Kentaro Minowa

FTY720 exerts a survival advantage through the prevention of end-stage glomerular inflammation in lupus-prone BXSB mice

FTY720 is a novel investigational agent targeting the sphingosine 1-phosphate (S1P) receptors with an ability to cause immunosuppression by inducing lymphocyte sequestration in lymphoid organs. Systemic lupus erythematosus (SLE) is refractory autoimmune disease characterized by the production of a wide variety of autoantibodies and immune complex (IC)-mediated lupus nephritis. Among several SLE-prone strains of mice, BXSB is unique in terms of the disease-associated monocytosis in periphery and the reduced frequency of marginal zone B (MZ B) cells in spleen. In the present study, we examined the effect of FTY720 on lupus nephritis of BXSB mice. FTY720 treatment resulted in a marked decrease in lymphocytes, but not monocytes, in peripheral blood, and caused relocalization of marginal zone B (MZ B) cells into the follicle in the spleen. These changes did not affect the production of autoantibodies, thus IgG and C3 were deposited in glomeruli in FTY720-treated mice. Despite these IC depositions, FTY720-treated mice showed survival advantage with the improved proteinuria. Histological analysis revealed that FTY720 suppressed mesangial cell proliferation and inflammatory cell infiltration. These results suggest that FTY720 ameliorates lupus nephritis by inhibiting the end-stage inflammatory process following IC deposition in glomeruli.

Elevated serum level of circulating syndecan-1 (CD138) in active systemic lupus erythematosus

Objective: Systemic lupus erythematosus (SLE) is characterized by loss of B cell tolerance and by the presence of polyclonal B cell activation. Syndecan-1 (CD138) is expressed on plasma cells derived from B cells, and is suspected to play a role in SLE. We evaluated the level of soluble CD138 (sCD138) and cell surface expression of CD138 in patients with active SLE, and also examined correlations among the serum levels of BAFF, a proliferation-inducing ligand (APRIL), and CD138 in these patients. Methods: Peripheral blood samples were obtained from 22 SLE patients in an active disease state and 14 normal controls. The levels of serum sCD138, sBAFF, and sAPRIL were measured using ELISA, and cell surface CD138 was analyzed by flow cytometry. The levels of CD138 mRNA were analyzed by RT-PCR. Blood samples were obtained longitudinally when the patients were in an inactive disease state. Results: The levels of circulating CD138, CD138 mRNA in PBMC, and the numbers of CD20− CD38+CD138+ plasma cells were increased in patients with active SLE in comparison with normal controls. Furthermore, the serum sCD138 level in SLE patients was found to correlate with the proportion of CD20− CD38+CD138+ plasma cells. On the other hand, patients with active SLE showed a reduced level of sCD138, and this was inversely correlated with the serum level of sAPRIL. Conclusions: These results suggest that sCD138 may be applicable as a surrogate marker of disease activity, and that syndecan-1/APRIL signaling may be a potential therapeutic target for patients with active SLE.

Predictive grade of ultrasound synovitis for diagnosing rheumatoid arthritis in clinical practice and the possible difference between patients with and without seropositivity

Objective. To determine the degree of contribution and the contributing factors of ultrasound in the diagnosis of rheumatoid arthritis (RA) in daily clinical practice and the predictive differences depending on seropositivity. Methods. We included 122 patients who presented with the main complaint of finger and/or wrist joint pain but for whom no definite diagnosis was reached or treatment strategy was provided. Ultrasound was performed on at least 22 joints (both wrist joints, proximal interphalangeal joint, and metacarpophalangeal joints), and patients were followed for ≥6 months. Factors contributing to RA diagnosis were determined and compared between seropositive and seronegative RA patients. Results. RA was diagnosed in 52 of 122 patients, in whom the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria (odds ratio [OR] = 4.74, P = 0.01) and gray scale (GS) grade of 3 (OR = 3.64, P = 0.04) for ≥ 1 joint were the contributing factors. In seropositive RA, the ACR/EULAR criteria (OR = 15.53, P < 0.001) and power Doppler (PD) ≥ 2 for ≥ 1 joint (OR = 10.48, P = 0.0048) were the contributing factors. In seronegative RA, PD ≥ 1 for ≥ 1 joint contributed the most (OR = 20.00, P = 0.0044), but the ACR/EULAR criteria did not contribute to RA diagnosis (P = 0.57). Conclusion. Ultrasound findings contributed to RA diagnosis in clinical practice. The contributing factors are different in the presence or absence of seropositivity, and ultrasound complementation was particularly useful in seronegative RA patients.

