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Aim To explore the characteristics of psychiatric morbidity in chronic pain patients who present with or without fibromyalgia. Methods Patients are referred to our chronic pain clinic from primary medical institutions, as we are a secondary medical institution. Although some patients have chronic pain, they have no clear organic disorder such as rheumatoid arthritis to account for the pain. Among the 367 new patients seen during the period from March 2009 to August 2012, 347 patients underwent psychiatric evaluation in face‐to‐face interviews with mental health specialists before a physical examination. Results Of the 347 patients examined, at least one psychiatric diagnosis was made for 94.6%. The average number of DSM‐IV‐TR diagnoses was 1.46 in the 330 chronic pain patients who had at least one psychiatric diagnosis. The breakdown of the number of psychodiagnoses was one in 60.8%, two in 27.1%, three in 4.9%, and more than three in 2.3% chronic pain patients with or without fibromyalgia. In fibromyalgia patients, the highest relative frequencies were found for somatoform disorders (76%), followed by dysthymic disorder (17%) and major depressive disorder (15%). In patients without fibromyalgia, the highest relative frequencies were found for somatoform disorders (64%), followed by major depressive disorder (15%) and dysthymic disorder (14%). Psychiatric disorders were found in 96.9% of fibromyalgia patients, and in 93.5% of chronic pain patients without fibromyalgia in Japan (no significant difference using chi‐square test). Conclusion Results show that chronic pain patients with or without fibromyalgia are extremely likely to be diagnosed with a psychiatric disorder., Psychodiagnoses of fibromyalgia patients and chronic pain patients without fibromyalgia.

Background Current worldwide clinical practice guidelines recommend acetaminophen as the first option for the treatment of acute low back pain. However, there is no concrete evidence regarding whether acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) is more effective for treating acute low back pain (LBP) in Japan. The present study aimed to investigate whether acetaminophen treatment for acute musculoskeletal pain was comparable with loxoprofen (a traditional NSAID in Japan) treatment. Methods Of the 140 patients with acute LBP who visited out-patient hospitals, 127 were considered eligible and were randomly allocated to a group taking acetaminophen or one taking loxoprofen. As primary outcome measure, pain intensity was measured using a 0–10-numeric rating scale (NRS). Moreover, pain disability, pain catastrophizing, anxiety, depression, and quality of life, as well as adverse events, were assessed as secondary outcomes. The primary outcome was tested with a noninferiority margin (0.84 on changes in pain-NRS), and the secondary outcomes were compared using conventional statistical methods at week 2 and week 4. Results Seventy patients completed the study (acetaminophen: 35, loxoprofen: 35). The dropout rates showed no significant difference between the two medication-groups. We found that the mean differences of changes in pain-NRS from baseline to week 2 or 4 between the two medication groups were not statistically beyond the noninferiority margin (mean [95% confidence interval]: −0.51 [−1.70, 0.67], at week 2 and −0.80 [−2.08, 0.48] at week 4). There were no consistent differences between the two medication groups in terms of secondary outcomes. Conclusions The results suggest that acetaminophen has comparable analgesic effects on acute LBP, based on at least a noninferiority margin, compared with loxoprofen at 4 weeks. Acetaminophen seems to be a reasonable first-line option for patients with acute LBP in Japan.

Xanthogranuloma is a benign disease represented as histiocytosis with lipoid deposition which usually occurs in children, but rarely in adults. We report a case of an adult patient with multiple subcutaneous xanthogranuloma at juxta-articular sites with bone cystic changes, manifesting similar clinical profiles to rheumatoid arthritis. Although very rare, we should consider the possibility of xanthogranulomatosis in the diagnosis of rheumatoid arthritis, especially in atypical cases.

Objective Semaphorin 4D (Sema4D)/CD100 has pleiotropic roles in immune activation, angiogenesis, bone metabolism, and neural development. We undertook this study to investigate the role of Sema4D in rheumatoid arthritis (RA). Methods Soluble Sema4D (sSema4D) levels in serum and synovial fluid were analyzed by enzyme-linked immunosorbent assay. Cell surface expression and transcripts of Sema4D were analyzed in peripheral blood cells from RA patients, and immunohistochemical staining of Sema4D was performed in RA synovium. Generation of sSema4D was evaluated in an ADAMTS-4–treated monocytic cell line (THP-1 cells). The efficacy of anti-Sema4D antibody was evaluated in mice with collagen-induced arthritis (CIA). Results Levels of sSema4D were elevated in both serum and synovial fluid from RA patients, and disease activity markers were correlated with serum sSema4D levels. Sema4D-expressing cells also accumulated in RA synovium. Cell surface levels of Sema4D on CD3+ and CD14+ cells from RA patients were reduced, although levels of Sema4D transcripts were unchanged. In addition, ADAMTS-4 cleaved cell surface Sema4D to generate sSema4D in THP-1 cells. Soluble Sema4D induced tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) production from CD14+ monocytes. IL-6 and TNFα induced ADAMTS-4 expression in synovial cells. Treatment with an anti-Sema4D antibody suppressed arthritis and reduced proinflammatory cytokine production in CIA. Conclusion A positive feedback loop involving sSema4D/IL-6 and TNFα/ADAMTS-4 may contribute to the pathogenesis of RA. The inhibition of arthritis by anti-Sema4D antibody suggests that Sema4D represents a potential therapeutic target for RA.

