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Objectives: In clinical trials, tocilizumab (TCZ) is efficacious in patients with giant cell arteritis (GCA). This study evaluated the real-world tolerability and effectiveness of TCZ in Japanese patients with GCA., Methods: In this multicentre, prospective, Phase 4, large-scale, observational study, patients with GCA (with no TCZ treatment 6 months before the study) were recruited from 71 centres across Japan. Patients received subcutaneous TCZ 162 mg weekly (observation period, 52 weeks)., Results: Of the 117 patients [female, 70.1%; mean age, 74.2 years; mean disease duration, 1.4 years; treated for new-onset GCA, 71.8%; presence of large-vessel lesions (LVLs), 61.5%; previous immunosuppressant use, 28.2%; glucocorticoids at baseline, 95.7% (mean: 22.4 mg/day)], 38.5% reported adverse events. The most common adverse events of special interest were neutropaenia and leukopaenia (7.7%), followed by serious infection (6.0%). The relapse-free proportion was 85.0%; relapse after remission, 6.0%; and no remission, 9.0%. At the last observation, 94.2% of relapse-free patients received a concomitant glucocorticoid dose of <10 mg/day. Fatigue, headache, neck pain, and absence of LVLs were positively associated with the relapse., Conclusions: TCZ was effective and well tolerated in Japanese patients with GCA and may be an effective treatment option combined with glucocorticoids., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Objectives: We evaluated the real-world tolerability and effectiveness of tocilizumab in Japanese patients with Takayasu arteritis (TAK)., Methods: Patients with TAK who had not received tocilizumab in the previous 6 months were enrolled in ACTEMRA® (ACT)-Bridge, a phase 4, observational study, from 66 Japanese institutions (enrolment period, September 2017 to September 2020) and received weekly subcutaneous tocilizumab 162 mg (observation period, 52 weeks)., Results: Among 120 patients included (mean age, 38.4 years; mean disease duration, 7.7 years; treated for relapse, 50.8%; previous immunosuppressant use, 57.5%; glucocorticoid use at baseline, 97.5%), 49 (40.8%) reported adverse events. The most common adverse event of special interest was serious infection (7.5%). Relapse was observed in 24 (20.0%) patients (0.8%, 2.5%, and 16.7% reporting ≥3, 2, and 1 relapses, respectively). The reasons for diagnosing relapse included chest and back pain (45.8%), neck pain (25.0%), fatigue (16.7%), fever and headache (12.5% each), abnormal imaging findings (50.0%), and elevated inflammatory markers (16.7%). At the last observation, 83.0% of relapse-free patients recorded a concomitant glucocorticoid dose (prednisolone equivalent) <10 mg/day., Conclusions: This study demonstrated the effectiveness of tocilizumab in patients with TAK, with no new safety concerns. Tocilizumab plus glucocorticoids may be considered a treatment option for TAK., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

Objectives: To assess the safety and effectiveness of mycophenolate mofetil (MMF) in Japanese adults with lupus nephritis (LN) in real-world clinical practice., Methods: This multicentre, prospective, post-marketing surveillance study investigated the effectiveness and safety of MMF, as induction or maintenance therapy, in LN patients. Primary endpoints were adverse drug reactions (ADRs), changes in renal function from baseline, and relapse rate (RR) after 6 months in the maintenance group, estimated using the Kaplan-Meier method. Complete remission (CR) and partial remission (PR) were estimated by renal measurements., Results: Overall, 112 patients were enrolled in the induction group and 340 in the maintenance group. Of these 452 patients, 418 were evaluable for safety and 396 for effectiveness. Eighty-three patients (19.85%) experienced ADRs, most commonly herpes zoster (3.34%) and diarrhoea (3.11%). Serious ADRs occurring in more than three patients were cytomegalovirus infections (1.43%), acute pyelonephritis (0.71%), and herpes zoster (0.71%). One patient died from herpes zoster disseminated. CR and PR were 19.54% and 44.82%, respectively, in the induction group, and 40.62% and 66.16%, respectively, in the maintenance group. RR in the maintenance group was 0.70%., Conclusions: The tolerability of MMF is in line with that reported in other studies. Since the average dose of MMF was <1.5 g/day, research into the optimal dose for achieving effectiveness is required., (© Japan College of Rheumatology 2021. Published by Oxford University Press.)

