Susumu Nishiyama

IntroductionThis study established an independent evaluation index for patients with childhood-onset chronic diseases in Japan.MethodsFrom November to December 2020, three Delphi rounds were conducted. Thirty-nine participants completed at least one survey. We asked them about targets of social independence for 10 types of activities (education/labor/finance/acquisition of necessities/housing/transportation/leisure/social relationship/intimate relationships/sexuality). The Delphi technique was to be repeated until a consensus of over 80% of participants was reached.ResultsThe targets chosen for measuring independence in patients with childhood-onset chronic diseases were as follows: “Graduation from high school,” “Labor for livelihood (including temporary turnover),” “Financially independent (including temporary turnover, excluding students),” “Buy or rent a house and buy the daily necessities and get the public services you need to live,” “Do housework alone,” “Plan alone and use t...

We investigated the relationship between distal interphalangeal (DIP) joint involvement and disease activity in 10,038 patients with adult-onset rheumatoid arthritis (RA). The affected joint distribution was investigated using the joint indices (JI) x, y, and z, corresponding to the upper and lower joints, and the predominance of large-joint involvement, respectively. DIP joint involvement (defined by the presence of tenderness and/or swelling in DIP joints) was present in 206 (2.1%) of 10,038 patients with RA. Patients with RA exhibiting DIP joint involvement were significantly younger, and more frequently women. DIP joint involvement was positively associated with Disease Activity Score-28 using C-reactive protein, and clinical variables related to high RA disease activity, including JIs x and y, and was negatively associated with JI z. JI x was significantly higher than JI y in RA patients with DIP joint involvement. An odds ratio analysis revealed that small-to-medium sized and ...

Additional file 1. DataSet of 11,013 patients without missing values for SDAI or HAQ-DI and serial registration data from patients without orthopedic surgery between 2013 and 2014 (n = 10,206) and between 2015 and 2016 (n = 10,118). Transformation matrices and estimated vectors are also included.

Objective To clarify the efficacy and safety of intravenous abatacept for glandular and extraglandular involvements in Sjögren’s syndrome (SS) associated with rheumatoid arthritis (RA). Materials and methods We performed an open-label, prospective, 1-year, observational multicenter study (ROSE and ROSE II trials). The primary endpoint was the remission rate as measured by SDAI at 52 weeks. The secondary endpoints included the changes in the Saxon’s test, Schirmer’s test, ESSDAI and ESSPRI. Adverse events and adherence rates were also analyzed. Results 68 patients (36 in ROSE and 32 in ROSE II, all women) were enrolled. SDAI decreased significantly from 23.6 ± 13.2 at baseline to 9.9 ± 9.5 at 52 weeks. Patients with SDAI remission increased from 0 (0 weeks) to 19 patients (27.9%) at 52 weeks. Saliva volume increased significantly at 24 weeks. Tear volume increased significantly at 52 weeks. Both ESSDAI and ESSPRI were significantly decreased at 12 weeks, and these responses were main...

Objectives Evaluate the efficacy and safety of anifrolumab in the subpopulation of Japanese patients with systemic lupus erythematosus (SLE) in phase 3 TULIP-2 trial. Methods TULIP-2 was a 52-week randomized placebo-controlled trial (N = 362) that evaluated efficacy and safety of anifrolumab 300 mg IV every 4 weeks vs. placebo in patients with moderate to severe SLE who were receiving standard therapy. We performed a post hoc analysis of the primary and key secondary endpoints, and safety, of TULIP-2 in the Japanese subpopulation. Results In the Japanese subpopulation (anifrolumab, n = 24; placebo, n = 19), the proportion of patients who achieved a British Isles Lupus Assessment Group–based Composite Lupus Assessment response at Week 52 (primary endpoint) was greater in the anifrolumab group vs. placebo [50.0% (12/24) vs. 15.8% (3/19); treatment difference: 34.2%, 95% confidence interval 6.9, 61.5; nominal p = .014]. Improvement in skin activity and flare rates (key secondary endpoi...