Increased serum concentration of BAFF/APRIL and IgA2 subclass in patients with mixed connective tissue disease complicated by interstitial lung disease

Abstract B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are known to be crucial for B cell maturation and survival, and increased expression of these factors in various autoimmune diseases has been reported. Human B cells produce two IgA subclasses: IgA1 and IgA2, the latter being abundant in the distal intestine, saliva, colostrum and bronchial fluid. We investigated these parameters in patients with mixed connective tissue disease (MCTD) complicated by interstitial lung disease (ILD+), and compared them with those in MCTD patients without ILD (ILD−). Sixty-three MCTD patients were divided into two groups: 21 ILD+ patients and 42 ILD− patients. In each patient group we analyzed soluble BAFF/APRIL using ELISA, and IgA1 and IgA2 using double immunodiffusion. Furthermore, we analyzed BAFF–APRIL receptors, BCMA, BAFF-R and TACI, using flow cytometry. The ILD+ patients had significantly higher levels of BAFF/APRIL than the ILD− patients. There were significant correlations between BAFF/APRIL, BAFF/KL-6 and APRIL/KL-6. Although there was no significant inter-group difference in the serum IgA1 level, ILD+ patients had a significantly elevated IgA2 level in comparison with ILD− patients. Moreover, although there were no significant inter-group differences in the expression of BCMA, BAFF-R and TACI on B cells, the expression of BAFF-R was significantly decreased in the ILD+ patients. In recent years, relationships between BAFF/APRIL and IgA subclass have been reported. Our results suggest that an elevated level of BAFF/APRIL drives the maturation of B cells, subsequently leading to IgA2 class switching, and possibly to the development of ILD in patients with MCTD.

Weighting with the Lansbury articular index improves the correlation of ultrasound score with serum matrix metalloproteinase-3 level in rheumatoid arthritis patients

Abstract Objective. To determine whether weighting improves the correlation of ultrasound (US) score with serum matrix metalloproteinase-3 (MMP-3) level in rheumatoid arthritis (RA). Methods. As ultrasound examination was performed on 100 RA patients, and the severity of synovial effusion and synovial hypertrophy and the blood flow were semi-quantitatively graded from 0 to 3 by using the gray-scale (GS) and power Doppler (PD) modes. We then calculated the sums of the scores of the 28 joints of each patient in the 2 modes, that is, the GS28 and PD28 scores, as well as the respective scores weighted using the Lansbury articular index (LAI, shoulder and elbow, × 12; wrist, × 8; and knee, × 24)—Lans GS28 and Lans PD28 scores. Result. The Lans PD28 score showed a higher correlation with MMP-3 (r = 0.591; 95% confidence interval, 0.446–0.705, p < 0.0001) than the existing measures. The scores of the large joints—the knee, shoulder, and elbow—correlated well with the serum MMP-3 level. Conclusion. Weighting with the LAI can improve the correlation of US findings with serum MMP-3 level. Bidirectional approach based on both serum MMP-3 level and US scores can further improve the assessment of disease activity in RA patients.

Disease flare patterns and predictors of systemic lupus erythematosus in a monocentric cohort of 423 Japanese patients during a long-term follow-up: The JUDE study

Abstract 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.