Objectives: This study aimed to compare Takayasu arteritis (TAK) with giant cell arteritis (GCA) through immunohistochemistry principally of inflammatory cells; these two disorders may be on the spectrum within a single disease state. Methods: Nine TAK and 5 GCA surgically resected vessel specimens were selected. TAK specimen was divided into each three acute-, chronic-, and healed-phase samples based on intimal and adventitial thickening. Immunohistochemical analysis was performed of smooth muscle cells and inflammatory cells including lymphocytes, plasma cells, macrophages, and dendritic cells, where three healed-phase TAK specimens were excluded due to paucity of inflammation. Immunopositive cells per three different fields in intima, media, and adventitia were counted in each specimen, and their numbers in these three layers along with total 3 layers were compared between the two disorders. Results: Intimal smooth muscle maturity estimated by ratio of h-Caldesmon + cells to α-SMA + cells significantly increased in chronic- and healed- over acute-phase increases in TAK. Mann-Whitney tests demonstrated significantly more adventitial lymphoplasmacytic infiltration and less intimal fascin + dendritic cells, as well as overall more CD8 + T-cells, more CD20 + B-cells and lower CD4/8 ratio in TAK than in GCA. Conclusion: Different inflammatory involvement is suggested in the pathogenesis of TAK and GCA.

Purpose: To determine mortality and its predictive factors in elderly Japanese patients with severe microscopic polyangiitis (MPA)., Method: This retrospective single-center study determined the mortality of 52 patients with MPA who were admitted to our geriatric medical center from 2002 to 2014. The variables at baseline, including patient demographics, clinical characteristics, and treatment, were analyzed for their association with mortality., Result: Mean age at onset of MPA was 73.2 years, and the one-year survival rate was 65.9%. Relapse was observed in 32.7%. Among variables at diagnosis, age, cardiomyopathy, central nervous system (CNS) involvement, alveolar hemorrhage, disease severity, the 1996 Five-Factor Score (FFS), and the 2009 FFS were associated with mortality in univariate analysis. Cardiomyopathy, CNS involvement, age >65 years, disease severity, Birmingham Vasculitis Activity Score, the 1996 FFS, and the 2009 FFS were associated with relapse-free survival in univariate analysis., Conclusion: We investigated mortality and relapse-free survival and their predictive factors in elderly Japanese patients with severe MPA. Age, disease severity, the 1996 FFS, and the 2009 FFS at diagnosis were prognostic factors for both mortality and relapse-free survival.

Objective: To clarify the clinical features of systemic lupus erythematosus (SLE) patients, factors associated with flares, and changes over time., Methods: Patients having SLE with a visiting history were entered into the Juntendo University Database of Erythematosus. We included 423 cases in the long-term follow-up analysis, and 383 cases were followed for 10 years after the initiation of any therapeutic intervention (comparative analysis: 1973-1982, 82 cases; 1983-1992, 141, and 1993-2002, 160). We assessed changes in the patients' background characteristics, disease symptoms, flare rates, etc., Results: Among the 423 cases, the mean follow-up period was 25.9 years, and mean number of flares was 0.51. Of those, 31.9% had ≥1 flares. Thrombocytopenia at onset contributed to the flares. For disease symptoms at onset, a recent trend in increasing thrombocytopenia was observed. The combination rate of immunosuppressive agents for diseases other than lupus nephritis was slightly increased, and there was no improvement until the first flare or in the flare rate., Conclusions: Thrombocytopenia at onset is predictive factor for flares. Since SLE is a diverse disease with varying symptoms at recurrence, the treatment guidelines should be improved for thrombocytopenia from a long-term perspective.

