Min-Chan Park

Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial

BACKGROUND Clinical remission and low disease activity are essential treatment targets in patients with rheumatoid arthritis. Although moderately active rheumatoid arthritis is common, treatment effects in moderate disease have not been well studied. Additionally, optimum use of biologics needs further investigation, including the use of induction, maintenance, and withdrawal treatment strategies. The aim of the PRESERVE trial was to assess whether low disease activity would be sustained with reduced doses or withdrawal of etanercept in patients with moderately active disease. METHODS In a randomised controlled trial, patients aged between 18 and 70 years with moderately active rheumatoid arthritis (disease activity score in 28 joints [DAS28] >3.2 and ≤5.1) despite treatment with methotrexate were enrolled at 80 centres in Europe, Latin America, Asia, and Australia between March 6, 2008, and Sept 9, 2009. To be eligible, patients had to have been receiving 15-25 mg of methotrexate every week for at least 8 weeks. In an open-label period of 36 weeks, all patients were given 50 mg etanercept plus methotrexate every week. To be eligible for a subsequent double-blind period of 52 weeks, participants had to have achieved sustained low disease activity. These patients were randomly assigned (1:1:1) by an interactive voice-response system to one of three treatment groups: 50 mg etanercept plus methotrexate, 25 mg etanercept plus methotrexate, or placebo plus methotrexate. Patients were stratified in blocks of three by DAS28 response (low disease activity or remission) at week 36. Patients, investigators, data analysts, and study staff were all masked to treatment allocation. The primary endpoint was the proportion of patients with low disease activity at week 88 in the groups given 50 mg etanercept or placebo in the double-blind period. A conditional primary endpoint was the proportion of patients receiving 25 mg etanercept who achieved low disease activity. Modified intention-to-treat populations were used for analyses. This trial is registered with ClinicalTrials.gov, number NCT00565409. FINDINGS 604 (72.4%) of 834 enrolled patients were eligible for the double-blind period, of whom 202 were assigned to 50 mg etanercept plus methotrexate, 202 to 25 mg etanercept plus methotrexate, and 200 to placebo plus methotrexate. At week 88, 166 (82.6%) of 201 patients who had received at least one dose of 50 mg etanercept and one or more DAS28 evaluations had low disease activity, compared with 84 (42.6%) of 197 who had received placebo (mean difference 40.8%, 95% CI 32.5-49.1%; p<0.0001). Additionally, 159 (79.1%) of 201 patients given 25 mg etanercept had low disease activity at week 88 (mean difference from placebo 35.9%, 27.0-44.8%; p<0.0001). INTERPRETATION Conventional or reduced doses of etanercept with methotrexate in patients with moderately active rheumatoid arthritis more effectively maintain low disease activity than does methotrexate alone after withdrawal of etanercept. FUNDING Pfizer.

Clinical characteristics and outcomes of Takayasu's arteritis: analysis of 108 patients using standardized criteria for diagnosis, activity assessment, and angiographic classification

Objectives: To investigate the clinical characteristics and outcomes of Takayasus arteritis (TA) using standardized criteria for diagnosis, disease activity, and angiographic classification, and to identify the predictive factors for remission, angiographic progression, and mortality in patients with TA. Methods: One hundred and eight patients who fulfilled the 1990 American College of Rheumatology (ACR) classification criteria for TA were studied. Their clinical features, laboratory findings, angiographic findings, and clinical outcomes were evaluated retrospectively. The disease activities were assessed using the National Institutes of Health (NIH) criteria for active disease, and the angiographic types were classified using the International TA Conference in Tokyo 1994 angiographic classification. Results: Angiographic classification showed that type I was the most common, followed by types V and IV. Ninety‐one patients had active disease at diagnosis, and remission was achieved in 81.3% of them. Among those who experienced remission and those who had stable disease at diagnosis, 28.6% experienced a relapse. A low erythrocyte sedimentation rate (ESR) at diagnosis and treatment with glucocorticoid were found to be independent predictors for remission, and the stable disease activity at diagnosis was an independent predictor for the quiescence of vascular lesions on follow‐up angiography. Survival rates were 92.9% at the fifth year and 87.2% at the tenth year, and the presence of two or more complications was a risk factor for mortality. Conclusions: These findings could provide useful information on the clinical features, angiographic findings, and outcomes in TA, particularly on the assessment of patients at risk of a poor outcome.

