Comparison of effectiveness of methotrexate in patients with late-onset versus younger-onset rheumatoid arthritis: Real-world data from an inception cohort in Japan (NICER-J).

OBJECTIVE: To compare the effectiveness of methotrexate (MTX) as initial therapy in patients with late-onset and younger-onset rheumatoid arthritis (LORA and YORA). METHODS: Of 114 patients with YORA and 96 patients with LORA, defined as RA occurring at ≥65 years of age, enrolled in a multicentre RA inception cohort study, 71 and 66 patients who had been followed up to 6 months after starting MTX treatment were included in this study. RESULTS: Proportions of patients on MTX treatment at 6 months were 96% and 92% in the YORA and LORA groups, respectively. Despite lower doses of MTX in the LORA group compared with the YORA group, no significant difference was observed in clinical disease activity index scores between the two groups throughout the follow-up period. The proportion of patients in clinical disease activity index remission at 6 months was 35% in both groups. Logistic regression analysis revealed that knee joint involvement and high Health Assessment Questionnaire-Disability Index were significant negative predictors of achieving clinical disease activity index remission at 6 months in the LORA group. CONCLUSION: Observations up to 6 months revealed that the effectiveness of MTX administered based on rheumatologist discretion in patients with LORA is comparable to that in patients with YORA in clinical settings.

Choice of and response to treatment in patients with early-diagnosed rheumatoid arthritis: Real-world data from an inception cohort in Japan (NICER-J).

OBJECTIVE: Various guidelines recommend that patients with early rheumatoid arthritis (RA) try to achieve clinical remission within 6 months, and early therapeutic intervention is important to this end. This study aimed to investigate short-term treatment outcomes of patients with early-diagnosed RA in clinical practice and to examine predictive factors for achieving remission. METHODS: Of the 210 patients enrolled in the multicenter RA inception cohort, 172 patients who were followed up to 6 months after treatment initiation (baseline) were included. Logistic regression analysis was used to examine the impact of baseline characteristics on achievement of Boolean remission at 6 months. RESULTS: Participants (mean age, 62 years) initiated treatment after a mean of 19 days from RA diagnosis. At baseline and 3 and 6 months after treatment initiation, proportions of patients using methotrexate (MTX) were 87.8%, 89.0%, and 88.3%, respectively, and rates of Boolean remission were 1.8%, 27.8%, and 34.5%, respectively. Multivariate analysis revealed that physician global assessment (PhGA) (Odds ratio (OR): 0.84, 95% confidence interval (CI): 0.71-0.99) and glucocorticoid use (OR: 0.26, 95% CI: 0.10-0.65) at baseline were independent factors that predicted Boolean remission at 6 months. CONCLUSION: After a diagnosis of RA, satisfactory therapeutic effects were achieved at 6 months after the initiation of treatment centered on MTX according to the treat to target strategy. PhGA and glucocorticoid use at treatment initiation are useful for predicting the achievement of treatment goals.

Relationships between concomitant biologic DMARDs and prednisolone administration and blood tacrolimus exposure or serum CYP3A4/5-related markers in rheumatoid arthritis patients.

