[Diagnosis and Treatment of 43 Patients with IgG4-related Disease].

OBJECTIVE: To summarize the clinicopathological characteristics, diagnosis and treatment of IgG4-related disease (IgG4-RD). METHODS: The clinical data of 43 cases with IgG4-RD diagnosed from January 2013 to December 2017 were retrospectively analyzed. The clinical data of the patients including clinical characteristics, accessory examinations, diagnosis, and treatment were collected. RESULTS: Among the 43 patients with IgG4-RD, the ratio of male to female was 3∶1, the mean age was (51.3±15.9) years. Eleven patients had gastrointestinal symptoms, including 5 cases of IgG4-related cholangitis with the feature of dilation of the biliary system and narrowing of the lumen in the abdominal enhanced CT scans, and 6 cases of IgG4-related autoimmune pancreatitis with the feature of pancreatic enlargement or soft tissue density shadow in the abdominal enhanced CT scans. There were 10 cases (23.3%) with periorbital involvement, with the feature of intraorbital soft tissue nodule in the CT scan. Besides, 9 cases (20.9%) had lymphadenopathy, 6 cases (14.0%) had fever. The results of autoimmune antibody tests showed that 14 of 42 patients had increased antinuclear antibody (ANA). Among 40 patients who underwent immunoglobulin tests, 25 cases had elevated IgG, 12 cases had increased IgA, and 29 cases had increased IgE. Coombs test were performed for 6 cases and 4 patients were positive. Serum immunoglobulin G4 subtypes showed that the IgG4 levels of 35 patients were higher than 1 350 mg/L. The immunohistochemistry showed that IgG4 (+) cells (3->500/HPF) were infiltrated, with the CD20 (+), CD3ε (+) or CD138 (+). Among the 43 patients, 5 patients underwent operations due to misdiagnosis. All patients were treated with steroid and immunosuppressive agents after diagnosis, and their clinical symptoms were improved. CONCLUSION: The clinical symptoms of IgG4-RD are various, involving multiple organs. Therefore, the standardized diagnosis and treatment of IgG4-RD should be strengthened.

Lipid peroxidation-mediated inflammation promotes cell apoptosis through activation of NF-κB pathway in rheumatoid arthritis synovial cells.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of multiple joints. The central pathogenesis of RA is the proliferation of synovial fibroblasts in response to inflammatory cytokines. However, some of the targeted therapies for inflammation reactions do not display significant clinical improvement after initiation of therapy. Thus, the relationship between inflammatory responses and RA therapy is still incompletely understood. In the present study, we proposed to determine whether enhanced inflammations may lead to cell apoptosis in rheumatoid arthritis synoviocytes. Our results indicated that products of lipid peroxidations, 4-HNE, may induce synovial intrinsic inflammations by activating NF-κB pathways and it may lead to cell apoptosis. Pharmacological inhibition of NF-κB activation may reduce the 4-HNE mediated inflammation responses and subsequent cell apoptosis. Our results may help to clarify the role of inflammations on RA development and imply that blocking NF-κB activation may be partly beneficial for human RA therapy. These findings might provide a mechanism-based rationale for developing new strategy to RA clinical therapy.

[Comparison of four assessment criteria for disease activity of rheumatoid arthritis].

OBJECTIVE: To compare of the efficacy of four assessment criteria for evaluating disease activity in rheumatoid arthritis. METHODS: Clinical data were collected from 172 patients ofrheumatoid arthritis. Disease activity was evaluated by four assessment criteria, which are disease activity score 28-C-reactive protein (DAS28-CRP), disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR), simplified disease activity index (SDAI) and clinical disease activity index (CDAI). The patients were divided into four groups which were remission, low, middle and high disease activity. The correlations and consistencies among four methods were compared. RESULTS: Disease activities evaluated by four methods in 172 RA patients were significantly positive correlated (P<0.01). It was significantly consistent between SDAI and CDAI, also between DAS28-ESR and DAS28-CRP, the Kappa values were 0.949 and 0.862 respectively. The differences of the four methods in remission and high disease activity groups were no statistical significance. The proportion of the patients in low disease activity and middle disease activity groups evaluated by DAS28-ESR and DAS28-CRP were statistical different from that evaluated by CDAI and SDAI (P<0.05). CONCLUSION: Strong correlation was observed between the four methods. CDAI could be used to evaluate whether RA is remission or activity. For disease activity assessment, DSA28-ESR and DAS28-CRP seems superior to CDAI and SDAI.