Objectives: Anti-neutrophil cytoplasmic autoantibodies (ANCA) are useful diagnostic markers in systemic vasculitic disorders with small-vessel involvement, but depending on the particular test used, the myeloperoxidase (MPO)-ANCA results are variable. In the present study, we performed a comparative analysis between our originally developed nMPO-ANCA assay that targets the native MPO antigen and other commercially available assays using sera of patients with clinical features of ANCA-associated vasculitis (AAV)., Methods: Sera of 24 patients strongly suspected of having AAV were examined for the presence of MPO-ANCAs by our nMPO-ANCA assay and by other commercial-based MPO-ANCA assays. These results were correlated to indirect immunofluorescence microscopy staining patterns and patient clinical parameters., Results: Eighteen out of 24 patients (75 %) were positive for nMPO-ANCA, compared with 13 out of 24 patients (54 %) by one of the most frequently used commercial-based MPO-ANCA enzyme-linked immunosorbent assays (ELISAs) in Japan. Interestingly, the patients who tested positive with our nMPO-ANCA assay alone showed clinical features of AAV marked by continuous fever, polyarthritis, and mild nephritis. The titers of nMPO-ANCA decreased in association with clinical improvement after treatment., Conclusions: Our data suggest that a positive nMPO-ANCA result, which identifies antibodies to human native MPO antigen, correlates with AAV disease activity. Moreover, the nMPO-ANCA test has clinical utility in detecting AAV-affected patients who have tested negative using commercially available assays.

Objective: The primary objective of this study was to evaluate the tolerability of single and multiple doses of abatacept in Japanese patients with rheumatoid arthritis. Secondary objectives included evaluating its pharmacokinetics, pharmacodynamics, immunogenicity, and efficacy., Methods: This dose-escalation, single- and multiple-dose, multicenter, open-label study was conducted at nine sites in Japan. Seven patients were enrolled at each of three dose levels (2, 8 and 16 mg/kg) and received a single intravenous dose of abatacept on day 1 of the single-dose phase. The multiple-dose phase, at the same dose, started once the patients had completed the single-dose phase and when it was confirmed that there were no safety issues., Results: Twenty patients started the single-dose phase. Single and multiple doses of abatacept were well tolerated, and adverse events were of mild to moderate intensity. There were no discontinuations or deaths due to adverse events. The pharmacokinetics of abatacept were linear, with no notable accumulation. There were no immunogenic effects on the safety, efficacy, or pharmacokinetics of abatacept. Multiple doses of abatacept improved individual items of the American College of Rheumatology core set., Conclusion: Single and multiple doses of abatacept showed favorable tolerability and efficacy in Japanese patients with rheumatoid arthritis.

We (JMAAV [Japanese patients with MPO-ANCA-associated vasculitis] Study Group) performed a prospective, open-label, multi-center trial to evaluate the usefulness of severity-based treatment in Japanese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA)-associated vasculitis. Patients with MPO-ANCA-associated vasculitis received a severity-based regimen according to the appropriate protocol: low-dose corticosteroid and, if necessary, cyclophosphamide or azathioprine in patients with mild form; high-dose corticosteroid and cyclophosphamide in those with severe form; and the severe-form regimen plus plasmapheresis in those with the most severe form. We followed up the patients for 18 months. The primary end points were the induction of remission, death, and end-stage renal disease (ESRD). Fifty-two patients were registered, and 48 patients were enrolled in this study (mild form, n = 23; severe form, n = 23; most severe form, n = 2). Among the 47 patients who received the predefined therapies, 42 achieved remission within 6 months, 5 died, and 1 developed ESRD. Disease flared up in 8 of the 42 patients with remission during the 18-month follow-up period. The JMAAV trial is the first prospective trial for MPO-ANCA-associated vasculitis to be performed in Japan. The remission and death rates were comparable to those in several previous clinical trials performed in western counties. The regimen employed in this trial was tailor-made based on patients' disease severity and disease type, and it seems that standardization can be consistent with treatment choices made according to severity.

