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Background: In osteoarthritis (OA), cartilage matrix is lost gradually despite enhanced matrix synthesis by chondrocytes. This paradox may be explained, at least partly, by reduced chondrocyte anabolism in degenerated area of OA cartilage. However, to date, it is not known why chondrocyte anabolism is suppressed in those areas.Methods: Cartilage was obtained from control knees and end-stage OA knees in macroscopically preserved areas and degenerated areas, and gene expression was analyzed in respective regions of cartilage using laser capture microdissection and qPCR. For the cartilage protein analysis, cartilage was obtained from preserved areas and degenerated areas of OA knees in pairs, and proteins were extracted using urea buffer. Protein concentrations were determined by Luminex and compared between the areas. Cartilage explants prepared from preserved areas and degenerated areas of OA knees were cultured in the presence or absence of an AKT inhibitor, and the gene expression was evaluated by qPCR. Finally, the expression of SP1 was evaluated in OA and control cartilage, and the significance of Sp1 on the expression of IGF1R and IRS1 was investigated in experiments using primary cultured chondrocytes.Results: Within OA cartilage, the expression of IGF-1, IGF-2, IGF1R and IRS1 was reduced in degenerated areas compared to preserved areas, while the expression of all six IGF-binding protein genes examined was enhanced in the former areas. Consistent results were obtained by a protein analysis. In explant culture, the inhibition of AKT signaling abrogated the abundant matrix gene expression in the preserved areas over the degenerated areas, indicating that suppressed matrix synthesis in degenerated areas may be ascribed, at least partly, to attenuated IGF signaling. Within OA cartilage, the expression of Sp1 was considerably reduced in severely degenerated areas compared to preserved areas, which correlated well with the expression of IGF1R and IRS1. In experiments using primary cultured chondrocytes, the expression of IGF1R and IRS1 was enhanced by the induction of Sp1 expression and reduced by the suppression of Sp1 expression. Conclusions: The results of this study suggest that attenuated IGF signaling may be responsible, at least partly, for the reduced matrix synthesis in degenerated areas of OA cartilage.

Background In osteoarthritis (OA), cartilage matrix is lost gradually despite enhanced matrix synthesis by chondrocytes. This paradox may be explained, at least partly, by reduced chondrocyte anabolism in degenerated area of OA cartilage. However, to date, it is not known why chondrocyte anabolism is suppressed in those areas. Methods Cartilage was obtained from control knees and end-stage OA knees in macroscopically preserved areas and degenerated areas, and gene expression was analyzed in respective regions of cartilage using laser capture microdissection and qPCR. For the cartilage protein analysis, cartilage was obtained from preserved areas and degenerated areas of OA knees in pairs, and proteins were extracted using urea buffer. Protein concentrations were determined by Luminex and compared between the areas. Cartilage explants prepared from preserved areas and degenerated areas of OA knees were cultured in the presence or absence of an AKT inhibitor, and the gene expression was evaluated by qPCR. Finally, the expression of SP1 was evaluated in OA and control cartilage, and the significance of Sp1 on the expression of IGF1R and IRS1 was investigated in experiments using primary cultured chondrocytes. Results Within OA cartilage, the expression of IGF-1, IGF-2, IGF1R and IRS1 was reduced in degenerated areas compared to preserved areas, while the expression of all six IGF-binding protein genes examined was enhanced in the former areas. Consistent results were obtained by a protein analysis. In explant culture, the inhibition of AKT signaling abrogated the abundant matrix gene expression in the preserved areas over the degenerated areas, indicating that suppressed matrix synthesis in degenerated areas may be ascribed, at least partly, to attenuated IGF signaling. Within OA cartilage, the expression of Sp1 was considerably reduced in severely degenerated areas compared to preserved areas, which correlated well with the expression of IGF1R and IRS1. In experiments using primary cultured chondrocytes, the expression of IGF1R and IRS1 was enhanced by the induction of Sp1 expression and reduced by the suppression of Sp1 expression. Conclusions The results of this study suggest that attenuated IGF signaling may be responsible, at least partly, for the reduced matrix synthesis in degenerated areas of OA cartilage.

Objective: Nontuberculous mycobacterial (NTM) pulmonary disease is occasionally associated with rheumatoid arthritis (RA), influencing the therapeutic strategy of RA. Since chronic lung diseases are frequently associated with RA, the diagnosis of NTM pulmonary disease is quite difficult in RA patients. Recently, a serological diagnostic test detecting serum immunoglobulin A against the glycopeptidolipid (GPL) core antigen was developed. We investigated the serum levels of anti-GPL antibodies in RA patients to determine the usefulness for detecting NTM pulmonary disease. Methods: Anti-GPL antibodies were detected in the sera from RA patients with or without NTM pulmonary disease. Results: The positivity of anti-GPL antibodies in RA patients with NTM pulmonary disease was higher than in RA without (p = 1.76 × 10−14, odds ratio 70.29, 95% confidence interval [CI] 22.28–221.83). Anti-GPL Ab titers were increased in RA with NTM pulmonary disease (mean titer ± standard deviation [U/ml], RA with NTM pulmonary disease: 4.1 ± 7.0, RA without NTM pulmonary disease: 0.4 ± 1.6, p = 1.51 × 10−10). The area under the curve (AUC) value of the receiver operating characteristic (ROC) curve for anti-GPL antibodies was 0.917 (95%CI 0.860–0.974, p = 3.32 × 10−47). Conclusions: Serum anti-GPL antibodies are useful for detecting NTM pulmonary disease in RA patients.

