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Yuji Nozaki, Yasuaki Nagare, Chisato Ashida, Daisuke Tomita, Akinori Okada, Asuka Inoue, Koji Kinoshita, Masanori Funauchi, Itaru Matsumura Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan Purpose: We evaluated the clinical responses and radiographic outcomes of 90 patients with rheumatoid arthritis (RA) undergoing continuous or dose-adjusted infliximab treatment over 104weeks.Patients and methods: Patients received 3mg/kg infliximab continuously (the contin group; n=50), or the dose escalation and de-escalation of infliximab (3, 6, and 10mg/kg) from week 14 (the adjusted group; n=40) based on the patient’s Disease Activity Score in 28 joints (DAS28). The retention rate, clinical response, and radiographic assessment were determined at week 104.Results: The contin and adjusted groups’ retention rates at week 104 were 56.8 and 66.7%, and the groups’ low disease activity in the DAS28 was 39.1 and 66.7%, respectively. Remission based on the DAS28 and the American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) Boolean-based criteria was significantly increased in the adjusted group. In the radiographic assessment, there was also a significant reduction in the mean changes in total Sharp score. The cumulative rates of any adverse effects showed no significant difference between the groups.Conclusion: In an assessment of adequate DAS28 results, the RA patients who did not respond to the initial dose of infliximab showed improved clinical responses and radiographic assessment after a dose adjustment of infliximab, without an increased risk of serious adverse events. Keywords: rheumatoid arthritis, DAS28, infliximab, mTSS, dose adjustment, REVIVE&nbsp

Ultrasound (US) is more sensitive and reliable than a clinical examination, and is better correlated with the disease activity in rheumatoid arthritis (RA). We conducted the present study to assess the value of US as a screening tool to predict therapeutic responses in RA patients treated with anti-tumor necrosis factor (TNF) drugs.We retrospectively analyzed the cases of 86 consecutive RA patients who were classified by their DAS28-CRP scores at the 54th week. We assessed two US findings (i.e., the synovial hypertrophy index [SHI] and synovial vascularization) by grey-scale imaging and the Doppler synovitis index (DSI).When we applied cut-off points determined by a ROC curve analysis, patients with a lower total SHI (≤34) or DSI (≤7) at baseline were significantly more likely to reach remission (44 patients, 51.2%) as shown by the DAS28-CRP at 54 weeks. On the basis of these cut-off values, we dichotomized all variables and performed a logistic regression analysis using the 54-weeks data; the only predictive factors of remission with anti-TNF therapy were the patients' baseline DAS28-CRP ≤2.7 as low disease activity/remission, and the SHI.An ultrasound assessment would be a highly useful predictor of the achievement of clinical remission.

The proinflammatory cytokine interleukin (IL)-18 is an important mediator of the organ failure induced by endotoxemia. IL-18 (known as an interferon-gamma (IFN-γ) inducing factor), and other inflammatory cytokines have important roles in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). We investigated the effect of inflammatory cytokines and Toll-like receptor 4 (TLR4) expression, an event that is accompanied by an influx of monocytes, including CD4⁺ T cells and antigen-presenting cells (APCs) in IL-18Rα knockout (KO) mice and wild-type (WT) mice after LPS injection. In the acute advanced phase, the IL-18Rα KO mice showed a higher survival rate and a suppressed increase of blood urea nitrogen, increased levels of proinflammatory cytokines such as IFN-γ and IL-18, the infiltration of CD4⁺ T cells and the expression of kidney injury molecule-1 as an AKI marker. In that phase, the renal mRNA expression of the M1 macrophage phenotype and C-C chemokine receptor type 7 as the maturation marker of dendritic cells (DCs) was also significantly decreased in the IL-18Rα KO mice, although there were small numbers of F4/80⁺ cells and DCs in the kidney. Conversely, there were no significant differences in the expressions of mRNA and protein TLR4 after LPS injection between the WT and IL-18Rα KO groups. Our results demonstrated that the IL-18Rα-mediated signaling pathway plays critical roles in CD4⁺ T cells and APCs and responded more quickly to IFN-γ and IL-18 than TLR4 stimulation in the pathogenesis of LPS-induced AKI.