Antineutrophil cytoplasmic antibodies (ANCAs) against myeloperoxidase (MPO), proteinase 3 (PR-3), lactoferrin (LF), cathepsin G (CG) and elastase (EL) were determined to investigate whether the presence of ANCAs is closely related to extra-articular manifestations in Japanese patients with rheumatoid arthritis (RA). Antibodies against MPO, PR-3, LF, CG and EL were determined in sera from 125 patients with RA and 83 sera from patients with other rheumatic diseases by enzyme-linked immunosorbent assay. Clinical manifestations and laboratory parameters of the patients were studied from medical records. Thirty of the 125 (24.0%) RA patients were positive for ANCAs for at least one of these 5 ANCA antigens. Among the 5 ANCAs, anti-LF antibody (anti-LF) (16.8%) was most commonly observed in patients with RA. A higher joint score (JS) and an elevated ESR were demonstrated in ANCA-positive RA patients compared to those of ANCA-negative patients (40.8 ± 43.3, 24.3 ± 26.2, p < 0.05, 44.4 ± 22.4, 28.9 ± 23.6, p < 0.05, respectively). No statistical differences in the presence of interstitial pneumonia, cutaneous vasculitis, rheumatoid nodules and mononeuropathy multiplex were observed between ANCA-positive and ANCA-negative patients. The presence of anti-LF is expected to be of pathological relevance, as the action of anti-LF towards LF results in the inhibition of the anti-inflammatory activity of LF.

A 59-year-old asymptomatic man was incidentally found to have a periaortic mass and an elevated serum amylase level during his medical check-up. Additional findings, such as infiltration of immunoglobulin G4 (IgG4)-producing plasma cells in the mass lesion, elevation of serum IgG4 (1000 mg/dl), and pancreatic duct narrowing as evidenced on a magnetic resonance cholangiopancreatography scan, confirmed the diagnosis as retroperitoneal fibrosis complicated with autoimmune pancreatitis. The patient responded favorably to steroid treatment before the appearance of symptoms.

The aims of this study were to analyze the clinical and pathological features of lupus nephritis (LN) and examine the association between these features and pathological condition, treatment, and prognosis. Of the 177 systemic lupus erythematosus patients who died while receiving inpatient care at Juntendo University Hospital between 1960 and 2001, we investigated the clinical features, treatment, and pathological features of 73 of these who underwent pathological autopsy and had a clear medical history. We divided these cases into two groups, i.e., those up to 1979 (Group A) and those during and after 1980 (Group B) in order to investigate changes in tendencies by age. We also divided the cases into three groups by time interval between diagnosis and death to investigate long-term prognosis. Uremia was the direct cause of death in 38.9% of cases in Group A and only 10.8% of cases in Group B. Pathological features showed a tendency to change to a sclerotic lesion as the duration of the disorder became longer. Uremia attributable to LN was the direct cause of death in relatively fewer cases, although it is still found in the majority of LN cases and remains a problem requiring stringent management. The treatment of sclerotic lesions may be an issue that needs further attention.

Antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitides are major causes of rapidly progressive glomerulonephritis (RPGN). Although recent papers suggest differences in clinicoepidemiological manifestations of ANCA-associated vasculitis between Japan [microscopic polyangiitis (MPA) " Wegener's granulomatosis (WG)] and Europe (WG"MPA), little is known about the prevalence and serological pattern. We retrospectively analyzed 27 RPGN patients who were admitted in our hospital over the past 11 years and who could be basically followed for more than 1 year, concerning the incidence of ANCA-related vasculitis, the presence of (MPO)/proteinase 3 (PR3)-ANCA and their clinical outcomes. As there were no PR3-ANCA single positive and/or WG patients, all patients were serologically divided into four groups; Groups I: MPO-ANCA single-positive patients (N = 11), II: MPO-ANCA and PR3-ANCA double-positive patients (N = 3), III: antiglomerular basement membrane antibody (anti-GBM Ab)-positive patients (N = 6), and IV: all negative patients (N = 7). Patients in Groups II/III showed more severe manifestation at admission. However, in Group I, only 36.3% patients avoided death and/or dialysis-dependent end-stage renal disease. Most patients in Group IV were women (85.7%), and 50% of these patients was diagnosed as having rheumatic diseases. Every patient in Groups I-III was treated with oral corticosteroid and/or methylprednisolone pulse therapy. Most patients treated with immunosuppressants showed severe prognosis because of frequent recurrences of vasculitis and infectious episodes after repeated and prolonged treatments with immunosuppressants. Present analysis further confirms the epidemiological and serological differences in ANCA-related RPGN between Japan and Europe, and reinforced the fact that ANCA-associated vasculitis is the most serious causal disease for RPGN.