Objective.To evaluate the longterm safety and efficacy of subcutaneous tocilizumab (TCZ-SC) as monotherapy in patients with rheumatoid arthritis (RA).Methods.Of 346 patients who received 24 weeks of double-blind treatment with either TCZ-SC monotherapy, 162 mg every 2 weeks (q2w); or intravenous TCZ (TCZ-IV) monotherapy, 8 mg/kg every 4 weeks; 319 patients continued to receive TCZ-SC q2w in the 84-week open-label extension (OLE) of the MUSASHI study (JAPICCTI-101117). Efficacy, safety, and immunogenicity were evaluated for all patients treated with TCZ during 108 weeks.Results.The proportions of patients who achieved American College of Rheumatology 20/50/70 responses, low disease activity [28-joint Disease Activity Score (DAS28) ≤ 3.2], or remission (DAS28 < 2.6) at Week 24 were maintained until Week 108. The incidences of adverse events and serious adverse events were 498.3 and 16.9 per 100 patient-years (PY), respectively. The overall safety of TCZ-SC monotherapy was similar to that of TCZ-IV monotherapy. Rates of injection site reactions (ISR) through 108 weeks remained similar to rates through 24 weeks. ISR were mild and did not cause any patient withdrawals. No serious hypersensitivity events (including anaphylactic reactions) occurred. Anti-TCZ antibodies were present in 2.1% of patients treated with TCZ-SC monotherapy.Conclusion.TCZ-SC monotherapy maintained a favorable safety profile and consistent efficacy throughout the 108-week study. Like TCZ-IV, TCZ-SC could provide an additional treatment option for patients with RA.

Hallux valgus (HV) deformity is associated with hindfoot valgus deformity. We experienced a case that suggests the possibility that valgus correction for varus hindfoot with bony ankylosis of the subtalar joint by total ankle arthroplasty may have caused a forefoot HV deformity, despite adequate valgus correction.

Objectives The present study sought to examine associations between the pain-catastrophizing subcomponents and multiple pain-related outcomes in Japanese individuals with chronic pain. Methods A cross-sectional study design was employed with 213 chronic pain outpatients. The participants were recruited from 3 units at a university hospital and from a pain clinic at a municipal hospital. Study measures were used to assess pain catastrophizing, anxiety, depression, pain interference, and pain severity. Results Path analysis with multiple pain-related outcomes while controlling for age and gender revealed that the Helplessness subcomponent was associated with anxiety, depression, pain interference, and pain severity. The Magnification subcomponent was related to anxiety and depression, and the Rumination subcomponent accounted for the variance of pain interference. Discussion The present results suggested the important role of helplessness across cultural backgrounds. It also provides guidance on the application of cognitive behavioral techniques for chronic pain management in Japan.

Objective The objective of this study was to define the validity, reliability, and assessment sensitivity of the Japanese version of the Short-Form McGill Pain Questionnaire 2 (SF-MPQ-2-J). Design This is a cross-sectional study. Patients and Methods The original SF-MPQ-2 was translated into Japanese to create the SF-MPQ-2-J, and the cross-cultural equivalence of assessment tool for Japanese patients was validated. The reliability of the SF-MPQ-2-J was assessed using internal consistency, reliability coefficients (Cronbach's α), and reproducibility coefficients (intraclass correlation coefficient) obtained using 234 patients with chronic pain. SF-MPQ-2-J validity was assessed based on associations identified between total and subscale scores compared with other assessment methods. A confirmatory factor analysis (CFA) was also performed to test the theoretical structure of the SF-MPQ-2-J. Results The internal consistencies calculated included continuous pain, α = 0.893; intermittent pain, α = 0.875; predominantly neuropathic pain, α = 0.917; affective descriptors, α = 0.857; and total score, α = 0.907. The reproducibility coefficients calculated included continuous pain, ρ = 0.81; intermittent pain, ρ = 0.78; predominantly neuropathic pain, ρ = 0.85; affective descriptors, ρ = 0.75; and total score, ρ = 0.83. The CFA showed that the model fit of the readily interpretable subscales was acceptable, and the goodness of fit index value was 0.917. In addition, the mean predominantly neuropathic pain subscale score was found to be significantly higher for patients with neuropathic pain vs non-neuropathic pain. Conclusion These findings suggest that the reliability and validity of the SF-MPQ-2-J are excellent, and the SF-MPQ-2-J represents a cross-cultural equivalent to SF-MPQ-2. Consequently, the latter is suitable for research and clinical use, and for discriminating neuropathic pain from non-neuropathic pain.

Summary Patients with rheumatoid arthritis showed greater response to 18-month administration of daily teriparatide especially in the increase of bone formation markers at 1 month and femoral neck bone mineral density at 18 months compared to postmenopausal osteoporosis patients.

