Risks of femoral localized periosteal thickening in patients with autoimmune inflammatory rheumatic diseases.

OBJECTIVES: The incidence of femoral localized periosteal thickening (LPT), which can precede atypical femoral fracture (AFF), is not low (1-10%) in Japanese patients with autoimmune inflammatory rheumatic diseases (AIRDs). We explored the associations between underlying AIRDs and the prevalence of LPT. METHODS: We conducted post hoc analyses of two cohorts that included a total of 280 Japanese women, 105 of whom had AIRDs and had been taking bisphosphonate (BP) and prednisolone (PSL) and 175 of whom had rheumatoid arthritis (RA). RESULTS: LPT was detected in a total of 18 patients (6.4%) and 3 (1.1%) developed AFFs. RA was negatively correlated with LPT. A disease other than RA requiring glucocorticoid treatment, BP use ≥5 years, PSL use ≥7 years, and a PSL dose ≥5.5 mg/day were positively correlated with LPT. After adjusting for age, diabetes mellitus, and BP duration or daily PSL dose, RA was no longer associated with LPT. CONCLUSIONS: LPT in Japanese patients with AIRDs was associated with BP and glucocorticoid treatment rather than underlying AIRDs. When PSL dose ≥5.5 mg/day is required long-term [typically combined with long-term BP treatment (≥5 years)], clinicians need to pay particular attention in cases LPT and AFF as well as glucocorticoid-induced osteoporosis.

The Combination of Modified Mitchell's Osteotomy and Shortening Oblique Osteotomy for Patients with Rheumatoid Arthritis: An Analysis of Changes in Plantar Pressure Distribution.

The present study aims to evaluate changes in plantar pressure distribution after joint-preserving surgery for rheumatoid forefoot deformity. A retrospective study was performed on 26 feet of 23 patients with rheumatoid arthritis (RA) who underwent the following surgical combination: modified Mitchell's osteotomy (mMO) of the first metatarsal and shortening oblique osteotomy of the lateral four metatarsals. Plantar pressure distribution and clinical background parameters were evaluated preoperatively and one year postoperatively. A comparison of preoperative and postoperative values indicated a significant improvement in the visual analog scale, Japanese Society for Surgery of the Foot scale, and radiographic parameters, such as the hallux valgus angle. A significant increase in peak pressure was observed at the first metatarsophalangeal joint (MTPJ) (0.045 vs. 0.082 kg/cm2; p < 0.05) and a significant decrease at the second and third MTPJs (0.081 vs. 0.048 kg/cm2; p < 0.05, 0.097 vs. 0.054 kg/cm2; p < 0.05). While overloading at the lateral metatarsal heads following mMO has been reported in previous studies, no increase in peak pressure at the lateral MTPJs was observed in our study. The results of our study show that this surgical combination can be an effective and beneficial surgical combination for RA patients with mild to moderate joint deformity.

The advances in dealing with the safety of medicated drugs in pregnancy.

The Japan Drug Information Institute in Pregnancy (JDIIP) was established with the aims of providing information on drug safety to women who are worried about drug use during pregnancy and creating evidence through epidemiological studies based on counseling cases. Since being established, JDIIP has made many contributions to the wellness of mothers and children by promoting the proper use of drugs during pregnancy. A network consisting of Core hospitals in 47 prefectures plays an important role in providing information for women living anywhere in Japan. Because cases of exposure to drugs whose safety we want to analyze are usually rare, networks of domestic and foreign teratology information services are necessary in order to produce high-quality evidence. JDIIP has been contributing to the education of pharmacists and doctors and to the creation of clinical practice guidelines in various medical societies by using keywords such as "pregnancy" and "medication". Future issues include creating an environment that is easily accessible for those seeking consultation, building a mechanism that makes it easy to create a basis for safety, and aiming for the continuing development of the organization.

Long-term Use of Golimumab in Daily Practice for Patients with Rheumatoid Arthritis.