BACKGROUND: This study aimed to evaluate the relationships between concomitant biologic disease-modifying anti-rheumatic drugs (DMARDs) and prednisolone administration and blood tacrolimus exposure or serum CYP3A4/5-related markers in rheumatoid arthritis (RA) patients without severe disease activity. METHODS: Forty-six RA patients treated with oral tacrolimus once daily for maintenance of clinical remission to moderate disease activity were enrolled. The blood concentrations of tacrolimus and its major metabolite were determined at 12 h after the evening dosing. Blood samples for determination of serum markers including 4ß-hydroxycholesterol (4ß-OHC), 25-hydroxyvitamin D (25-OHD) and interleukin-6 (IL-6), and CYP3A5 genotype were collected. RESULTS: Most enrolled patients had RA with clinical remission to mild disease activity. Concomitant tocilizumab or low-dose prednisolone administration did not alter the blood tacrolimus exposure. Serum 4ß-OHC level was lower in tocilizumab co-treated patients than in the biologic DMARD non-treated patients. The blood tacrolimus concentration was inversely correlated with the serum level of 25-OHD, but not 4ß-OHC and IL-6. The serum level of 4ß-OHC was positively associated with that of 25-OHD. No correlations were observed between the serum levels of CYP3A4/5 activity markers and IL-6. The patients with the homozygous CYP3A5*3 had the higher blood tacrolimus concentration, while CYP3A5*3 allele was not associated with the serum levels of 4ß-OHC and 25-OHD. CONCLUSIONS: Concomitant use of tocilizumab or low-dose prednisolone had no effect on the pharmacokinetics of tacrolimus, while tocilizumab lowered serum 4ß-OHC. Blood tacrolimus exposure was negatively associated with serum 25-OHD in RA patients with clinical remission to moderate disease activity.

Involvement of IL-33 in the pathogenesis of rheumatoid arthritis: the effect of etanercept on the serum levels of IL-33.

To investigate the role of interleukin (IL)-33 in rheumatoid arthritis (RA) patients, we measured the serum levels of IL-33 in RA patients before and after the administration of etanercept. Twenty-four patients with RA were treated with etanercept. Clinical and laboratory examinations, including serum levels of C-reactive protein (CRP) and hemoglobin (Hb); white blood cell (WBC) and red blood cell (RBC) counts; and the Disease Activity Score of 28 joints including CRP (DAS28-CRP), were performed at the baseline and at 3 and 6 months after the initial treatment with etanercept. The mean serum IL-33 levels had decreased significantly at 3 and 6 months after the initial treatment with etanercept. Serum IL-33 levels showed a significant correlation with the number of tender joints, CRP, DAS28-CRP, and the WBC count, and an inverse correlation with the RBC count and Hb level. These findings indicated that the decrease of serum IL-33 levels was a novel function of etanercept, shown for the first time in this study. Measurement of serum levels of IL-33 may become a useful control marker for RA treatment.

Arthroscopic treatment of a medial meniscal cyst using a posterior trans-septal approach: a case report.

Arthroscopic partial menisectomy followed by cyst decompression is currently recommended for treatment of a meniscal cyst. However, it is doubtful whether partial menisectomy should be performed on cysts communicating with the joint in cases without a meniscal tear on its surface since meniscal function will be sacrificed. In this report, a meniscal cyst arising from the posterior horn of the medial meniscus without meniscal tear on its surface was resected using an arthroscopic posterior trans-septal approach. A 59 year-old male presented to our hospital with popliteal pain when standing up after squatting down. Magnetic resonance imaging revealed a multilobulated meniscal cyst arising from the posterior horn of the medial meniscus extending to the posterior septum with a grade 2 meniscal tear by Mink's classification. The medial meniscus was intact on the surface on arthroscopic examination. The meniscal cyst and posterior septum were successfully resected using a posterior trans-septal approach without harming the meniscus. This is the first report on a meniscal cyst being resected using an arthroscopic posterior trans-septal approach with a 9-month follow-up period.

Comparison between resection arthroplasty alone and resection arthroplasty with arthrodesis of the first MTP joint for rheumatoid forefoot deformities.

It has been reported that nearly 90% of patients with rheumatoid arthritis (RA) have problems with their feet. Several methods of treating hallux valgus deformity in RA have previously been reported, including arthrodesis and joint resection, and good results have been observed with surgical procedures. In this report, we compare the clinical and radiological outcomes of resection arthroplasty alone (the first method) and resection arthroplasty with arthrodesis of the first MTP joint (the second method) for the treatment of forefoot deformities of RA patients. On clinical assessment, the American Orthopaedic Foot and Ankle Society (AOFAS) scale score significantly improved in both methods; however, the second method gave better results than the first method in relation to the footwear and alignment components. On radiographic assessment, in the first method there were no significant changes in the valgus angle (H-V angle) and the fifth metatarsal bone (M1/5) angle between preoperation and last follow-up. In contrast, these angles were decreased in the second method. One of the most important issues in the treatment of forefoot deformities in RA patients is to correct splaying foot deformity. We believe that the second method, which can correct splaying foot deformity, is currently the most reliable treatment method.

