The clinical characteristics of subcutaneous and mediastinal emphysema in anti-melanoma differentiation-associated 5 positive dermatomyositis associated with interstitial lung disease.

OBJECTIVES: To investigate the clinical characteristics of subcutaneous emphysema (SE) and mediastinal emphysema (ME) occurring in patients with anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis associated with interstitial lung disease (anti-MDA5-positive DM-ILD). METHODS: In this retrospective study, a total of 117 anti-MDA5-positive DM-ILD patients were admitted to our hospital. All patients underwent an assessment of autoantibodies, serum ferritin levels, and lung high-resolution CT scans. RESULTS: In patients with anti-MDA5-positive DM-ILD, the incidence of SE/ME was found to be 11.1%, which was significantly higher compared to patients with anti-synthetase syndrome (p<0.01). The mortality rate among anti-MDA5-positive DM-ILD patients with SE/ME was significantly higher than those without SE/ME (p=0.0022). There was no statistically significant difference in the occurrence of SE/ME between patients with positive anti-Ro-52 antibodies and those with negative anti-Ro-52 antibodies (p=0.18). Patients with higher serum ferritin levels (1000 ng/ml ≤serum ferritin ≤1500 ng/ml) had a higher likelihood of developing SE/ME compared to patients with lower serum ferritin levels (serum ferritin <500 ng/ml) (p<0.01). Among 13 anti-MDA5-positive DM-ILD patients with SE/ME, six (46.2%) developed SE/ME within 1 month of being diagnosed and 53.8% of patients underwent positive pressure ventilation prior to the onset of SE/ME. CONCLUSIONS: We found that SE/ME is not uncommon in anti-MDA5-positive DM-ILD and is an important factor associated with poor patient prognosis. The occurrence of SE/ME is correlated with high levels of serum ferritin and is not related to anti-Ro-52 antibodies. Rheumatologists should pay close attention to SE/ME caused by positive pressure ventilation in anti-MDA5-positive DM-ILD patients.

Evaluating the value of superoxide dismutase in anti-MDA5-positive dermatomyositis associated with interstitial lung disease.

OBJECTIVE: This study aimed to investigate the relationship between serum superoxide dismutase (SOD) and interstitial lung disease (ILD) among patients with anti-melanoma differentiation-associated gene 5 antibody (MDA5)-positive DM. METHOD: In this retrospective study, serum SOD of 90 health check-ups were tested in our hospital. A total of 94 hospitalized patients with anti-MDA5-positive DM had ILD. Their serum SOD, serum ferritin and autoantibody levels were determined and lung high-resolution CT was performed. RESULTS: The serum SOD level was significantly lower in the anti-MDA5-positive DM group compared with the control group. The SOD level was significantly lower in patients positive for both anti-MDA5 antibodies and anti-Ro-52 antibodies than in those positive for only anti-MDA5 antibodies before treatment. The SOD level was significantly lower in the higher serum ferritin group compared with the lower serum ferritin group before treatment. After treatment, the serum SOD level decreased in patients with exacerbation of ILD, while it increased in those with alleviated ILD. The SOD level was significantly lower in the death group than in the survival group before treatment. CONCLUSIONS: In patients with anti-MDA5-positive DM, the low SOD level before treatment indicated the presence of oxidative stress in the disease; the serum SOD level was affected by anti-Ro-52 antibodies and ferritin; there is a close relationship between serum SOD level and ILD among patients with anti-MDA5-positive DM, suggesting that SOD might serve as an effective indicator to evaluate the changes in ILD in these patients; and the low SOD level is an important indicator of poor prognosis in these patients, which deserves attention from rheumatologists.

Measurement of superoxide dismutase: clinical usefulness for patients with anti-neutrophil cytoplasmic antibody-associated vasculitis

Abstract Objective To investigate the clinical usefulness of serum superoxide dismutase (SOD) measurement in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods In this single-center retrospective study, demographic data, serum SOD levels, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), the Birmingham Vasculitis Activity Score (BVAS), ANCA, organ involvement, and outcomes were analyzed for 152 AAV patients hospitalized in the Second Affiliated Hospital of Chongqing Medical University. Meanwhile, the serum SOD levels of 150 healthy people were collected as the control group. Results Compared to the healthy control group, serum SOD levels of the AAV group were significantly lower (P < 0.001). SOD levels of AAV patients were negatively correlated to ESR, CRP, and BVAS (ESR rho = − 0.367, P < 0.001; CRP rho = − 0.590, P < 0.001; BVAS rho = − 0.488, P < 0.001). SOD levels for the MPO-ANCA group were significantly lower than the PR3-ANCA group (P = 0.045). SOD levels for the pulmonary involvement group and the renal involvement group were significantly lower than those for the non-pulmonary involvement group and the non-renal involvement group (P = 0.006; P < 0.001, respectively). SOD levels in the death group were significantly lower than the survival group (P = 0.001). Conclusions In AAV patients, low SOD levels might indicate disease associated oxidative stress. SOD levels in AAV patients were decreased with inflammation, suggesting that SOD levels could potentially be a surrogate marker for disease activity. SOD levels in AAV patients were closely related to ANCA serology, pulmonary involvement, and renal involvement, with low SOD levels an important indicator of a poor prognosis for AAV patients.

