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ObjectiveAntimelanoma differentiation–associated gene 5 (anti-MDA5)–positive dermatomyositis with interstitial lung disease (DM-ILD) progresses rapidly and has a poor prognosis. Previously, we reported the efficacy of a combination therapy comprising high-dose glucocorticoids (GCs), calcineurin inhibitors (CNIs), and intravenous cyclophosphamide (IV CYC) in a multicenter clinical trial (UMIN000014344). In the present study, we evaluated the long-term outcomes and effects of induction therapy on the maintenance of remission.MethodsAll participants from our previous trial were followed up for > 5 years. Seventy-three other patients with anti-MDA5–positive DM-ILD from our institute were retrospectively integrated into the previous trial for further analysis. Sixty-eight patients achieved remission and survived for > 6 months. Based on the induction treatment, we classified the patients into 2 groups: (1) group T (n = 56), with triple combination therapy (GCs, CNIs, and IV CYC), and (2) group C (n = 12), with monotherapy/dual therapy. The recurrence-free and drug-withdrawal rates of immunosuppressive agents were compared.ResultsThe overall survival and recurrence-free survival rates at 5 years were 100% for the participants in the previous trial. The 5-year cumulative withdrawal rates for CNIs and GCs were 70% and 53%, respectively. In a comprehensive analysis, the recurrence-free rates in group T were higher than those in group C (90% vs 56%; P< 0.05). The drug-withdrawal rates of CNIs and GCs at 10 years in group T were also higher than those in group C (79% vs 0% and 43% vs 0%, respectively; P< 0.05).ConclusionTriple combination therapy in the induction phase can reduce the risk of recurrence and facilitate drug withdrawal in anti-MDA5–positive DM-ILD.

Objective.The optimal treatment strategy for anti-aminoacyl-tRNA synthetase antibody–positive polymyositis/dermatomyositis-associated interstitial lung disease (anti-ARS-PM/DM-ILD) is yet to be established. We aimed to evaluate the efficacy of glucocorticoids and calcineurin inhibitors (CNI) in patients with ARS-PM/DM-ILD.Methods.Progression-free survival (PFS) and overall survival rates were retrospectively evaluated in 32 consecutive patients with ARS-PM/DM-ILD. Disease progression was defined as deterioration in PM/DM-ILD (including recurrence). Predictive factors associated with PFS were analyzed by Cox hazards analysis. The efficacy of first-line prednisolone (PSL) plus CNI therapy was compared with that of PSL monotherapy using propensity score–matched analysis.Results.Overall, 20 (62.5%) and 12 (37.5%) patients received first-line therapy with PSL + CNI and PSL, respectively. The 2-year PFS and 5-year survival rates in the overall cohort were 68.8% and 96.9%, respectively. On multivariate analysis, arterial oxygen pressure (HR 0.86) and PSL monotherapy (vs PSL + CNI; HR 7.29) showed an independent association with PFS. Baseline characteristics of propensity score-matched PSL + CNI and PSL groups were similar. The 2-year PFS rate was significantly higher in the matched PSL + CNI group than in the matched PSL group. All patients who experienced disease progression during first-line therapy were subsequently treated with second-line therapies. The 5-year survival rates of both the matched PSL + CNI and PSL groups were favorable.Conclusion.Propensity score–matched analysis demonstrated that first-line PSL + CNI therapy for patients with ARS-PM/DM-ILD significantly improved the PFS compared with PSL monotherapy, although there was no significant difference regarding longterm survival.

Objective.HLA-DRB1is the most important locus associated with rheumatoid arthritis (RA) and anticitrullinated protein antibodies (ACPA). However, fluctuations of rheumatoid factor (RF) over the disease course have made it difficult to define fine subgroups according to consistent RF positivity for the analyses of genetic background and the levels of RF.Methods.A total of 2873 patients with RA and 2008 healthy controls were recruited. We genotyped HLA-DRB1 alleles for the participants and collected consecutive data of RF in the case subjects. In addition to RF+ and RF− subsets, we classified the RF+ subjects into group 1 (constant RF+) and group 2 (seroconversion). We compared HLA-DRB1 alleles between the RA subsets and controls and performed linear regression analysis to identify HLA-DRB1 alleles associated with maximal RF levels. Omnibus tests were conducted to assess important amino acid positions.Results.RF positivity was 88%, and 1372 and 970 RF+ subjects were classified into groups 1 and 2, respectively. RF+ and RF− showed similar genetic associations to ACPA+ and ACPA− RA, respectively. We found that shared epitope (SE) was more enriched in group 2 than 1, p = 2.0 × 10−5, and that amino acid position 11 showed a significant association between 1 and 2, p = 2.7 × 10−5. These associations were independent of ACPA positivity. SE showed a tendency to be negatively correlated with RF titer (p = 0.012). HLA-DRB1*09:01, which reduces ACPA titer, was not associated with RF levels (p = 0.70).Conclusion.The seroconversion group was shown to have distinct genetic characteristics. The genetic architecture of RF levels is different from that of ACPA.

