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Macrophage activation syndrome (MAS) is a potentially life-threatening complication of systemic autoinflammatory/autoimmune diseases, generally systemic juvenile idiopathic arthritis and adult-onset Still's disease. It is characterized by an excessive proliferation of macrophages and T lymphocytes. Recent research revealed that cytokine storm with elevated pro-inflammatory cytokines, including IFN-γ, IL-18, and IL-6, may be central to the pathogenesis of MAS. Though the mainstream of MAS treatment remains corticosteroids and cyclosporine, targeted therapies with anti-cytokine biologics are reported to be promising for controlling systemic inflammation in MAS.

To improve the diagnosis of Lupus Nephritis (LN), a multilevel LN image segmentation method is developed in this paper based on an improved slime mould algorithm. The search of the optimal threshold set is key to multilevel thresholding image segmentation (MLTIS). It is well known that swarm-based methods are more efficient than the traditional methods because of the high complexity in finding the optimal threshold, especially when performing image partitioning at high threshold levels. However, swarm-based methods tend to obtain the poor quality of the found segmentation thresholds and fall into local optima during the process of segmentation. Therefore, this paper proposes an ASMA-based MLTIS approach by combining an improved slime mould algorithm (ASMA), where ASMA is mainly implemented by introducing the position update mechanism of the artificial bee colony (ABC) into the SMA. To prove the superiority of the ASMA-based MLTIS method, we first conducted a comparison experiment between ASMA and 11 peers using 30 test functions. The experimental results fully demonstrate that ASMA can obtain high-quality solutions and almost does not suffer from premature convergence. Moreover, using standard images and LN images, we compared the ASMA-based MLTIS method with other peers and evaluated the segmentation results using three evaluation indicators called PSNR, SSIM, and FSIM. The proposed ASMA can be an excellent swarm intelligence optimization method that can maintain a delicate balance during the segmentation process of LN images, and thus the ASMA-based MLTIS method has great potential to be used as an image segmentation method for LN images. The lastest updates for the SMA algorithm are available in https://aliasgharheidari.com/SMA.html.

Objective. Iguratimod, a novel disease-modifying anti-rheumatic drug for the treatment of rheumatoid arthritis, has been approved in China and Japan. Here, we aimed to find whether iguratimod can inhibit the aggressive behavior and promote apoptosis of rheumatoid fibroblast-like synoviocytes (RA-FLSs). Methods. The proliferation of RA-FLSs was assessed by 5-ethynyl-2′-deoxyuridine test and Cell Counting Kit-8. Migration and invasion were determined by the wound test and a transwell assay. Apoptosis was tested by flow cytometry. The mRNA expression of matrix metalloproteinases (MMPs) and proinflammatory cytokines in RA-FLSs were measured by quantitative PCR and ELISA. To gain insight into the molecular signaling mechanisms, we determined the effect of iguratimod on the activation of mitogen-activated protein kinases (MAPK) signaling pathways by the cellular thermal shift assay (CETSA) and western blot. Results. Iguratimod treatment significantly reduced the proliferation, migration, and invasive capacities of RA-FLSs in a dose-dependent manner in vitro. MMP-1, MMP-3, MMP-9, Interleukin-6 (IL-6), and monocyte chemoattractant protein-1 mRNA and protein levels were all decreased after treatment with iguratimod. Furthermore, tumor necrosis factor-alpha- (TNF-α-) induced expression of phosphorylated c-Jun N-terminal kinases (JNK) and P38 MAPK were inhibited by iguratimod. Additionally, iguratimod promoted the apoptosis of RA-FLSs. Most importantly, iguratimod was shown to directly interact with JNK and P38 protein by CETSA assay. Moreover, activating transcription factor 2 (ATF-2), a substrate of both JNK and P38, was suppressed by iguratimod. Conclusions. Our findings suggested that the therapeutic effects of iguratimod on RA might be, in part, due to targeting the aggressive behavior and apoptosis of RA-FLSs.