The synovial grade corresponding to clinically involved joints and a feasible ultrasound-adjusted simple disease activity index for monitoring rheumatoid arthritis

Abstract Objectives: To determine which grade of ultrasound (US) synovitis corresponds to clinically involved joints in rheumatoid arthritis (RA) and develops a new US-adjusted composite measure. Methods: Clinical and US examinations were performed on 137 patients with RA (28 joints). Synovial effusion, hypertrophy, and blood flow were semiquantitatively graded from 0 to 3 using gray scale (GS) and power Doppler (PD) modes. We calculated US-adjusted simple disease activity index (SDAI) and assessed feasibility, and external validity by comparing with erythrocyte sedimentation rate (ESR), and modified health assessment questionnaires (MHAQ). Results: GS ≥2 and PD ≥0 corresponds to clinically swollen joints, and GS ≥2 and PD ≥1 corresponds to tender joints. The US-adjusted SDAI showed the highest correlation when US-determined swollen joints were defined as PD ≥2 with ESR, and GS ≥3 and PD ≥2 with MHAQ. A feasible US-adjusted SDAI examining only clinically involved joints still showed a higher correlation with ESR and MHAQ than SDAI. Conclusion: Our composite measure complemented by US only for clinically involved joints is feasible and reliable for monitoring disease activity.

FRI0402 Disease Flare Patterns and Predictors in a Long-Term Follow-Up of 423 Japanese SLE Patients from Monocentric Cohort Jude Study

Background Although the prognosis for systemic lupus erythematosus (SLE) has greatly improved, many patients experience the disease flare-up. Little is known about the disease flare-up patterns and predictors in a long-term follow up. Objectives The aim of this study was to clarify the outcomes and predictors for disease flare-up in a monocentric cohort of Japanese patients with SLE. Methods Among 2390 SLE patients registered in our JUDE (Juntendo University Database of Erythematosus) study, diagnosed between 1964 and 2004, 423 for whom long-term follow-up was possible between 1973 and 2012 were investigated. Disease activity patterns were defined using the SLE Disease Activity Index-2000 (SLEDAI-2K)1.Disease flare-up was defined according to the SELENA-SLEDAI flare composite2. SLE patients were included if they fulfilled the ARA3 or ACR4 criteria for SLE. Data on disease activity, severe flare-up and treatment were collected, and the initial clinical manifestations of disease flare-up were analyzed. The censoring period for analysis was May to October 2013. Results The mean follow-up duration was 25.9 years. During follow-up, 118 (27.9%) of the 423 patients experienced at least once flare-up after initial treatment with corticosteroid or corticosteroid plus immunosuppressant. More than half (58.5%) of the patients who suffered flare-up were accumulated within 5 years, irrespective of the initial therapy. Comparison of the age at onset among patients who suffered flare-up more than twice in 10 years after the initial therapy showed that teenage onset accounted for a greater proportion than patients who developed SLE in their thirties and beyond. The most common manifestation associated with flare-up was thrombocytopenia. Cluster analysis showed that renal disturbance was distinct from arthritis among manifestations of both onset and flare-up. Conclusions This long-term monocentric cohort follow-up study of 423 Japanese SLE patients revealed that 27.9% suffered flare-up after the initial therapy, irrespective of the initial treatment regimen. References Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002 29(2):288-91. Petri M, Kim MY, Kalunian KC, Grossman J, Hahn BH, Sammaritano LR, Lockshin M, Merrill JT, Belmont HM, Askanase AD, McCune WJ, Hearth-Holmes M, Dooley MA, Von Feldt J, Friedman A, Tan M, Davis J, Cronin M, Diamond B, Mackay M, Sigler L, Fillius M, Rupel A, Licciardi F, Buyon JP; OC-SELENA Trial. Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J Med. 2005 15;353(24):2550-8. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982 25(11):1271-7. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997 40(9):1725 Disclosure of Interest None declared