Objectives The present study aimed to develop the Japanese version of the Pain Self-Efficacy Questionnaire (PSEQ-J) and to evaluate its psychometric properties. Design Cross-sectional design. Setting A pain clinic, a neurosurgery unit, and an orthopedic surgery unit in one university hospital and a pain clinic in a municipal hospital. Methods One hundred and seventy-six participants completed study measures, which included 1) the PSEQ-J, 2) the Hospital Anxiety and Depression Scale, 3) the Pain Catastrophizing Scale, 4) the Medical Outcome Study Short-Form 36, 5) the Pain Disability Assessment Scale, and 6) the Short-Form McGill Pain Questionnaire. Results The PSEQ-J demonstrated adequate reliability and validity. Hierarchical multiple regression analyses showed that pain self-efficacy as measured with the PSEQ-J accounted for a significant proportion of the variance on the measures administered in the present study. The PSEQ-J was most strongly associated with social activity. Conclusions The results demonstrated that the PSEQ-J has adequate psychometric properties, supporting its use in clinical and research settings and suggest that the PSEQ-J may be particularly strongly associated with more social and less physical activity.

It is important to perform accurate bone cutting for the tibia and talus and to adjust soft-tissue balance when performing total ankle arthroplasty in rheumatoid arthritis cases with complex deformities to avoid prosthesis edge loading. We studied 38 cases with rheumatoid arthritis. A custom-made surgical guide was used for 24 cases since January 2007 to produce accurate osteotomies; the remaining cases used a conventional osteotomy guide. The tibial/talar component angular surface angles and tilting angle between components were measured with x-rays during standing. The error angle of the tibial bone cut was 1.9 ± 1.5 degrees in the conventional group compared with 1.0 ± 0.8 degrees in the custom-made group (P = 0.02). The tilting angle between components was 0.3 ± 0.4 degrees in the custom-made group compared with 1.1 ± 1.4 degrees in the conventional group (P = 0.01). The custom-made surgical guide based on preoperative 3-dimensional evaluation helped produce accurate and stable bone cutting. These benefits were enhanced by using malleolar sliding osteotomy to control the soft-tissue balance, with subsequent tilt between components being nearly parallel in the standing postoperative radiograph.

It is often that patients with rheumatoid arthritis (RA) who require ankle surgeries already have the degeneration of talocalcaneal joints. When talocalcaneal joint was fused, whether operatively or spontaneously, ankle kinematics would be affected. The purpose of this paper was to study in vivo kinematics of mobile-bearing total ankle replacement (TAR) in rheumatoid ankle with concomitant talocalcaneal arthrodesis or with preexisting spontaneous talocalcaneal fusion.Thirteen TARs in ten patients with RA, in whom talocalcaneal joints had already been fused spontaneously or surgically, were studied. Fluoroscopic images were obtained while each patient was walking with full weightbearing on the implanted ankle. Thereafter tibio-talar motion was analyzed by 2D/3D registration technique.Average tibio-talar motion was 4.0 ± 5.3° for plantarflexion and 6.6 ± 0.3° for dorsiflexion. Average range of internal/external rotation, inversion/eversion and AP translation was 3.8 ± 1.3°, 2.7 ± 1.0° and 1.6 ± 0.6 mm, respectively.Mobility of mobile-bearing TAR with talocalcaneal fusion was small during the stance phase of gait, but clinically measured ROM was mostly preserved. The movements of internal/external rotation and AP translation were allowed to a certain degree, but not of inversion/eversion. Even though the movement of inversion/eversion is limited, talocalcaneal arthrodesis could be accompanied with mobile-bearing TAR in rheumatoid ankles.

We performed a modified Sauvé-Kapandji procedure for treating disorders of distal radioulnar joint in patients with rheumatoid arthritis (RA). This procedure involves resecting the distal part of the ulna, rotating the resected portion by 90° and fixating it with the distal part of the radius for shelf plasty. The purpose of this study was to examine the clinical and radiographic outcomes of this procedure with more than 5 years' follow-up.We studied 32 wrists of 27 RA patients with the mean follow-up of 93.1 months after operation. Pain, grip strength and range of motion of the wrist were examined clinically, while two indices for evaluation of ulnar and palmar translation of the carpus, carpal translation index and palmar carpal subluxation ratio were calculated on radiographs.The wrist pain reduced in all cases. Range of motion increased significantly regarding pronation and supination but decreased significantly regarding flexion. Change in grip power was not significant. No significant differences were recognized between radiographic indices, suggesting carpal alignment was maintained well throughout the follow-up period.We think this procedure could be applied for distal radioulnar joint disorders in RA patients with promising clinical as well as radiographic outcomes over a long period.

