Factors contributing to the improvement in J-HAQ after 3 years of treatment with abatacept in biologic-naïve rheumatoid arthritis patients: Interim results of a long-term, observational, multicentre study in Japan (ORIGAMI).

OBJECTIVES: We investigated the long-term effectiveness, safety, and factors affecting Japanese Health Assessment Questionnaire (J-HAQ) improvement during abatacept treatment in Japanese rheumatoid arthritis (RA) patients. METHODS: The ORIGAMI study is an ongoing observational study of biologic-naïve RA patients with moderate disease activity treated with subcutaneous abatacept (125 mg, once-weekly). Patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) were extracted from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) registry as an historical, weighted control group. The primary endpoint for this interim analysis was the proportion of patients with J-HAQ remission (score ≤0.5) at 3 years. RESULTS: Among 279 abatacept-treated and 220 csDMARD-treated patients, J-HAQ remission was achieved at 3 years in 40.5% (95% confidence interval [CI] 34.7%-46.2%) and 28.9% (95% CI 9.9%-47.8%), respectively. Age, RA duration <1 year, baseline J-HAQ score, and Simplified Disease Activity Index remission at 6 months were associated with 3-year J-HAQ remission in the abatacept group. Overall, 24/298 patients (8.1%; safety analysis set) experienced serious adverse drug reactions with an incidence of 5.3 per 100 person-years. CONCLUSIONS: This study confirmed the 3-year effectiveness and safety, and revealed potential factors associated with J-HAQ remission in biologic-naïve RA patients treated with abatacept in real-world clinical practice.

The impact of glucocorticoid use on the outcomes of rheumatoid arthritis in a multicenter ultrasound cohort study.

OBJECTIVE: Glucocorticoids are effective in treating rheumatoid arthritis (RA) when used appropriately considering the balance of the risks and benefits, especially at low doses. We aimed to evaluate the response of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients having already been treated with glucocorticoids. METHODS: We reviewed RA patients treated with b/tsDMARDs in a prospective multicenter ultrasound cohort study. We compared the differences in the clinical characteristics at baseline and outcomes at 12 months between the two groups having been treated with and without glucocorticoids at baseline. The differences in the clinical characteristics and the treatments were balanced by the inverse probability weighting (IPW) with the propensity score. RESULTS: Of 307 patients with RA, 160 patients were treated with glucocorticoids at baseline. The median dose of glucocorticoids was equivalent to 5.0 mg/day of prednisolone. Significant differences were in age and concomitant methotrexate use, composite measures for the disease activity, and the ultrasound grayscale score at baseline. Patients treated with glucocorticoids had less frequent remissions defined by composite measures and ultrasound findings than those treated without glucocorticoids. These significant differences in the achievement of remissions remained robust even after adjusting differences in the clinical characteristics and the treatments between the two groups by IPW. CONCLUSION: RA patients treated with glucocorticoids had a higher disease activity at baseline and a poorer response to treatments with b/tsDMARDs than those without glucocorticoids. The states of patients requiring glucocorticoids might be associated with the poor response to the b/tsDMARDs.

Outcomes and risk factors for mortality in Pneumocystis pneumonia patients with rheumatoid arthritis: A multicentre retrospective cohort study.

OBJECTIVES: The aim is to evaluate outcomes and risk factors for death in patients with rheumatoid arthritis (RA) who developed Pneumocystis pneumonia (PCP). METHODS: We included RA patients who were diagnosed with PCP at seven participating community hospitals between July 2005 and October 2020. Clinical features were compared between survivors and non-survivors. Disease-modifying antirheumatic drugs (DMARDs) before PCP onset and after PCP recovery were also examined. RESULTS: Seventy RA patients developed PCP, and among them, 60 (85.7%) received methotrexate (MTX) monotherapy (40%) or MTX combination therapy with other DMARDs (45.7%). PCP was more likely to occur after 12 months of MTX monotherapy and within 3 months of MTX combination therapy. Thirteen patients (18.6%) died despite PCP treatment. Multivariable logistic regression analysis revealed that coexisting RA-associated interstitial lung disease (odds ratio, 6.18; 95% confidence interval, 1.17-32.63) and delayed PCP treatment with anti-Pneumocystis drugs (odds ratio, 15.29; 95% confidence interval, 1.50-156.15) are significant risk factors for PCP mortality in RA patients. Most survivors successfully resumed DMARD therapy without PCP prophylaxis; one recurrent PCP case was observed during follow-up (median, 4.1 years). CONCLUSIONS: To avoid a treatment delay, RA patients should be followed up for signs and symptoms of PCP development, especially those with RA-associated interstitial lung disease.