Objectives: Interstitial lung disease (ILD) is a life-threatening extra-articular manifestation of rheumatoid arthritis (RA). We aimed to clarify the relationship between chronic ILD with a pattern of usual interstitial pneumonia (UIP) or non-UIP and mortality in RA patients.Methods: We retrospectively surveyed information of consecutive RA patients who visited our hospital from 2009 to 2014. The relationship between their mortality and chronic ILD (UIP or non-UIP) detected by high-resolution computed tomography was examined.Results: Of 2702 patients enrolled, 261 (9.7%) had chronic ILD and among these 120 had a UIP pattern. At the onset of RA, the prevalence of chronic ILD was 6%. Patients with chronic ILD had a higher mortality than those without. The most frequent cause of death was pneumonia including acute exacerbation (AE) of chronic ILD. Lung cancer death was frequently identified in deceased patients with chronic ILD with a UIP pattern compared with the other decedents (p=.062). The estimated mortality of lung cancer in patients with chronic ILD with a UIP pattern was five times higher than the general population.Conclusion: RA patients with ILD with a UIP pattern have a high mortality rate and are prone to die of AE or lung cancer.

Background To understand the roles of serum exosomes in rheumatoid arthritis (RA), we comprehensively investigated the protein profiles of serum exosomes in patients with RA. Methods Exosomes were isolated from serum samples obtained from 33 patients (12 with active RA [aRA], 11 with inactive RA [iRA], 10 with osteoarthritis [OA]) and 10 healthy donors (HLs). Proteins extracted from the exosomes were separated by two-dimensional differential gel electrophoresis (2D-DIGE) and identified by mass spectrometry. Results In total, 204 protein spots were detected by 2D-DIGE. In the aRA, iRA, and OA groups, 24, 5, and 7 spots showed approximately ≥ ±1.3-fold intensity differences compared with the HL group, respectively. We were able to identify proteins in six protein spots. Among them, the protein spot identified as Toll-like receptor 3 (TLR3) showed approximately 6-fold higher intensity in the aRA group than in the other groups. Conclusions Patients with active RA possessed considerably different protein profiles of serum exosomes from patients with iRA, patients with OA, and healthy donors. The unique protein profile of serum exosomes, such as the possession of abundant TLR3 fragments, may reflect the pathophysiology of active RA. Electronic supplementary material The online version of this article (10.1186/s41927-018-0041-8) contains supplementary material, which is available to authorized users.

To evaluate the utility of quantifying CD64 expression on neutrophils in rheumatoid arthritis patients with malignancy, especially its diagnostic role in lymphoma.We used flow cytometry to quantify CD64 expression on neutrophils from patients diagnosed with malignancy during the follow-up period prior to initiating treatment.Neutrophils from 18 patients with lymphoma expressed significantly higher levels of CD64 (9635.6 ± 2123.7 molecules/cell) than those from 32 patients with other solid cancers (carcinoma) (1250.5 ± 91.1 molecules/cell) (p 0.001). When the cutoff value was set at 2060 molecules/cell, the sensitivity and specificity of CD64 for diagnosing lymphoma was 88.9% and 94.4%, respectively.The quantitative measurement of neutrophil CD64 by flow cytometry may be useful as a subsidiary diagnostic marker in patients with suspected lymphoma. Although neutrophil CD64 is currently a well-known marker of infection, it is necessary to bear in mind that lymphoma is also a candidate in differential diagnosis when CD64 expression on neutrophils is upregulated.

Objective. Rheumatoid arthritis (RA) may be complicated by different infections, but risk factors for these are not fully elucidated. Here, we assessed the incidence of and risk factors for infections requiring hospitalization (IRH) including pneumocystis pneumonia (PCP) in patients with RA. Methods. We retrospectively surveyed all RA patients treated at our hospital from 2009 to 2013, for whom data were available on demographic features, medications, comorbidities, and severity of RA. Multivariate logistic regression analysis was applied to calculate adjusted odds ratios (ORs) for factors associated with the occurrence of IRH. Results. In a total of 9210 patient-years (2688 patients), there were 373 IRH (3.7/100 patient-years). Respiratory tract infections were most frequent (n=154, and additionally 16 PCP), followed by urinary tract infections (n=50). Significant factors for PCP included higher age (≥70 years; OR 3.5), male sex (6.6), underlying lung disease (3.0), use of corticosteroids (4.8), and use of biologics (5.4). Use of methotrexate (5.7) was positively associated with PCP but negatively with total infections (0.7). Additionally, functional disorders and higher RA disease activity were also related to total infections. Conclusions. Risk factors for infection should be taken into account when deciding treatment for the individual RA patient.