It has been suggested that interleukin-6 (IL-6) plays a key role in the pathogenesis of rheumatoid arthritis (RA), including osteoporosis not only in inflamed joints but also in the whole body. However, previous in vitro studies regarding the effects of IL-6 on osteoblast differentiation are inconsistent. The aim of this study was to examine the effects and signal transduction of IL-6 on osteoblast differentiation in MC3T3-E1 cells and primary murine calvarial osteoblasts. IL-6 and its soluble receptor significantly reduced alkaline phosphatase (ALP) activity, the expression of osteoblastic genes (Runx2, osterix, and osteocalcin), and mineralization in a dose-dependent manner, which indicates negative effects of IL-6 on osteoblast differentiation. Signal transduction studies demonstrated that IL-6 activated not only two major signaling pathways, SHP2/MEK/ERK and JAK/STAT3, but also the SHP2/PI3K/Akt2 signaling pathway. The negative effect of IL-6 on osteoblast differentiation was restored by inhibition of MEK as well as PI3K, while it was enhanced by inhibition of STAT3. Knockdown of MEK2 and Akt2 transfected with siRNA enhanced ALP activity and gene expression of Runx2. These results indicate that IL-6 negatively regulates osteoblast differentiation through SHP2/MEK2/ERK and SHP2/PI3K/Akt2 pathways, while affecting it positively through JAK/STAT3. Inhibition of MEK2 and Akt2 signaling in osteoblasts might be of potential use in the treatment of osteoporosis in RA.

The retention of the anti-rheumatic agent tocilizumab (TCZ) has not been well documented in patients with rheumatoid arthritis (RA). We conducted an observational study to compare the retention of TCZ and anti-tumour necrosis factor (TNF) drugs in the treatment of patients with RA.We reviewed continuation rates and causes of discontinuation of biological agents (biologics) by assessing medical records of patients with RA who were administered biologics at our institute from September 1999 to April 2012, using the Osaka University Biologics for Rheumatic Diseases (BiRD) registry.A total of 401 patients were included. TCZ, infliximab (IFX), etanercept (ETN), and adalimumab (ADA) were administered to 97, 103, 143, and 58 patients, respectively. There were some differences between the baseline characteristics of the groups. The median duration (range) of TCZ, IFX, ETN, and ADA administration was 2.5 (0.1-12.6), 1.9 (0.0-7.7), 2.9 (0.0-11.3), and 1.3 (0.0-3.4) years, respectively. Continuation rates for TCZ and ETN were significantly higher than those for IFX and ADA. Multivariate analyses showed that discontinuation due to lack or loss of efficacy was significantly less common in the TCZ group than in the other groups. Discontinuation due to overall adverse events was not significantly different between treatment groups.TCZ and ETN show better retention than IFX or ADA in the treatment of RA.

Gastroesophageal reflux disease (GERD) is common in patients with many chronic diseases, but has not been well recognized in rheumatoid arthritis (RA). We investigated the prevalence of GERD symptoms in 278 outpatients with RA and their association with such clinical factors as age, sex, height, weight, body mass index, medications drugs, and functional status evaluated by the Modified Health Assessment Questionnaire (MHAQ). GERD symptoms were evaluated by Frequency Scale for the Symptoms of GERD (FSSG). The mean FSSG score for all patients was 5.6, and 82 patients were considered to have GERD symptoms (FSSG score ≥8), thus the overall prevalence of GERD symptoms was 29.5%. MHAQ score and height were significantly higher and lower, respectively, and prednisolone usage was significantly more in the patients with GERD symptoms than those without. These three clinical factors were also significantly associated with GERD symptoms by univariate logistic regression. Multivariate logistic regression analysis demonstrated that MHAQ was the only clinical factor related to GERD symptoms. In conclusion, the prevalence of GERD symptoms in RA patients was high and strongly associated with decreased functional status, suggesting that physicians should pay attention to GERD symptoms in RA management, especially for patients with low functional status.

To clarify the difference of patient-based outcome between joint-preserving arthroplasty and resection-replacement arthroplasty in forefoot surgery for patients with rheumatoid arthritis (RA).A total of 63 feet of 49 RA patients who underwent forefoot surgery were asked to answer pre-operative and post-operative self-administered foot evaluation questionnaire (SAFE-Q). Patients were treated with either (1) metatarsal head resection-replacement arthroplasty (28 feet, post-operative mean age 63.8 years, follow-up 4.2 years, DAS28-CRP 2.2) or (2) metatarsophalangeal joint-preserving arthroplasty (35 feet, post-operative mean age 63.1 years, follow-up 3.6 years, DAS28-CRP 2.1) at each surgeon's discretion.Mean pre-operative and post-operative subscale scores of SAFE-Q of group (1) and (2) were as follows. Pain and pain-related [(1) pre-op 36.8 to post-op 75.0 vs. (2) pre-op 42.2 to post-op 82.6], physical functioning and daily-living [(1) 43.2-68.8 vs. (2) 52.778.1], social functioning [(1) 44.3-72.0 vs. (2) 52.5-81.9], general health and well-being [(1) 48.4-68.4 vs. (2) 45.5-84.4], and shoe-related [(1) 30.1-50.3 vs. (2) 30.6-64.4]. Both general health and well-being subscale scores (p 0.05) and shoe-related subscale scores (p 0.05) were significantly more improved in group (2) compared with group (1).Joint-preserving arthroplasty resulted in better patient-based outcomes than resection-replacement arthroplasty.

