Takao Kodera

Identification of breakpoint cluster regions at 1p36.3 and 3q21 in hematologic malignancies with t(1;3)(p36;q21)

The reciprocal translocation t(1;3)(p36;q21) is associated with myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) characterized by trilineage dysplasia, in particular dysmegakaryocytopoiesis, and a poor prognosis. As yet no molecular genetic analyses of the t(1;3) have been reported. In four patients with t(1;3), all of whom had AML‐M4, which evolved from MDS, the breakpoints at 3q21 clustered within a 60‐kb region centromeric to the breakpoint of the inv(3)(q21q26), whereas the breakpoints at 1p36 clustered within a 90‐kb region at 1p36.3. The presence of novel clusters in both the 3q21 and 1p36 breakpoints (BCRs) suggests a common, underlying molecular mechanism for the development of t(1;3)‐positive MDS/AML. The Ribophorin I (RPN1) gene close to the BCR at 3q21 was highly expressed without gross structural changes, whereas the GR6 gene located within the BCR at 3q21 was not expressed. No other highly expressed genes were isolated in a 150‐kb region at 3q21. Thus, it is likely that a gene at 1p36.3 is activated by the translocation of the 3q21 region or a gene important for transformation lies on 3q21, outside the 150‐kb region. Further characterization of the BCRs at 1p36.3 and 3q21 should provide important insights into the molecular genetic mechanisms involved in the genesis of t(1;3)‐positive MDS/AML. Genes Chromosomes Cancer 27:229–238, 2000.

Microsatellite instability in lymphoid leukemia and lymphoma cell lines but not in myeloid leukemia cell lines.

Microsatellite instability (MSI) represents a defect in the DNA mismatch repair system and has been shown to take part in the genesis and/or progression of several human malignancies. In hematological malignancies, the relevance of MSI has been a matter of controversy. Therefore, 29 microsatellite loci were examined for MSI in 57 leukemia and lymphoma cell lines by PCR analysis. Ladder formation of bands representing MSI was observed at multiple loci in 6 of 24 lymphoid leukemia/lymphoma cell lines and in 0 of 33 myeloid leukemia cell lines. Analysis for the BAT‐26 and BAT‐25 loci confirmed the presence of MSI in five of six lymphoid cell lines exhibiting ladder formation of bands. Thus, at least 5 out of 24 (21%) lymphoid leukemia/lymphoma cell lines were considered as being MSI‐positive. These results indicate that MSI contributes to the development of lymphoid but not to myeloid malignancies. Genes Chromosomes Cancer 26:267–269, 1999.

Evaluation of anti-parvovirus B19 activity in sera by assay using quantitative polymerase chain reaction

Human parvovirus B19 (B19) infects cells of erythroid lineage. Production of neutralizing antibodies (Abs) is indispensable for recovery from B19-related disease state. In this study, we used a convenient method to measure neutralizing activities in human sera by using a real-time quantitative PCR based assay. Erythroid cell line KU812Ep6 was incubated with test sera before infection with B19 virus. The copy number of B19-DNA in cultures was decreased in the presence of the sera from patients who recovered from acute B19 infection, whereas no decrease in B19-DNA was in cultures incubated with sera from healthy volunteers who had no B19 infection. The decrease in B19-DNA copy number was calculated and the inhibition percentage was expressed as neutralizing activity to B19. A clinical study showed that the levels of neutralizing ability were high in patients who recovered soon after acute B19 infection, but were low in some patients with a prolonged clinical course for recovery from B19 infection. This method is simple and convenient compared with methods described previously, showing its usefulness to evaluate the neutralizing activity to B19.

Mononeuritis multiplex, protein-losing gastroenteropathy, and choroidopathy seen together in a case of systemic lupus erythematosus

Abstract A 43-year-old woman with systemic lupus erythematosus (SLE) had an episode of mononeuritis multiplex prior to developing protein-losing gastroenteropathy. Four years later, she had another episode of mononeuritis multiplex, followed by choroidopathy. These manifestations are uncommon in SLE, but may be attributed to vasculitis. The laboratory findings indicated that the elevation of D-dimer and thrombin–antithrombin complex levels seen in this case might be useful in evaluating vascular lesions in SLE.