We evaluated the efficacy and safety of tacrolimus in patients receiving glucocorticoid therapy for lupus nephritis. Patients with persistent nephritis were randomized to receive 28 weeks of double-blind treatment with tacrolimus (3 mg/day) or placebo. The primary endpoint was the change in the lupus nephritis disease activity index (LNDAI) calculated from scores for daily urinary protein excretion, urinary red cells, serum creatinine, anti-double-stranded DNA antibody, and serum complement. Statistical analysis was performed using the full analysis set. The LNDAI was decreased by 32.9 +/- 31.0% (mean +/- SD) in the tacrolimus group (n = 28) and was increased by 2.3 +/- 38.2% in the placebo group (n = 35) at final evaluation. There was significant improvement in the tacrolimus group. Daily urinary protein excretion showed a significant decrease in the tacrolimus group (p < 0.001). The complement (C3) level showed a significant increase in the tacrolimus group (p = 0.001). Treatment-related adverse events occurred in 92.9% of the tacrolimus group and 80.0% of the placebo group, but the difference was not significant. In patients on glucocorticoid therapy for lupus nephritis, addition of tacrolimus to basal therapy achieved significant improvement compared with placebo. Tacrolimus may therefore be a useful alternative treatment for lupus nephritis.

Tyrosine kinase 2 (TYK2) is a type I interferon (IFN) signaling pathway gene and was previously reported to be a risk factor for systemic lupus erythematosus (SLE) in Caucasian populations. In order to test for its genetic association with SLE in a Japanese population, TYK2 single nucleotide polymorphisms (SNPs), rs2304256, rs12720270 and rs280519, were genotyped. A case-control association study was performed in a total of 411 Japanese SLE patients and 467 healthy controls. Linkage disequilibrium (LD) among TYK2 SNPs was examined. According to the data from 94 healthy controls, non-synonymous rs2304256 resulting in Val --> Phe substitution was revealed to be in a LD with rs12720270 and rs280519. Therefore, we further genotyped rs2304256 as a tag SNP in the full sample sets. As a result, no differences in genotype distribution and allelic frequencies of rs2304256 were found between SLE patients and healthy controls. In conclusion, TYK2 is not a genetic risk factor for SLE in a Japanese population. Our result suggests that there is an ethnic difference in the susceptibility genes for SLE.

The expression of CD25 or CD28 on T cells was examined in patients with rheumatic diseases associated with interstitial pneumonitis (IP), in order to investigate the conditions of CD4+CD25+ regulatory T cells and CD8+CD28- suppressor T cells. Fifty-five patients with various rheumatic diseases and 23 normal controls were enrolled. CD4+CD25+ T cells of patients with IP were significantly decreased in comparison with non-IP patients, and the ratio of CD8+CD28- T cells in patients with IP was significantly higher than that in non-IP patients or normal controls. These results for CD8+CD28- T cells were in accord with the decrease in CD8+CD28+ T cells, and may be related to activation-induced CD8+CD28+ T-cell death. Thus, the abnormality of CD4+CD25+ regulatory T cells may be related to the pathogenesis of IP, and the survival and activation of CD8+ T cells.

Intravenous immunoglobulin (IVIG) therapy was administered to 15 patients who were refractory to traditional steroid therapy [eight with polymyosis (PM), seven with dermamyosis (DM)] to evaluate its efficacy. Serum creatine kinase (CK) significantly decreased from week 1, and manual muscle test scores (MMT) and activities of daily living (ADL) significantly increased from week 2. Efficacy rates were 93.3% (14/15 patients) as assessed using the MMT score, 80.0% (12/15 patients) using the ADL score, and 100% (15/15 patients) using the serum CK level. When changes in the serum CK level over two four-week periods, one before IVIG therapy (from week -4 to week 0) and one after IVIG therapy (from week 0 to week 4), were transformed to natural logarithms, the four-week change after IVIG therapy was significantly greater than that before IVIG therapy. The estimated duration of the serum CK level remaining normal in 50% of the patients after IVIG therapy was 334.5 days. Adverse reactions were observed in seven of 16 patients (43.8%) during the study period, but none of the adverse reactions were considered to be serious or required emergency treatment. In conclusion, the present study indicates that IVIG therapy is effective for steroid-resistant PM/DM.