Adult-onset Still disease (AOSD) is a rare autoinflammatory condition. The presence of an evanescent, salmon-pink, nonpruritic rash is one of the major diagnostic criteria for the disease. The rash occurs with fever and subsides with defervescence. The presence of dyskeratotic keratinocytes in the upper one-third layer of the epidermis is a distinctive histopathological feature of persistent pruritic lesions associated with AOSD. Here, we report 2 cases of AOSD characterized by persistent pruritic lesions resembling those observed in dermatomyositis. Identifying the clinical and histopathological manifestation of the cutaneous lesions is essential for the early diagnosis of AOSD and for differentiating this condition from those presenting with dyskeratotic cells in the epidermis.

Objective.To clarify the prevalence, risk factors, outcome, and outcome-related factors of hemophagocytic lymphohistiocytosis (HLH) in patients with dermatomyositis (DM), polymyositis (PM), or clinically amyopathic dermatomyositis (CADM).Methods.Data of patients with DM, PM, or CADM who were admitted to the First Affiliated Hospital of Zhejiang University from February 2011 to February 2019 were retrospectively collected. Patients diagnosed with HLH constituted the case group. A 1:4 case-control study was performed to identify risk factors for HLH in patients with DM, PM, or CADM through comparison, univariate, and multivariate logistic regression analysis. Intragroup comparison was made among patients with HLH to identify factors influencing unfavorable short-term outcome.Results.HLH was a rare (4.2%) but fatal (77.8%) complication in patients with DM, PM, or CADM. The retrospective case-control study revealed that higher on-admission disease activity (p = 0.008), acute exacerbation of interstitial lung disease (AE-ILD, p = 0.002), and infection (p = 0.002) were risk factors for complication of HLH in patients with DM, PM, or CADM. The following intragroup comparison showed that higher on-admission disease activity (p = 0.035) and diagnosis of CADM (p = 0.039) might influence the short-term outcome of patients with HLH. However, no risk factor was identified after false discovery rate correction.Conclusion.In this study, secondary HLH was a fatal complication, with higher on-admission disease activity, AE-ILD, and infection working as risk factors. The underlying role of infection and autoimmune abnormality in HLH in connective tissue disease was subsequently noted. Clinical factors influencing the short-term outcome of patients with secondary HLH require further study.

Small case series and case reports indicated that atypical persistent pruritic eruptions (PPEs), another type of skin lesions seen in adult-onset Still's disease (AOSD), imply a worse prognosis than typical evanescent rashes.To investigate clinical characteristics and macrophage activation syndrome (MAS) occurrence in AOSD with PPEs.A retrospective cohort study analyzed 150 patients with AOSD with rashes at the First Affiliated Hospital of Zhejiang University from January 2013 to December 2019.Patients with AOSD with PPEs had higher lactate dehydrogenase (492.00 U/L vs 382.00 U/L; P .001) and ferritin (6944.10 ng/ml vs 4286.60 ng/ml; P = .033), and lower fibrinogen (5.05 g/L vs 5.77 g/L; P = .014) than those with evanescent rashes. Patients with AOSD with PPEs had a higher incidence (17.4% vs 3.1%, P = .006) and cumulative event rate for MAS (P = .008) and tended to receive high-dose glucocorticoid (36% vs 20.3%; P = .036). Multivariate analysis indicated that PPEs (hazard ratio [HR], 5.519; 95% confidence interval [CI], 1.138-26.767; P = .034), aspartate aminotransferase of greater than 120 U/L (HR, 8.084; 95% CI, 1.728-37.826; P = .008), and splenomegaly (HR, 21.152; 95% CI, 2.263-197.711; P = .007) were independent risk factors for MAS.Single-center, retrospective nature, small sample size.PPEs indicated increased severity and MAS occurrence versus evanescent rashes. PPEs, aspartate aminotransferase of greater than 120 U/L, and splenomegaly were risk factors for MAS in AOSD with skin involvement.

To determine the pathogenic role of adipokines, such as adiponectin and leptin, in rheumatoid arthritis (RA) by investigating whether serum levels of these adipokines correlated with disease activity in RA patients. Medline, Cochrane, EMBASE and Google Scholar were searched for studies published until 5 November 2015 reporting serum levels of leptin and adiponectin and measures of disease activity including DAS scores and radiographic progression scores (such as total change in SHS scores and number of erosions). Secondary outcomes included pain scores, functional status and health questionnaires. Only randomized controlled trials, cohort studies, or two-armed prospective or retrospective studies were included. A χ2-based test of homogeneity was performed using Cochran’s Q statistic and I2. A total of 917 predominantly female participants (average age range, 39–56 years) from six prospective cohort studies were included for assessment. A fixed-effects analysis was applied for leptin levels due to ...