Influence of concomitant methotrexate use on the clinical effectiveness, retention, and safety of abatacept in biologic-naïve patients with rheumatoid arthritis: Post-hoc subgroup analysis of the ORIGAMI study.

OBJECTIVES: We performed post-hoc analyses of the ORIGAMI study to investigate whether concomitant methotrexate (MTX) influences the clinical outcomes of abatacept in biologic-naïve patients with rheumatoid arthritis. METHODS: Enrolled patients (n = 325) were divided into two groups according to whether abatacept was prescribed without (MTX-) or with (MTX+) concomitant MTX. We compared the changes in Simplified Disease Activity Index (SDAI), Disease Activity Score-28 with C-reactive protein (DAS28-CRP), and Japanese Health Assessment Questionnaire (J-HAQ) through to 52 weeks of treatment, the abatacept retention rate, and safety. RESULTS: At Week 52, the mean SDAI (8.9 vs. 8.8), DAS28-CRP (2.6 vs. 2.6), and J-HAQ (0.92 vs. 0.91) scores were comparable in the MTX- (n = 129) and MTX+ (n = 150) groups. Multivariable logistic regression revealed no significant association between MTX use and SDAI (low disease activity) or J-HAQ (minimum clinically important difference). The abatacept retention rates, estimated using the Kaplan-Meier method, were 73.2% and 66.7% in the MTX- and MTX+ groups, respectively. Adverse events occurred in 47.5% (of 139) and 52.2% (of 159) of patients in the MTX- and MTX+ groups, respectively. CONCLUSION: The effectiveness and safety of abatacept appeared comparable with or without concomitant MTX in this real-world clinical setting.

Effect of abatacept treatment on serum osteoclast-related biomarkers in patients with rheumatoid arthritis (RA): A multicenter RA ultrasound prospective cohort in Japan.

ABSTRACT: We evaluated the effect of abatacept treatment on osteoclast-related biomarkers and explored whether the biomarkers are associated with the therapeutic response in rheumatoid arthritis (RA) patients treated with abatacept.We enrolled 44 RA patients treated with abatacept from a multicenter prospective ultrasound cohort study of patients who received biologic or targeted synthetic disease-modifying antirheumatic drug therapy. We evaluated the disease activity score (DAS) 28-CRP (C-reactive protein), musculoskeletal ultrasound scores including the total grayscale score (GS)/power Doppler (PD) score and the serum concentrations of isoform 5b of tartrate-resistant acid phosphate (TRACP-5b) and soluble receptor activator of nuclear factor-κB ligand (sRANKL) at baseline and at 3 and 6 months of treatment. "PD responder" was defined as a patient whose Δtotal PD score over 6 months was greater than the median change of that.Abatacept significantly improved DAS28-CRP as well as the total GS/PD score over 6 months. Serum TRACP-5b was significantly elevated and serum sRANKL was significantly decreased at 6 months (P < .0001 and P < .01, respectively). At 6 months, serum sRANKL was significantly decreased in the patients who achieved DAS28-CRP remission and the PD responders but not in those who did not. However, serum TRACP-5b rose regardless of the therapeutic response.Among RA patients treated with abatacept, serum sRANKL decreased in the patients with a good therapeutic response, but serum TRACP-5b elevated paradoxically regardless of the therapeutic response.

Association between serum bone biomarker levels and therapeutic response to abatacept in patients with rheumatoid arthritis (RA): a multicenter, prospective, and observational RA ultrasound cohort study in Japan.