[Disease activity and therapeutic strategy of patients with late-onset rheumatoid arthritis].

OBJECTIVE: To compare the disease activity and therapeutic strategy of late-onset rheumatoid arthritis (LORA) with young-onset rheumatoid arthritis (YORA). METHODS: Medical records of 259 patients with rheumatoid arthritis (RA) were reviewed retrospectively. The cut-off between LORA and YORA was operationally set at 60 years of age at disease onset. Gender ratio, disease duration, feature of involved joint, extra-articular features, laboratory features, disease activity score and treatment strategy were compared between LORA and YORA. RESULTS: The LORA patients had a gender ratio (male/female) of 1/1.88, which was approaching 1/1 in the older age group. It took longer for LORA to be diagnosed than YORA (P<0.001). LORA had more frequent involvement of shoulders (P < 0.001), while elbow, wrist, metacarpophalangeal joint ( MCP), proximal interphalangeal joint (PIP) and ankle joints were more common in YORA (P<0.001). LORA patients were more likely to have anemia than YORA patients (P<0.05). No significant differences were found between LORA and YORA in specific serologic index, including rheumatoid factor and anticyclic citrullinated peptide antibody, and disease activity score 28-C-reactive protein (DAS28-CRP) and clinical disease activity index (CDAI). But LORA had a higher simplified disease activity index (SDAI) (P=0.002). Glucorcoticoid was used in 67.4% LORA patients, compared with 29.3% in YORA patients (P<0.001). In contrast, disease-modifying anti-rheumatic drugs (DMARDs) were used in 73.7% LORA patients, compared with 97.6% in YORA patients (P<0.001). CONCLUSION: Delayed diagnose of LORA is common due to atypical presentation at disease onset. RA should be considered in elderly patients with large joints for differential diagnosis. LORA is more likely to have anemia than YORA, albeit no significant differences in serological index and extraarticular presentations. LORA patients should be treated with DMARDs as aggressively as YORA patients, if their comorbidities allow to do so.

[CCL19/IL-1beta positive feedback loop involved in the progress of inflammation in rheumatoid arthritis].

OBJECTIVE: To explore the function and mechanism of CCL19 in the pathogenesis of rheumatoid arthritis. METHODS: Synovial fibroblasts were collected from 5 cases of rheumatoid arthritis. Peripheral blood mononuclear cells (PBMCs) were obtained from 5 healthy people by Ficoll-Hypaque density gradien centrifugation. The cells were stimulated with IL-1beta, TNF-alpha, IL-17 and other cytokines, and then the expression of CCL19 was detected by RT-PCR. The cells also were treated with different concentration of CCL19, then the expressions of IL-1beta, TNF-alpha were detected by RT-PCR, the expressions of p-ERK, p-p38 were detected by western blot. RESULTS: IL-1beta promoted the CCL19/CCR7 expression in both synovial fibroblasts and PBMCs. CCL19 upregulated the expression of IL-10 in both synovial fibroblasts and PBMCs. The stimulation of CCL19 also increased its receptor CCR7 expression. CCL19 activated p-ERK and p-p38 in PBMCs. CONCLUSION: The positive feedback loop between CCL19 and IL-1 participate in the development of rheumatoid arthritis.

[Controlled clinical study on compound Decumbent Corydalis Rhizome and diclofenac in treatment of knee osteoarthritis].

To evaluate the efficacy and safety of compound Decumbent Corydalis Rhizome (DCR) in treating patients with knee osteoarthritis (OA). Totally 79 patients with knee osteoarthritis were selected from out-patient and inpatient departments of West China Hospital and randomly divided into the test group and the control group. The test group (n = 41) was given Compound DCR with the dosage of 1.8 g · d(-1), while the control group (n = 38) was administered with diclofenac sodium with the dosage of 75 mg · d(-1). After 12 weeks of treatment, the total efficacy rates based on patients/physicians evaluation for experimental and control groups were 68.29%, 63.41% and 71.05%, 63.16%, respectively, without significant difference between the two groups. Both of the two groups showed significant improvements in the main efficacy indexes (pain on walking 20 m) and minor indexes (tenderness on palpation, Western Ontario and McMaster Universities OA index (WOMAC) and Short-Form Health Survey (SF-36 ), but without significant difference in efficacy between them. The incidence of related adverse events was 24.39% in the test group and 47.37% in the control group, respectively, with significant differences between the two groups (P < 0.05). In the controlled study, compound DCR is as efficient as diclofenac sodium but more tolerable, with a good clinical application prospect.