Reactivation of hepatitis B viral infection in inactive HBsAg carriers following anti-tumor necrosis factor-α therapy.

Objective. To investigate whether anti-tumor necrosis factor-α (TNF-α) therapy can influence the reactivation of hepatitis B virus (HBV) infection in inactive HBsAg carriers. Methods. The medical records of 103 patients [59 with ankylosing spondylitis (AS), 41 with rheumatoid arthritis (RA), 2 with juvenile RA, and 1 with psoriatic arthritis] who had been treated with anti-TNF-α therapy were reviewed retrospectively. Data on seropositivity of HBV, HBV load, and serum aminotransferases prior to and after initiation of anti-TNF-α therapy were obtained. Results. Eight patients were inactive HBsAg carriers, and all of them had normal liver function and undetectable HBV load prior to anti-TNF-α therapy. Reactivation of hepatitis B occurred in 1 patient during the course of anti-TNF-α therapy. After the third infusion of infliximab 5 mg/kg at Week 6, a blood test showed that the patient had normal liver function. When the patient returned for the fourth infusion of infliximab at Week 14, a blood test showed markedly elevated aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels (457 and 1054 IU/l, respectively) and increased viral DNA by HBV polymerase chain reaction (PCR). The fourth infliximab infusion was canceled, and entecavir 0.5 mg/day was prescribed. Then AST/ALT levels began to decrease and returned to normal range after 3 months. Followup HBV PCR showed negative results. Conclusion. We found 1 HBV reactivation case among 8 inactive HBsAg carriers following anti-TNF-α therapy. This finding supports the prophylactic use of antiviral agents in HBV carriers, even if they have normal liver function or an undetectable viral load.

Osteopontin might be involved in bone remodelling rather than in inflammation in ankylosing spondylitis

OBJECTIVES To determine whether osteopontin (OPN) is increased in patients with AS and to investigate its relationship to inflammatory disease activity and bone remodelling process. METHODS This cross-sectional study included 30 patients with AS and 23 age- and sex-matched healthy controls. We assessed clinical characteristics and laboratory parameters including the ESR, CRP, lipid profiles, the Bath AS disease activity index (BASDAI) and the Bath AS radiographic index (BASRI). To evaluate bone metabolism, we tested ALP, OCN and C-telopeptide of type I collagen (CTX-I). Plasma levels of OPN, TNF-alpha and IL-6 were measured by ELISA, and mRNA expression in peripheral blood mononuclear cells (PBMCs) was performed by RT-PCR. Changes in OPN level were also evaluated in eight patients after the treatment with a TNF-alpha blocker. RESULTS Patients with AS had significantly higher plasma OPN, TNF-alpha and IL-6 levels and more mRNA expression than healthy controls. Plasma OPN levels were correlated with serum ALP, OCN and CTX-I levels, but not with ESR, CRP, lipid profiles, BASDAI or BASRI. Treatment with a TNF-alpha blocker did not alter OPN levels, although it reduced the disease activity. CONCLUSIONS Patients with AS had higher levels of OPN compared with controls. The plasma OPN level was correlated with serum ALP, OCN and CTX-I levels, but not with disease activity in AS. OPN might be involved in bone remodelling rather than in inflammation in AS.

Risk of ovarian failure and pregnancy outcome in patients with lupus nephritis treated with intravenous cyclophosphamide pulse therapy

This study was designed to investigate the risk of ovarian failure and the pregnancy outcomes in women treated with intravenous cyclophosphamide (IVCYC) pulse therapy for lupus nephritis. Sixty-seven women with proliferative lupus nephritis were studied. The clinical and laboratory data, SLEDAI and damage indices at IVCYC initiation, doses and numbers of IVCYC pulses, pregnancy and fetal outcomes were evaluated. During a follow-up of 74.4 + 20.6 months, amenorrhea occurred in 25 (37.3%) and was sustained permanently in 10 patients (14.9%). Thirteen women became pregnant with a total of 19 pregnancies. Seventeen pregnancies ended without complications and all babies were born healthy without any congenital anomalies or perinatal illnesses. Two pregnancies were terminated by induced abortion but no congenital anomaly was noted in these cases. Logistic regression analysis showed that old age, high damage index at the initiation of IVCYC pulse therapy and high cumulative dosage of IVCYC were the independent risk factors of ovarian failure, and that the presence of amenorrhea, regardless of its duration, was the risk factor of pregnancy failure. Pregnancy was possible with a favorable outcome after the withdrawal of IVCYC pulse therapy, unless amenorrhea develops.