BACKGROUND: To evaluate the effect of treatment on serum bone biomarkers and explore whether serum bone biomarkers are associated with therapeutic response in rheumatoid arthritis (RA) patients treated with abatacept. METHODS: We enrolled 59 RA patients treated with abatacept from a multicenter, exploratory, short-term, prospective and observational ultrasound cohort study of patients who received biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) therapy. We evaluated the patients' clinical disease activity and musculoskeletal ultrasound (MSUS) scores. The serum concentrations of five bone biomarkers were evaluated (dickkopf-1 [Dkk-1], sclerostin [SOST], osteocalcin [OC], osteopontin [OPN], and osteoprotegerin [OPG]) by multiplex bead assays at baseline, 3, and 6 months: the change over 6 months was defined as the Δ value. 'Power Doppler (PD) responder' was defined as a patient whose Δtotal PD score over 6 months was greater than the median change. RESULTS: Abatacept significantly improved the clinical disease activity and MSUS score over 6 months. Serum OPG was significantly elevated at 6 months after the abatacept introduction (p = 0.016). The ΔSOST and ΔOPG were significantly greater in the PD responders versus the non-PD responders (p = 0.0041 and 0.0073, respectively). The serum Dkk-1 at baseline was significantly lower in the PD responders (n = 30) vs. the non-PD responders (n = 29) (p = 0.026). A multivariate logistic regression analysis showed that the serum Dkk-1 at baseline (odds ratio 0.50, 95% confidence interval [CI] 0.23-0.91, p = 0.043) was an independent predictor of PD responder status. CONCLUSION: Serum levels of bone biomarkers may be useful for predicting RA patients' therapeutic responses to abatacept. TRIAL REGISTRATION: Name of the registry: Assessment of therapeutic responsiveness by imaging of the joints in patients with rheumatoid arthritis; A observational cohort study Trial registration number: UMIN000012524 Date of registration: 12/9/2013 URL of trial registry record: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000014657.

Tofacitinib versus tocilizumab in the treatment of biological-naïve or previous biological-failure patients with methotrexate-refractory active rheumatoid arthritis.

OBJECTIVES: To compare effectiveness between tofacitinib and tocilizumab treatments for biological disease-modifying antirheumatic drug (bDMARD)-naïve patients or previous bDMARD-failure patients with active rheumatoid arthritis (RA) refractory to methotrexate (MTX). METHODS: We used two ongoing real-world registries of patients with RA who had first started tofacitinib or tocilizumab between August 2013 and February 2019 at our institutions. Clinical disease activity index (CDAI)-based improvements at 12 months were used for comparisons between tofacitinib and tocilizumab treatments, separately for bDMARD-naïve and previous bDMARD-failure patients. RESULTS: A total of 464 patients with RA with high or moderate CDAI were enrolled (247 with tofacitinib and 217 with tocilizumab). After adjustments for treatment-selection bias by propensity score matching, we showed that tofacitinib was more likely to induce and maintain ≥85% improvement in CDAI (CDAI85), CDAI70 and remission at 12 months compared with tocilizumab in bDMARD-naïve patients. After adjusting for concurrent use of MTX and prednisolone, the ORs of tofacitinib versus tocilizumab were 3.88 (95% CI 1.87 to 8.03) for CDAI85, 2.89 (95% CI 1.43 to 5.84) for CDAI70 and 3.31 (95% CI 1.69 to 6.48) for remission. These effects were not observed in bDMARD-failure patients. In tofacitinib treatment for bDMARD-failure patients, the number of previously failed bDMARD classes was not associated with CDAI-based improvements. The rate of overall adverse events was similar between both treatments. Similar ORs were obtained from patients adjusted by inverse probability of treatment weighting. CONCLUSIONS: Compared with tocilizumab, tofacitinib can induce greater improvements during the first 12-month treatment in bDMARD-naïve patients, but this difference was not observed in previous bDMARD-failure patients.

Utility of a simplified ultrasonography scoring system among patients with rheumatoid arthritis: A multicenter cohort study.