Objective To evaluate the effectiveness and drug retention rate of golimumab (GLM) for long-term use in daily practice for patients with rheumatoid arthritis (RA). Methods Patients with RA who started GLM therapy with a minimum follow-up period of 52 weeks were included. The patients were divided into a biologic-naïve group and switch group. The disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) (DAS28-ESR), grip power, and Japanese version of the health assessment questionnaire (J-HAQ) score were assessed. In addition, the treatment continuation rate was evaluated at the final follow-up. Patients Sixty-five patients [58 women and 7 men; median (range) age, 69 (61-74) years; median (range) disease duration, 9 (5-16) years] were included. Twenty-eight patients were biologic-naïve (naïve group), and 37 were switched to biologics (switch group). Results The median (range) follow-up period was 134 (58-162) weeks. The DAS28-ESR improved from a median (range) of 4.31 (3.52-5.25) to 2.65 (2.28-3.77) in the naïve group and from 4.27 (3.19-4.89) to 2.89 (2.49-3.88) in the switch group. The grip power improved in both groups (p<0.01); however, the J-HAQ score showed no marked improvement in either group. The continuation rates were 22/28 (78.6%) in the naïve group, and 26/37 (70.3%) in the switch group at the final follow-up. Conclusion We herein report for the first time that the long-term use of GLM improves the grip power. Improving the grip power may help prevent sarcopenia and frailty in the future. Given the efficacy and high continuation rate, we suggest that GLM would be a well-tolerated treatment option for RA.

Two-year Outcomes of Infliximab Discontinuation in Patients with Rheumatoid Arthritis: A Retrospective Analysis from a Single Center.

Objective To investigate the clinical outcomes of rheumatoid arthritis (RA) patients who discontinued infliximab (IFX) treatment at our hospital. Methods Among 249 patients receiving IFX from 2007 to 2015, we retrospectively investigated the clinical courses of 18 who discontinued IFX after achieving the 28-joint disease activity score based on the erythrocyte sedimentation (DAS28-ESR) clinical remission (CR) and whose clinical courses were available continuously for 96 weeks after discontinuation. Results At IFX introduction, the median age was 56.9 (range 36.1-72.4) years, and the disease duration was 5.2 (0.4-25.6) years. The median duration of maintaining either CR or a low disease activity (LDA) with IFX was 37.2 (4.0-91.4) months, and the total duration of IFX therapy was 45.8 (17.1-96.9) months. After discontinuation, 8 patients (44.4%) maintained CR/LDA for 96 weeks (no-flare group), and 10 (55.6%) experienced flares (DAS28-ESR≥3.2) within 96 weeks (flare group). In the no-flare group, six patients receiving intensified conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy to prevent flare ups simultaneously either with or immediately after discontinuing IFX. In the flare group, four patients received intensified csDMARD therapy. Six patients restarted biological DMARDs (bDMARDs), and all achieved CR again. Ultimately, 12 patients (66.7%) maintained a Bio-free disease control for 96 weeks. A comparison of the clinical backgrounds between the flare and no-flare groups showed no marked difference in their disease duration, IFX dosage, duration of maintaining CR with IFX, or concomitant csDMARDs use. Conclusion Irrespective of the RA disease duration, more than half of all patients maintained a Bio-free condition for 96 weeks. Continuing LDA with IFX for a sufficiently long period of time before discontinuation and preventive intensification of csDMARD therapy may help maintain a Bio-free condition.

Serum hepcidin level, iron metabolism and osteoporosis in patients with rheumatoid arthritis.

Hepcidin, a major regulator of iron metabolism and homeostasis, is regulated by inflammation. Recent studies have suggested that hepcidin and iron metabolism are involved in osteoporosis, and the aim of this study was to determine whether serum hepcidin levels are correlated with the degree of osteoporosis in patients with rheumatoid arthritis (RA). A total of 262 patients with RA (67.5 ± 11.4 years; 77.5% female) were enrolled. Serum iron, ferritin, and hepcidin levels were positively correlated each other. Multiple regression analyses revealed that the serum iron level was positively correlated with femoral T and Z scores, whereas the serum hepcidin level was not. Serum hepcidin level was correlated with the serum 25-hydroxy vitamin D level, which was in turn positively related to the femoral Z score. Serum hepcidin and serum iron were indirectly and directly related to osteoporosis in patients with RA.

Changes in radiographic findings and plantar pressure distribution following forefoot reconstructive surgery for patients with rheumatoid arthritis.

Objectives: To evaluate changes in radiographic findings and plantar pressure distribution after rheumatoid forefoot surgery.Methods: This study was performed on patients with rheumatoid arthritis (RA) who underwent Swanson implant arthroplasty for the 1st metatarsophalangeal (MTP) joint combined with shortening oblique osteotomy at the 2nd through 5th metatarsal necks (group Sw, 55 feet). The following two groups were used as controls: group NS, consisting of 75 feet in RA patients without scheduled forefoot surgery, and group HC, consisting of 24 feet in healthy female subjects. Plantar pressure distribution, and radiographic findings of hallux valgus angle, the angle between the metatarsal bones, talocalcaneal angle, calcaneal pitch angle and calcaneo-first metatarsal angle (CFMA) were measured pre- and one year postoperatively. Peak pressure was measured in nine sections.Results: Calcaneal pitch angle decreased and CFMA increased in group Sw. Peak pressure at the 1st interphalangeal joint (IP) and the 2nd and 3rd MTPs in group Sw decreased, while that at midfoot increased.Conclusion: While the clinical outcome in group Sw was favorable, postoperative longitudinal arch decreased. Postoperative peak pressure at the 2nd through 5th MTPs was comparable with that in group NS; however, it was significantly lower than that in group HC.