Issues related to transitioning from paediatric to adult healthcare are currently receiving international attention. In Japan, 1000 patients with childhood-onset chronic rheumatological diseases reach adulthood every year and require transition from care by paediatric to care by adult rheumatologists. Here, we propose a guide for the latter, wherein the adult caregiver poses the clinical questions about transitional support that they need to have answered, and the paediatric caregiver mainly compiles the plans for the transition. To formulate the guide, we sought comments from both the Japan College of Rheumatology and the Pediatric Rheumatology Association of Japan and obtained their approval. Here, we present the outcome of this consultation in the form of a Guide for Supporting Transitional Care, aiming to provide essential knowledge to physicians in the fields of adult internal medicine and orthopaedics who may be involved in treating patients with rheumatic disease during the t...

ObjectivesThe discordance between patient global assessment (PGA) and physician global assessment (PhGA) of rheumatoid arthritis (RA) disease activity may be problematic in clinical practice. The aim of this study was to identify determinants of this discordance using a nationwide RA database in Japan (NinJa) with special attention to large joint involvement.MethodsWe investigated 12 043 adults with RA and used a discordance cutoff of 3 cm. Large joint involvement was investigated using novel joint indices (x, y, z), where x and y were the indices for upper and lower joints, respectively, and z was for large joint predominance. Predictors of PGA‐PhGA discordance and determinants of PGA and PhGA were analyzed by multivariate logistic and linear regression models, respectively.ResultsMultivariate logistic regression identified age, pain and high modified Health Assessment Questionnaire score as predictors of positive discordance (PGA ≥ PhGA), whereas parameters of disease activity in ...

Objectives To identify effective predictors of remission in patients with rheumatoid arthritis (RA). Methods Total Joint indices (TJI) of upper/large, upper/small, lower/large, and lower/small regions were calculated as the sum of tender and swollen joint counts divided by the number of evaluable joints in each region of interest (1). Data of 369 RA patients receiving MTX from Kurashiki Medical Center were applied to obtain logistic models for predicting the probability of remission. These models were validated using data of 6202 patients from NinJa 2010, an annually updated nationwide database in Japan. Results TJI of all the regions were effective predictors for new ACR/EULAR (A/E), SDAI, CDAI, boolean and DAS28 remission definitions (table 1). Larger odds ratio (OR) means higher probability of remission. Upper joints, especially in upper/small were more effective predictors for A/E and SDAI remission than lower joints. OR for each region, except for upper/small region in DAS28 remission was similar to that in A/E and SDAI remission. OR for every joint region in CDAI remission was relatively high and upper/larger region was the highest of all. OR for upper/large region in boolean remission was relatively low compared to other remission definitions. Overall percentage of correct classification of NinJa data were 83.9% for A/E, 85.3% for SDAI, 85.7% for CDAI, 80.7% for boolean, and 78.0% for DAS28 remission. Data satisfied A/E were classified into 2 groups: physician global assessment ≤1cm and >1cm. The rates of positive TJI in upper/large and lower/large regions were 18.5 and 19.7% for >1cm group, respectively, and were significantly higher than those for ≤1cm group (10.9 and 9.5%, respectively). Table 1. Comparison of OR (95% CI) for Total joint index (TJI) in each region between remission definitions TJI = 0 vs. TJI > 0 Upper/large Upper/small Lower/large Lower/small ACR/EULAR 10.0 (4.9 to 20.2) 12.2 (4.8 to 30.6) 3.7 (1.8 to 7.3) 3.5 (1.5 to 8.0) SDAI 10.0 (4.8 to 20.6) 24.5 (7.3 to 82.7) 3.3 (1.6 to 6.7) 4.1 (1.7 to 9.6) CDAI 14.9 (5.1 to 43.7) 9.0 (2.6 to 31.6) 9.0 (3.0 to 27.0) 9.0 (2.0 to 40.8) Boolean 5.6 (2.6 to 12.0) 5.7 (2.1 to 15.2) 2.2 (1.1 to 4.7) 4.1 (1.5 to 11.3) DAS28 8.2 (4.6 to 14.4) 5.0 (2.8 to 8.9) 3.7 (2.1 to 6.5) 2.6 (1.5 to 4.7) Conclusions Upper/small joints were emphasized in A/E and SDAI remission compared to DAS28 remission. Physicians had respect for affected large joints in patients with A/E remission. References Nishiyama S, et al, Proposing a method of regional assessment and a novel outcome measure in rheumatoid arthritis. Rheumatol Int. DOI 10.1007/s00296-011-2058-9, 2011 Disclosure of Interest None Declared