To evaluate the utility of neutrophil CD64 as a marker for monitoring the activity of nontuberculous mycobacteria (NTM) infection in patients with rheumatoid arthritis (RA).We compared neutrophil CD64 expression in nine RA patients with NTM infection in the active and inactive phase of NTM disease chronologically. "Active phase" was here defined as present in patients admitted to hospital to receive intensive treatment for NTM, as well as outpatients with an infectious episode showing positive acid- and alcohol-fast bacillus (AFB) staining of sputa (Grade 2-3) who needed to start treatment for NTM with a multiple antibiotics regimen. The cut-off value for CD64 positivity was 2000 molecules/cell.Neutrophils from patients with active-phase NTM infection expressed high levels of CD64 with a mean ± SEM of 7335 ± 784 molecules/cell. However, during the inactive phase of disease, this was significantly lower (1481 ± 103 molecules/cell, p0.001). The sensitivity and specificity of neutrophil CD64 to detect active-phase NTM infection was 96.3% and 84.6%, respectively. Expression of neutrophil CD64 was not affected by disease activity of the RA itself.Neutrophil CD64 is useful for monitoring disease activity in NTM infection of patients with RA.

Rapidly progressive interstitial lung disease (ILD) associated with clinically amyopathic dermatomyositis (CADM) is often lethal despite corticosteroid therapy combined with cyclophosphamide and cy...

Objective.Recent advances in the management of patients with rheumatoid arthritis (RA) increased the rates of disease remission and patient life expectancy, while malignancy has become a more common cause of death. Here, we report the incidence of malignancy in a nationwide survey of Japanese patients with RA compared to the general population, focusing on the risk of lymphoma, which often arises in patients with RA.Methods.Data on the occurrence of malignancy were collected from patients registered in a nationwide Japanese cohort database, the National Database of Rheumatic Diseases by iR-net in Japan, from 2003 to 2012. To adjust for different population composition and to compare the incidence of malignancy with the general population, standardized incidence rates (SIR) were calculated. To identify risk factors for lymphoma, individual patient data were obtained for multivariate analysis for the year before lymphoma diagnosis.Results.In 10 years, the cohort composed of 66,953 patient-years yielded 559 malignancies, most frequently lung cancer, followed by gastric cancer, breast cancer, and lymphoma. The overall incidence of malignancies in patients with RA was slightly lower than in the general population (SIR 0.89, 95% CI 0.82–0.97). However, lymphoma risk was significantly higher (SIR 3.43, 95% CI 2.59–4.28), whereas risk of colon, rectal, or liver cancer was lower. Significant risk factors for lymphoma were the use of methotrexate or tacrolimus, and higher age.Conclusion.Patients with RA had no higher overall incidence of malignancies, but lymphoma was significantly more frequent than in the general population.

Purpose To elucidate effects of salazosulfapyridine (SASP) and methotrexate (MTX), major anti-rheumatic drugs, on exosomes derived from SW982 of a human synovial sarcoma cell line. Experimental design SW982 was treated with SASP and/or MTX under interleukin-1β (IL-1β)-treated or nontreated conditions. Exosomes were isolated from the culture media, and exosomal proteome was analyzed by 2D-DIGE. Protein spots whose intensity was significantly altered by the above treatments were identified by MS. Results Two hundred ninety-four protein spots were detected in the exosome preparations by 2D-DIGE. Compared to the nontreated cells, SASP-, MTX-, and (SASP + MTX)-treated cells displayed 8, 10, and 21 exosomal protein spots with more than ±2.0-fold intensity differences (p < 0.05), respectively. Similarly, the IL-1β-treated cells displayed 58 exosomal protein spots with more than ±1.5-fold intensity differences (p < 0.05). In about half of the 58 spots, the IL-1β-induced intensity changes were suppressed by simultaneous addition of SASP and/or MTX. Most of the identified proteins were immunity- or anti-oxidation-related proteins. Conclusions and clinical relevance The SASP and/or MTX treatments altered the protein profiles of exosomes and suppressed the effects of IL-1β on the exosomal proteome. Exosomes may play roles in the actions of these anti-rheumatic drugs.

We report a 53-year-old male with Cogan's syndrome. He was admitted to our hospital because of a fever of 2-weeks duration, blurred vision for 10 days, hypoacusis, and numbness of the left hand for 3 days. In addition to uveitis, hypoacusis, and aseptic meningitis, multiple mononeuropathy was diagnosed based on a nerve conduction study. Furthermore, positron emission tomography/computed tomography (PET/CT) revealed diffuse aortitis. Accordingly, the patient was diagnosed with Cogan's syndrome. After starting steroid-pulse therapy followed by 1 mg oral prednisolone/kg/day, the uveitis and hypoacusis improved immediately, while the peripheral neuropathy persisted until effectively treated with intravenous gamma globulin therapy. Prompt steroid therapy for Cogan's syndrome based on a diagnosis made using PET/CT prevented progression of the hypoacusis.

To the Editor, Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder characterized by persistent high-grade fever, arthralgias, evanescent rash and leukocytosis with neutrophilia. ...