Weekly split-dose regimen for oral methotrexate reduced polyglutamation in red blood cells in patients with rheumatoid arthritis compared with single-dose regimen: Results from a multicentered randomized control trial.

AIMS: We compared the incidence of adverse events between single and divided-dose regimens of methotrexate (MTX) by using a multicenter randomized controlled trial. METHODS: Eighty-nine patients with insufficient control on MTX 8 mg/wk were randomly assigned into single-dose (39 patients) or triple dose (39 patients) groups. The MTX dose for all patients was gradually increased to 16 mg/wk. The primary endpoint was the occurrence of liver dysfunction during the observation period (20 weeks). RESULTS: There were no differences in baseline data and MTX dose at Week 20 between groups. There was no significant difference in the incidence of liver dysfunction between groups (single dose, 3 [7.7%] patients vs. triple dose, 5 [13.2%] patients; P = .455). The incidence of adverse event increased in triple dose (single dose, 12 [30.8%] patients vs. triple dose, 20 [51.3%]), but the difference was not significant (P = .066). There was no significant difference in disease activity between groups, although MTX-triglutamate (PG3), MTX-PG4, and MTX-PG5 were significantly higher in the single dose group. CONCLUSIONS: Weekly split dosing reduced the polyglutamation of MTX. There was no significant difference in efficacy and safety between the 2 groups.

Maintenance treatment using abatacept with dose reduction after achievement of low disease activity in patients with rheumatoid arthritis (MATADOR) - A prospective, multicenter, single arm pilot clinical trial.

OBJECTIVES: To preliminarily evaluate the feasibility of maintenance therapy with reduced dose of intravenous abatacept (ABT) to 250 mg/body/month after achieving remission or low disease activity (LDA). PATIENTS AND METHODS: RA patients treated with ABT at 13 sites were enrolled in this prospective interventional pilot study during the period between March 2013 and March 2015. Inclusion criteria were (1) age at 20 years or older, (2) under treatment with monthly intravenous ABT at approved doses, (3) DAS28-CRP lower than 2.7 at least for 6 months, (4) agreed to join this trial with written informed consent and (5) body weight under 125 kg. Enrolled patients were maintained with intravenous monthly ABT at a reduced dose of 250 mg/body (MATADOR protocol). The primary end point was the proportion of the patients continued with MATADOR protocol at week 48. MATADOR protocol was discontinued upon disease flare or other reasons such as patients' request or severe adverse event (AE). Disease activities and structural changes were also evaluated. RESULTS: Fifty-three patients fulfilled the entry criteria and were followed for 1-year. MATADOR protocol was continued for 1-year in 43 (81%) of the evaluated patients. Three patients experienced severe AEs. Mean DAS28-CRP and remission rate were 1.56 and 88% when ABT reduced and 1.80 and 81% at 1-year, respectively. Structural remission was achieved in 34 out of 42 evaluated patients. CONCLUSIONS: Reduced dose of intravenous ABT was proposed as a feasible choice for maintenance therapy for RA after achievement of remission/LDA, although further randomized trials would be awaited.

Up-regulated expression of HLA-DRB5 transcripts and high frequency of the HLA-DRB5*01:05 allele in scleroderma patients with interstitial lung disease.

OBJECTIVE: Interstitial lung disease (ILD) is a serious complication of SSc. We aimed to identify markers associated with SSc-related ILD. METHODS: RNA was prepared from the peripheral blood mononuclear cells of 14 SSc patients, divided into four different RNA pools according to the presence or absence of ILD and to the treatment, and subjected to microarray analysis. Real-time quantitative PCR was used to confirm the microarray results in 43 SSc patients, 42 autoimmune controls and 10 healthy controls. Genomic DNA samples were collected from 149 patients with SSc (70 in Hokkaido and 79 in Tokyo) who underwent a high-resolution CT for the evaluation of ILD and from 230 healthy controls. Genotyping was performed using sequence-specific primers. RESULTS: The microarray analysis revealed HLA-DRB5 to be the only gene commonly up-regulated in patients with ILD compared with those without ILD in both comparison groups. High expression levels of HLA-DRB5 in SSc patients with ILD were confirmed by real-time quantitative PCR. The prevalence of HLA-DRB5 gene carriers increased in the SSc patients with ILD relative to those without ILD or to healthy controls in both cohorts. Among the four detected alleles, the HLA-DRB5*01:05 allele was significantly more frequent in SSc patients with ILD than in SSc patients without ILD or in healthy controls. These associations were confirmed in the second cohort. CONCLUSION: HLA-DRB5 was highly expressed in PBMCs from patients with SSc-related ILD. The HLA-DRB5*01:05 allele is a risk factor for ILD in patients with SSc.

