ILD patients who died within 3 months, and a moderate correlation was recognized between the two values. CONCLUSIONS: Elevated bilateral lung SUVmean, abnormal mediastinal lymph nodes and decreased DLCO% were significantly associated with RP-ILD in IIM-ILD patients. The "DLM" model was valuable in predicting RP-ILD and requires further validation.

Clinical efficacy and safety of sirolimus in systemic lupus erythematosus: a real-world study and meta-analysis.

OBJECTIVE: To provide real-world data and summarize current clinical evidence on the efficacy and safety of sirolimus in active systemic lupus erythematosus (SLE) patients. METHODS: This was a prospective real-world clinical study. Included SLE patients should have Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) ⩾ 2. They were treated with sirolimus and followed up regularly. The SLEDAI-2K, Physician Global Assessment (PGA), serological activity indices, and remission of organ manifestations were evaluated. We also performed a meta-analysis to integrate current evidence of sirolimus in SLE. RESULTS: A total of 49 patients were included in the final analysis. After treatment, the SLEDAI-2K (6.2 ± 3.1 versus 4.0 ± 3.4, p = 0.001) decreased significantly, and the prednisone dosage was tapered successfully (9.9 ± 8.8 mg/day versus 5.9 ± 4.0 mg/day, p = 0.002). Serological activity indices also improved [complement 3 (C3): 0.690 ± 0.209 g/l versus 0.884 ± 0.219 g/l, p < 0.001; complement 4: 0.105 ± 0.059 g/l versus 0.141 ± 0.069 g/l, p < 0.001; anti-dsDNA antibody, 200 ± 178 IU/ml versus 156 ± 163 IU/ml, p = 0.022]. The remission proportions of arthritis, skin rash, and thrombocytopenia were 100%, 88.8%, and 46.2%, respectively. A total of 41.2% of lupus nephritis (LN) patients achieved renal remission, but the average 24-h urine protein level was not significantly changed. Meta-analysis enrolled five studies with 149 patients included, and revealed similar results regarding the changes of SLEDAI-2K [-3.5 (-5.0, -2.1)], C3 [0.224 (0.136, 0.311) g/l] and daily dosage of prednisone [-12.7 (-19.9, -5.6) mg/day]. CONCLUSION: Sirolimus might be effective and tolerated in SLE. The role of sirolimus in LN requires further study.

Systemic lupus erythematosus-associated diffuse alveolar hemorrhage: a single-center, matched case-control study in China.

BACKGROUND: This study described clinical characteristics and outcome in systemic lupus erythematosus (SLE) patients with diffuse alveolar hemorrhage (DAH), and investigated risk factors and prognostic factors for DAH. METHODS: We conducted a retrospective nested case-control analysis in a single-center cohort. We enrolled 94 SLE patients with DAH. For each case of DAH, two age-, sex-, and SLE courses-matched controls were randomly selected from our cohort. All patients were enrolled between 2004 and 2019 and were followed until death, end of registration with the physician's practice, or end of January 2019. We estimated the risk factors for DAH and prognostic factors for mortality using multivariate analysis. RESULTS: We included 4744 patients diagnosed with SLE, with 94 cases of DAH, for an incidence rate of 2.0%. DAH may occur in any stage of SLE but mostly in the early phase of disease course. Lupus nephritis (LN) was the most common concomitant involvement at DAH diagnosis. By multivariate analysis, LN, anti-SSA positivity, thrombocytopenia and elevated C-reactive protein (CRP) were significantly associated with DAH in SLE patients. All-cause mortality was increased in SLE with DAH compared with SLE without DAH (adjusted hazard ratio 6.0, 95% confidence interval 2.8-13.0, p < 0.0001). Intravenous cyclophosphamide (CTX) showed an increased tendency for better survival in DAH after adjusting for Systemic Lupus Erythematosus Disease Activity Index 2000, acute kidney injury and mechanical ventilation. CONCLUSIONS: LN, anti-SSA positivity, thrombocytopenia and elevated CRP were independent risk factors of DAH in lupus patients. Due to a high early death rate of DAH and little long-term damage, DAH patients may benefit from early diagnosis and intensive treatment, and CTX-based therapy can be a preferential choice.

A comparison of the effects of agricultural pesticide uses on peripheral nerve conduction in China.

Evidence on the adverse effects of agricultural pesticide use by farmers under the actual field conditions on their peripheral nerve conduction in China is limited. This study was to investigate the association of agricultural pesticide use with the abnormalities of farmers' peripheral nerve conduction based on two rounds of conventional nerve conduction studies. The level of pesticide exposure was assessed by measuring total amount of pesticides used by farmers in 2012. The logistic and negative binomial regression analyses were performed on a cohort study of 218 farmers. Results show that agricultural use of neither glyphosate nor non-glyphosate herbicides was not found to induce the abnormalities of farmers' peripheral nerve conduction. However, agricultural use of organophosphorus compounds was significantly associated with increased risk of demylination disease of peripheral nerve conduction described by the reduced velocity. Moreover, the use of organonitrogen compounds by farmers would not only increase risk of demylination disease but axonal damages described by the reduced amplitude. By contrast, agricultural uses of organosulfur and pyrethroid compounds would not induce the abnormalities of farmers' peripheral nerve conduction. The findings demonstrated the importance of developing health-friendly pesticides to replace organophosphorus and organonitrogen insecticides and fungicides in China.

[Ocular Metastasis in Lung Cancer: a Retrospective Analysis in a Single Chinese Hospital and Literature Review].

BACKGROUND: Eye is a rare site of lung cancer metastasis, and ocular metastasis is one of the largest challenges to cancer patients' quality of life (QOL). Here we present our experience on ocular metastasis of lung cancer and review relevant literature in an attempt to investigate the clinical features, treatment, and prognosis of these tumors. METHODS: The records of 9 patients with ocular metastasis of lung cancer treated at our hospital were analyzed. A literature review identified 42 cases reported in the last 10 years and their medical records were retrospectively estimated. RESULTS: The median age of our patients was 51 years (range 41-61). Diagnosis of lung cancer included non-small cell lung carcinoma (NSCLC) in 7 patients, in which adenocarcinoma (ADC) were recorded in 6 patients, small cell lung carcinoma (SCLC) in 1 patient, and unknown in 1 patient. The site of ocular metastasis included choroid (n=8) and iris (n=1). In the literature review, SCLC constituted 21.4% (n=9) and ADC constituted 47.6% (n=20). Choroid presented to be the most common site for eye metastasis (66.7%, n=28). As for disease control rate, systemic chemotherapy for lung cancer patients with ocular metastasis presented to be only 28%. Meanwhile, combination of systemic treatment with ocular treatment could improve patients' eye symptoms effectively. CONCLUSIONS: The most common lung cancer that metastasizes to the eye is ADC. The choroid is the most common site for ocular metastasis. Ocular treatment can improve patients' eye symptoms, while the effect of systemic chemotherapy treatment is limited.