Interleukin (IL)-18 is produced by leukocytes and renal parenchymal cells (tubular epithelial cells, podocytes, and mesangial cells). The IL-18 receptor (IL-18R) is expressed on these cells in cisplatin-induced acute kidney injury, but the role of IL-18R is unknown. To help define this, we compared IL-18Rα knockout with wild-type mice in cisplatin-induced acute kidney injury and found deteriorated kidney function, tubular damage, increased accumulation of leukocytes (CD4 + and CD8 + T-cells, macrophages, and neutrophils), upregulation of early kidney injury biomarkers (serum TNF, urinary IL-18, and KIM-1 levels), and increased expression of pro-inflammatory molecules downstream of IL-18. In vitro , leukocytes from the spleen and kidneys of the knockout mice produced greater amounts of pro-inflammatory cytokines upon stimulation with concanavalin A compared to that in wild-type mice. Levels of the suppressor of cytokine signaling 1 and 3 (negative regulators of cytokine signaling) were reduced in the spleen and kidneys of IL-18Rα-deficient compared to wild-type mice. Adoptive transfer of wild-type splenocytes by IL-18Rα-deficient mice led to decreased cisplatin nephrotoxicity compared to control IL-18Rα-deficient mice. In contrast, anti-IL-18Rα and anti-IL-18Rβ antibody treatment tended to increase cisplatin nephrotoxicity in wild-type mice. Thus, signaling through IL-18Rα activates both inflammation-suppressing and pro-injury pathways in cisplatin-induced acute kidney injury.

CHOP (cyclophosphamide, adriamycin, vincristine, and prednisolone) plus rituximab is a standard chemotherapy used to treat patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL). However, among elderly patients, this regimen has not been completely satisfactory in its efficacy and safety. We report our clinical experience in 8 collaborative institutions to determine if the VNCOP-B (etoposide, mitoxantrone, cyclophosphamide, vincristine, prednisolone, and bleomycin) combination therapy plus rituximab was effective and safe to treat elderly patients with aggressive B-NHL. Between September 2004 and December 2007, 23 previously untreated patients, median age 73 years, 50.0% classified as high-intermediate/high-risk on the standard International Prognostic Index (IPI) entered this trial. Complete remission rate was 90.5%, with a 100% overall response rate (RR) at the end of induction therapy; overall survival (OS) rate at 3 years was 76.4% (median follow-up 744 days), with an 82.6% 3-year progression-free survival (PFS) rate (median follow-up 744 days). The most common grade 3/4 toxicities were hematologic, including neutropenia in 75.0% of the patients despite prophylactic administration of granulocyte colony-stimulating factor (G-CSF), febrile neutropenia in 30.0%, respectively. There was no treatment-related mortality (TRM). Rituximab not only combined with chemotherapy but also given sequentially improved survival. R-VNCOP-B could be another option for elderly patients who are not considered to tolerate in receiving R-CHOP.

MRL-Faslpr mice spontaneously develop a systemic autoimmune disease resembling human systemic lupus erythematosus. The glomerulonephritis in MRL-Faslpr mice is mediated by autoantibodies and autoreactive lymphocytes. To investigate the effect of combination therapy by angiotensin-converting enzyme inhibitor (ACEI) and hydroxymethylglutaryl-coenzyme A reductase inhibitor (statin) for lupus nephritis, we treated MRL-Faslpr mice with imidapril, pravastatin or both agents. Compared with other groups, the mice treated by combination therapy survived longer and showed a significant reduction in proteinuria, renal pathology, including glomerular IgG deposit, and serum anti-DNA Ab. Furthermore, monocyte chemoattractant protein-1 (MCP-1) in the kidney was reduced significantly in the combination therapy group, compared with that in the control group. We conclude that combination therapy with ACEI and statin for MRL-Faslpr mice significantly alleviates autoimmune renal disorder and prolongs survival. These results suggest that combination therapy by ACEI and statin may represent a new approach to the treatment of patients with lupus.

To predict the response of patients with rheumatoid arthritis (RA) to infliximab, patient profile and laboratory findings were compared to determine whether there was any association with the clinical course of the disease, and the clinical significance of serum rheumatoid factor (RF) in the response to this treatment was considered. Sixty-two RA patients were treated with infliximab, 87.9% of whom were positive for RF. At baseline and 12 months after the start of treatment, RF titers were significantly lower in the low-CRP group (CRP at 12 months0.3 mg/dl) compared with that in the high-CRP group (CRP at 12 months1.5 mg/dl). Furthermore, at baseline and 12 months, RF titers were significantly lower in the good-CRP-response group (DeltaCRPor=1.5 mg/d) compared with the poor-CRP-response group (DeltaCRPor=0.3 mg/d). The percent changes in RF and CRP from baseline were correlated throughout the clinical course. The duration of disease in good-CRP-response group was shorter than that in poor-CRP-response group significantly. The rate of positivity for HLA-DR4 in good response group tends to be higher than that in poor-CRP-response group. We concluded that several factors, including disease duration, positivity for HLA-DR4, and the serum RF titer at baseline, might predict the patient response to infliximab.