Autoimmunity in focus: from mechanisms to treatment.

The 5th Asian Congress on Autoimmunity took place in Suntec City, Singapore, on the 17-19 November 2011 under the presidency of Yehuda Shoenfeld (Chaim Sheba Medical Center, Ramat Gan, Israel). Senior investigators from a range of fields--including immunology, autoimmunity, rheumatology, neurology and hepatology--attended the conference. The scientific program placed an emphasis on the pathogenesis, genetic basis and mechanistic aspects of autoimmune diseases, as well as their clinical outcomes and treatment options. Particular focus was placed on systemic lupus erythematosus, rheumatoid arthritis, Type I diabetes, antiphospholipid syndrome and autoimmune hepatitis. Participants from over 50 countries attended the conference.

Monitoring anti-interleukin 6 receptor antibody treatment for rheumatoid arthritis by quantitative magnetic resonance imaging of the hand and power Doppler ultrasonography of the finger.

OBJECTIVES: To compare quantitative magnetic resonance imaging (MRI) and power Doppler ultrasonography (PDUS) with conventional measures of disease activity in rheumatoid arthritis (RA) patients treated with the anti-interleukin 6 (anti-IL 6) receptor antibody tocilizumab in terms of responsiveness at a few months to disease activity and ability to predict structural damage at 1 year. METHODS: A cohort of patients with RA (n = 29) was evaluated clinically including disease activity score 28 (DAS28) and by semiquantitative (SQ-) and quantitative (Q-) PDUS (bilateral metacarpophalangeal joints) and MRI (one hand and wrist) at initiation of treatment with anti-IL 6 receptor antibody agents and after 2 and 5 months. Conventional radiography for both hands and wrists was performed at baseline and at 12 months. Responsiveness was assessed by standardized response means (SRM). Areas under the curve (AUC) for measures at baseline, 2 and 5 months were correlated with structural damage at 1 year. RESULTS: Among the laboratory and clinical parameters, DAS28-ESR was the most responsive with a large effect size of SRM. Structural damage progressions for radiography and MR erosion were correlated with AUC of MR bone erosion and Q-PDUS, respectively. CONCLUSIONS: In the evaluation of disease activity in RA patients in the first few months after starting anti-IL 6 receptor antibody tocilizumab treatment, the semiquantitative MR bone erosion score of the hand and quantitative value for power Doppler signal in the finger joint were both responsive and predictive of structural damage progression at 1 year.

Simplified approach to MR image quantification of the rheumatoid wrist: a pilot study.

OBJECTIVES: To determine an optimal threshold in a simplified 3D-based volumetry of abnormal signals in rheumatoid wrists utilizing contrast and non-contrast MR data, and investigate the feasibility and reliability of this method. MATERIALS AND METHODS: MR images of bilateral hands of 15 active rheumatoid patients were assessed before and 5 months after the initiation of tocilizumab infusion protocol. The volumes of abnormal signals were measured on STIR and post-contrast fat-suppressed T1-weighted images. Three-dimensional volume rendering of the images was used for segmentation of the wrist by an MR technologist and a radiologist. Volumetric data were obtained with variable thresholding (1, 1.25, 1.5, 1.75, and 2 times the muscle signal), and were compared to clinical data and semiquantitative MR scoring (RAMRIS) of the wrist. Intra- and interobserver variability and time needed for volumetry measurements were assessed. RESULTS: The volumetric data correlated favorably with clinical parameters almost throughout the pre-determined thresholds. Interval differences in volumetric data correlated favorably with those of RAMRIS when the threshold was set at more than 1.5 times the muscle signal. The repeatability index was lower than the average of the interval differences in volumetric data when the threshold was set at 1.5-1.75 for STIR data. Intra- and interobserver variability for volumetry was 0.79-0.84. The time required for volumetry was shorter than that for RAMRIS. CONCLUSIONS: These results suggest that a simplified MR volumetric data acquisition may provide gross estimates of disease activity when the threshold is set properly. Such estimation can be achieved quickly by non-imaging specialists and without contrast administration.