Etanercept reduces the oxidative stress marker levels in patients with rheumatoid arthritis.

This study was performed to evaluate the effects of the TNF-alpha inhibitor etanercept on oxidation stress markers representing DNA damage, lipid peroxidation, and protein glycosylation. Twenty-two rheumatoid arthritis (RA) patients underwent etanercept treatment. The levels of serum total, urinary total, and urinary free pentosidine, which is an advanced glycation end-product (AGE), of urinary N(epsilon)-hexanoyl lysine (N(epsilon)-HEL), and of 8-hydroxy-deoxy guanosine (8-OHdG) were measured at baseline and at 3 and 6 months after the initial treatment with etanercept. Serum total and urinary total pentosidine levels were reduced at 6 months after the initial treatment with etanercept, and urinary free pentosidine levels were reduced at 3 and 6 months. Urinary N(epsilon)-HEL levels were also reduced at 3 and 6 months, and urinary 8-OHdG levels were reduced at 6 months. Serum total and urinary total pentosidine levels in RA patients correlated with the number of swelling joints and tender joints, and urinary total pentosidine levels correlated with the Disease Activity Score using 28 joints (DAS28). This study demonstrated that etanercept acts as a regulator against pentosidine formation, oxidative DNA damage, and lipid peroxidation in RA patients.

Photodynamic therapy using talaporfin sodium for synovial membrane from rheumatoid arthritis patients and collagen-induced arthritis rats.

We investigated the efficacy of photodynamic therapy (PDT) using talaporfin sodium as a new method of synovectomy for rheumatoid arthritis (RA). We first used RA synovial membrane (RASM) for in vitro and in vivo study. The RASM was obtained from patients with RA during total knee replacement. In the in vitro study, RA fibroblast-like synoviocytes (RASCs) obtained from the RASM were examined by fluorescent microscopy to measure the intracellular localization of talaporfin sodium. The cells were then subjected to PDT, and their viability was examined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-tetrazolium inner salt assay. In the in vivo assay, RASM was obtained as described above, grafted onto severe combined immunodeficiency (SCID) mice and subjected to PDT. The damaged area of RASM was evaluated histologically at 1 day after PDT. Next, we performed a separate experiment using rats with collagen-induced arthritis (CIA). After intra-articular injection of talaporfin sodium, the concentration of talaporfin sodium accumulated in the CIA synovial membrane (CIASM) was compared with that in cartilage, periarticular muscle, and skin. We then performed PDT with intra-articular injection of talaporfin sodium and intra-articular irradiation. The damaged area of the CIASM was measured at 1 day after the PDT, and the articular histological and radiological changes of the ankle were observed at 56 days after the PDT. In RASM, talaporfin sodium accumulated in lysosomes in vitro, and the phototoxicity to RASCs in vitro and to RASM grafted onto SCID mice in vivo depended on the concentration of talaporfin sodium and the laser energy. In CIA rats, there was a greater accumulation of talaporfin sodium in the CIASM than in normal tissue. The CIASM was selectively damaged at 1 day after the PDT, and the bone and cartilage destruction were ameliorated at 56 days after the PDT. In conclusion, PDT using talaporfin sodium might be a new method for synovectomy in patients with RA.

Methotrexate reduces the levels of pentosidine and 8-hydroxy-deoxy guanosine in patients with rheumatoid arthritis.