To examine the clinical features of vertebral and non-vertebral fractures in patients with rheumatoid arthritis (RA), including insufficiency fractures, and to assess the risk factors for fracture, we prospectively studied 209 outpatients with rheumatoid arthritis for 1 year. The age, gender, Steinbrocker's functional class, glucocorticoid use, history of lower limb surgery, serum C-reactive protein (CRP), and use of bisphosphonates were evaluated. Examination for fractures was performed by radiography, computed tomography (CT), magnetic resonance imaging (MRI), and bone scanning. Thirty-three fractures occurred in 24 patients over the 1-year study period, and the incidence was 15.8 fractures per 100 patient-years. Fractures occurred at various sites. The majority (70%) was insufficiency fracture, and more than 50% caused ambulatory dysfunction. Radiographic findings were absent in 39% of the fractures at the onset of pain. The functional class and glucocorticoid dose were significantly associated with fracture development. This prospective study showed that the incidence of fractures, especially insufficiency fractures, was very high in patients with rheumatoid arthritis and that most of their fractures caused gait disturbance. Early intervention to prevent secondary osteoporosis is recommended to maintain the quality of life in patients with rheumatoid arthritis, especially those with functional impairment or undergoing glucocorticoid therapy.

The aim of this study was to evaluate the characteristics of autoreactive T cells to myeloperoxidase (MPO) in patients with MPO-antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Peripheral blood T cells from 15 patients with MPO-ANCA-associated vasculitis and 14 healthy individuals were cultured with three recombinant proteins that together comprised the entire MPO sequence (L, all 112 amino acids (AA) of the light chain; HI, AA 1-227 of the heavy chain; HII, AA 212-467 of the heavy chain), and the antigen-specific T-cell proliferative response was measured by 3H-thymidine incorporation. T-cell responses to MPO-L and HI were both detected in four patients and three healthy donors, and responses to MPO-HII were detected in four patients and seven healthy donors. These findings indicate that at least three independent T-cell epitopes exist on the MPO molecule. Interestingly, the patients whose T cells showed these MPO-induced responses were mainly in remission. Peripheral blood T cells reactive with MPO were primarily of the HLA-DR-restricted CD4+ phenotype. In summary, we successfully used recombinant MPO fragments to detect autoreactive CD4+ T cells to multiple MPO epitopes in blood samples from patients with MPO-ANCA-associated vasculitis and healthy individuals.

We conducted a 52-week clinical study of iguratimod in 394 Japanese patients with rheumatoid arthritis to evaluate the long-term safety of the drug. Iguratimod was administered orally at a daily dose of 25 mg for the first 4 weeks and 50 mg for the subsequent 48 weeks. Some of the patients continued the treatment for 100 weeks for their benefit. The cumulative incidence of adverse events for 100 weeks was 97.6%. The cumulative incidence of adverse reactions was 65.3%; unfavorable symptoms and signs (excluding abnormal laboratory data changes) accounted for 33.2% of the reactions, and abnormal laboratory data changes accounted for 50.4%. The continued treatment rate was 66.8% at week 28 and 53.6% at week 52. For reference, the American College of Rheumatology (ACR) 20 response rate was calculated for the patients who had assessable disease activity, who did not violate the study protocol, and who continued the study treatment at weeks 28 and 52. The rate was 46.9% at week 28 and 41.0% at week 52. To use iguratimod safely for a long time, patients should be observed closely for adverse reactions such as increased hepatic enzymes.

We report a 34-year-old woman who developed primary antiphospholipid antibody syndrome (APS) presenting with dysfunctional uterine bleeding and cerebral infarction. Antiphospholipid antibody syndrome presenting with bleeding manifestations is rare. We should recognize that APS may be associated with not only thrombosis but also bleeding.