[Comparison of four diagnostic criteria for idiopathic inflammatory myopathy].

OBJECTIVE: To compare the clinical values of four different criteria for diagnosing idiopathic inflammatory myopathy (IIM). METHODS: The four different criteria published in 1975, 1995, 1997 and 2004 were applied to 94 IIM patients and 98 patients with other myopathies in West China Hospital. RESULTS: The sensitivity of the four criteria for diagnosing IIM was 56. 4% (1975), 87. 2% (1995), 61.7 % (1997), and 52. 1% (2004) respectively. The specificity of the four criteria for diagnosing IIM was 78. 6% (1975), 20. 4% (1995), 78. 6% (1997), and 90. 8% (2004) respectively. The Youden index was 35.0% (1975), 7.6% (1995), 40. 3% (1997), and 42.9% (2004), with an odd product of 4. 74 (1975), 1. 75 (1995), 5. 91 (1997) and 10. 77 (2004) respectively. The Kappa value of the four criteria was 0. 351 (1975, P<0.05), 0. 075 (1995, P>0. 05), 0. 404 (1997, P<0.05 ) and 0. 433 (2004, P<0.05), and their area under the ROC curve was 0. 675 (1975, P=0. 00), 0. 538 (1995, P=0.36),0. 701 (1997, P=0.00) and 0. 715 (2004, P=0.00) respectively. CONCLUSION: The 2004 criteria have a better value in diagnosing IIM.

[Clinical features and risk factors associated with interstitial lung disease in patients with classic dermatomyositis or clinical amyopathic dermatomyositis].

OBJECTIVE: To investigate the clinical features and risk factors associated with interstitial lung disease (ILD) in patients with classic dermatomyositis (classic DM) or clinical amyopathic dermatomyositis (CADM). METHODS: Medical records of 121 DM patients (77 with classic DM and 44 with CADM) were reviewed retrospectively. The risk factors associated with ILD were identified through Binary Logistic Regression analyses. RESULTS: ILD presented in 40. 3% (31/77) of patients with classic DM and 50. 0% (22/44) of patients with CADM. Overall, the DM patients had a prevalence of ILD of 43. 8%. Univariate analyses showed that arthralgia, cough, dyspnea, anti-Jo-1 antibody, malignant tumors, and the levels of Erythrocyte sedimentation rate (ESR) and Albumin (ALB) were associated with ILD. The Multivariate Logistic Regression analysis identified arthralgia (beta= 1. 119, P= 0. 023), cough (beta= 2. 423, P= 0. 003) and ESR (beta= 0. 041, P= 0. 009) as risk factors of ILD. CONCLUSION: ILD is a common complication of classic DM/CADM and arthralgia, cough and high level of ESR are independent risk factors of ILD.

[Detecting anti-cyclic citrullinated peptide antibody in patients with connective tissue diseases].

OBJECTIVE: To determine the clinical significance of anti-cyclic citrullinated peptide antibody (anti CCP) in mixed connective tissue diseases (MCTD). METHODS: Enzyme linked immunosorbent assay was performed to detect anti-CCP in 57 patients with MCTD, 78 with rheumatoid arthritis (RA), 64 with systemic lupus erythematosus (SLE), 56 with polymyositis/dermatomyositis (PM/DM), 53 with Sjögren syndrome (SS) and with 33 systemic sclerosis (SSc). The association between anti-CCP and clinical features of MCTD was analysed. RESULTS: Anti-CCP was detected in 87.5% RA cases, 15.8% MCTD cases, 57.1% MCTD with RA cases, 14.1% SLE cases, 15.2% PM/DM cases, 18.9% SS cases and 9.1% SSc cases. Patients with RA (or MCTD with RA) were more likely to be anti-CCP positive than those without RA (P < 0.05). The MCTD patients with positive anti-CCP had higher prevalence of RA and SS related manifestations than those MCTD patients with negative anti-CCP (P < 0.05). The MCTD patients with RA had higher prevalence of RA-related symptoms, diffuse sclerosis and positive anti-CCP than those MCTD patients without RA (P < 0.01). Significant deviation of disease spectrum was found in the MCTD patients with RA compared with the anti-CCP positive MCTD patients without RA. CONCLUSION: High titer of anti-CCP in combination with RA, SLE and SSc manifestations in MCTD patients can be an indicator of erosive arthritis.