22-year old woman who was previously diagnosed as having juvenile idiopathic arthritis (JIA) was treated with anti-TNF-α agents. Her disease activity was assessed as Stage IV and Class III by Steinbrocker's classification and resistant to steroids and methotrexate. Initially clinical findings responded well to infliximab (IFX), but polyarthritis recurred 15 months after the start of the treatment, and IFX was switched to etanercept (ETN) with good response. On the other hand, effects on the osteoarticular lesions were continuously observed through the period of the treatment with these two biologics. It was thought very rare that weight-bearing joint like the hip joint was restored as was seen in this case, while its mechanism is unknown. Because mechanism for inhibition of inflammation or joint destruction might be independent, we should investigate further the relationship between inflammation and joint destruction in the future.

Effects of a dual endothelin receptor antagonist, bosentan on peripheral circulatioin and skin lesions as well as pulmonary arterial hypertension (PAH) were investigated in Japanese patients with connective tissue diseases (CTD). Fifteen patients with PAH associated with CTD [systemic sclerosis (SSc) 13, mixed connective tissue disease (MCTD) 2] were treated with bosentan for 40-96 weeks, and changes of exercise capacity (6-min walk distance and Borg's dyspnea scale), cardio-pulmonary hemodynamics (right ventricular pressure, specific activity scale and cardiac index), Raynaud's phenomenon, digital ulcers and dermal sclerosis were observed. Bosentan improved exercise capacity, had a positive effect on hemodynamic parameters, and was well tolerated as previously reported. After a median 8 weeks of treatment, 13 out of 15 patients had improved Raynaud's phenomenon. Digital ulcers also improved after a median 12 weeks' treatment in all of 8 patients. Modified Rodnan total skin score decreased from 21.0 +/- 5.9 to 11.5 +/- 3.9 in diffuse cutaneous SSc and from 17.0 +/- 6.5 to 9.5 +/- 4.5 in limited cutaneous SSc after 24 months' treatment, reaching significance after 6 months in both groups. These data suggest that bosentan is effective for both PAH and peripheral vascular diseases in Japanese patients with CTD. The pathological background to the improvement in dermal sclerosis observed in this study should be further investigated.

A 22-year old female suffering from recurrent oral ulcers, genital ulcers, erythema nodosum, and folliculitis, was diagnosed as having Behcet's disease (BD). She has also hypopigmentation of skin and hair, and optic changes associated with albinism including hypopigmentation of the retina, nystagmus, strabismus, and reduced visual acuity. In this report, we discuss the possibility of precipitating factor in BD that the hypersensitivity, mental stress, and drug resistance which is caused by albinism.

Background: Retinoic acids, a group of natural and synthetic vitamin A derivatives, have potent anti-proliferative, anti-inflammatory and anti-fibrotic properties. We investigated the therapeutic effect of all-trans-retinoic acid (ATRA) on unilateral ureteral obstruction (UUO) model mice. Methods: First, to evaluate the prophylactic effect, we administered 0.5 mg of ATRA for 3 days before UUO (UUO ATRA). Then, to evaluate the therapeutic effects, we administered 0.5 mg of ATRA 3 days after UUO (Day3 ATRA). We compared the histological changes and immunostaining of macrophages, α-smooth muscle actin (α-SMA) and collagen I, and mRNA expression of monocyte chemotactic protein-1 (MCP-1), transforming growth factor (TGF)-β1 and TGF-β R-II by RT-PCR 7 days after UUO. Results: In the UUO ATRA and Day3 ATRA groups, we observed a significant improvement in histological and immunological findings, including macrophage infiltration and improved expression of MCP-1, TGF-β1, α-SMA and collagen I compared with the UUO Day7 group. Conclusion: ATRA treatment is not only an effective prophylactic strategy, but also a therapeutic strategy for the treatment of progressive renal fibrosis in diseased kidneys.