Evaluation of Prognostic Factors in Anti-MDA5 Antibody-Positive Patients in Chongqing, China: A Retrospective Study.

OBJECTIVE: The aim of our study was to elucidate the potential prognostic factors in anti-melanoma differentiation-associated gene 5 (anti-MDA5)-positive patients. METHODS: We divided anti-MDA5-positive patients into death and survival groups. The differences in clinical characteristics were analyzed. RESULTS: A total of 56 cases were included. The death group comprised 10 (17.9%) cases, and the survival group comprised 46 (82.1%) cases. Median age of the death group was greater than the survival group, 59.50 years vs 39.25 years, p<0.05. The death group had lower lymphocyte count and albumin and higher erythrocyte sedimentation rate, ferritin and lactate dehydrogenase initially (p<0.05, respectively). Ground-glass opacity on chest computed tomography was found more often in the death group (p<0.05), in which there was an absence of honey-combed shadow initially. The diagnosis of interstitial pneumonia with autoimmune features was higher in the death group than the survival group (70% vs 13%, p<0.05). The median dose of maximum daily methylprednisolone in the death group (160 mg/d) was higher than that in the survival group (48 mg/d) (p<0.05). CONCLUSION: Advanced age, low lymphocyte count and albumin, and increased levels of inflammatory markers may portend poor prognosis in anti-MDA5-positive patients. Extra-large doses of glucocorticoid may have no additional benefit in these patients.

Clinical Characteristics of Lipid Metabolism in Untreated Patients with Anti-MDA5 Antibody-Positive.

OBJECTIVE: Clinical characterization of lipid metabolism in untreated patients with anti-melanoma differentiation-associated gene 5 antibodies-positive (anti-MDA5+). METHODS: Body-mass index (BMI), autoantibodies, lipid levels, and serum ferritin levels in 57 anti-MDA5+ patients were determined in the Department of Rheumatology and Immunology of the Second Affiliated Hospital of Chongqing Medical University. RESULTS: Plasma high-density lipoprotein (HDL) and apolipoprotein A1 (ApoA1) levels were significantly lower in deceased group than in the survival group (P < 0.05). Plasma levels of HDL and ApoA1 were significantly lower in patients who were simultaneously anti-MDA5+ and anti-Ro-52+ than in patients who were anti-MDA5+ alone (P < 0.05). Plasma levels of total cholesterol, low-density lipoprotein, HDL, and ApoA1 were significantly decreased in patients with high levels of serum ferritin compared with patients with low levels (P < 0.05). There were no significant differences in blood lipid levels between patients grouped according to BMI. CONCLUSION: 1) HDL and ApoA1 levels are important indicators of poor prognosis in anti-MDA5+ patients; 2) Dysregulated lipid metabolism in anti-MDA5+ patients is closely associated with anti-Ro-52 antibody and ferritin levels but independent of BMI; 3) HDL involvement in inflammation and immune regulation merits close attention by rheumatologists.

Characteristics of Ang-(1-7)/Mas-Mediated Amelioration of Joint Inflammation and Cardiac Complications in Mice With Collagen-Induced Arthritis.