[Application value of combining brain natriuretic peptide, creatine phosphokinase and echocardiogram in the evaluation of polymyositis-related chronic heart failure].

OBJECTIVE: To explore the application value of combining brain natriuretic peptide (BNP), creatine phosphokinase (CPK) and echocardiogram in the evaluation of olymyositis-related chronic heart failure (CHF). METHODS: Twenty-five polymyositis (PM) patients with CHF (NYHA grade II-IV) were evaluated with New York Heart Association (NYHA) criteria for heart failure. Serum concentration of BNP and CPK were detected by the methods of enzyme linked immunosorbent assay and automatic biochemistry analyzer respectively. Echocardiogram was used to calculate left ventricular ejection fraction (LVEF). Thirty PM patients without CHF were also investiaged as control. RESULTS: Serum concentrations of BNP, CPK in PM with CHF were significantly higher than those in PM without CHF (P < 0.01). Compared with the level before intervention, BNP concentration in PM with CHF decreased sharply after 14 days therapy (P < 0.05), while the decrease of BNP concentration was not statistically significant (P > 0.05) in PM without CHF after the therapy. The concentration of CPK was much lower in PM patients either with or without CHF after therapy (P < 0.05). Among each group of NYHA grade II-IV, there was statistical significant difference of BNP concentration (P < 0.05). Statistical significant difference of CPK concentration was only found between grade II and grade IV patients. The difference of BNP was not statistical significant between PM patients without CHF but CPK > 2 000 IU/L and PM with grade II CHF. BNP concentration was significantly different between PM patients with LVEF > 40% and those with LVEF < or = 40% (P < 0.05). CONCLUSION: BNP is a good marker for PM with CHF and correlates well with LVEF and NYHA grades. In addition, it plays a suggestive role in diagnosing CHF in PM with CPK > 2 000 IU/L.

Successful closure of ileostomy in a patient with intestinal Behçet's disease after therapy with adalimumab: A case report.

RATIONALE: Behçet's disease (BD) is a chronic immune-mediated inflammatory disorder involving multiple organ systems. In BD, intestinal ulcers can present as a refractory lesion capable of perforation, which makes the choice of treatment difficult. PATIENT CONCERNS: A 34-year-old male who was diagnosed with intestinal BD and suffered with an ileocecal perforation. He underwent surgery for an ileostomy and was given corticosteroids as treatment. However, the ulcerative lesion remained resistant to the therapy that was provided which delayed the closure operation. DIAGNOSIS: Intestinal BD with severe post-operative complication. INTERVENTIONS: A course of adalimumab (ADa) therapy was started. Subsequently surgery was performed. And ADa and thalidomide were used as a maintenance therapy. OUTCOMES: In this case, a course of ADa therapy was given which healed the intestinal ulcers and allowed us to successfully perform the closure operation. LESSONS: This case indicates that ADa may be an effective treatment option in future cases, minimizing complications and allowing the closure operation to be performed successfully.

DEPTOR-mTOR Signaling Is Critical for Lipid Metabolism and Inflammation Homeostasis of Lymphocytes in Human PBMC Culture.