Clinical application of the dried milk spot method for measuring tocilizumab concentrations in the breast milk of patients with rheumatoid arthritis.

AIMS: Tocilizumab (TCZ), a humanized anti-interleukin-6 receptor monoclonal antibody, is used to treat rheumatic diseases. There is limited information about the administration of TCZ during lactation. The dried spot method, a simple technique for processing biological samples which involves placement of a drop of specimen onto filter paper, has been used in clinical pharmacology to determine various drug concentrations. This study examined the feasibility of sample collection using the dried milk spot (DMS) method for obtaining data about the transfer of TCZ into breast milk. METHODS: Concentrations of TCZ determined using DMSs prepared by patients were compared with those using liquid breast milk. RESULTS: In an enzyme-linked immunosorbent assay of TCZ in DMSs, the accuracy ranged from 93.0% to 113.8% and the precision ranged from 0.3% to 8.4%. All concentrations of TCZ were within 15% of the reference value when analyzed on separate days. TCZ in DMSs at room temperature, 4°C, and -20°C were stable for 28 days. Extracted TCZ concentrations from patient-prepared DMSs were strongly correlated with those of liquid samples (r = 0.996). In a pharmacokinetic study, the median (range) maximum and minimum concentrations were 113 ng/mL (68-205) and 8.5 ng/mL (4.8-13.4), respectively. The milk-to-serum ratio at the trough TCZ concentration of 3 lactating mothers were 0.0015, 0.00082 and 0.0014. CONCLUSIONS: The DMS method for measuring TCZ transfer into breast milk may be reliable and feasible, and should contribute to evaluating the safety of breast-fed infants whose mothers receive TCZ during lactation.

An Analysis of the Biological Disease-modifying Antirheumatic Drug-free Condition of Adalimumab-treated Rheumatoid Arthritis Patients.

Objectives The present study was performed with the aim of analyzing the biological disease-modifying antirheumatic drug (bDMARD)-free (Bio-free) condition of adalimumab (ADA)-treated rheumatoid arthritis (RA) patients in a real-world setting. Methods ADA was used in the treatment of 130 (male, n=21; female, n=109 females) RA patients. Among them, 26 patients (20.0%) discontinued ADA due to a good response. We analyzed 20 patients who were followed up for more than 6 months after the discontinuation of ADA. The Disease Activity Score 28 based on C-reactive protein (DAS28-CRP) and modified health assessment questionnaires (mHAQs) were evaluated. Results The mean age of the patients was 53.4±11.1 years. The mean disease duration was 4.5±4.3 years. Sixteen patients were bDMARD-naïve, while 4 switched from bDMARDs to ADA. At 6 months after the discontinuation ADA, 19 patients had achieved a clinical remission, and 1 had achieved a low disease activity. The Bio-free period was 26.4±15.5 months. The dose of prednisolone was significantly reduced from baseline (3.45±3.17 mg/day) at 6 months after the discontinuation of ADA (2.63±2.78 mg/day). The dose of methotrexate was unchanged. The number of conventional synthetic DMARDs (csDMARDs) was significantly increased (0.8±0.6 to 1.4±1.06). The mHAQ values were significantly ameliorated by ADA and remained good in patients with a Bio-free condition. A multivariate analysis showed that the dose of methotrexate (MTX) was an important factor for achieving a Bio-free condition. Conclusion A sustainable Bio-free condition in a real clinical setting can be achieved and may be a suitable way of reducing medical costs. The dose of MTX and the additional administration of csDMARDs is therefore thought to be important for ensuring a good outcome in these patients.

[The treatment of patients with elderly-onset rheumatoid arthritis at Niigata Rheumatic Center].