To determine whether preoperative pain intensity in callosities of the lesser toe metatarsopharangeal (MTP) joint was associated with the grade of fore-mid-hindfoot deformities, because rheumatoid arthritis (RA) foot deformity includes the whole part of foot, and curiously differences between cases in the pain intensity of MTP joint callosities are often observed.We evaluated 24 feet that had undergone forefoot surgery [August, 2014 - December, 2015] for painful lesser toe MTP joint deformity (callosities) in RA cases. A preoperative self-administered foot evaluation questionnaire (SAFE-Q) and pressure distribution information for foot function were also investigated. X-rays of the whole lower extremities and foot at weight-bearing were used to check fore-mid-hindfoot deformities.Group M (mild) [n = 9] included patients with the pain visual analog scale (VAS) less than 40 mm, while group S (severe) [n = 15] included patients whose VAS was over 40 mm. Group M showed stronger hindfoot valgus and pronated (abducted) deformity, and group M showed higher pressure on the first MTP joint compared with group S.These observations reconfirm that hindfoot valgus deformity and/or pronated (abducted) foot deformity affects the forefoot loading distribution, subsequently the pain of callosities in lesser toe MTP joints could be decreased.

Previous studies have demonstrated that oxygen environment is an important determinate factor of cell phenotypes and differentiation, although factors which affect pericellular oxygen concentration (POC) in murine chondrogenic cell culture remain unidentified. Oxygen concentrations in vivo were measured in rabbit musculoskeletal tissues, which were by far hypoxic compared to 20% O(2) (ranging from 2.29 ± 1.16 to 4.36 ± 0.51%). Oxygen concentrations in murine chondrogenic cell (C3H10T1/2) culture medium were monitored in different oxygen concentrations (20% or 5%) in the incubator and in different medium volumes (3,700 or 7,400 μl) within 25-cm(2) flasks. Chondrogenic differentiation was assessed by glycosaminoglycan production with quantitative evaluation of Alcian blue staining in 12-well culture dishes. Expression of chondrogenic genes, aggrecan, and type II collagen α1, was examined by quantitative real-time polymerase chain reaction. Oxygen concentrations in medium decreased accordingly with the depth from medium surface, and POC at Day 6 was 18.99 ± 0.81% in 3,700-μl medium (1,480-μm depth) and 13.26 ± 0.23% in 7,400-μl medium (2,960-μm depth) at 20% O(2) in the incubator, which was 4.96 ± 0.08% (1,480-μm depth) and 2.83 ± 0.42% (2,960-μm depth) at 5% O(2), respectively. The differences of POC compared by medium volume were statistically significant (p = 0.0003 at 20% and p = 0.001 at 5%). Glycosaminoglycan production and aggrecan gene expression were most promoted when cultured in moderately low POC, 1,000 μl (2,960-μm depth) at 20% O(2) and 500 μl (1,480-μm depth) at 5% O(2) in 12-well culture dishes. We demonstrate that medium volume and oxygen concentration in the incubator affect not only POC but also chondrogenic differentiation.

Two cases of subcutaneous soft tissue infection in 30 RA patients treated with tocilizumab are reported. In both patients, local redness, swelling, and heat were observed around the affected site. WBC spikes and such local findings were suggested to be clinically useful for the early detection of low-grade subcutaneous infection in RA patients whose disease is tightly controlled with tocilizumab. Of note, the C-reactive protein (CRP) level and temperature lacked clinical utility for such detection.

A 76-year-old man with rheumatoid arthritis, who had been treated with oral prednisolone and methotrexate, presented with high fever and generalized fatigability. Laboratory data demonstrated marked pancytopenia, which we first regarded as a side effect of methotrexate, and leucovorin was administered with granulocyte-colony stimulating factor and transfusions. Because no recovery was recognized, however, bone marrow aspiration was performed, by which hemophagocytic syndrome was diagnosed. After corticosteroid pulse therapy was initiated, the patient's symptoms were rapidly attenuated and laboratory data rapidly normalized.

A 59-year-old woman with rheumatoid arthritis was treated quite successfully with infliximab, but her serum aminotransferase levels were markedly elevated; this was diagnosed as acute exacerbation of hepatitis B and she was treated with lamivudine, and infliximab was discontinued. The rheumatoid arthritis disease activity was uncontrollable after the discontinuation of infliximab, and we therefore initiated tocilizumab treatment (after obtaining the patient's informed consent) together with lamivudine prophylaxis. After tocilizumab administration her rheumatoid arthritis disease activity was significantly attenuated, and the activity has remained low, without re-exacerbation of the hepatitis, for more than 2 years since the initiation of the tocilizumab.