Anticentromere antibody (ACA) is generally considered to be a serological marker for systemic sclerosis (SSc). ACA-positive patients with primary Sjögren's syndrome (pSS) have also been reported. ACA often recognizes centromere proteins (CENPs): CENP-A, CENP-B, and CENP-C, and sometimes reacts to heterochromatin protein 1 (HP1)α. We compared the reactivity against six different epitopes for three ACA-positive clinical subgroups: 29 patients with pSS, 36 SSc patients with sicca symptoms, and 28 SSc patients without sicca symptoms. We utilized enzyme-linked immunosorbent assays (ELISAs) with recombinant proteins covering six different epitope regions of ACA (the amino terminus (Nt) of CENP-A, CENP-B, and CENP-C, the carboxyl terminus (Ct) of CENP-B and CENP-C, and HP1α). The patients with pSS were found to have IgG-class autoantibodies against CENP-C-Nt and HP1α, and IgA-class autoantibodies against CENP-C-Ct with significantly higher frequencies than the SSc patients with or with...

<p><strong>Objectives: </strong>The Health Assessment Questionnaire (HAQ) identifies reversible activity-related factors (ActHAQ) and ones that are irreversible due to joint damage (DamHAQ). We aimed to examine which joints are associated with ActHAQ and DamHAQ from the viewpoint of affected joint size and distribution.</p><p><strong>Methods:</strong> Data from 7,408 patients who had not undergone orthopedic surgery were extracted from the National Database of Rheumatic Diseases by iR-net in Japan (<em>NinJa</em>) database. The regression coefficient between the HAQ and the Simplified Disease Activity Index (SDAI) was 0.036 in 141 patients with very early rheumatoid arthritis (RA) whose DamHAQ is presumed to be zero. We calculated the two components of the HAQ using the following formulas: ActHAQ = 0.036 × SDAI and DamHAQ = HAQ – ActHAQ.</p><p><strong>Results:</strong> Large joint involvement was positively correlated with both ActHAQ and DamHAQ. Although upper/small joint involvement was the most significant predictor of ActHAQ elevation, it was inversely correlated with DamHAQ. Lower/small joint involvement was not a significant factor in either component.</p><strong>Conclusions:</strong> Compared to small joints, large joint involvement was associated with an increase in damage-related HAQ. In light of this finding, large joint involvement should be thoroughly treated to prevent RA patients from experiencing worsening physical function.

To define disease activity levels, minimal clinically important improvement (MCII) and patient-acceptable symptom state (PASS) with the primary Sjögren's syndrome (SS) disease activity indexes: European League Against Rheumatism (EULAR) SS disease activity index (ESSDAI) and EULAR SS patient-reported index (ESSPRI). For 790 patients from two large prospective cohorts, ESSDAI, physician evaluation of disease activity, ESSPRI and patients' satisfaction with their current health status were recorded. Receiver operating characteristic curve analyses and anchoring methods were used to estimate disease activity levels of ESSDAI and the PASS of ESSPRI. At follow-up visit, patients and physicians assessed, respectively, whether symptoms and disease activity have improved or not. An anchoring method based on this evaluation was used to estimate MCII of ESSDAI and ESSPRI. Low-activity (ESSDAI<5), moderate-activity (5≤ESSDAI≤13) and high-activity (ESSDAI≥14) levels were defined. MCII of ESSDAI was defined as an improvement of at least three points. The PASS estimate was defined as an ESSPRI<5 points and MCII as a decrease of at least one point or 15%. This study determined disease activity levels, PASS and MCII of ESSDAI and ESSPRI. These results will help designing future clinical trials in SS. For evaluating systemic complications, the proposal is to include patients with moderate activity (ESSDAI≥5) and define response to treatment as an improvement of ESSDAI at least three points. For addressing patient-reported outcomes, inclusion of patients with unsatisfactory symptom state (ESSPRI≥5) and defining response as an improvement of ESSPRI at least one point or 15% seems reasonable.