AIM: To investigate the clinical course of patients with elderly-onset rheumatoid arthritis (RA). METHODS: We compared the characteristics, and clinical course of 55 patients who developed RA at over 80 years of age (elderly-onset [EO] group) with 119 patients who developed RA at 40-59 years of age (non-elderly onset [non-EO] group). We also investigated the characteristics and clinical course of 19 patients who developed RA at over 80 and who received biological disease-modifying anti-rheumatic drugs (bDMARDs). RESULTS: The mean DAS28-ESR (DAS) and HAQ-DI (HAQ) of the EO were significantly higher in comparison to the non-EO group (4.91±1.31 vs 4.41±1.47, p=0.043, 1.2±0.9 vs 0.5±0.6, p<0.01). For the first treatment, 87.3% in the EO group received conventional synthetic DMARDs (csDMARDs), none received MTX. The rate of prednisolone (PSL) administration in the EO group was significantly higher than the non-EO group (56.4% vs 30.3%, p<0.01). The DAS and HAQ were significantly decreased in both groups, while the HAQ of the EO group was higher than the non-EO group. The decrease in DAS and HAQ of the PSL users was significantly greater than the non-PSL users (ΔDAS: 2.55±1.83 vs 1.83±1.23, p<0.01, ΔHAQ: 0.9±1.0 vs 0.3±0.6, p=0.027). Among the 19 patients with bDMARDs, the mean DAS and HAQ at baseline were significantly decreased 6 months later. CONCLUSION: Early use of csDMARDs and PSL was effective for functional disability of elderly-onset RA; however, some of them required bDMARDs. Further study should be performed to investigate the effectiveness of the early induction of MTX and bDMARDs.

The Efficacy of Minodronate in the Treatment of Glucocorticoid-induced Osteoporosis.

Objective To investigate the efficacy of minodronate in the treatment of glucocorticoid-induced osteoporosis (GIO). Methods The study population included patients in whom the administration of minodronate (50 mg, once every 4 weeks) had been newly started for the treatment of GIO in Niigata Rheumatic Center from 2012 to 2015. Patients who were bisphosphonate-naïve and those who switched from other bisphosphonates were classified into the naïve and switch groups, respectively. The changes in the bone mineral density (BMD) and bone metabolic markers after one year of minodronate treatment were retrospectively evaluated. We also compared the BMD and bone turnover marker changes of minodronate-naïve patients with those in whom alendronate or risedronate had been prescribed as a first bisphosphonate (control group). Results Minodronate was prescribed to 142 patients, and data were successfully obtained from 120 patients. New vertebral fractures were observed in 5 of the 142 patients; 1 fracture occurred during the cessation of minodronate for dental treatment, and 3 patients already had multiple vertebral fractures before the initiation of minodronate. The patients' tartrate-resistant acid phosphatase 5b (TRACP-5b) (-27.0%, p<0.001) and bone alkaline phosphatase (BAP) (-15.7%, p<0.01) levels were decreased, but no patients showed a decrease to below the normal range. One year of treatment with minodronate significantly increased the lumbar BMD in the naïve (+3.9%, p<0.001) and switch (+2.3%, p<0.001) groups. Although the femoral BMD did not change to a significant extent overall, the patients with a low young adult mean (YAM) (<80%) at baseline showed a significant increase in their femoral BMD (+2.1%, p=0.034) values. Compared with the control group, the minodronate-naïve group showed a significant decrease in the TRACP-5b levels and a significant increase in the lumbar BMD. Conclusion The administration of minodronate appears to be an effective treatment for GIO.

Efficacy and safety of infliximab: A comparison with other biological disease-modifying anti-rheumatic drugs.

OBJECTIVES: The intensification of infliximab (IFX) treatment, involving escalation of the dose and shortening of interval, was approved in Japan in July 2009. We consider IFX intensification therapy to be preferable for patients with treatment-resistant active rheumatoid arthritis (RA). We retrospectively compared the efficacy of IFX with that of other bDMARDs in methotrexate (MTX)-resistant patients. METHODS: Patients who satisfied the following criteria were enrolled: (i) those who started bDMARDs between February 2011 and December 2016, and (ii) those who required bDMARDs after 180 d of MTX treatment. We compared 33 patients who had been treated with IFX (IFX group) and 146 who had received other bDMARDs treatment (non-IFX group). RESULTS: IFX was administered at a dose of 6.98 mg/kg/8-week equivalent at 52 weeks. Clinical disease activity index clinical remission (CDAI-CR) was achieved in 49 of the 179 patients at 52 weeks and 13 of these 49 patients received IFX. Logistic regression analysis showed that treatment with IFX was an important variable for the achievement of CDAI-CR at 52 weeks (odds ratio 2.69, 95% confidence interval 1.13-6.42). The severity and frequency of adverse events did not differ. CONCLUSION: Intensification of IFX was effective and well tolerated for MTX resistant patients.

