Th17/IL-17A axis is critical for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc): SSc patients with high levels of serum IL-17A exhibit reduced lung functions and increased prevalence of PAH.

BACKGROUND: It is thought that systemic sclerosis (SSc) might be a T helper 17 (Th17) cell-driven autoimmune disease. Noticeably, pulmonary arterial hypertension (PAH) is a leading cause of death in patients with SSc. Here, we investigated the association between serum Th17-related cytokines and prevalence of PAH in SSc patients. METHODS: This study included 72 SSc patients and 51 healthy controls (HC). We determined clinical manifestations, immunophenotypes including Th subsets in peripheral blood lymphocytes, and the serum levels of interleukin (IL)-17A, IL-17A/F, IL-17B. IL-17C, IL-17D. IL-1ß, IL-6, IL-21, IL-22, and IL-23. RESULTS: The frequency of Th17 cells was significantly increased in SSc patients compared to HC and was positively correlated with the modified Rodnan skin scores. Furthermore, the serum levels of IL-17A, IL-17D, IL-1ß, and IL-6 were significantly increased in SSc patients compared to HC. SSc patients with detected IL-17A showed high levels of IL-17A/F, IL-1ß, IL-6, and IL-22, and high frequency of Th17 cells. Interestingly, these patients exhibited the reduced lung functions and increased prevalence of PAH significantly compared to patients with undetected IL-17A. Similarly, SSc patients with detected IL-17A and high IL-6 (≥1.2 pg/mL) exhibited the decreased lung functions and increased prevalence of PAH compared to patients with undetected IL-17A and low IL-6. CONCLUSION: We found that SSc patients with high levels of serum IL-17A or both IL-17A and IL-6 show reduced lung functions and high prevalence of PAH. Consequently, it is highly probable that Th17/IL-17A axis is critical for the prevalence of PAH in SSc patients.

Potential Efficacy of Janus Kinase Inhibitors in the Treatment of a Patient With Coexisting Peripheral and Axial Spondyloarthritis and Ulcerative Colitis.

Tumor necrosis factor inhibitors are effective and recommended in treating patients with coexisting spondyloarthritis (SpA) and ulcerative colitis (UC); however, the evidence of their superiority over other drugs is insufficient.1 Although Janus kinase inhibitors (JAKi) have shown effectiveness in treating UC and psoriatic arthritis, there are no reports of treating coexisting SpA and UC with JAKi monotherapy.

Disease-specific expansion of CD29+IL-17RA+ T effector cells possessing multiple signalling pathways in spondyloarthritis.

OBJECTIVES: T cells adhere to enthesis fibrocartilage via integrins and intrinsically require IL-17RA-mediated signals to maintain their effector function. We analysed CD29+IL-17RA+ T cells in inflamed lesions and peripheral blood in patients with SpA and investigated their association with disease activity and therapeutic response. METHODS: Transcriptome analysis of synovial fluid T cells from PsA was performed using publicly available bulk cell RNA sequencing data. Blood samples were obtained from healthy controls (n = 37), RA (n = 12), IgG4-related disease (IgG4-RD; n = 12), large vessel vasculitis (LVV; n = 12) and SpA (n = 28) and were analysed by flow cytometry. RESULTS: T cells in the inflamed joints of PsA showed CD29 and IL-17RA expression. CD29+IL-17RA+ T cells showed enriched CXCR3+CD45RA+ effector cells and activation of spleen tyrosine kinase (Syk), nuclear factor κB (NF-κB) and Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. The proportion of peripheral blood CD29+IL-17RA+ T cells was significantly increased in patients with SpA compared with patients with RA, IgG4-RD or LVV and in healthy controls. Based on the ASDAS-CRP scores, the proportion of CD29+IL-17RA+ T cells was positively correlated with disease activity in treatment-naïve patients with active SpA. Anti-IL-17 but not anti-TNF monoclonal antibodies reduced CD29+IL-17RA+ T cells. CONCLUSIONS: CD29+IL-17RA+ T effector cells with enhanced Syk, NF-κB and JAK-STAT pathways were specifically increased in SpA and were correlated with disease activity, implicating a role of this newly identified T cell population in the pathogenesis. Anti-IL-17 monoclonal antibodies may be effective for patients by reducing this pathogenic T cell population.

A severe cerebral infarction associated with giant cell arteritis, which developed during tocilizumab therapy and was successfully treated with intravenous cyclophosphamide.

Giant cell arteritis (GCA) is a large vessel vasculitis that primarily involves aorta and its major branches. Cerebral infarction is a serious complication that can occur secondary to GCA in up to 3% of patients with a mortality rate of over 50%. Due to the rarity of this severe complication, no therapeutic strategies are currently available. Furthermore, despite the recent progress in molecular-targeted therapy for GCA, it remains unknown whether tocilizumab is effective for severe ischemic complications such as cerebral infarction. The accumulation of individual cases in which this fatal complication could be treated is apparently required to build a better management of the disease. We present our case of GCA that developed severe cerebral infarction during high-dose glucocorticoid and tocilizumab therapy, and its symptoms and image findings were improved by switching to intravenous cyclophosphamide. Our case suggests that an intensive immunosuppressive therapy, including cyclophosphamide, may be necessary to stabilise this fatal complication of GCA.