The objective of this study is to develop clinical practice guideline (CPG) for Sjögren's syndrome (SS) based on recently available clinical and therapeutic evidences. The CPG committee for SS was organized by the Research Team for Autoimmune Diseases, Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW), Japan. The committee completed a systematic review of evidences for several clinical questions and developed CPG for SS 2017 according to the procedure proposed by the Medical Information Network Distribution Service (Minds). The recommendations and their strength were checked by the modified Delphi method. The CPG for SS 2017 has been officially approved by both Japan College of Rheumatology and the Japanese Society for SS. The CPG committee set 38 clinical questions for clinical symptoms, signs, treatment, and management of SS in pediatric, adult and pregnant patients, using the PICO (P: patients, problem, population, I: interventions, ...

Background Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by lymphocyte infiltration in exocrine glands. Although most of the patients developed the disease in middle age, there are younger onset patients. Objectives To examine relationship between age at onset and clinical features including disease activity in patients with pSS. Methods Clinical data of 75 women with pSS who visited our hospital from Aug. 2010 to Dec. 2014 were collected from medical charts. Of them, ESSPRI1 and ESSDAI2 were assessed in 72 and 71 patients, respectively. Results Average age, age at onset, and duration of disease were 60.9±12.6, 48.3±13.9, and 12.8±7.3 years, respectively. Number of patients with low (ESSDAI <5), moderate (ESSDAI 5 ∼ 13), and high disease activity (ESSDAI 14) were 45, 20, and 6, receptivity. Corticosteroid was used in 60.8% of patients. Average dose of steroid (equivalent dose of prednisolone) was 3.1±2.1 mg/day, and that of high disease activity group (6.3±4.4mg/day) was significantly higher than that of moderate (1.6±1.4 mg/day) or low disease activity group (1.6±1.6mg/day). Patients with younger onset (under 40) had significantly high score of ESSDAI (7.8±5.9) compared with middle age or elderly onset patients (3.7±4.3), and there was a marked difference in its domain of lymphadenopathy between younger onset and middle age or elderly onset patients. There was no difference of ESSPRI between them (5.1±2.1 vs. 4.3±2.1); however, its item of fatigue score was significantly higher in younger onset group than in middle age or elderly onset group (5.9±2.9 vs. 4.3±2.9). Positive rate of anti-Ro/SSA and anti-La/SSB antibody in younger onset group was 100% and 36.8%, respectively and it did not differ from that in middle or elderly onset group (89.3% and 33.9%, respectively). Conclusions Younger onset pSS patients had higher disease activity than middle age or elderly onset patients. Severity of fatigue and lymphadenopathy were the clinical characteristics in younger onset pSS. References Seror R, et al. Ann Rheum Dis 2011; 70:968-72. doi: 10.1136/ard.2010.143743 Seror R, et al. Ann Rheum Dis 2010;69:1103-9. doi: 10.1136/ard.2009.110619 Disclosure of Interest None declared

Methods: A study was undertaken to investigate patients with MD and IgG 4 -related disorders registered in Japan and to set up provisional criteria for the new clinical entity IgG 4 -positive multiorgan lymphoproliferative syndrome (IgG 4 +MOLPS). The preliminary diagnostic ...

To validate the two recently developed disease activity indexes for assessment of primary Sjögren's syndrome (SS): the European League Against Rheumatism (EULAR) SS Patient Reported Index (ESSPRI) and the EULAR SS Disease Activity Index (ESSDAI). A prospective international 6-month duration validation study was conducted in 15 countries. At each visit, physicians completed ESSDAI, SS disease activity index (SSDAI), Sjögren's Systemic Clinical Activity Index (SCAI) and physician global assessment (PhGA); and patients completed ESSPRI, Sicca Symptoms Inventory (SSI), Profile of Fatigue and Discomfort (PROFAD) and patient global assessment (PGA). Psychometric properties (construct validity, responsiveness and reliability) were evaluated and compared between scores. Of the 395 patients included, 145 (37%) and 251 (64%) had currently active or current or past systemic manifestations, respectively. EULAR scores had higher correlation with the gold standard than other scores (ESSDAI with PhGA: r=0.59; ESSRPI with PGA: r=0.70). Correlations between patient and systemic scores were very low (ranging from 0.07 to 0.29). All systemic scores had similar large responsiveness in improved patients. Responsiveness of patient scores was low but was significantly higher for ESSPRI compared with SSI and PROFAD. Reliability was very good for all scores. ESSDAI and ESSPRI had good construct validity. All scores were reliable. Systemic scores had a large sensitivity to change in patients whose disease activity improves. Patient scores had a small sensitivity to change, however, significantly better for ESSPRI. Systemic and patient scores poorly correlated, suggesting that they are 2 complementary components that should be both evaluated, but separately.