Plantar pressure and surgical indication of toe arthroplasty for rheumatoid forefoot deformity.

OBJECTIVES: The objective of this study is to clarify the surgical indication for rheumatoid forefoot deformity according to background characteristics and plantar pressure. METHODS: Patients with rheumatoid arthritis were divided into a non-surgical group (group N) and a surgical group (group S). The former consisted of 225 ft, and the latter consisted of 88 ft. DAS28, Japanese Society for Surgery of the Foot rheumatoid arthritis foot and ankle scale (JSSF scale) and hallux valgus angle (HVA) were evaluated as background characteristics. Distribution of peak pressure as plantar pressure was measured in nine sections. RESULTS: In groups N and S, the mean DAS28 was 3.6 and 3.0, the mean JSSF scale was 81.1 and 63.0, and the mean HVA was 19.9° and 35.3°, respectively. The mean peak pressure of group S at the first and third metatarsophalangeal joints was significantly higher compared with group N. Significant differences between the two groups were also seen in Δ pressure (the difference between the maximum and minimum peak pressure values). The cut-off values were 75.0 for JSSF scale, 24.9° for HVA and 3.94 kg/cm2 for Δ pressure. CONCLUSIONS: The combined assessment of HVA and Δ pressure was found to be useful as an indication for surgical treatment of the forefoot.

TIARP attenuates autoantibody-mediated arthritis via the suppression of neutrophil migration by reducing CXCL2/CXCR2 and IL-6 expression.

TNFα-induced adipose-related protein (TIARP) is a six-transmembrane protein expressed on macrophages, neutrophils and synoviocytes. We reported recently that mice deficient in TIARP (TIARP-/-) spontaneously develop arthritis and are highly susceptible to collagen-induced arthritis (CIA) with enhanced interleukin (IL)-6 production. However, the effects of TIARP on neutrophils and fibroblast-like synoviocytes (FLS) have not been elucidated. We analyzed the roles of TIARP in K/BxN serum transfer model using TIARP-/- mice. Arthritis in TIARP-/- mice transferred with K/BxN serum was significantly exacerbated compared with WT mice. We characterized the differences in neutrophils between wild-type (WT) and TIARP-/- mice by DNA microarray. Overexpression of CXCR1 and CXCR2 was noted in TIARP-/- neutrophils. Neutrophils of TIARP-/- mice showed strong migration activity, which was markedly facilitated by CXCL2 in vitro and in vivo. Moreover, enhanced production of CXCL2 and IL-6 and cell proliferation was noted in TIARP-/- TNFα-stimulated FLS. Blockade of IL-6R significantly attenuated serum-transferred TIARP-/- arthritis with diminished neutrophil recruitment in joints. Our findings suggested that TIARP independently down-regulated CXCL2 and IL-6 production by FLS, and the expression of chemokine receptors (CXCR1 and CXCR2) in neutrophils, with resultant reduction of neutrophil migration into arthritic joints.

High triglyceride is a risk factor for silent osteonecrosis of the femoral head in systemic lupus erythematosus.

The purpose of this study was to clarify the factors related to silent osteonecrosis of the femoral head (ONFH) in patients with systemic lupus erythematosus (SLE). Seventy-eight patients with SLE were selected on the basis of having been newly diagnosed and requiring high-dose prednisolone, including pulse therapy with methylprednisolone, as the initial treatment. All the patients initially underwent MRI at 3 months after the start of corticosteroid treatment to detect any early changes in the femoral head. These examinations were then performed again 3 months later. Laboratory parameters were evaluated at the start of steroid treatment and at 1 month thereafter. By 3 months after the start of corticosteroid treatment, silent ONFH was diagnosed by MRI in 21 patients (26.9 %), being bilateral in 11 patients and unilateral in 10. The occurrence of silent ONFH was not related to SLE disease activity index, serological activity, or renal function; it was also unrelated to body mass index (BMI), body surface area (BSA), and the initial dose of prednisolone per unit body weight. However, the total cholesterol level at 4 weeks after the start of steroid treatment tended to be higher in patients with silent ONFH. Patients with a higher triglyceride level showed a significantly higher frequency of silent ONFH both before (p = 0.002) and 4 weeks after (p = 0.036) steroid initiation.A high triglyceride level is an important risk factor for silent ONFH in patients with SLE, and large-scale epidemiologic surveys of such early events are needed in this patient population.