Adiponectin mitigates the severity of arthritis in mice with collagen‐induced arthritis

Objective: Adiponectin (AD) is considered an inflammation modulator. In this study, we investigated the effect of AD on rheumatoid arthritis (RA) using a collagen‐induced arthritis (CIA) mouse model and RA synovial fibroblasts (RASF). Methods: Fifteen DBA/1 mice were divided into three groups. All mice, except the control group, were injected with type II collagen. AD was intra‐articularly injected in the left hind legs after arthritis development (the AD‐treated group). The severity of the arthritis was measured using an arthritis score and paw thickness. A histopathological assessment of joint sections was performed by haematoxylin/eosin (H&E) staining. Tumour necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐6, and matrix metalloproteinase (MMP)‐3 expression was evaluated by immunohistochemical staining in the CIA mice. Synovial tissue was obtained from four RA patients during total joint replacement. RASF cultures were established from this tissue. RASF were pretreated with AD and stimulated by TNFα or IL‐1β. TNFα, IL‐1β, IL‐6, and MMP‐3 production was measured by enzyme‐linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT‐PCR). RASF proliferation was evaluated using the MTT assay. Results: AD significantly mitigated the severity of the arthritis and histopathological findings indicative of RA in CIA mice. TNFα, IL‐1β, and MMP‐3 expression decreased, but IL‐6 expression in AD‐treated joint tissues increased. Moreover, AD reduced TNFα, IL‐1β, and MMP‐3 expression in stimulated RASF and increased IL‐6 expression in IL‐1β‐stimulated RASF. AD significantly inhibited IL‐1β‐induced RASF proliferation, despite increased IL‐6 expression. Conclusion: These data suggest that AD may play an anti‐inflammatory role in the pathophysiology of RA.

The role of 18F-fluorodeoxyglucose–positron emission tomography in the assessment of disease activity in patients with Takayasu arteritis

OBJECTIVE The assessment of disease activity in Takayasu arteritis (TA) is difficult in clinical situations because clinical symptoms and laboratory parameters do not always reflect the actual inflammation of the arterial wall. We undertook this study to comprehensively investigate the role of (18) F-fluorodeoxyglucose-positron emission tomography (FDG-PET) in the assessment of disease activity in patients with TA. METHODS We performed a retrospective chart review of 53 FDG-PET scans in 38 patients with TA. We measured (18) F-fluorodeoxyglucose ((18) F-FDG) accumulation in the vascular wall of the large vessel using semiquantitative (visual grade) and quantitative (standard uptake value intensity) analyses. Clinical disease activity was evaluated based on the National Institutes of Health criteria for active TA, and erythrocyte sedimentation rates (ESRs) and C-reactive protein (CRP) levels were measured. RESULTS At baseline, active vascular (18) F-FDG uptake (visual grade ≥2) was observed in 18 of 24 patients with active disease and in 5 of 14 patients with inactive disease. There was a significant association between clinical disease activity and disease activity judged by FDG-PET (P = 0.008). Visual grade, standard uptake value intensity, and the number of vascular lesions with active (18) F-FDG uptake were significantly higher in patients with active disease and correlated well with the ESR and CRP levels. In 15 followup FDG-PET scans, the changes in visual grade, areas of active vascular (18) F-FDG uptake, and standard uptake value intensity reflected changes in clinical disease activity. CONCLUSION (18) F-FDG uptake was associated with clinical disease activity and markers of inflammation, and FDG-PET reflected changes in clinical disease activity in patients with TA. FDG-PET may be a useful tool for aiding in the assessment of disease activity in patients with TA.

Serum leptin levels correlate with interleukin‐6 levels and disease activity in patients with ankylosing spondylitis