Abnormal immune response of the body against substances and tissues causes autoimmune diseases, such as polymyositis, dermatomyositis, and rheumatoid arthritis. Irregular lipid metabolism and inflammation may be a significant cause of autoimmune diseases. Although much progress has been made, mechanisms of initiation and proceeding of metabolic and inflammatory regulation in autoimmune disease have not been well-defined. And novel markers for the detection and therapy of autoimmune disease are urgent. mTOR signaling is a central regulator of extracellular metabolic and inflammatory processes, while DEP domain-containing mTOR-interacting protein (DEPTOR) is a natural inhibitor of mTOR. Here, we report that overexpression of DEPTOR reduces mTORC1 activity in lymphocytes of human peripheral blood mononuclear cells (PBMCs). Combination of DEPTOR overexpression and mTORC2/AKT inhibitors effectively inhibits lipogenesis and inflammation in lymphocytes of PBMC culture. Moreover, DEPTOR knockdown activates mTORC1 and increases lipogenesis and inflammations. Our findings provide a deep insight into the relationship between lipid metabolism and inflammations via DEPTOR-mTOR pathway and imply that DEPTOR-mTOR in lymphocytes of PBMC culture has the potential to be as biomarkers for the detection and therapies of autoimmune diseases.

Identification of Palmitoleic Acid Controlled by mTOR Signaling as a Biomarker of Polymyositis.

Polymyositis (PM) is a chronic disease characterized by muscle pain, weakness, and increase in muscle-related enzymes, accompanied with inflammations in lymphocytes. However, it is not well understood how the molecular alternations in lymphocytes contribute to the development of polymyositis. The mechanistic target of rapamycin (mTOR) signaling is the central regulator of metabolism and inflammation in mammalian cells. Based on previous studies, we proposed that mTOR signaling may control inflammatory reactions via lipid metabolism. In this study, we aim to figure out the role of mTOR signaling in the development of polymyositis and identify novel biomarkers for the detection and therapy of polymyositis. After screening and validation, we found that palmitoleic acid, a monounsaturated fatty acid, is highly regulated by mTOR signaling. Inhibition of mTORC1 activity decreases palmitoleic acid level. Moreover, mTORC1 regulates the level of palmitoleic acid by controlling its de novo synthesis. Importantly, increased palmitoleic acid has been proven to be a marker of polymyositis. Our work identifies palmitoleic acid in peripheral blood mononuclear cells (PBMC) as a biomarker of polymyositis and offers new targets to the clinical therapy.

mTOR complex 1 signalling regulates the balance between lipid synthesis and oxidation in hypoxia lymphocytes.

Mammalian cells adapt to different environmental conditions and alter cellular metabolic pathways to meet the energy demand for survival. Thus, the metabolic regulation of cells under special conditions, such as hypoxia, should be precisely regulated. During the metabolic regulation, mammalian target of rapamycin (mTOR) plays a vital role in the sensing of extracellular stimulations and regulating intracellular adaptations. Here, we report that mTOR complex 1 (mTORC1) signalling is a central regulator of lipid homoeostasis in lymphocytes. In hypoxia, mTORC1 activity is reduced and shifts lipid synthesis to lipid oxidation. Moreover, knockdown tuberous sclerosis complex 1 (TSC1) constitutively activates mTORC1 activity and impairs the hypoxia-induced metabolic shift. Therefore, TSC1 knockdown enhances hypoxia-induced cell death. Re-inactivation of mTORC1 activity via rapamycin may resist hypoxia-induced cell death in TSC1 knockdown lymphocytes. Our findings provide a deep insight into mTORC1 in the metabolic balance of lipid synthesis and oxidation, and imply that mTORC1 activity should be precisely regulated for the lipid homoeostasis in lymphocytes.

Pim-2/mTORC1 Pathway Shapes Inflammatory Capacity in Rheumatoid Arthritis Synovial Cells Exposed to Lipid Peroxidations.

Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic inflammation of multiple joints, with disruption of joint cartilage. The proliferation of synovial fibroblasts in response to multiple inflammation factors is central to the pathogenesis of rheumatoid arthritis. Our previous studies showed that 4-HNE may induce synovial intrinsic inflammations by activating NF-κB pathways and lead to cell apoptosis. However, the molecular mechanisms of how synovial NF-κB activation is modulated are not fully understood. Here, the present findings demonstrated that 4-HNE may induce synovial intrinsic inflammations by mTORC1 inactivation. While ectopic activation of mTORC1 pathway by the overexpression of Pim-2 may disrupt the initiation of inflammatory reactions and maintain synovial homeostasis, our findings will help to uncover novel signaling pathways between inflammations and oxidative stress in rheumatoid arthritis development and imply that Pim-2/mTORC1 pathway may be critical for the initiation of inflammatory reactions in human rheumatoid arthritis synovial cells.