Clinical and structural remission rates increased annually and radiographic progression was continuously inhibited during a 3-year administration of tocilizumab in patients with rheumatoid arthritis: A multi-center, prospective cohort study by the Michinoku Tocilizumab Study Group

Abstract Objective: To evaluate the clinical and structural efficacy of tocilizumab (TCZ) during its long-term administration in patients with rheumatoid arthritis (RA). Methods: In total, 693 patients with RA who started TCZ therapy were followed for 3 years. Clinical efficacy was evaluated by DAS28-ESR and Boolean remission rates in 544 patients. Joint damage was assessed by calculating the modified total Sharp score (mTSS) in 50 patients. Results: When the reason for discontinuation was limited to inadequate response or adverse events, the 1-, 2-, and 3-year continuation rates were 84.0%, 76.8%, and 72.2%, respectively. The mean DAS28-ESR was initially 5.1 and decreased to 2.5 at 6 months and to 2.2 at 36 months. The Boolean remission rate was initially 0.9% and increased to 21.7% at 6 months and to 32.2% at 36 months. The structural remission rates (ΔmTSS/year ≤ 0.5) were 68.8%, 78.6%, and 88.9% within the first, second, and third years, respectively. The structural remission rate at 3 years (ΔmTSS ≤ 1.5) was 66.0%, and earlier achievement of swollen joint count (SJC) of 1 or less resulted in better outcomes. Conclusions: TCZ was highly efficacious, and bone destruction was strongly prevented. SJC was an easy-to-use indicator of joint destruction.

Prognostic Factors Toward Clinically Relevant Radiographic Progression in Patients With Rheumatoid Arthritis in Clinical Practice: A Japanese Multicenter, Prospective Longitudinal Cohort Study for Achieving a Treat-to-Target Strategy

AbstractTo determine prognostic factors of clinically relevant radiographic progression (CRRP) in patients with rheumatoid arthritis (RA) in clinical practice.We performed a multicenter prospective study in Japan of biological disease-modifying antirheumatic drug (bDMARD)-naive RA patients with moderate to high disease activity treated with conventional synthetic DMARDs (csDMARDs) at study entry. We longitudinally observed 408 patients for 1 year and assessed disease activity every 3 months. CRRP was defined as yearly progression of modified total Sharp score (mTSS) > 3.0 U. We also divided the cohort into 2 groups based on disease duration (<3 vs ≥3 years) and performed a subgroup analysis.CRRP was found in 10.3% of the patients. A multiple logistic regression analysis revealed that the independent variables to predict the development of CRRP were: CRP at baseline (0.30 mg/dL increase, 95% confidence interval [CI] 1.01–1.11), time-integrated Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) during the 1 year postbaseline (12.4-unit increase, 95%CI 1.17–2.59), RA typical erosion at baseline (95%CI 1.56–21.1), and the introduction of bDMARDs (95%CI 0.06–0.38). The subgroup analysis revealed that time-integrated DAS28-ESR is not a predictor whereas the introduction of bDMARDs is a significant protective factor for CRRP in RA patients with disease duration <3 years.We identified factors that could be used to predict the development of CRRP in RA patients treated with DMARDs. These variables appear to be different based on the RA patients’ disease durations.

Acute Cytomegalovirus Infection and Transient Carotid Intimal-Medial Thickening in a Young, Otherwise Healthy Woman

ABSTRACT Carotid intimal-medial thickening was observed in a 23-year-old woman with acute cytomegalovirus (CMV) infection. The thickening disappeared after her recovery from the infection. As endothelial cells are common targets of CMV, this thickening suggests that CMV infection causes vascular lesions, even in otherwise healthy individuals.