Successful treatment of refractory enteritis and arthritis with combination of tumour necrosis factor and interleukin-6 inhibition in patients with ulcerative colitis.

An 18 year-old man with autoimmune hepatitis-primary sclerosing cholangitis-overlap syndrome and ulcerative colitis was admitted due to relapsed enteritis and polyarthritis after cessation of infliximab. Colonoscopy and articular ultrasonography revealed large ulcers in the colon with crypt abscess in the specimens and active enthesitis and synovitis, respectively. His intestinitis was improved with golimumab but arthritis was persistent. Golimumab was switched to secukinumab, which was effective for arthritis. However, colitis was flared resulting in total colorectal resection. One month after colectomy, polyarthritis was relapsed. Tocilizumab ameliorated arthritis but enteritis emerged again, and switching tocilizumab to adalimumab improved enteritis but arthritis exacerbated. Finally, we restarted tocilizumab for arthritis with continued adalimumab for enteritis. The dual cytokine blocking strategy, tumour necrosis factor-α and interleukin-6 inhibition, subsided both of his refractory enteritis and arthritis and maintained remission for more than 3 years without any serious adverse event. Our case suggests that enteritis and arthritis in inflammatory bowel disease may be different in pathophysiology and raises the possible usefulness of simultaneous inhibition of two inflammatory cytokines in such cases.

A case of eosinophilic granulomatosis with polyangiitis after prolonged intervals of an anti-interleukin-6 receptor antibody for rheumatoid arthritis.

An 83-year-old woman with a history of asthma complained of left abdominal pain and was admitted to our hospital. She was treated with tocilizumab, an anti-interleukin (IL)-6 receptor antibody, with a prolonged interval for rheumatoid arthritis (RA). Laboratory tests revealed a remarkable increase in eosinophil count and inflammatory markers with negative antineutrophil cytoplasmic antibodies. Echocardiography revealed pericardial fluid retention, and contrast-enhanced computed tomography revealed the thickening of the gastric antrum wall. Upper gastrointestinal endoscopy and biopsy revealed eosinophilic infiltration into the gastric mucosal epithelium. She was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA) with pericarditis and eosinophilic gastroenteritis. High-dose glucocorticoids with intermittent intravenous cyclophosphamide (IVCY) were initiated, resulting in remission. As IL-6 is involved in the pathogenesis of allergic diseases such as asthma, our case can provide insights into the pathogenic role of IL-6 in EGPA as the development of EGPA in our case may have been triggered by IL-6 signals enhanced with tocilizumab interval prolongation.

Successful Treatment of Anti-MDA5 Antibody-Positive Dermatomyositis-Associated Rapidly Progressive-Interstitial Lung Disease by Plasma Exchange: Two Case Reports.

BACKGROUND: Patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM) are frequently accompanied by rapidly progressive-interstitial lung disease (RP-ILD). They are often refractory to intensive immunosuppressive therapy and have poor prognosis. CASE PRESENTATION: A 73-year-old woman presented with fever, cold symptoms, and skin eruption for a month. She also exhibited muscle weakness on upper extremities slightly. The titer of anti-MDA5 antibody was extremely high, and computed tomography showed ground glass opacity and reticular shadows in the lungs. She was diagnosed as anti-MDA5 antibody-positive classical DM-associated RP-ILD and treated with intensive immunosuppressive therapy. However, the titer of anti-MDA5 antibody did not decrease satisfactorily, and plasma exchange was alternatively initiated. The titer decreased remarkably, and she obtained disease remission. Similarly, a 63-year-old woman presented with stiffness of the neck and hands, fever and cough. She was also diagnosed as anti-MDA5 antibody-positive classical DM-associated RP-ILD, because she had skin eruptions, slight muscle weakness, an elevation in anti-MDA5 antibody, and RP-ILD. She was unresponsive to intensive immunosuppressive therapy, but plasma exchange successfully improved the titer of anti-MDA5 antibody, the symptoms, and the findings of computed tomography. CONCLUSIONS: Although anti-MDA5 antibody-positive DM-associated RP-ILD has a high mortality rate, this report suggests the usefulness of plasma exchange to improve the prognosis.

Interleukin-1 pathway in active large vessel vasculitis patients with a poor prognosis: a longitudinal transcriptome analysis.