We report a case of rheumatoid arthritis (RA) complicated by myelodysplastic syndrome (MDS) successfully treated by tacrolimus. A 57-year-old woman had persistent pain and swelling in bilateral wrist and knee joints, in addition to severe anemia and leukopenia. She was diagnosed with MDS and RA based on the results of bone marrow aspiration and the criteria of RA. Combination therapy with tacrolimus (1.5 mg day(-1)) and prednisolone (10 mg day(-1)) improved her bicytopenia and polyarthralgia.

[Background and Objectives] CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) plus rituximab is a standard chemotherapy used to treat patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL). However, among elderly patients, this regimen has not been completely satisfactory in its efficacy and safety because of agespecific comorbidity, increased toxicities of chemo-agents, and the more aggressive aspect of the lymphoma itself. Zinzani reported that a combination therapy including etoposide, mitoxantrone, cyclophosphamide, vincristine, prednisolone, and bleomycin (VNCOP-B) was effective in elderly aggressive NHL patients (Blood1999;94:33–38). We conducted a phase II multicenter study in 8 collaborative institutions to determine if VNCOP-B plus rituximab was effective and safe to treat elderly patients with aggressive B-NHL. The primary endpoint was to detect overall survival (OS). The second endpoint was to detect the response rate (RR) and progression-free survival (PFS). [Patients and Treatment] Eligible patients were those aged over 60 years, with aggressive B-NHL documented as CD20 surface antigen positive, performance status (PS) 0 to 2, clinical stage over II or I with a bulky disease, measurable lesions, no prior chemotherapy nor radiation, no severe complications, no major organ dysfunction, no other active cancer, not a HBV carrier, no central nervous system involvement with lymphoma, and who gave the required written informed consent. VNCOP-B plus rituximab was administered as an induction therapy. This protocol was completed in 8 weeks and consisted of weekly doses of chemotherapy combined with rituximab every two weeks. During the 8 weeks of therapy, granulocyte colony-stimulating factor (G-CSF) was administered on a prophylactic base. Rituximab was administered weekly four times a month as a sequential therapy, following one month after the end of the induction therapy. [Results] Between September 2004 and December 2007, 23 patients, median age 73 years, 50.0% classified as high-intermediate/high risk on the age-adjusted International Prognostic Index (IPI), entered this trial and 21 were evaluated for feasibility, toxicity, and efficacy. Twenty-two patients (95.2%) were diagnosed with diffuse large B-cell lymphoma and one (4.8%) with mediastinal large B-cell lymphoma. The nineteen patients (90.5%) completed the induction therapy and all these then received a sequential rituximab therapy. Complete remission rate was 90.5%, with a 100% overall RR at the end of induction therapy; OS rate at 3 years was 76.4% (median follow-up 744days); with an 82.6% 3-year PFS rate (median follow-up 744days). Average Relative dose intensity (RDI) in MIT was 0.61, no significant difference in survival was found regarding RDI. Although IgG level decreased during the induction therapy, it recovered to the prior level after sequential rituximab (IgG means±standard error: pre-treatment 1355.2±146.4mg/dl, post-induction therapy 785.3±107.0mg/dl, post-sequential rituximab 1010.4±60.2mg/dl). According to the IPI, there was a trend suggesting a lower probability of OS and PFS in high/high-intermediate risk than in low/low-intermediate risk cases (3-year OS: 67.5% versus 100.0%, P=0.51; 3-year PFS: 66.7% versus 100.0%, P NA). The most common grade 3/4 toxicities were hematologic, including neutropenia in 75.0% of the 21 patients despite prophylactic administration of G-CSF, febrile neutropenia in 30.0%, and thrombocytopenia in 10.0%, respectively. Regarding non-hematologic grade 3/4 toxicities, hepatitis occurred in one patient (5.0%) from HCV reactivation, intestinal perforation involving the lymphoma in one patient (5.0%). There was no treatment-related mortality. We had conducted a phase II study of VNCOP-B therapy in 16 elderly patients with aggressive B-NHL (Gan To Kagaku Ryoho2005;32:39–44, in Japanese). Against this historical comparison, the present protocol seemed better in PFS than that without rituximab (3-year PFS: 82.6% versus 56.0%, P=0.11), although OS was almost the same (3-year OS: 76.4% versus 73.4%, P=0.22). [Conclusion] Although our enrolled patients were quite elderly with a median age of 73 years, and half of them had a poor prognosis index, VNCOP-B combined with rituximab was well tolerated and showed promise.