Although total ankle replacement is routinely used for rheumatoid arthritis of the ankle, it has been hampered by early implant failures such as loosening and subsidence of the tibial component due to poor bone quality. To prevent this complication, total ankle replacement augmented by a specially designed hydroxyapatite coating was used in 14 patients (16 feet). Patients were reviewed after an average follow-up of 23.1 months, and the mean clinical rating scale significantly improved from 30.7/100 points preoperatively to 65.9/100 at final follow-up, especially with respect to pain relief. Radiographs taken immediately postoperatively and at final follow-up were analyzed for the position and sinking of the tibial component. The position was evaluated by measurement of the alpha and beta angles, formed by the tibial long axis and tibial component on anteroposterior and lateral radiographs, respectively. The mean alpha and beta angles were 87.4 degrees and 79.3 degrees postoperatively and 87.7 degrees and 81.0 degrees at final follow-up, respectively. No significant change was noted in either angle between the immediate postoperative views and at final follow-up, and no significant subsidence was noted. Radiographs were also assessed for the presence of a lucent zone: 1 case demonstrated a clear zone between hydroxyapatite and bone, 9 cases between hydroxyapatite and the tibial component, and 6 cases between the tibial component and bone. These results suggest that hydroxyapatite helps to secure implant fixation firmly to the bone, making it a useful augmentation for tibial bone atrophy in total ankle replacement for rheumatoid arthritis.

The matrix extracellular phosphoglycoprotein (MEPE) gene is highly expressed in tumors that cause oncogenic hypophosphatemic osteomalacia (OHO). MEPE is also known as one of the bone-tooth matrix proteins and is associated with bone mineralization. We developed a rabbit polyclonal antibody directed against recombinant human MEPE (rhMEPE) after cloning its cDNA from the cDNA library of a nasal tumor tissue causing OHO. Using this antibody, we analyzed the distribution of MEPE in human bones by immunohistochemistry. In bone specimens from normal subjects, MEPE was predominantly expressed by osteocytes and not by osteoblasts. In bone specimens from patients with osteomalacia, however, MEPE was focally expressed by deeply located osteocytes. We also compared the MEPE positivity of osteocytes in mineralized bone and non-mineralized osteoid obtained from patients with osteomalacia and osteoporosis. Among osteomalacia patients, MEPE positivity was seen in 87.5 +/- 8.6% of the osteocytes from mineralized bone compared with 7.8 +/- 6.4% of those from osteoid. Among osteoporosis patients, MEPE positivity was found in 95.3 +/- 0.5% of the osteocytes from mineralized bone compared with 4.9 +/- 5.7% of those from osteoid. MEPE was mainly expressed by osteocytes embedded in the matrix of mineralized bone from patients with osteomalacia or osteoporosis. Our data provide the first histological evidence that MEPE is predominantly expressed by osteocytes in human bone, with significant expression by osteocytes within mineralized bone.

Objective To investigate the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) at sites of joint destruction in rheumatoid arthritis (RA) and to correlate it with the production of matrix metalloproteinases (MMPs). Methods Reverse transcription-polymerase chain reaction was performed to study the existence of EMMPRIN in synovial tissue derived from RA and osteoarthritis (OA) patients. In situ hybridization with a human complementary DNA specific for EMMPRIN and immunohistochemistry were performed to characterize the EMMPRIN-expressing cells at sites of joint destruction, including bone. Northern blot analysis was performed to detect the level of expression of EMMPRIN messenger RNA (mRNA) in synovial tissue. The production of MMP-1 and MMP-3 by synovial tissue from RA patients was examined by enzyme-linked immunosorbent assay. Results Expression of EMMPRIN mRNA was detected in synovium from 9 of 11 patients with RA and 1 of 5 patients with OA. The presence of mRNA encoding EMMPRIN was recognized in the invasive synovium at sites of joint destruction in RA but not OA. Fibroblast-like synovial cells and granulocytes were demonstrated to express EMMPRIN mRNA. MMP-1 and MMP-3 production by synovial tissue was correlated with levels of expression of EMMPRIN mRNA, as detected by Northern blotting. Conclusion The expression of EMMPRIN stimulates the production of MMP-1 and MMP-3 in the synovial tissue of affected joints in RA. The results of this study suggest that EMMPRIN may be one of the important factors in progressive joint destruction in RA.

Specific HLA class II alleles are strongly associated with susceptibility to rheumatoid arthritis (RA); however, how HLA class II regulates susceptibility to RA has remained unclear. Recently, we found a unique function of HLA class II molecules: their ability to aberrantly transport cellular misfolded proteins to the cell surface without processing to peptides. Rheumatoid factor (RF) is an autoantibody that binds to denatured IgG or Fc fragments of IgG and is detected in 70-80% of RA patients but also in patients with other diseases. Here, we report that intact IgG heavy chain (IgGH) is transported to the cell surface by HLA class II via association with the peptide-binding groove and that IgGH/HLA class II complexes are specifically recognized by autoantibodies in RF-positive sera from RA patients. In contrast, autoantibodies in RF-positive sera from non-RA individuals did not bind to IgGH/HLA class II complexes. Of note, a strong correlation between autoantibody binding to IgG complexed with certain HLA-DR alleles and the odds ratio for that allele's association with RA was observed (r = 0.81; P = 4.6 × 10(-5)). Our findings suggest that IgGH complexed with certain HLA class II alleles is a target for autoantibodies in RA, which might explain why these HLA class II alleles confer susceptibility to RA.