This study was performed to investigate whether methotrexate (MTX) affects the levels of oxidative stress markers, including pentosidine one of the glycation end products (AGEs) or 8-hydroxy-deoxy guanosine (8-OHdG). These stress markers represent DNA damage; 19 rheumatoid arthritis (RA) patients underwent MTX treatment. The levels of serum total, urinary total, urinary-free pentosidine and also urinary 8-OHdG, as well as clinical parameters, including disease activity scores for 28 joints (DAS28) were measured at baseline and at 3 and 6 months after the initial treatment with MTX. After the initial treatment with MTX, serum total and urinary total pentosidine levels were reduced at 6 months, and urinary-free pentosidine levels were reduced at 3 and 6 months. Urinary 8-OHdG levels also were significantly reduced at 6 months after the initial treatment with MTX. This study demonstrated that MTX plays a role as a regulator against pentosidine formation and oxidative DNA damage in RA patients.

Etanercept reduces the serum levels of interleukin-23 and macrophage inflammatory protein-3 alpha in patients with rheumatoid arthritis.

The purpose of this study was to analyze the effect of the soluble TNF-alpha receptor etanercept on the serum levels of IL-16, IL-17, IL-23, and macrophage inflammatory protein-3alpha (MIP-3alpha) in rheumatoid arthritis (RA) patients. Twenty-two patients with RA were administered etanercept once or twice a week for more than 6 months, and we evaluated clinical and laboratory parameters and serum levels of IL-16, IL-17, IL-23, and MIP-3alpha at the baseline and at 3 and 6 months. Additionally, the production of IL-23 and MIP-3alpha of cultured synovial cells stimulated with TNF-alpha from RA patients was determined by ELISA. We also used ELISA kits to determine synovial fluid (SF) levels of IL-17, IL-23, and MIP-3alpha in patients with RA, osteoarthritis (OA), pseudogouty arthritis (PGA), and gouty arthritis (GA). A significant decrease in serum levels of IL-23 and MIP-3alpha was observed at 3 and 6 months after initial treatment of etanercept. TNF-alpha induced MIP-3alpha but not IL-23 production in cultured synovial cells from RA patients. SF levels of IL-17, IL-23, and MIP-3alpha in RA patients showed significantly higher levels than those of OA, PGA, and GA patients. This study demonstrated that the reduction of IL-23 and MIP-3alpha production in RA patients was a newly determined function of etanercept.

The effect of infliximab on chemokines in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by infiltration of lymphocytes, macrophages, and plasma cells into synovial membrane. The chemokines family promotes chemotactic activity in various leukocyte cell types. Chemokines thus play an essential role in the pathological formation of RA. The aim of the present study was to evaluate the influence of infliximab on serum levels of various chemokines. Twenty-four RA patients were involved in this study, which took place between March 2003 and February 2006. Infliximab was administered by intravenous infusion at a dosage of 3 mg/kg. All patients underwent general and physical examinations and routine blood and urinary analysis at the baseline, at 14 weeks, and at 30 weeks after the initial treatment. To determine whether serum and synovial fluid from RA also contained significant levels of chemokines compared with osteoarthritis patients (OA), GRO-alpha, MIP-1alpha, MIP-1beta and regulated on activation normal T cell expressed and secreted (RANTES) levels of serum and synovial fluid were measured by ELISA in 20 RA patients and 20 OA patients. GRO-alpha, MIP-1beta, and RANTES levels were significantly higher in RA compared with normal volunteers, while MIP-1alpha levels showed no significant differences. The mean GRO-alpha levels in serum from RA patients treated with infliximab decreased significantly after the initial treatment. The mean RANTES and MIP-1beta levels did not change significantly after the treatment. Infliximab treatment significantly lowered the serum GRO-alpha levels of RA patients. GRO-alpha is one of the crucial cytokines affected by infliximab treatment. The blocking therapy of RANTES and MIP-1beta combined with infliximab treatment may have an additional effect without competition in the TNFalpha cascade.

Treatment with anti-TNF-alpha antibody infliximab reduces serum IL-15 levels in patients with rheumatoid arthritis.