Anti-citrullinated peptide antibodies are the strongest predictor of clinically relevant radiographic progression in rheumatoid arthritis patients achieving remission or low disease activity: A post hoc analysis of a nationwide cohort in Japan

Objectives To determine prognostic factors of clinically relevant radiographic progression (CRRP) in patients with rheumatoid arthritis (RA) achieving remission or low disease activity (LDA) in clinical practice. Methods Using data from a nationwide, multicenter, prospective study in Japan, we evaluated 198 biological disease-modifying antirheumatic drug (bDMARD)-naïve RA patients who were in remission or had LDA at study entry after being treated with conventional synthetic DMARDs (csDMARDs). CRRP was defined as the yearly progression of modified total Sharp score (mTSS) >3.0 U. We performed a multiple logistic regression analysis to explore the factors to predict CRRP at 1 year. We used receiver operating characteristic (ROC) curve to estimate the performance of relevant variables for predicting CRRP. Results The mean Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) was 2.32 ± 0.58 at study entry. During the 1-year observation, remission or LDA persisted in 72% of the patients. CRRP was observed in 7.6% of the patients. The multiple logistic regression analysis revealed that the independent variables to predict the development of CRRP were: anti-citrullinated peptide antibodies (ACPA) positivity at baseline (OR = 15.2, 95%CI 2.64–299), time-integrated DAS28-ESR during the 1 year post-baseline (7.85-unit increase, OR = 1.83, 95%CI 1.03–3.45), and the mTSS at baseline (13-unit increase, OR = 1.22, 95%CI 1.06–1.42). Conclusions ACPA positivity was the strongest independent predictor of CRRP in patients with RA in remission or LDA. Physicians should recognize ACPA as a poor-prognosis factor regarding the radiographic outcome of RA, even among patients showing a clinically favorable response to DMARDs.

THU0121 Characteristic of the Japanese Patients with Rheumatoid Arthritis (RA) of Rapid Radiographic Progression (RRP) Treated with Synthetic Disease Modifying Anti-Rheumatic Drugs (DMARDS) in Daily Practice: A Large-Scale Prospective Longitudinal Cohort Study

Background Disease modifying anti-rheumatic drugs (DMARDs) are known to inhibit radiographic progression in patients with rheumatoid arthritis (RA). However, there has been few epidemiological report of longitudinal radiographic progression in RA patients captured in daily practice. Objectives In 26 related-centers of the Nagasaki University and Tohoku University in Japan, we are conducting a large-scale prospective study to investigate extent of radiographic progression. We have tried to assess the extent of rapid radiographic progression (RRP) in DMARDs-treated RA patients. Methods Nine hundred forty-two patients with RA, treated not by biologic DMARDs but by synthetic DMARDs at entry, were registered between May 09 and March 12 in this study. We have selected 742 RA patients having DAS28-ESR at entry >3.2 or apparent radiographic bone erosion and followed at least 1 year. Regarding to the RA patients treated by synthetic DMARDs without biologic DMARDs for 1 year, three hundred ninety-two patients had evaluable data at present. Patients gave their informed consent to be subjected to the protocol that was approved by the Institutional Review Board of Nagasaki University, Tohoku University and related centers. DAS28-ESR was assessed every 3 months. Radiographs of the hands and feet were taken every 6 months. The images were scored by trained readers through modified total Sharp score (mTSS). RRP was defined as yearly progression of mTSS >3.0. We have examined what variables are associated with the development of RRP at 1 year. Results RRP was found in 42 out of 392 patients (10.7%). Fourteen variables including gender, age, disease duration at baseline, DAS28-ESR/CRP at baseline, time-integrated DAS28-ESR/CRP during 1 year, ESR and CRP at baseline (mg/dl), presence of autoantibodies (RF or ACPA), the introduction of MTX or non-MTX DMARDs, the use of prednisolone, HAQ at baseline, mTSS at baseline were evaluated to explore the development of RRP at 1 year. Logistic regression analysis has found that female gender (p=0.023), high time-integrated DAS28-ESR/CRP (p=0.0094, 11.85 increase/p=0.0099, 10.91 increase) and high ESR/CRP at baseline (p=0.017, 22 mm/hr increase/p=0.049, 1.65 mg/dl increase) are independent variables to predict the development of RRP. Conclusions Considering the development of RRP, the accumulated disease activity appeared to be most involved in this process. Therefore, tight disease control by treat-to-target strategy is needed in daily clinical practice. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4035