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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.

Introduction Community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP) are common complications in idiopathic inflammatory myopathy (IIM) patients, and are frequently associated with unfavorable outcome as well as prolonged antibiotic therapy. In this study, we intended to clarify whether clinical pulmonary infection score (CPIS) and multiple serum biomarkers are valuable in predicting unfavorable outcomes and prolonged antibiotic therapy in adult IIM patients complicated with CAP or HAP. Methods Data of IIM patients with CAP or HAP who were admitted to three tertiary centers from December 2010 to November 2019 were retrospectively collected. Cox proportional hazards regression analysis and logistic regression analysis were adopted to identify risk factors for unfavorable outcomes and prolonged antibiotic therapy in these patients. The predictive values of potential predictors were assessed using receiver operating characteristic analysis. Results The mortality rate was 60.6% in 109 IIM patients complicated with CAP or HAP. Myositis Disease Activity Assessment Visual Analogue Scales (MYOACT) score, CPIS and timely adjustment to antibiotics based on drug susceptibility test (DST-based antibiotic) were significantly associated with long-term outcome in these patients. With an optimal cutoff value of 6.5 and area under the curve (AUC) of 0.813, CPIS was a more satisfying predictor compared with MYOACT score. The peak C-reactive protein (CRP) level, DST-based antibiotics, and complication of interstitial lung disease (ILD) were also significantly correlated with prolonged antibiotic therapy. Conclusions IIM patients complicated with CAP or HAP frequently suffer from unfavorable outcomes. Compared with IIM disease activity, CPIS worked as a better predictor of outcome in these patients. Also, the peak CRP level during hospitalization might be valuable in predicting prolonged antibiotic therapy. The existence of ILD might impede early discontinuation of antibiotics. Timely adjustment to antibiotics based on drug susceptibility testing would decrease the mortality rate and reduce the incidence of prolonged antibiotic therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-020-00268-7.

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.

Objectives: To initially clarify the efficacy and tolerability of nintedanib in patients with idiopathic-inflammatory-myopathy-related interstitial lung disease (IIM-ILD).Methods: A retrospective, real-world analysis was conducted in IIM-ILD patients who regularly received outpatient visit or hospitalization from January 2018 to March 2020 in three centers. And the patients were divided into two groups depending on presence or absence of nintedanib therapy. Comparisons, Kaplan-Meier survival analysis and propensity score matching were made to identify difference in time to death from any cause, incidence of rapidly progressive interstitial lung disease (RP-ILD) and comorbidity of pulmonary infection between the two groups. The following logistic regression analyses and Cox proportional-hazard regression analyses were used to verify the therapeutic value of nintedanib as well as clinical significance of other factors. Adverse events were descriptively recorded.Results: Thirty-six patients receiving nintedanib therapy and 115 patients without use of nintedanib were included. Before and after propensity score matching, the primary comparisons revealed better survival (P = 0.015, P = 0016, respectively) and lower incidence of RP-ILD (P = 0.017, P = 0.014, respectively) in patients with nintedanib therapy. Logistic regression analysis identified that disease activity (P < 0.001), percent-predicted diffusing capacity of the lung for carbon monoxide (DLCO%, P = 0.036), nintedanib therapy (P = 0.004, OR value = 0.072) and amyopathic dermatomyositis (ADM, P = 0.012) were significantly correlated with RP-ILD. Cox proportional hazards regression analysis suggested that disease activity (P < 0.001), anti-MDA5 antibody (P < 0.001) and nintedanib therapy (P = 0.013, HR value=0.268) were significantly associated with survival of IIM-ILD patients. Similar results can also be seen in analyses after propensity score matching. In the 36 patients with nintedanib therapy, diarrhea was the most common adverse event (44.4%) and hepatic insufficiency contributed to most dosage reduction (44.4% of nine patients) or therapy discontinuation (60.0% of five patients).Conclusions: Nintedanib was found to reduce incidence of RP-ILD and improve survival in IIM-ILD patients in a real-world setting. Anti-MDA5 antibody could be taken as a risk factor for unfavorable outcome. ADM was significantly correlated with occurrence of RP-ILD. In addition to the most frequent diarrhea, hepatic insufficiency was closely related to dosage reduction or therapy discontinuation.

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.