The aim of this study was to analyze the change of serum cytokines and pentosidine levels in patients with rheumatoid arthritis (RA) by infliximab treatment. Twenty-three patients with RA were studied for 30 weeks on the effects of infliximab treatment. Serum levels of IL-15, IL-16, IL-17, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured with ELISA methods and pentosidine levels were determined using high-performance liquid chromatography, both at baseline and at 14 and 30 weeks after the initial treatment with infliximab. In addition, the patients also underwent physical and routine blood examinations. The higher levels of serum IL-15 in RA patients before treatment with infliximab significantly decreased at 14 and 30 weeks after the initial treatment with infliximab, but serum IL-16, IL-17, GM-CSF, and pentosidine levels did not decrease. The serum IL-17 and GM-CSF levels remained to be a limited detectable level at the pre- and posttreatment with infliximab. Infliximab treatment significantly lowered the serum levels of IL-15 in patients with RA. IL-15 is one of the crucial cytokines affected by infliximab.

Anti-tumor necrosis factor-alpha antibody treatment reduces serum CXCL16 levels in patients with rheumatoid arthritis.

The aim of this study was to analyze the change of serum chemokins levels of CXCL16, CX3CL1/Fractalkine, and CXCL10/interferon-gamma inducible protein-10 (IP-10) with rheumatoid arthritis (RA), by infliximab treatment. The effects of infliximab treatment were studied in 23 patients with RA, over a period of 30 weeks. The serum levels of CXCL16, Fractalkine, and IP-10, were measured at the baseline, just before initial treatment, and at 14 and 30 weeks after the initial treatment, with infliximab by ELISA. The higher levels of serum CXCL16 in the RA patients before treatment with infliximab significantly decreased at 14 and 30 weeks after the initial treatment with infliximab, but the serum Fractalkine and IP-10 levels did not decrease significantly. Infliximab treatment significantly lowered the serum levels of CXCL16 in patients with RA. CXCL16 is one of the crucial chemokines regulated by infliximab treatment.

The effect of methotrexate on bone metabolism markers in patients with rheumatoid arthritis.

The aim of the present study was to evaluate the influence on urinary excretion levels of N-telopeptide of type I collagen (NTX) and deoxypyridinoline (DPD) as a useful marker for bone resorption, and on serum-bone alkaline phosphate (BAP) levels as a useful marker for bone formation and an early marker of osteoblast differentiation in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX). Thirty patients with RA, diagnosed according to the criteria of the American College of Rheumatology, were involved in this study between March 2003 and January 2005. None of the patients had a history of hormone (estrogen) replacement therapy. All patients were treated with MTX. Methotrexate was administered perorally at a dosage of 4-10 mg/week. All patients underwent general and physical examinations and routine blood and urinary analysis at the baseline, 3 months and 6 months after the initial treatment. Then the levels of NTX and DPD in urine and BAP in serum were measured in all patients. For comparison with the effect of other DMARDs on bone metabolism markers in RA patients, we measured the levels of NTX and DPD in urine and BAP in serum of RA patients, 13 patients treated with salazosulfapyridine (SASP), and 14 patients treated with actarit (ACT). In patients treated with MTX, NTX levels decreased significantly at 3 months after the initial treatment and remained low at 6 months after the initial treatment, and DPD levels significantly decreased at 6 months after the initial treatment. The mean serum BAP levels changed without significant differences from the baseline at 3 months and 6 months. In patients treated with SASP and ACT, all bone metabolism markers had not changed significantly at the three time points. On disease activity erythrocyte sedimentation rate, C-reactive protein, the number of swollen joints and tender joints, and mHAQ score decreased significantly at 3 months after the initial treatment, and remained at low levels at 6 months after the initial treatment with MTX. Methotrexate therapy looks promising in inhibiting generalized bone loss in patients with RA. In addition, NTX is a more sensitive marker than DPD.

The occurrence of a geode in the olecranon of a patient with rheumatoid arthritis.

Geode, a subchondral cyst, is sometimes seen in the femur, knee, or wrist in a patient with rheumatoid arthritis (RA). But the onset of a giant geode at the olecranon is extremely rare in a patient with RA. We describe herein a rare case of a giant geode at the olecranon in a patient with RA.