Cyclosporin A (CsA) inhibits interleukin (IL)-2 production, activation and proliferation of human peripheral T cells (HPTC) costimulated with simultaneous engagement of T cell receptor (TCR)/CD3 and CD28. We demonstrated that 10 ng/ml CsA, which reduced the proliferation of HPTC costimulated with anti-CD3 and anti-CD28 by half, prevented NF-AT and NF-κB from migrating into the nucleus. Whereas CsA added even 30 min after the costimulation caused NF-AT to remain in the cytoplasm, the delayed addition of CsA could not prevent NF-κB from translocating into the nucleus. CsA, which was added to HPTC simultaneously with the engagement of both CD3 and CD28 or the 1-h-delayed engagement of CD28 after prior TCR/CD3-triggering, inhibited NF-κB p65/RelA from binding to the target DNA fragment, followed by reduction of HPTC proliferation in response to the costimulation. When CsA was added 30 min after the delayed engagement of CD28 following the prior engagement of TCR/CD3, these inhibitory effects were diminished. Antisense NF-κB p65/RelA oligonucleotides inhibited p65/RelA mRNA expression, diminished IL-2 mRNA expression in the costimulated HPTC and reduced HPTC proliferation to the same extent as CsA added simultaneously with the costimulation. The CsA- or antisense p65/RelA oligonucleotide-induced reduction in the proliferation of costimulated HPTC was overcome by the addition of exogenous IL-2. These findings indicate that the major effects of CsA on the early phase of CD28-mediated costimulation in the presence of TCR/CD3 signaling are to inhibit NF-κB/RelA from translocating into the nucleus and binding to the target DNA sequence in the IL-2 gene promoter region, which induces IL-2 expression leading to HPTC proliferation.

A 66-year-old woman with systemic scleroderma developed pancytopenia (white blood cell 750/microliter, neutrophilic cell 201/microliter, red blood cell 166 x 10(4)/microliter, hemoglobin 5.3 g/dl, hematocrit 18.1%, platelet cell 8.2 x 10(4)/microliter) 7 months after the initiation of intravenous hyper-alimentation for chronic ileus. Serum copper and zinc levels were 3 and 46 micrograms/dl, respectively. Provision of trace elements led to increase blood cell counts as well as serum copper and zinc levels. She also developed watery diarrhea frequent times a day and hypoproteinemia during the lack of trace elements. Evidence of protein-losing gastroenteropathy was shown by gastrointestinal scintigraphy using 99mTc-human serum albumin half a year after provision of trace elements and it was not shown one and a half years after continuous provision of trace elements. As patients with scleroderma sometimes develop gastrointestinal problems and are needed intravenous nutrition of long dur...

IgG4-related disease is a new disease classification established in Japan in the 21st century. Patients with IgG4-related disease display hyper-IgG4-gammaglobulinemia, massive infiltration of IgG4+ plasma cells into tissue, and good response to glucocorticoids. Since IgG4 overexpression is also observed in other disorders, it is necessary to diagnose IgG4-related disease carefully and correctly. We therefore sought to determine cutoff values for serum IgG4 and IgG4/IgG and for IgG4+/IgG+ plasma cells in tissue diagnostic of IgG4-related disease. Patients and Methods. We retrospectively analyzed serum IgG4 concentrations and IgG4/IgG ratio and IgG4+/IgG+ plasma cell ratio in tissues of 132 patients with IgG4-related disease and 48 patients with other disorders. Result. Serum IgG4 >135  mg/dl demonstrated a sensitivity of 97.0% and a specificity of 79.6% in diagnosing IgG4-related disease, and serum IgG4/IgG ratios >8% had a sensitivity and specificity of 95.5% and 87.5%, respec...