We conducted a 28-week, randomized, double-blind, parallel-group study of iguratimod in 376 Japanese patients with active rheumatoid arthritis to compare the efficacy and safety of the drug with those of placebo and salazosulfapyridine. In the American College of Rheumatology (ACR) 20 response rate, iguratimod was superior to placebo (53.8% versus 17.2%; Fisher's exact test, P < 0.001) and was not inferior to salazosulfapyridine (63.1% versus 57.7%, 95% confidence interval for the rate difference, -7.9% to 18.7%). Iguratimod began exhibiting its therapeutic effect within 8 weeks after the initiation of treatment and was effective even in patients who had a poor response to previous treatment with disease-modifying antirheumatic drugs. No statistically significant difference was noted in the incidence of adverse reactions between iguratimod and salazosulfapyridine. The study results suggest that iguratimod could become a new option for the treatment of rheumatoid arthritis.

To investigate the mechanism of antirheumatic action of mizoribine (MZR), we examined the expression of matrix metalloproteinase-1 (MMP-1) and MMP-3 utilizing THP-1 derived macrophage-like cells (THP-1 macrophages) and human synovial fibroblasts (SFs). The cells were respectively stimulated with lipopolysaccharide (LPS) and interleukin-1beta in the presence or absence of MZR in vitro. The concentrations of MMP-1 and MMP-3 in the supernatant were measured by enzyme-linked immunosorbent assay. The secretion of MMP-1 from SFs, as well as THP-1 macrophages, was inhibited by MZR in a dose-dependent manner. Furthermore, a quantitative real-time polymerase chain reaction revealed that MZR decreased the expression of MMP-1 messenger RNA. These findings may be an explanation for the clinical effect of MZR in patients with rheumatoid arthritis.

The relationship between clinical manifestations and prognosis was examined and evaluated among systemic lupus erythematosus (SLE) patients. A total of 542 patients with SLE were selected and divided into nine groups according to their main clinical manifestation at the time of initial diagnosis. The relationship between these clinical manifestations and long-term prognosis was evaluated in respect to the survival, remission, relapse rates, the development of a new clinical manifestation, and/or damage index. Patients with neuropsychiatric SLE (NPSLE), accompanied with acute confusional state/seizure disorder, cerebral vascular disease, or pneumonitis had poor survival rates with cause of death related to their major organ involvement. Patients with nephropathy or leukopenia had lower remission rates, and an increase in relapse rates was frequently recognized in patients with pneumonitis. Body damage (damage index) was higher in patients with lupus psychosis, pneumonitis, and/or arthritis. The translation of the main manifestations after diagnosis was confirmed in 64 patients (11.8%), and often observed in patients with autoimmune hemolytic anemia and arthritis. The majority of these manifestations were nephropathy, NPSLE, thrombocytopenia, and pneumonitis, and the prognosis of patients with nephropathy and thrombocytopenia as a new main manifestation had a poor outcome. The results of long-term prognosis in SLE greatly differed with respect to the initial clinical manifestation at the time of diagnosis.

We describe a patient with reactive arthritis (ReA) induced by influenza vaccination. A healthy 79-year-old Japanese man began suffering from migrating polyarthritis 2 days after receiving influenza vaccine. He proved negative for rheumatoid factor, showing no evidence for microbial infections such as Streptoccocci, Chlamydia, or Parbovirus B19. Human leukocyte antigen (HLA) typing analysis revealed positive results for HLA-B54 (22), which is one of the cross-reactive antigens to HLA-B27. His arthritis improved with administration of nonsteroidal anti-inflammatory drugs, and recovery was attained within 6 weeks. Reactive arthritis is a rare adverse effect induced by influenza vaccination; however, it is important that it is recognized by all physicians.

The clinical significance of anticyclic citrullinated peptide (CCP) antibodies in patients with mixed connective tissue disease (MCTD) was assessed. Altogether, 86 sera from MCTD patients, 96 from rheumatoid arthritis (RA) patients, 42 from systemic lupus erythematosus (SLE) patients, 23 from systemic sclerosis (SSc) patients, 21 from polymyositis/dermatomyositis (PM/DM) patients, and 17 from those with Sjögren's syndrome (SjS) were tested for anti-CCP antibodies using an enzyme-lined immunosorbent assay. Among the 96 RA patients, anti-CCP antibodies were detected in 85%, with the frequency being significantly higher than in MCTD, SLE, SSc, PM/DM, and SjS patients (9%, 14%, 13%, 14%, and 18%, respectively; P < 0.001). Among eight MCTD patients who fulfilled the diagnostic criteria for RA, only 50% had anti-CCP antibodies, and the prevalence was significantly lower than for all RA patients (p < 0.01). All eight patients who fulfilled the criteria for RA had overlap of SLE and SSc, except one patient, whereas the four anti-CCP-positive patients who did not fulfill the criteria for RA had SjS without overlapping features of SLE and SSc; moreover, most of their antibody titers were low. These results suggested that anti-CCP antibodies are associated with RA in MCTD patients, but careful diagnosis of RA is required if patients with low titers of anti-CCP antibodies lack overlapping SLE and SSc.