Change of synovial vascularity in a single finger joint assessed by power doppler sonography correlated with radiographic change in rheumatoid arthritis: comparative study of a novel quantitative score with a semiquantitative score.

OBJECTIVE: To investigate the relationship between synovial vascularity assessed by quantitative power Doppler sonography (PDS) and progression of structural bone damage in a single finger joint in patients with rheumatoid arthritis (RA). METHODS: We studied 190 metacarpophalangeal (MCP) joints and 190 proximal interphalangeal (PIP) joints of 19 patients with active RA who had initial treatment with disease-modifying antirheumatic drugs (DMARDs). Patients were examined by clinical and laboratory assessments throughout the study. Hand and foot radiography was performed at baseline and the twentieth week. Magnetic resonance imaging (MRI) was performed at baseline. PDS was performed at baseline and the eighth week. Synovial vascularity was evaluated according to both quantitative and semiquantitative methods. RESULTS: Quantitative PDS was significantly correlated with the enhancement rate of MRI in each single finger joint. Comparing quantitative synovial vascularity and radiographic change in single MCP or PIP joints, the level of vascularity at baseline showed a significant positive correlation with radiographic progression at the twentieth week. The change of vascularity in response to DMARDs, defined as the percentage change in vascularity by the eighth week from baseline, was inversely correlated with radiographic progression in each MCP joint. The quantitative PDS method was more useful than the semiquantitative method for the evaluation of synovial vascularity in a single finger joint. CONCLUSION: The change of synovial vascularity in a single finger joint determined by quantitative PDS could numerically predict its radiographic progression. Using vascularity as a guide to consider a therapeutic approach would have benefits for patients with active RA.

Screening for rheumatoid arthritis with finger joint power Doppler ultrasonography: quantification of conventional power Doppler ultrasonographic scoring.

Power Doppler ultrasonography (PD-US) has proved to be a useful technique to measure synovial vascularity due to its capability to provide data that can be used to evaluate the level of joint inflammation and assess rheumatoid arthritis (RA). We have developed a novel PD-US finger joint scoring method that introduces quantitative measurements into the conventional PD-US assessment method. A comparison of the two methods revealed that our novel PD-US method strongly correlates with the conventional method in terms of RA assessment. We performed finger joint PD-US on 69 patients with RA and 70 patients who had multiple joint pain but showed no evidence of inflammatory diseases (non-inflammatory disease, NI) and measured the synovial vascularity of the metacarpophalangeal joints 1-5 and proximal interphalangeal (PIP) joints 1-5 for each patient. We analyzed the data with receiver operating characteristic analysis and, based on the results for the total vascularity of 20 finger joints, defined a cut-off value of 36% as discriminating between RA and NI. This cut-off value was found to be a valuable tool in screening for RA. We conclude that our finger joint PD-US scoring system is both useful and applicable for diagnosing RA.

Microscopic polyangitis triggered by fungal infection.

We report a case of microscopic polyangitis associated with fungal infection. A 64-year-old man was admitted to our hospital because of renal dysfunction and high fever. He complained of arthralgia and myalgia. He was diagnosed with antineutrophil cytoplasmic antibody-related vasculitis and also had a fungal infection. We treated him with antibiotics including fluconazole. All symptoms disappeared as the infection resolved without the use of steroid therapy. We speculate that the deteriorating vasculitis could have been triggered by overproduction of cytokines in response to the fungal infection.

A woman with infectious endocarditis caused by Abiotrophia defectiva.

A 74-year-old woman with recurrent fever and multiple joint pain was admitted to Hokkaido University Hospital. Trans-esophageal echocardiogram revealed bacterial vegetation and destruction of the aortic valve. Although few bacteria grew in regular blood agar, Gram-positive coccobacillus was specifically grown in chocolate blood agar and Brucella agar, and it was identified to be Abiotrophia defectiva. Infectious endocarditis caused by Abiotrophia defectiva was diagnosed, she was treated with diuretics, penicillin G and gentamicin, and she immediately improved. Infectious diseases caused by Abiotrophia defectiva are extremely rare, and identification of this pathogen is important, as its bacterial characteristics require proper attention.