To standardize quantitative parotid gland scintigraphy for diagnosing Sjögren's syndrome (SS). Forty-five patients with SS and 23 controls were studied. Dynamic images were obtained up to 50 min after the injection of 185 MBq 99mTc-pertechnetate and salivary excretion was stimulated with lemon juice orally at 40 min after the injection. Peak count and uptake speed in the uptake phase, and excretion speed and excretion fraction in the excretion phase were calculated. The levels of peak count, uptake speed, and excretion speed in the patients with SS were significantly lower than the levels in the controls, whereas there was no significant difference of excretion fraction level between the patients with SS and the controls. The calculations of peak count and excretion speed levels, which were closely related with the focus scores of minor salivary glands and the amount of stimulated whole saliva, showed higher reproducibility, sensitivity, and specificity than those of uptake spee...

To evaluate the clinical and serological heterogeneity in patients with anticentromere antibodies (ACA). One hundred twenty patients with ACA were analyzed retrospectively. ACA were detected initially on the basis of indirect immunofluorescence on HEp-2 cells, and then antibodies to CENP-B were measured by ELISA. Antibodies to other nuclear antigens were also detected by double immunodiffusion and/or ELISA. Eighty-four patients (70.0%) had systemic sclerosis (SSc; scleroderma) and 36 patients (30.0%) had other rheumatic diseases or miscellaneous disorders. Among patients with SSc, 35 patients (41.7%) had SSc in overlap mostly with Sjögren's syndrome (SS), in part with rheumatoid arthritis and/or primary biliary cirrhosis (PBC). Five of 36 patients (13.9%) without SSc also had overlap syndrome of more than 2 rheumatic diseases or PBC. All CREST features (calcinosis, Raynaud's, esophageal dysmotility, sclerodactyly, telangiectasias) were found significantly more in SSc than in...

Cyclosporin A (CsA) inhibits interleukin (IL)-2 production, activation and proliferation of human peripheral T cells (HPTC) costimulated with simultaneous engagement of T cell receptor (TCR)/CD3 and CD28. We demonstrated that 10 ng/ml CsA, which reduced the proliferation of HPTC costimulated with anti-CD3 and anti-CD28 by half, prevented NF-AT and NF-kappaB from migrating into the nucleus. Whereas CsA added even 30 min after the costimulation caused NF-AT to remain in the cytoplasm, the delayed addition of CsA could not prevent NF-kappaB from translocating into the nucleus. CsA, which was added to HPTC simultaneously with the engagement of both CD3 and CD28 or the 1-h-delayed engagement of CD28 after prior TCR/CD3-triggering, inhibited NF-kappaB p65/RelA from binding to the target DNA fragment, followed by reduction of HPTC proliferation in response to the costimulation. When CsA was added 30 min after the delayed engagement of CD28 following the prior engagement of TCR/CD3, these i...

A 60-year-old woman with systemic sclerosis, lung fibrosis, and primary biliary cirrhosis was admitted to our hospital because of heart failure. Ventricular aneurysms were found in the apex and the posterior wall of the left ventricle by angiocardiography; however, there was no sign of coronary artery stenosis. A myocardial biopsy specimen revealed diffuse focal myocardial fibrosis. In this case, the patient with systemic sclerosis developed a rare complication of ventricular aneurysms without coronary disease.

Abstract  A 39-year-old woman with systemic lupus erythematosus (SLE) developed severe acute pancreatitis during a well-controlled disease stage. Treatment with intraarterial injections of antipancreatic enzyme and a small amount of prednisone (20 mg/day) led to remission of the pancreatitis. Disease activity of the SLE did not flare up throughout the course of this treatment. The development of severe acute pancreatitis in SLE is rare. We discuss the cause of pancreatitis in SLE, and whether corticosteroids may induce or improve pancreatitis.