ABSTRACT: We aimed to evaluate the utility of a simplified ultrasonography (US) scoring system, which is desired in daily clinical practice, among patients with rheumatoid arthritis (RA) receiving biological/targeted synthetic disease-modifying antirheumatic drugs (DMARDs).A total of 289 Japanese patients with RA who were started on tumor necrosis factor inhibitors, abatacept, tocilizumab, or Janus kinase inhibitors between June 2013 and April 2019 at one of the 15 participating rheumatology centers were reviewed. We performed US assessment of articular synovia over 22 joints among bilateral wrist and finger joints, and the 22-joint (22j)-GS and 22-joint (22j)-PD scores were evaluated as an indicator of US activity using the sum of the GS and PD scores, respectively.The top 6 most affected joints included the bilateral wrist and second/third metacarpophalangeal joints. Therefore, 6-joint (6j)-GS and -PD scores were defined as the sum of the GS and PD scores from the 6 synovial sites over the aforementioned 6 joints, respectively. Although the 22j- or 6j-US scores were significantly correlated with DAS28-ESR or -CRP scores, the correlations were weak. Conversely, 6j-US scores were significantly and strongly correlated with 22j-US scores not only at baseline but also after therapy initiation.Using a multicenter cohort data, our results indicated that a simplified US scoring system could be adequately tolerated during any disease course among patients with RA receiving biological/targeted synthetic DMARDs.

Non-TNF inhibitor switchers versus TNF inhibitor cyclers from multicentre rheumatoid arthritis ultrasonography prospective cohort in Japan.

To compare therapeutic efficacy of tumour necrosis factor inhibitor (TNFi) cyclers and non-TNFi switchers in patients with rheumatoid arthritis (RA) having inadequate response to previous TNFis (TNF-IR patients) using composite measures including imaging assessment with power Doppler ultrasonography (PDUS). Patients with RA who had inadequate response to one or more previous TNFi agents with moderate or higher disease activity were enrolled. The outcomes of 56 TNF-IR patients were analysed. Patients were divided into 19 TNFi cyclers and 37 non-TNFi switchers (16 abatacept [ABT] and 21 tocilizumab [TCZ] switchers). Retention ratio at 6 months was significantly higher in non-TNFi switchers than in TNFi cyclers (p < .05). Although there was no significant difference, non-TNFi switchers tended to have a larger decrease than TNFi cyclers in efficacy indicators based on clinical disease activity index and PDUS. Multivariate logistic regression analysis identified a following independent factor associated with both EULAR good response and retention of a biologic agent: non-TNFi switch (p < .05 for both). Non-TNFi switchers were shown to have significantly higher percentage of EULAR good response and higher retention than TNFi cyclers. A non-TNFi biologic agent may hence be a preferential next-line treatment for TNF-IR patients.

Retention of tocilizumab with and without methotrexate during maintenance therapy for rheumatoid arthritis: the ACTRA-RI cohort study.

OBJECTIVES: To compare retention of tocilizumab (TCZ) as monotherapy vs combination therapy with MTX in RA patients achieving clinical improvements during the first year. METHODS: We performed a multicentre cohort study using a real-life registry containing RA patients who had begun TCZ with or without MTX between April 2008 and November 2016. Among patients with ≥50% improvement of clinical disease activity index (CDAI) during the first year (CDAI50 responders), we evaluated whether MTX use may have affected TCZ discontinuation during the second and subsequent years (maintenance therapy). RESULTS: Among 510 patients with high or moderate CDAI, 328 (64.3%) were CDAI50 responders. The rate of MTX use was 53.0% among responders and 54.4% among non-responders. During maintenance therapy (mean follow-up 30.7 months), 43.9% of CDAI50 responders discontinued TCZ. The most common cause was efficacy loss followed by adverse events. Kaplan-Meier estimates for TCZ retention were 48.3 months (95% CI 42.0, 54.5) for monotherapy and 50.0 months (95% CI 45.9, 54.0) for combination therapy. According to Gray's test, there was no significant impact of MTX use on cumulative incidence of efficacy loss or adverse events. In the Fine-Gray competing risk regression model, CDAI >10 at the start of maintenance therapy and age were predictive factors for TCZ discontinuation due to efficacy loss (hazard ratio 2.58, 95% CI 1.41, 4.72) and adverse events (hazard ratio 1.04, 95% CI 1.01, 1.08), respectively. CONCLUSION: There was no significant difference in TCZ retention between monotherapy and combination therapy with MTX.

Ultrasonographic Efficacy of Biologic and Targeted Synthetic Disease-Modifying Antirheumatic Drug Therapy in Rheumatoid Arthritis From a Multicenter Rheumatoid Arthritis Ultrasound Prospective Cohort in Japan.