Background Interstitial lung disease (ILD) is a common and frequently fatal extra-muscular complication in patients with idiopathic inflammatory myopathy (IIM), and is refractory to the conventional immunosuppressive medications. Nintedanib has previously been proven to be effective and tolerable in idiopathic pulmonary fibrosis, systemic-sclerosis-related ILD, etc. However, the efficacy and safety of nintedanib in idiopathic-inflammatory-myopathy-related ILD (IIM-ILD) remain unknown. The purpose of this study was to initially explore the efficacy and tolerability of nintedanib in IIM-ILD patients. Methods A real-world analysis was conducted to explore the efficacy and tolerability of nintedanib in IIM-ILD patients who regularly received outpatient visit or hospitalization from January 2018 to October 2019 in one medical center. The primary end point was occurrence of rapid progression of interstitial lung disease (RP-ILD) in the follow-up. And time to death from any cause, complication of pulmonary infection and difference in immunosuppressive regimen were taken as secondary end points in this study. Adverse events were descriptively recorded. Results 22 patients receiving nintedanib therapy and 82 patients under conventional medications were included. After propensity score matching, the primary comparison revealed that better survival (P = 0.036) and prominently less RP-ILD (P = 0.031) in patients with nintedanib therapy. Logistic regression analysis identified that disease activity (P = 0.032), anti-PM-Scl75 antibody (P = 0.027) and nintedanib therapy (P = 0.023, OR value = 0.063) were significantly correlated with RP-ILD. Cox proportional hazards regression analysis demonstrated that disease activity (P = 0.007), anti-MDA5 antibody (P = 0.004) and nintedanib therapy (P = 0.027, HR value = 0.190) were significantly associated with survival of IIM-ILD patients. Similar results can also be seen in analyses before propensity score matching. In the 22 patients with nintedanib therapy, diarrhea was the most common adverse event (54.5%) and hepatic insufficiency contributed to most dosage reduction (50%) or therapy discontinuation (50%). Conclusion Nintedanib therapy might reduce incidence of RP-ILD and improve survival in IIM-ILD patients. Anti-PM-Scl75 and anti-MDA5 antibodies could predict RP-ILD and survival respectively. In addition to the most frequent diarrhea, hepatic insufficiency was closely related to dosage reduction or therapy discontinuation. Trial registration: ISRCTN.com, ISRCTN 10507540. Retrospectively registered.

Objective: This study aimed at clarifying the prevalence, risk factors, outcome, and outcome-related factors of acute exacerbation of interstitial lung disease (AE-ILD) in patients with idiopathic inflammatory myopathy (IIM). Methods: Data of IIM patients who were admitted to the First Affiliated Hospital of Zhejiang University (FAHZJU) from September 2007 to September 2019 were retrospectively collected. And the IIM patients with AE-ILD formed the case group. In addition, age and sex matched IIM patients without AE-ILD were randomly selected to constitute the control group. A 1:2 case-control study and intragroup analysis were performed to identify risk factors for development of AE-ILD in IIM patients and unfavorable short-term outcome in AE-ILD patients through comparison, univariate and multivariate logistic regression analysis. Results: AE-ILD occurred in 64 out of 665 IIM patients (9.6%) with a short-term mortality rate of 39.1%. And the 64 IIM patients with AE-ILD formed the case group. Besides, 128 age and sex matched IIM patients without AE-ILD were randomly selected to constitute the control group. The retrospective case-control study revealed that elevated on-admission disease activity (P < 0.001), lower percent-predicted diffusing capacity of the lung for carbon monoxide (DLCO%, P = 0.013) and diagnosis of clinically amyopathic dermatomyositis (CADM, P = 0.007) were risk factors for development of AE-ILD in IIM patients. The following intragroup analysis indicated that elevated on-admission disease activity (P = 0.008) and bacterial infection (P = 0.003) were significantly correlated with the unfavorable short-term outcome of patients complicated with AE-ILD. In addition, combined use of steroid and disease modifying antirheumatic drugs (DMARDs, P = 0.006) was found to significantly reduce the short-term mortality in IIM patients with AE-ILD. Conclusion: AE-ILD is a less frequent but fatal complication in IIM patients with elevated on-admission disease activity, lower DLCO% and diagnosis of CADM working as risk factors, indicating the potential roles of autoimmune abnormality and hypoxia in development of AE-ILD. Elevated on-admission disease activity and bacterial infection could predict unfavorable short-term outcome of IIM patients with AE-ILD. A therapeutic regimen of steroid and DMARDs was found to reduce short-term death in these patients.

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 ofκB (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/εin 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/βand pIKKγwere both negative. And pIKKεpositively related to expression of p-p65. Furthermore, pIKKεand 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 IKKγand IκBαbetween 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 IKKεexpression and deregulation of NF-κB pathway.

The present study describes the case of an 18-year-old adolescent male exhibiting acute lymphocytic leukemia (ALL), complicated by the onset of the symptom of sacroiliitis mimicking spondyloarthritis. Atypical features including an enlarged spleen, poor effects of non-steroidal anti-inflammatory drug therapy, low levels of hemoglobin, a low platelet count, a low neutrophil count and increased levels of monocytes, indicated the possibility of hematological malignancy. Bone marrow examination confirmed the diagnosis of ALL. The patient received chemotherapy and the symptoms were dramatically relieved. To the best of our knowledge, the current study reports the second published case of a patient with ALL presenting with sacroiliitis. Sacroiliitis as an onset manifestation of ALL may result in misdiagnosis, therefore, a differential diagnosis is essential when atypical features are present.