Objective.Anti-carbamylated protein (anti-CarP) antibodies are possible diagnostic biomarkers of anticitrullinated protein antibody (ACPA)-negative rheumatoid arthritis (RA). We aimed to elucidate the prevalence of anti-CarP antibodies in non-RA connective tissue diseases (CTD) because CTD are important in the differential diagnosis of ACPA-negative RA.Methods.The sera from 266 patients with RA and 616 patients with CTD and 80 healthy controls were examined using an in-house anti-CarP ELISA.Results.The prevalence and the level of anti-CarP antibodies in several CTD were comparable to those in ACPA-negative RA.Conclusion.Anti-CarP antibodies are not useful for differentiating ACPA-negative RA from CTD.

Objective.Interstitial lung disease (ILD) is involved in polymyositis/dermatomyositis (PM/DM), a disease associated with poor prognoses. Chitinase-3-like-1 protein (YKL-40) has pleiotropic biological activities involved in inflammation, cell proliferation, and tissue remodeling; however, the clinical application of YKL-40 remains limited. We investigated the clinical significance of YKL-40 in PM/DM–ILD.Methods.Sixty-nine consecutive patients with PM/DM–ILD and 34 healthy controls were analyzed. We measured baseline and followup serum YKL-40 using an ELISA, evaluated the association of YKL-40 with clinical variables and survival, and examined YKL-40 expression in lung specimens from patients with PM/DM–ILD using immunohistochemistry.Results.Serum YKL-40 levels were significantly greater in patients with PM/DM–ILD compared with healthy controls (p < 0.0001). Serum YKL-40 was correlated with arterial oxygen pressure (r = –0.40, p < 0.001) and percent-predicted DLCO (r = –0.41, p = 0.01) in patients with PM/DM–ILD. Multivariate Cox hazard analysis demonstrated that higher serum YKL-40 and lower percent-predicted forced vital capacity were independently associated with a poor prognosis. Immunohistochemistry analysis demonstrated that YKL-40 expression was enhanced in aggregated intraalveolar macrophages and hyperproliferative alveolar epithelial cells in patients with PM/DM–ILD.Conclusion.YKL-40 is a promising biomarker for evaluating PM/DM–ILD activity/severity and predicting disease prognosis. Insights into YKL-40 might help elucidate the pathogenesis of PM/DM–ILD.

Objective.Methotrexate-associated lymphoproliferative disorders (MTX-LPD) often regress spontaneously during MTX withdrawal, but the prognostic factors remain unclear. The aim of our study was to clarify the clinical, histological, and genetic factors that predict outcomes in patients with MTX-LPD.Methods.Patients with MTX-LPD diagnosed between 2000 and 2012 were analyzed retrospectively regarding their clinical course, site of biopsy, histological typing, Epstein-Barr virus (EBV) in situhybridization and immunostaining, and HLA type.Results.Twenty-one patients, including 20 with rheumatoid arthritis (RA) and 1 with polymyositis, were analyzed. The mean dose of MTX was 6.1 mg/week and the mean duration of treatment was 71.1 months. Clinically, 5 patients were diagnosed with EBV-positive mucocutaneous ulcer (EBVMCU) and had polymorphic histological findings. The proportion of those patients successfully treated solely by withdrawal of MTX was significantly greater than that of those without EBVMCU (75% vs 7.7%, p = 0.015). The HLA-B15:11 haplotype was more frequent in patients with EBV+ RA with MTX-LPD than in healthy Japanese controls (p = 0.0079, Bonferroni’s method). EBV latency classification and HLA typing were not associated with the prognosis of MTX-LPD in our cohort.Conclusion.Our data demonstrate that patients in the EBVMCU, a specific clinical subgroup of MTX-LPD, had a better clinical outcome when MTX was withdrawn than did other patients with MTX-LPD.

OBJECTIVE: To investigate earlier prediction of future articular destruction in patients with early rheumatoid arthritis (RA). METHODS: We randomly allocated patients with RA with disease duration < 2 years to different nonbiologic disease modifying antirheumatic drug (DMARD) therapies in a double-blind trial. Progression of articular destruction over the 96-week treatment period was assessed using the modified Sharp method. RESULTS: Progression of articular destruction correlated more strongly with the American College of Rheumatology (ACR) core set measures after 12 weeks of treatment than with pretreatment values. Multiple regression analysis of data after 12 weeks yielded a correlation coefficient of 0.711. The sensitivity and specificity to predict articular destruction over the 75th percentile of the cohort were 78.6% and 84.6%, respectively. Patients who showed articular destruction over the 75th percentile of the cohort had low response to treatment at 12 weeks, and continued to have high clinical disease activity thereafter. Contrasting data were found in patients with slow progression of articular destruction. CONCLUSION: In patients with early RA, ACR core set measures after 12 weeks of nonbiologic DMARD treatment may predict articular destruction 2 years later. Low response to treatment at 12 weeks and continuing high disease activity thereafter were found in patients with rapid radiological progression. These data can be used to determine the appropriateness of treatment at 12 weeks and aid the decision to introduce biologic DMARD.