Objectives: Rheumatoid arthritis (RA) is a disabling disease with a high incidence that is regularly accompanied by cardiovascular complications. Several studies have suggested that renin-angiotensin-aldosterone system (RAAS) is closely associated with RA. The aim of this study was to investigate the mechanisms underlying Angiotensin-(1-7) [Ang-(1-7)] and its Mas receptor agonist (AVE0991) on joint inflammation and cardiac complications in a collagen-induced arthritis (CIA) model. Methods: Collagen type II was injected into DBA/1 mice to construct an arthritis model. CIA mice were treated with Ang-(1-7) (2.0 mg/kg intraperitoneally) and AVE0991 (3.0 mg/kg intraperitoneally). The serum levels of inflammatory cytokines [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1 ß, IL-6, and C-reactive protein (CRP)] were determined by ELISA. The mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-κB) signaling pathways in joint tissues and the transforming growth factor (TGF)-ß/Smad pathway and levels of α-Smooth muscle action (SMA) and ß-myosin heavy chain (MHC) protein expression in cardiac tissues were assessed by western blots. The levels of TGF-ß/Smad pathway, α-SMA, and ß-MHC RNA in cardiac tissues were analyzed by real time-PCR. The levels of receptor activator of nuclear factor kappa ligand (RANKL) and promoting matrix metalloproteinase (MMP)-3 expression in the ankle joints were detected by immunohistochemistry and real time-PCR. Results: Ang-(1-7) and AVE0991 reduced the levels of inflammatory cytokines and inhibited the MAPKs and NF-κB signaling pathways in ankle joint tissues, reduced RANKL and MMP3 expression, and ameliorated local joint inflammation and bone destruction compared with the control group. In addition, Ang-(1-7) and AVE0991 attenuated the TGF-ß/Smad signaling pathway, reduced the levels of α-SMA and ß-MHC expression, and diminished inflammatory cell infiltration into the myocardial interstitium and myocardial interstitial fibrosis in the hearts of CIA mice. Conclusions: Ang-(1-7) alleviated joint damage caused by inflammation likely through the attenuation of NF-κB and MAPK pathways and ameliorated inflammation-induced cardiac fibrosis and activation of the TGF-ß/Smad pathway. Moreover, Ang-(1-7) was likely mediated through the Mas receptor. This study provides theoretical evidence for exploring novel clinical therapeutic approaches for RA and its cardiac complications.

The characteristics of lymphocytes in patients positive for anti-MDA5 antibodies in interstitial lung disease.

OBJECTIVE: The aim was to investigate the characteristics of blood lymphocytes in patients positive for anti-melanoma differentiation-associated gene 5 antibodies (anti-MDA5+) in interstitial lung disease. METHODS: Thirty-eight anti-MDA5+ patients with interstitial lung disease were admitted to our hospital, and the lymphocyte count, lymphocyte subtypes and lung high-resolution CT were recorded. Some of the cases were examined by bone marrow aspiration. RESULTS: Compared with the control group, the blood lymphocyte counts of anti-MDA5+ patients before treatment were significantly lower (P < 0.05). After treatment, lung interstitial lesions in some cases were reduced and the lymphocyte counts increased, whereas their CD4:CD8 ratio decreased (P < 0.05). In contrast, lung interstitial lesions of other cases were exacerbated after treatment and the lymphocyte counts decreased, whereas the CD4:CD8 ratio increased (P < 0.05). In cases with exacerbated lung interstitial lesions after treatment, there were fewer CD4 and CD8 T cells than before treatment, and the change in CD8 T cells was significant (P < 0.05). Bone marrow aspiration biopsy indicated that there was no abnormality in the distribution of bone marrow lymphocytes. CONCLUSION: Anti-MDA5+ patients showed a decrease in blood lymphocyte counts. The presence of anti-MDA5+ in patients with pulmonary interstitial lesions was positively correlated with blood lymphocyte counts but negatively correlated with the CD4:CD8 ratio. The CD8 T cells decreased more significantly than CD4 T cells in patients with aggravation of interstitial lung disease. The change in blood lymphocytes in anti-MDA5+ patients might be attributable to transfer of lymphocytes to the lungs to participate in the local immune response.

Comparative analysis of connective tissue disease-associated interstitial lung disease and interstitial pneumonia with autoimmune features.