This was an open-labeled, prospective, control study to determine the efficacy of methotrexate (MTX) for improving serological abnormalities in patients with systemic lupus erythematosus (SLE). Thirty patients with a low serum complement and/or high anti-double-stranded DNA (dsDNA) antibody levels during a prednisolone taper received MTX orally at a dose of 7.5 mg/week over 12-18 months (MTX group). Eighteen SLE patients were selected as controls (control group). At the time of entrance into the study, all patients were receiving <15 mg/day of prednisolone. The C3, C4, and immunoglobulin (Ig)G, IgA, and IgM levels were measured using a turbidimetric immunoassay. The anti-dsDNA antibody level was measured using the Farr assay. Significant increases in C3 and C4 levels and significant decreases in anti-dsDNA antibody, IgG, IgA, and IgM levels from baseline were observed for 3-18 months after the trial in the MTX group but not in the control group. At the end of the study, C3 and/or C4 levels in 96.7% of the MTX patients and 33.3% of the control patients were normalized or elevated (p = 0.0001), and anti-dsDNA antibody levels were normalized or lowered in 24 of the 26 MTX patients (92.3%) and in 50.0% of the control patients (p = 0.0022). In addition, a significant reduction in SLE Disease Activity Index (SLEDAI) score and a prednisolone-sparing effect were observed for the MTX group but not the control group. A significant increase in mean corpuscular volume of red blood cells, which is indicative of an anti-folic-acid metabolic disorder induced by MTX, was observed only for patients in the MTX group. Five patients (16.7%) discontinued MTX treatment because of disease flare, and another three (10.0%) discontinued due to treatment side effects. MTX appears to be effective for improving serological abnormalities frequently observed before disease flares in SLE patients on a prednisolone taper.

Cyclosporin A (CsA) inhibits interleukin (IL)-2 production, activation and proliferation of human peripheral T cells (HPTC) costimulated with simultaneous engagement of T cell receptor (TCR)/CD3 and CD28. We demonstrated that 10 ng/ml CsA, which reduced the proliferation of HPTC costimulated with anti-CD3 and anti-CD28 by half, prevented NF-AT and NF-kappaB from migrating into the nucleus. Whereas CsA added even 30 min after the costimulation caused NF-AT to remain in the cytoplasm, the delayed addition of CsA could not prevent NF-kappaB from translocating into the nucleus. CsA, which was added to HPTC simultaneously with the engagement of both CD3 and CD28 or the 1-h-delayed engagement of CD28 after prior TCR/CD3-triggering, inhibited NF-kappaB p65/RelA from binding to the target DNA fragment, followed by reduction of HPTC proliferation in response to the costimulation. When CsA was added 30 min after the delayed engagement of CD28 following the prior engagement of TCR/CD3, these inhibitory effects were diminished. Antisense NF-kappaB p65/RelA oligonucleotides inhibited p65/RelA mRNA expression, diminished IL-2 mRNA expression in the costimulated HPTC and reduced HPTC proliferation to the same extent as CsA added simultaneously with the costimulation. The CsA- or antisense p65/RelA oligonucleotide-induced reduction in the proliferation of costimulated HPTC was overcome by the addition of exogenous IL-2. These findings indicate that the major effects of CsA on the early phase of CD28-mediated costimulation in the presence of TCR/CD3 signaling are to inhibit NF-kappaB/RelA from translocating into the nucleus and binding to the target DNA sequence in the IL-2 gene promoter region, which induces IL-2 expression leading to HPTC proliferation.

To evaluate efficacy of low dose prednisolone maintenance in patients with primary Sjögren's syndrome. An open, prospective pilot study of prednisolone for the treatment of 20 patients with primary Sjögren's syndrome was performed. Evaluations included the amount of whole saliva measured by the Saxon test, serological abnormalities and oral symptoms. Initial dosage of prednisolone was 15.0+/-1.5 (mean+/-SEM) mg/day. Maintenance dosage was 7.5-5.0 mg/day. Follow-up period was 26.3+/-3.8 months (range 3-48). The amount of whole saliva significantly increased after 1 month of prednisolone therapy and the increase continued up to 48 months by maintaining low-dose prednisolone. A mean percent increase of whole saliva from baseline ranged from +105.2+/-36.2% to +245.7+/-82.1%. Serum IgG, anti-SS-A/Ro, anti-SS-B/La antibodies and IgM rheumatoid factor levels significantly decreased throughout the study with partial decreases of IgA and IgM levels. The improvement of subjective oral symptoms was also confirmed. Low-dose prednisolone maintenance may have a worthwhile clinical benefit in patients with primary Sjögren's syndrome that deserves further evaluation in a controlled trial.