Rheumatoid arthritis (RA) is characterized by the accumulation of CD4+ memory T cells in the inflamed synovium. To address the mechanism, we analyzed chemokine receptor expression and found that the frequency of CXC chemokine receptor (CXCR)4 expressing synovial tissue CD4+ memory T cells was significantly elevated. CXCR4 expression could be enhanced by IL-15, whereas stromal cell-derived factor (SDF)-1, the ligand of CXCR4, was expressed in the RA synovium and could be increased by CD40 stimulation. SDF-1 stimulated migration of rheumatoid synovial T cells and also inhibited activation-induced apoptosis of T cells. These results indicate that SDF-1-CXCR4 interactions play important roles in CD4+ memory T cell accumulation in the RA synovium, and emphasize the role of stromal cells in regulating rheumatoid inflammation.

The authors evaluated a modified Lapidus technique for 21 rheumatoid hallux valgus deformities. The technique corrects the deformity by performing arthrodesis of the first tarsometatarsal joint and preservation of the first metatarsophalangeal (MTP) joint. The authors clinically studied patients' subjective improvement of pain and footwear comfort, as well as their satisfaction with the outcome of the surgery. The study also analyzed radiographic changes of the hallux valgus angle (HVA) and two intermetatarsal angles, one between the first and the second (M1/2) and the other between the first and the fifth (M1/5). They were measured before the surgery, 3 weeks after the surgery, and at the last follow-up. Pain relief was great or moderate in 17 feet and footwear comfort was improved in 16 feet. Fifteen patients were satisfied or satisfied with some reservations. The average HVA significantly decreased from 44.1 degrees preoperatively to 10.6 postoperatively and significantly increased again to 29.1 at the last follow-up. The average M1/2 and M1/5 significantly decreased postoperatively (from 13 to 8.3 and from 32.2 to 21.1, respectively), and the reduction of M1/2 remained at the last follow-up (8.7), while M1/5 significantly increased again (28.3). This modified Lapidus technique is a useful method for rheumatoid hallux valgus deformity, which can preserve the first MTP joint.

We report 3 cases of nonunited avulsion fracture of the intercondylar eminence of the tibia. Characteristics of the clinical symptoms were limitation of knee extension, pain at knee extension, and a small amount of anterior instability. For the patient with a normal anterior cruciate ligament (ACL), the fragment was fixed by sutures with a button after curettage of the fibrous tissue. Two patients underwent endoscopic ACL reconstruction using quadrupled semitendinosus tendon because their ACLs had degenerated. Since the technique of ACL reconstruction under arthroscopic control has been well refined, endoscopic ACL reconstruction is considered to be 1 of the surgical options for nonunited avulsion fracture with symptomatic anterior instability if the ACL is degenerated.

Objective. Numerous cytokines are expressed in lesions of synovial hyperplasia of patients with rheumatoid arthritis (RA), and their pathophysiological contributions have been the subject of speculation. These genes are regulated by the transcription factor NFkB which in turn is activated by tumour necrosis factor-a (TNF-a) and cytokines. In this study we examined the inhibition of the production of pro-inflammatory cytokines, adhesion molecule and matrix metalloproteinase (MMP) from synovial tissue of patients with RA by the introduction of synthetic double-stranded DNA with high affinity for the NFkB binding site. Method. NFkB decoy oligonucleotides (ODN ) were introduced with the aid of the haemagglutinating virus of Japan (HVJ )-liposome method into synovial tissue or synovial cells derived from patients with RA. The levels of interleukin-1b (IL-1b), IL-6, TNF-a, intercellular adhesion molecule-1 (ICAM-1) and MMP-1 were determined by means of enzyme-linked immunosorbent assay ( ELISA) and Northern blotting analysis. A cell counting kit was used to study the effect of NFkB decoy ODN on synovial cell proliferation. Results. The production of these mediators was significantly inhibited by the introduction of NFkB decoy ODN compared with the effect of scrambled decoy ODN. Transfection of NFkB decoy ODN resulted in a significant inhibition of synovial cell proliferation as compared with that of scrambled decoy ODN. Conclusion. The results demonstrated in this study suggest the potential usefulness of NFkB decoy ODN for gene therapy of inflammatory synovitis of RA. K : Transcription factor decoy, Gene therapy, Rheumatoid arthritis, HVJ-liposome, Synovial cells.

The Tec family of nonreceptor tyrosine kinases has been shown to play a key role in inflammation and bone destruction. Bruton tyrosine kinase (Btk) has been the most widely studied because of its critical role in B cells. Furthermore, recent evidence has demonstrated that blocking Btk signaling is effective in ameliorating lymphoma progression and experimental arthritis. The role of Btk in osteoblastic differentiation has not been well elucidated. In this study, we demonstrated the role of Btk in osteoblastic differentiation and investigated the effects of a Btk inhibitor on osteoblastic differentiation in mouse preosteoblastic MC3T3-E1 cells, primary calvarial osteoblasts, and bone marrow stromal ST2 cells. Btk expression was detected in all three cell lines. Btk inhibition stimulated mRNA expression of osteoblastic markers (alkaline phosphatase, osteocalcin, and osterix) and promoted mineralization of the extracellular matrix. In addition, Btk knockdown caused increased mRNA expression of osteoblastic markers. Furthermore, Btk inhibition suppressed the phosphorylation of mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NFκB), and protein kinase Cα (PKCα). Our results indicate that Btk may regulate osteoblastic differentiation through the MAPK, NFκB, and PKCα signaling pathways.