Objective: To determine whether serum leptin levels are elevated in men with ankylosing spondylitis (AS) and whether the levels correlate with serum cytokine profiles and disease activity of AS. Methods: Forty‐two male patients with newly diagnosed AS were enrolled. Their Bath AS Disease Activity Index (BASDAI), body mass index (BMI), and acute phase reactants, such as erythrocyte sedimentation rate (ESR) and C‐reactive protein (CRP) levels, were assessed. Serum leptin levels were determined using radioimmunoassay (RIA) and serum cytokine profiles, including tumour necrosis factor (TNF)‐α, interleukin (IL)‐6, and interferon (IFN)‐γ, were determined using enzyme‐linked immunosorbent assay (ELISA). These results were compared with those from 42 age‐matched healthy men. After a follow‐up period of 31.0±20.1 months, clinical and biochemical variables were reassessed in the men with AS. Results: At baseline, patients with AS had significantly elevated serum levels of leptin, leptin adjusted for BMI (leptin/BMI), TNFα, and IL‐6, but not IFN‐γ, as compared to the controls. Serum leptin/BMI levels correlated well with IL‐6 levels, and both leptin/BMI and IL‐6 levels correlated well with BASDAI and CRP levels in patients with AS. The changes in leptin/BMI and IL‐6 levels between the baseline and follow‐up measurements correlated well with one another (p<0.05) and both correlated well with the changes in BASDAI (p<0.05). Conclusion: Serum leptin/BMI levels were increased and significantly associated with IL‐6 levels and disease activity in men with AS, suggesting a possible role for leptin in the inflammatory reactions of AS.

Gallic acid, a natural polyphenolic acid, induces apoptosis and inhibits proinflammatory gene expressions in rheumatoid arthritis fibroblast-like synoviocytes

OBJECTIVES To investigate whether gallic acid (3, 4, 5-trihydroxybenzoic acid), a natural polyphenolic acid found in gall nuts, sumac, oak bark, tea leaves, grapes and wine, has pro-apoptotic and anti-inflammatory effects on fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). METHODS Viability of RA FLS was assessed using a MTT assay after gallic acid treatment. Apoptosis was assessed by TUNEL assay and caspase-3 activity was determined by a colorimetric assay. The levels of apoptosis-related proteins including Bcl-2, p-Akt, p53, and Bax were determined using western blot analyses, and the mRNA expressions of various pro-inflammatory mediators were measured using quantitative real-time PCR. RESULTS Cell viability of RA FLS was significantly decreased by treatment with 10 or more μM of gallic acid. Gallic acid treatment at the concentrations that do not affect cell viability (0.1 and 1 μM) induced cellular apoptosis of RA FLS. Treatment with 0.1 and 1 μM of gallic acid also resulted in a significant increase in caspase-3 activity and regulated the productions of Bcl-2, Bax, p53 and pAkt. The mRNA expression levels of pro-inflammatory cytokines (IL-1β, IL-6), chemokines (CCL-2/MCP-1, CCL-7/MCP-3), cyclooxygenase-2, and matrix metalloproteinase-9 from RA FLS were suppressed by the gallic acid treatment in dose-dependent manners. CONCLUSION Gallic acid treatment was found to induce apoptosis of RA FLS through regulation of apoptosis-related protein expressions and to reduce the expression of pro-inflammatory genes in RA FLS. These data suggest that pro-apoptotic and anti-inflammatory activities of gallic acid may be used as a possible therapeutic option for RA.

Liver X receptor agonist prevents the evolution of collagen-induced arthritis in mice

OBJECTIVE Liver X receptors (LXRs) have been characterized as regulators of macrophage inflammatory pathways. Synthetic LXR agonists inhibit the macrophage response to bacterial pathogens and antagonize the induction of a number of pro-inflammatory genes. The aim of this study was to investigate the preventive effects of synthetic LXR agonist, GW3965, treatment on the evolution of arthritis and inflammatory response in a murine CIA model. METHODS Intradermal injection of bovine type II CIA in DBA/1 mice. Along with the induction of CIA, mice were treated with oral GW3965 (0.1, 0.3 or 1.0 mg/kg/day) or vehicle from Day 1 to Day 40. Clinical assessment for arthritis scores and histopathological assessment of joint sections were performed. The expression of inflammatory mediators was evaluated by immunohistochemical staining. Serum pro-inflammatory cytokine levels were determined using ELISA. RESULTS The CIA incidence was 100% on Day 27 and the severity progressed until Day 35 with histological features of cartilage erosion in vehicle-treated mice. GW3965 treatment significantly reduced the arthritis incidence and attenuated the clinical and histological severity, compared with vehicle-treated mice. GW3965 treatment also significantly reduced inflammatory mediator production in joint sections and serum pro-inflammatory cytokine levels in a dose-dependent manner. CONCLUSIONS These results indicate that activation of LXRs suppresses the onset of CIA and reduces inflammation and joint destruction in CIA mice. The data could suggest that LXR treatment is an effective prophylactic approach to suppress the evolution of synovitis and resultant joint destruction observed in RA.