OBJECTIVE: To examine the role of HLA-DRB1 and tumor necrosis factor (TNF) promoter genotypes in the development and the autoantibody profiles of idiopathic inflammatory myopathy (IIM) in Japanese patients. METHODS: HLA-DRB1 and TNF promoter genotypes were determined, and serum antinuclear autoantibodies were identified in 120 adult Japanese patients with IIM [72 with dermatomyositis (DM), 30 with polymyositis (PM), 18 with myositis overlapping with other collagen vascular diseases], as well as in 265 controls. RESULTS: Forty-two patients (35%) were positive for myositis-specific autoantibodies (MSA), including 37 (31%) for anti-aminoacyl-tRNA synthetase (ARS) autoantibodies. Allele carrier frequency of HLA-DRB1*0803 was increased in the patients with IIM [p = 0.02, corrected p (pc) NS, 23% vs 14%, odds ratio (OR) = 1.9 (95% confidence interval, CI = 1.1–3.2)], with PM [p = 0.006, pc NS, 33%, OR 3.1 (95% CI 1.3–7.1)], and with anti-ARS autoantibodies [27%, p = 0.04, OR 2.3 (95% CI 1.0–5.1)] compared with controls. DRB1*0405 was increased in patients with anti-ARS autoantibodies compared with controls [41% vs 25%, p = 0.04, pc NS, OR 2.1 (95% CI 1.0–4.3)]. TNF promoter genotype was associated with the presence of interstitial lung disease (ILD). The carriage of a TNF-a haplotype formed by –1031C, –863A, and –857C was increased in the patients with ILD versus those without ILD [33% vs 18%, p = 0.05, pc NS, OR 2.3 (95% CI 0.94–5.5)]. CONCLUSION: HLA-DRB1 alleles were associated with development of IIM and MSA in a Japanese population.

OBJECTIVE: A 3 year prospective randomized study was conducted to clarify the efficacy of intermittent cyclical etidronate therapy on corticosteroid induced osteoporosis. METHODS: A group of 102 Japanese patients were enrolled, each taking > 7.5 mg of prednisolone daily for at least 90 days. Patients were randomly divided into 2 treatment groups: Group E (etidronate) took 200 mg etidronate disodium per day for 2 weeks with 3.0 g calcium lactate and 0.75 µg alphacalcidol daily; Group C (control) took 3.0 g calcium lactate and 0.75 µg alphacalcidol daily. Outcome measurements included changes from baseline in bone mineral density (BMD) of the lumbar spine and the rate of new vertebral fractures at 48 and 144 weeks. RESULTS: The mean (± SD) lumbar spine BMD increased 3.7 ± 5.6% (p < 0.01) and 1.5 ± 4.1% (NS) from baseline at 48 weeks and 4.8 ± 6.9% (p < 0.005) and 0.4 ± 5.0% (NS) from baseline at 144 weeks in Group E and Group C, respectively. The improvement of BMD in Group E was significantly greater than in Group C at 144 weeks (p < 0.01). In 3 subgroups, men and premenopausal and postmenopausal women, the postmenopausal women showed the greatest improvement. Mean percentage change in this subgroup was 10.1 ± 8.0% and 1.35 ± 6.4% in Group E and Group C, respectively. We noted that 2 patients in Group C had new vertebral fractures, whereas no fractures were observed in Group E. CONCLUSION: These results indicate that intermittent cyclical etidronate therapy is effective for the prevention and treatment of corticosteroid induced osteoporosis in patients with connective tissue diseases.

OBJECTIVE: CD26 is the cell surface activation antigen with dipeptidyl peptidase IV (DPPIV) enzyme activity at the extracellular domain that is preferentially expressed on memory T cells and has a role in T cell immune responses. The soluble form of CD26 is present in serum and recombinant soluble CD26 (rsCD26) can enhance in vitro antigen-specific T cell responses. To determine the role of soluble CD26 (sCD26) in the pathophysiology of patients with systemic lupus erythematosus (SLE), we measured levels of sCD26 and its specific DPPIV activity in serum. METHODS: Serum sCD26 levels and DPPIV activity were measured by sandwich ELISA in 53 patients with SLE and 54 healthy controls. Serum sCD26 was identified by immunoprecipitation and immunoblot analysis. Expression of CD26 on T cells was analyzed by flow cytometry. RESULTS: Serum levels of sCD26 and its specific DPPIV activity were significantly decreased in SLE and were inversely correlated with SLE disease activity index score, but not with clinical variables or clinical subsets of SLE. Close correlation between sCD26/DPPIV and disease activity was observed in the longitudinal study. CONCLUSION: Serum levels of sCD26 may be involved in the pathophysiology of SLE, and appear to be useful as a new disease activity measure for SLE.