OBJECTIVE: To explore the variables associated with initial favorable power Doppler (PD) ultrasound (US) response induced by biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients with rheumatoid arthritis (RA). METHODS: We have been prospectively investigating the course of active RA patients using US after the introduction of b/tsDMARDs in the Kyushu region of Japan since June 2013. A total of 150 patients have completed the first 6 months of observation at present and have been evaluated. US was assessed in 22 joints of bilateral hands using gray-scale and PD images on a scale from 0-3. The sum of these scores was used as the indicator of US disease activity. We defined PD remission as attaining a total PD score of 0 at 6 months and investigated the associated variables by multivariate logistic regression analysis. RESULTS: The total PD and gray-scale scores and the clinical composite measures significantly improved at 6 months, whereas these reductions were less in bDMARD switchers as compared with bDMARD-naive patients. Multivariate logistic regression analysis showed that short disease duration, the absence of any previous use of bDMARDs, and low total PD scores at baseline were independent predictors of PD remission at 6 months. CONCLUSION: This present prospective US cohort has for the first time shown the variables that are associated with initial PD response to b/tsDMARDs.

Tofacitinib Therapy for Rheumatoid Arthritis: A Direct Comparison Study between Biologic-naïve and Experienced Patients.

Objective This study was designed to directly compare the outcomes of tofacitinib therapy for methotrexate-refractory rheumatoid arthritis (RA) between biologic-naïve patients and patients who had experienced an inadequate response to biological agents. Methods We prospectively enrolled and followed 113 patients who had a high or moderate clinical disease activity index (CDAI) (36 biologic-naïve patients and 77 biologic-experienced patients). Patients received 5 mg of tofacitinib twice daily. Effectiveness and adverse events were examined at month 6 of treatment. Results At month 6, 65 patients (57.5%) reached CDAI50, which is defined as achieving ≥50% improvement. The number of previous biological agents was twice as high in CDAI50 non-responders as in responders (2.2 versus 1.1, p<0.001), but there was no significant difference in the type of previous agents or the reason for discontinuation. According to a multivariate logistic regression analysis, the previous use of biological agents [odds ratio (OR) 4.48, p=0.002] and the concurrent use of prednisolone (OR 2.40, p=0.047) were associated with a failure to achieve a CDAI 50 response. Biologic-naïve patients were more likely to achieve CDAI50 than biologic-experienced patients (80.6% versus 46.8%, p=0.001). Mean CDAI values were higher in biologic-experienced patients (11.4 versus 4.8, p=0.001), and remission rates were higher in biologic-naïve patients (41.7% versus 11.7%, p=0.001). Biologic-naïve patients more rapidly achieved remission. Rates of discontinuation resulting from adverse events were similar in both groups. Conclusion Although tofacitinib can provide an effective treatment option for intractable RA patients, its impact on outcomes is lower in patients with previous biologic failure.

Prevalence of and factors associated with renal dysfunction in rheumatoid arthritis patients: a cross-sectional study in community hospitals.

This study was designed to determine the prevalence of renal dysfunction in rheumatoid arthritis (RA) patients and to identify factors associated with this complication. Between October 2014 and May 2015, we consecutively recruited RA patients at rheumatology sections of community hospitals in Japan. Each patient's absolute and body surface area (BSA)-indexed estimated glomerular filtration rate (eGFR) values were measured twice over a 3-month interval. Renal dysfunction was defined as absolute eGFR or BSA-indexed eGFR < 60. Albuminuria and hematuria were also recorded. Associations between renal dysfunction and possible risk factors were examined by multivariate logistic regression analyses. A total of 1908 outpatients with RA were included in this study. The prevalence of renal dysfunction based on absolute eGFR and BSA-indexed eGFR was 33.8 and 18.6%, respectively. Albuminuria was observed in 8.1% of this patient cohort, and the prevalence of hematuria was 7.5%. Advanced age (odds ratio [OR] 7.24, p < 0.001), female sex (OR 3.12, p < 0.001), hypertension (OR 2.22, p < 0.001), and obesity (OR 0.59, p < 0.001) were independently associated with the risk of absolute eGFR-based renal dysfunction. Advanced age (OR 5.19, p < 0.001) and hypertension (OR 3.05, p < 0.001) also had associations with BSA-indexed eGFR-based renal dysfunction. RA duration, stages, severity, and cumulative steroid dose were considered significant risk factors in univariate analyses, but their associations were less potent after adjustment for other covariates. Renal dysfunction is relatively common in RA patients and is mainly associated with advanced age and hypertension but not with RA-related factors.