OBJECTIVE: This retrospective clinical study aimed to examine the similarities and differences between connective tissue disease-associated interstitial lung disease (CTD-ILD) and interstitial pneumonia with autoimmune features (IPAF) and to identify the influencing factors of CTD-ILD, with a goal of early detection and active treatment of the disease. METHODS: We conducted a retrospective study of 480 patients: 412 with CTD-ILD and 68 with IPAF. Demographic features, clinical characteristics, laboratory indicators, and chest high-resolution computed tomography (HRCT) imaging data were analyzed. RESULTS: Compared with the IPAF group, the CTD-ILD group contained more women, and the incidences of joint pain, dry mouth/dry eyes, and Raynaud's phenomenon were higher; erythrocyte sedimentation rate (ESR) and D-dimer levels were higher; red blood cell (RBC) and hemoglobin (Hb) levels were lower; a high rheumatoid factor (RF) titer (> 2 times the normal upper limit) was observed, and anti-cyclic citrullinated peptide antibody (anti-CCP), anti-keratin antibody (AKA), antinuclear antibody (ANA), and anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5) levels were higher. Compared with CTD-ILD patients, IPAF patients were more likely to present initially with respiratory symptoms, with higher rates of fever, cough and expectoration, dyspnea, and Velcro crackles; anti-Ro52 titers were higher; incidences of honeycombing opacity, reticulate opacity, patchy opacity, and pleural thickening were greater. Female sex, a high RF titer (> 2 times the normal upper limit), anti-CCP positivity, ANA positivity, and anti-MDA5 positivity were risk factors for CTD-ILD when the odds ratios were adjusted. CONCLUSION: CTD-ILD and IPAF patients differed in demographic features, clinical characteristics, laboratory indicators, and chest HRCT imaging data. Female sex, a high RF titer (> 2 times the normal upper limit), anti-CCP positivity, ANA positivity, and anti-MDA5 positivity were risk factors for CTD-ILD.Key Points• This retrospective clinical study comprehensively compared the demographic features, clinical characteristics, laboratory indicators, and chest HRCT imaging data of CTD-ILD and IPAF patients.• The evidence suggested that female sex, a high RF titer, anti-CCP positivity, ANA positivity, and anti-MDA5 positivity were risk factors for CTD-ILD.

Clinical features of thirty-two patients with anti-melanoma differentiation-associated gene 5 antibodies.

OBJECTIVES: To investigate the clinical characteristics of patients positive for anti-melanoma differentiation-associated gene 5 (MDA5) antibodies, and to analyse the potential pathogenesis of anti-MDA5 antibodies. METHODS: The clinical manifestations, serological tests, imaging features, treatments, and prognoses of 32 anti-MDA5 antibody-positive patients diagnosed in the Rheumatology and Immunology Department of the Second Affiliated Hospital of Chongqing Medical University from September 2015 to August 2018 were analysed. RESULTS: Of the 32 anti-MDA5 antibody-positive patients, eleven patients were clinically diagnosed with interstitial pneumonia with autoimmune features (IPAF), ten patients were diagnosed with clinically amyopathic dermatomyositis (CADM), six patients were diagnosed with dermatomyositis (DM) and five patients were diagnosed with anti-synthetase syndrome (ASS). Thirty patients had various degrees of pulmonary interstitial changes. The incidence of mortality, subcutaneous emphysema, hoarseness and dysphagia in patients who were positive for both anti-MDA5 and anti-Ro52 antibodies was significantly higher than in patients positive for only anti-MDA5 antibodies. The anti-MDA5 antibody-positive IPAF patients had a very poor prognosis, and mortality in these patients was as high as 54.55%. CONCLUSIONS: Anti-MDA5 antibodies are closely related to interstitial lung disease (ILD). The presence of both anti-MDA5 and anti-Ro52 antibodies indicates poor prognosis.

Anti-inflammatory effects of Ang-(1-7) via TLR4-mediated inhibition of the JNK/FoxO1 pathway in lipopolysaccharide-stimulated RAW264.7 cells.

Targeting inflammation is considered a challenging pharmacological strategy to prevent or delay the development of inflammatory diseases, such as severe asthma, Crohn's disease, and rheumatoid arthritis. The angiotensin-(1-7) -Mas axis ((Ang-(1-7)-Mas axis) was confirmed to antagonize the effects of the Angiotensin II-AT1 receptor axis and the latter is reported to regulate cardiovascular and renal function, as well as contribute to the inflammatory process. In this paper, we aim to explore the crucial effect of Ang-(1-7) in inflammation and disclose the mechanisms in lipopolysaccharide (LPS)-induced murine macrophages RAW264.7. We found that Ang-(1-7) inhibited the production and secretion of tumor necrosis factor-α and interleukin-6 in a concentration-dependent manner in LPS-induced macrophages. The overexpression of TLR4, phospho-JNK, and FoxO1 induced by LPS were also inhibited by incubation with Ang-(1-7). These inhibitory effects were reversed by A-779. Moreover, we also used a selective JNK inhibitor Sp600125 to further corroborate the involvement of TLR4, JNK, and FoxO1 in the anti-inflammatory action of Ang-(1-7). Our research reveals a new mechanism that Ang-(1-7) may drive anti-inflammatory effects via the Mas receptor through inhibition of the TLR4-mediated JNK/FoxO1 signaling pathway in LPS-induced macrophages. Our findings open new perspectives of Ang-(1-7)-Mas axis in local inflammation.