Abstract High-dose intravenous immunoglobulin (IVIG) therapy has been effective in treating many autoimmune and systemic inflammatory diseases. In the present prospective study, we evaluated the efficacy of IVIG for patients with polymyositis (PM) and dermatomyositis (DM) refractory to treatment with high-dose corticosteroids. PM/DM was defined as steroid-resistant when the muscle strength of a patient did not improve despite the administration of more than 50 mg prednisolone per day for more than 4 weeks. A total of 12 patients with biopsy-proven, steroid-resistant PM/DM received one infusion of polyethylene glycol-treated human IgG at a dose of 0.4 g per kg per day for five successive days. Three of the patients received a second infusion. All patients were followed for up to 3 months after the infusion. Finally, 8 patients (6 PM and 2 DM; 5 men and 3 women) aged 29-67 years (mean 48 years) were analyzed. Their clinical response was assessed by changes in (a) subjective signs, i.e., fatigue (visual analog scale, VAS), muscle pain (VAS), activities of daily living (ADL), (b) objective signs, i.e., manual muscle strength (MMT) and serum level of creatine kinase (CK). At 12 weeks after the infusion, the patients showed significant improvement in their scores of muscle strength (from a mean of 67.0 to 81.0) and their ADL scores (from a mean of 27.1 to 39.1). The mean serum CK level decreased significantly from 1287.4 to 612.6 IU/l. In addition, the mean VAS of fatigue decreased significantly from 5.5 to 1.3 cm. The physicians' assessment showed that 87.5% of patients had improved. The average reduced dose of prednisolone was 47.1 mg/day at 12 weeks after infusion in 7 patients who exhibited improvement. Adverse effects, i.e., asymptomatic myocardial infarction and increased blood urea nitrogen (BUN), were noted with two of the 15 infusion (13%). Overall, IVIG was found to be safe and effective for refractory PM and DM.

Abstract The expression of CD154 (CD40 ligand) on activated CD4+ T cells is known to be transient and tightly regulated for antigen-specific immune responses, and is increased and prolonged among patients with systemic lupus erythematosus (SLE). We investigated the regulation of CD154 expression by determining the protein and mRNA expression with PMA and ionomycin stimulation in CD4+ T cells, and confirmed their increase and prolongation in SLE T cells. Treatment with actinomycin D, a transcription inhibitor, after PMA and ionomycin stimulation was performed, and the findings revealed that the stability of CD154 mRNA increased significantly in activated SLE T cells compared with that of controls. However, alternations or abnormal sequences were not identified in the 3″ untranslated region, including AU-rich elements and CU-rich sequences, while their partial involvement in the posttranscriptional regulation of CD154 mRNA stability has been reported. With 96 h culture in vitro, the destabilization of CD154 mRNA was demonstrated, resulting in a corresponding decrease and normalization of surface expression on activated SLE T cells. We speculate that the CD154 expression on T cells from SLE patients may be increased and prolonged, with mRNA stabilization being related to a continuous stimulation in vivo.

Abstract A case of aplastic anemia with a 16-year history of systemic lupus erythematosus (SLE) is described. The diagnosis of aplastic anemia was established by bone marrow biopsy. Aplastic anemia is an extremely rare complication of SLE. The pathogenesis of aplastic anemia associated with SLE remains to be clarified.

Abstract  Human endogenous retroviruses (HERV) are known to be widely present in the human genome. Several investigations have suggested a possible etiological role of HERV in certain human disorders, including systemic lupus erythematosus (SLE). Here we review and discuss the possible role of HERV, especially HERV clone 4-1, in the onset of SLE, based on recent findings including our own data.