Comparative risk of hospitalized infection between biological agents in rheumatoid arthritis patients: A multicenter retrospective cohort study in Japan.

OBJECTIVE: Knowing the risk of hospitalized infection associated with individual biological agents is an important factor in selecting the best treatment option for patients with rheumatoid arthritis (RA). This study examined the comparative risk of hospitalized infection between biological agents in a routine care setting. METHODS: We used data for all RA patients who had first begun biological therapy at rheumatology divisions of participating community hospitals in Japan between January 2009 and December 2014. New treatment episodes with etanercept, infliximab, adalimumab, abatacept, or tocilizumab were included. Patients were allowed to contribute multiple treatment episodes with different biological agents. Incidence rates (IRs) of hospitalized infection during the first year of follow-up were examined. Cox regression analysis was used to calculate hazard ratios (HRs) for overall hospitalized infection and for pulmonary hospitalized infection, adjusting for possible confounders. RESULTS: A total of 1596 new treatment episodes were identified. The incidence of overall hospitalized infection during the first year was 86 with 1239 person-years (PYs), yielding a crude IR of 6.9 per 100 PYs (95% confidence interval [CI], 5.6-8.6). After correction for confounders, no significant difference in risk of hospitalized infection was observed between treatment groups: adjusted HRs (95% CI) were 1.54 (0.78-3.04) for infliximab, 1.72 (0.88-3.34) for adalimumab, 1.11 (0.55-2.21) for abatacept, and 1.02 (0.55-1.87) for tocilizumab compared with etanercept. Patient-specific factors such as age, RA functional class, body mass index (BMI), prednisolone use, and chronic lung disease contributed more to the risk of hospitalized infection than specific biological agents. The incidence of pulmonary hospitalized infection was 50 and a crude IR of 4.0 per 100 PYs (95% CI, 3.1-5.3). After adjustment for confounders, adalimumab had a significantly higher HR for pulmonary hospitalized infection compared with tocilizumab: an adjusted HR (95% CI) was 4.43 (1.72-11.37) for adalimumab. BMI, prednisolone use, diabetes mellitus, and chronic lung disease were also significant factors associated with the risk of pulmonary hospitalized infection. CONCLUSIONS: The magnitude of the risk of overall hospitalized infection was not determined by the type of biological agents, and patient-specific risk factors had more impact on the risk of hospitalized infection. For pulmonary hospitalized infections, the use of adalimumab was significantly associated with a greater risk of this complication than tocilizumab use.

Factors Associated with Myelosuppression Related to Low-Dose Methotrexate Therapy for Inflammatory Rheumatic Diseases.

OBJECTIVE: Severe myelosuppression is a serious concern in the management of rheumatic disease patients receiving methotrexate (MTX) therapy. This study was intended to explore factors associated with the development of MTX-related myelosuppression and its disease severity. METHODS: We retrospectively examined a total of 40 cases of MTX-related myelosuppression that had been filed in the registries of participating rheumatology and hematology divisions. Data before onset were compared with those of 120 controls matched for age and sex. Cytopenia was graded according to the National Cancer Institute criteria for adverse events. Data before and at onset were compared between the severe and non-severe groups. RESULTS: Non-use of folic acid supplements, concurrent medications, and low renal function were significantly associated with the development of myelosuppression (p < 0.001, p < 0.001, and p = 0.002, respectively). In addition, significantly lower MTX dosages, higher blood cell counts, and lower hemoglobin levels were seen in the myelosuppression group (p < 0.001). No patients exhibited leukocytopenia, neutropenia, or thrombocytopenia in routine blood monitoring taken within the past month. One-fourth developed myelosuppression within the first two months (an early-onset period). Myelosuppression was severe in approximately 40% of patients. Hypoalbuminemia and non-use of folic acid supplements were significantly associated with the severity of pancytopenia (p = 0.001 and 0.008, respectively). Besides these two factors, early onset and the use of lower doses of MTX were significantly associated with the severity of neutropenia (p = 0.003, 0.007, 0.003, and 0.002, respectively). CONCLUSIONS: Myelosuppression can occur abruptly at any time during low-dose MTX therapy, but severe neutropenia is more likely to occur in the early-onset period of this therapy. Contrary to our expectations, disease severity was not dependent on MTX doses. Serum albumin levels and folic acid supplementation are the important factors affecting the severity of MTX-related pancytopenia and neutropenia.