OBJECTIVES: Large vessel vasculitis (LVV) is characterised by a high relapse rate. Because accurate assessment of the LVV disease status can be difficult, an accurate prognostic marker for initial risk stratification is required. We conducted a comprehensive longitudinal investigation of next-generation RNA-sequencing data for patients with LVV to explore useful biomarkers associated with clinical characteristics. METHODS: Key molecular pathways relevant to LVV pathogenesis were identified by examining the whole blood RNA from patients with LVV and healthy controls (HCs). The data were examined by pathway analysis and weighted gene correlation network analysis (WGCNA) to identify functional gene sets that were differentially expressed between LVV patients and HCs, and associated with clinical features. We then compared the expression of the selected genes during week 0, week 6, remission and relapse. RESULTS: The whole-transcriptome gene expression data for 108 samples obtained from LVV patients (n = 27) and HCs (n = 12) were compared. The pathway analysis and WGCNA revealed that molecular pathway related to interleukin (IL)-1 was significantly upregulated in LVV patients compared with HCs, which correlated with the positron emission tomography vascular activity score, a disease-extent score based on the distribution of affected arteries. Further analysis revealed that the expression levels of genes in the IL-1 signalling pathway remained high after conventional treatment and were associated with disease relapse. CONCLUSION: Upregulation of the IL-1 signalling pathway was a characteristic of LVV patients and was associated with the extent of disease and a poor prognosis.

Early combination of pulmonary vasodilators prevents chronic kidney disease progression in connective tissue disease-associated pulmonary hypertension.

AIM: Pulmonary hypertension (PH) and chronic kidney disease (CKD) are interdependent for their development and exacerbation. We evaluated the effect of PH on CKD progression in patients with connective tissue disease (CTD)-associated PH. METHODS: We reviewed consecutive patients with CTD who were diagnosed with PH with right heart catheter (RHC) examinations in our hospital. Patients were divided into 2 groups according to the use of vasodilators: monotherapy or combination therapy. We further divided the patients with combination therapy into early and non-early combination groups. Early combination was defined as the addition of the second vasodilator within 1 month after starting the first drug. The clinical course of hemodynamics and CKD progression were compared. RESULTS: Thirty-eight patients were included in the analysis: 10 were treated with monotherapy and 28 with combination therapy (14 with early and 14 with non-early). At baseline, patients who received combination therapy had a significantly higher mean pulmonary arterial pressure with RHC and a higher right ventricular systolic pressure (RVSP) with echocardiography (P = .04) and showed a greater improvement in RVSP after treatment than those who underwent monotherapy. The incidence of CKD progression was significantly lower in patients who received combination therapy than in those who received monotherapy (P = .05). Among patients who received combination therapy, the early combination group had a lower incidence of CKD progression than the non-early combination group (P = .03). CONCLUSIONS: Early combination therapy is associated with a lower incidence of CKD progression in patients with CTD-associated PH.

Black pleural effusion caused by pancreatic pseudocyst rupture.

The images show the path of pancreatic pleural effusion from the pancreatic pseudocyst in a patient with alcoholic pancreatitis who presented with black pleural effusion, however, without symptoms. Pancreatic pseudocyst rupture rarely causes pleural effusion; however, it should be considered in patients with chronic pancreatitis with black pleural effusion.

Methotrexate-associated Lymphoproliferative Disorder of the Stomach Presumed to Be Mucosa-associated Lymphoid Tissue Lymphoma.

The number of patients with methotrexate-associated lymphoproliferative disorder (MTX-LPD) is increasing. We describe a case of MTX-LPD of the stomach. After treatment with methotrexate for rheumatoid arthritis, the patient developed left cervical lymphadenopathy and an ulcerative lesion in the stomach, which was presumed to be a mucosa-associated lymphoid tissue (MALT) lymphoma. However, we suspected MTX-LPD, based on the clinical course and the positivity of in situ hybridization for the detection of the Epstein-Barr encoding region. After the cessation of MTX, the left cervical lymphadenopathy and the gastric lesion disappeared. This is first report of gastric MTX-LPD that was presumed to be MALT lymphoma.

Are common names becoming less common? The rise in uniqueness and individualism in Japan.

We examined whether Japanese culture has become more individualistic by investigating how the practice of naming babies has changed over time. Cultural psychology has revealed substantial cultural variation in human psychology and behavior, emphasizing the mutual construction of socio-cultural environment and mind. However, much of the past research did not account for the fact that culture is changing. Indeed, archival data on behavior (e.g., divorce rates) suggest a rise in individualism in the U.S. and Japan. In addition to archival data, cultural products (which express an individual's psyche and behavior outside the head; e.g., advertising) can also reveal cultural change. However, little research has investigated the changes in individualism in East Asia using cultural products. To reveal the dynamic aspects of culture, it is important to present temporal data across cultures. In this study, we examined baby names as a cultural product. If Japanese culture has become more individualistic, parents would be expected to give their children unique names. Using two databases, we calculated the rate of popular baby names between 2004 and 2013. Both databases released the rankings of popular names and their rates within the sample. As Japanese names are generally comprised of both written Chinese characters and their pronunciations, we analyzed these two separately. We found that the rate of popular Chinese characters increased, whereas the rate of popular pronunciations decreased. However, only the rate of popular pronunciations was associated with a previously validated collectivism index. Moreover, we examined the pronunciation variation of common combinations of Chinese characters and the written form variation of common pronunciations. We found that the variation of written forms decreased, whereas the variation of pronunciations increased over time. Taken together, these results showed that parents are giving their children unique names by pairing common Chinese characters with uncommon pronunciations, which indicates an increase in individualism in Japan.