Aims Persistent pruritic eruptions (PPEs), presenting with dyskeratotic keratinocytes histologically, are characteristic skin rash in patients with adult-onset Still's disease (AOSD). The lesions may be histologically similar to other entities that present with dyskeratosis. In the present study, we compared the histopathological features between PPEs and other entities presenting with dyskeratosis. Methods and results To investigate whether histopathological findings can be used to discriminate among PPEs and other entities presenting with dyskeratotic keratinocytes, cutaneous histopathological changes of PPEs associated with AOSD (n = 26) were compared with those of systemic lupus erythematosus (SLE) (n = 16), dermatomyositis (n = 19), and drug eruption (n = 16). Dyskeratosis was observed in the upper one-third of the epidermal layer in all 26 PPEs. The rate of dyskeratosis for PPEs was higher than that for SLE (18.8%) and dermatomyositis (15.8%). In drug eruptions, the dyskeratotic cells were distributed in all levels of the epidermis. Variable densities of neutrophils were found in the dermis in all PPEs. Conclusions Although this was a retrospective study conducted at a single centre, presentation of dyskeratotic keratinocytes in the upper one-third of the epidermal layer is a distinctive histopathological reactive pattern of PPEs. This pattern may be a useful histopathological marker for early diagnosis of AOSD.

Rationale: Dysregulated immune function in rheumatoid arthritis (RA) might lead to the development of myelodysplastic syndrome (MDS). Serum interleukin-6 (IL-6) concentrations are increased in both RA and MDS patients. Patient concerns: A 58-year-old woman presented with severe RA. During a recent 8-month period, the patient experienced swelling in multiple joints, dizziness, and severe anemia. The symptoms responded poorly to oral corticosteroids and methotrexate (MTX). Even treatment of the patient's anemia by transfusion of red blood cells was ineffective. Laboratory tests showed high levels of IL-6 (214.24 pg/mL). Diagnoses: Combining her medical history with clinical and laboratory parameters, especially those obtained by bone marrow aspiration, a diagnosis of RA with MDS was made. Interventions: MTX was discontinued and the patient was given tocilizumab intravenously at a dose of 8 mg/kg every 4 weeks and oral corticosteroids (15 mg/QD). Outcomes: The patient's serological, physical, and pathological abnormalities improved significantly. Lessons: We report a case of RA with MDS successfully treated with tocilizumab. To our knowledge, this is the first case of an RA patient with MDS that was successfully treated with tocilizumab. In addition, our case emphasizes that IL-6 plays a critical role in the pathogenesis of RA with MDS. Tocilizumab might be an effective treatment for RA with MDS, especially in those with high levels of IL-6, elevated C-reactive protein, and severe anemia.

The activated NF-κB signaling pathway plays an important role in pathogenesis of primary Sjögren's syndrome (pSS). The inhibitor of κB (IκB) kinase (IKK) family such as IKKα, IKKβ, IKKγ, and IKKε, is required for this signaling. Our aim was to investigate the role of IKKα/β/γ/ε in patients with untreated pSS. In minor salivary glands from pSS patients, phosphorylated IKKε (pIKKε), pIκBα, and pNF-κB p65 (p-p65) were highly expressed in ductal epithelium and infiltrating mononuclear cells by immunohistochemistry, compared to healthy individuals. pIKKα/β and pIKKγ were both negative. And pIKKε positively related to expression of p-p65. Furthermore, pIKKε and p-p65 expression significantly correlated with biopsy focus score and overall disease activity. Meanwhile, in peripheral blood mononuclear cells from pSS patients, pIKKε, total IKKε, pIKKα/β, and p-p65 were significantly increased by western blot, compared to healthy controls. However, there was no difference in IKKγ and IκBα between pSS patients and healthy individuals. These results demonstrated an abnormality of IKKε, IκBα, and NF-κB in pSS, suggesting a potential target of treatment for pSS based on the downregulation of IKKε expression and deregulation of NF-κB pathway.