Sonographic measurements of low-echoic synovial area in the dorsal aspect of metatarsophalangeal joints in healthy subjects.

INTRODUCTION: Assessment of synovitis in the metatarsophalangeal (MTP) joints with ultrasound has been shown to improve the accuracy of assessment of rheumatoid arthritis (RA). However, the presence of intraarticular low-echoic synovial area (LESA) in the MTP joints in healthy subjects complicates the sonographic assessment of these joints. METHOD: Healthy subjects with no arthritic symptoms in their MTP joints were recruited. All subjects completed a questionnaire and underwent physical examination and sonographic assessment. LESAs in the dorsal aspect of all MTP joints were measured in the longitudinal view. RESULTS: One thousand non-arthritic MTP joints in 100 healthy subjects (female 73, mean age 41.0 years old) were evaluated. Measurable LESAs were identified in all joints assessed. Mean length of LESA in each of the 1st-5th MTP joints was 17.8, 13.9, 11.9, 10.6, and 9.2 mm, respectively, whereas mean thickness was 2.4, 2.4, 1.8, 1.2, and 0.8 mm, respectively. Multivariate linear regression models identified the difference between 1st and 5th MTP joints as the most independently influential factor on the measurement of LESA. CONCLUSIONS: Our data provide the normal reference values for the measurements of LESA in Japanese, which should be taken into consideration when the synovitis in MTP joints is evaluated with ultrasound.

Assessment of peripheral blood CD4+ adenosine triphosphate activity in patients with rheumatoid arthritis.

OBJECTIVE: The ability of the ImmuKnow (Cylex) assay to predict the risk of infection in rheumatoid arthritis (RA) patients receiving synthetic or biological disease-modifying antirheumatic drugs (DMARDs) was examined. METHODS: The amount of adenosine triphosphate (ATP) produced by CD4+ cells in response to phytohemagglutinin was measured in whole blood from 117 RA patients without infection versus 17 RA patients with infection, and compared with results in 75 healthy controls. RESULTS: The mean ATP level was significantly lower in patients with infection compared to both healthy controls (P < 0.0005) and patients without infection (P = 0.040). Also, the mean ATP level in patients without infection was significantly lower than that in healthy controls (P = 0.012). There was no correlation between the ATP level and the Disease Activity Score in 28 joints. CONCLUSION: ImmuKnow assay results may be effective in identifying RA patients at increased risk of infection, but the results showed no correlation with RA activity. Larger studies are required to establish the clinical advantages of this assay in RA treatment.

An investigation of the correlation between blood concentration of mizoribine and its efficacy in treatment of rheumatoid arthritis based on indices of drug survival and improvement in DAS28-CRP.

OBJECTIVES: The efficacy of mizoribine (MZR) in treatment of rheumatoid arthritis (RA) was retrospectively investigated in terms of drug survival, improvement in Disease Activity Score-28 (DAS28)-C-reactive protein (CRP), and blood MZR concentration obtained 3 h after dosing (MZR-C3). METHODS: To compare the efficacy of MZR administered via different regimens, the subjects were divided into 2 groups: those receiving a single dose of MZR at 100-150 mg every other day (group A) and those receiving 2 or 3 divided doses of the drug on consecutive days, which is the usual dosing method of the drug (group B). RESULTS: Group A had significantly higher MZR-C3 levels compared with group B, as well as significantly greater improvement in DAS28-CRP. Moreover, drug survival was significantly longer in group A. The primary regression equation suggested that the effective blood MZR concentration in RA treatment is MZR-C3 of 1.47 µg/mL or more. CONCLUSIONS: The results of the present study indicate that it is possible to increase the efficacy of MZR in a blood concentration-dependent manner, and also to control RA over a prolonged period, using single administration of MZR on alternate days at an increased dose.