Vitamin K2 (VitK2) is reported to induce not only bone mineralization of human osteoblasts and apoptosis of osteoclasts, but also apoptosis of rheumatoid arthritis (RA) synovial cells, while its clinical effect on disease activity of RA remains unknown.158 female RA patients (mean age 62.5 years) who had not been treated with warfarin, biologics, or teriparatide were enrolled in this study. VitK2 (45 mg/day) was administered in 70 patients with a serum undercarboxylated osteocalcin level of4.5 ng/ml or with decreased bone mineral density in spite of the treatment with other anti-osteoporosis medications, regardless of RA disease activity. A longitudinal study was conducted in 52 patients who were additionally treated with VitK2 without changing their other medications for three months.In the cross-sectional study, as compared to the VitK2-naïve group (n = 88), the VitK2-treated group (n = 70) showed lower serum CRP (1.7 ± 0.2 vs. 0.5 ± 0.1 mg/dl; P 0.001), MMP-3 (220.4 ± 21.9 vs. 118.0 ± 14.4 ng/ml; P 0.001), and DAS28-CRP (2.9 ± 0.1 vs. 2.4 ± 0.1; P 0.05). In the longitudinal study, patients who were additionally treated with VitK2 showed significant decreases in serum CRP (1.1 ± 0.2 to 0.6 ± 0.2 mg/dl; P 0.001), MMP-3 (160.1 ± 25.6 to 125.0 ± 17.8 ng/ml; P 0.05), and DAS28-CRP (3.1 ± 0.2 to 2.4 ± 0.1; P 0.001).VitK2 may have the potential to improve disease activity besides osteoporosis in RA.

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Background The Nkx3.2 transcription factor promotes chondrogenesis by forming a positive regulatory loop with a crucial chondrogenic transcription factor, Sox9. Previous studies have indicated that factors other than Sox9 may promote chondrogenesis directly, but these factors have not been identified. Here, we test the hypothesis that Nkx3.2 promotes chondrogenesis directly by Sox9-independent mechanisms and indirectly by previously characterized Sox9-dependent mechanisms. Methodology/Principal Findings C3H10T1/2 pluripotent mesenchymal cells were cultured with bone morphogenetic protein 2 (BMP2) to induce endochondral ossification. Overexpression of wild-type Nkx3.2 (WT-Nkx3.2) upregulated glycosaminoglycan (GAG) production and expression of type II collagen α1 (Col2a1) mRNA, and these effects were evident before WT-Nkx3.2-mediated upregulation of Sox9. RNAi-mediated inhibition of Nkx3.2 abolished GAG production and expression of Col2a1 mRNA. Dual luciferase reporter assays revealed that WT-Nkx3.2 upregulated Col2a1 enhancer activity in a dose-dependent manner in C3H10T1/2 cells and also in N1511 chondrocytes. In addition, WT-Nkx3.2 partially restored downregulation of GAG production, Col2 protein expression, and Col2a1 mRNA expression induced by Sox9 RNAi. ChIP assays revealed that Nkx3.2 bound to the Col2a1 enhancer element. Conclusions/Significance Nkx3.2 promoted primary chondrogenesis by two mechanisms: Direct and Sox9-independent upregulation of Col2a1 transcription and upregulation of Sox9 mRNA expression under positive feedback system.

Regarding the pathobiology of rheumatoid arthritis, oxidative stress induced by reactive oxygen species is an important mechanism that underlies destructive and proliferative synovitis. Abundant amounts of reactive oxygen species have been detected in the synovial fluid of inflamed rheumatoid joints. It is reported that drugs that block tumor necrosis factor-α reduce the oxidative stress marker levels in patients with rheumatoid arthritis. In this study, we measured reactive oxygen species using a free radical analytical system in patients with rheumatoid arthritis treated with disease-modifying antirheumatic drugs, tumor necrosis factor-α-blocking drugs (infliximab, etanercept), and an interleukin-6-blocking drug (tocilizumab). The serum level of oxidative stress was drastically low in patients with rheumatoid arthritis treated with tocilizumab, suggesting that interleukin-6 blocking therapy reduces not only joint damage, but also vascular degeneration in patients with rheumatoid arthritis. We believe that such a drastic effect would reduce the incidence of cardiovascular events and mortality in patients with rheumatoid arthritis.

Hallux valgus is very common in rheumatoid arthritis (RA) and mostly accompanied by varus deformity of the first metatarsal bone, which is often corrected in surgeries for hallux valgus in nonarthritic condition, but rarely in RA. We performed the replacement of the first metatarsophalangeal (MTP) joint with a Swanson hinge toe implant accompanied with open-wedge osteotomy of the first metatarsal bone, aiming at reconstruction of a functioning first MTP joint without recurrence of hallux valgus. Fifteen feet of 11 patients with RA were studied with a mean follow-up period of 45.1 months. The American Orthopaedic Foot and Ankle Society (AOFAS) scale improved significantly from 39 points preoperatively to 81.7 at the last follow-up. The hallux valgus angle (HVA), angle between the first and second metatarsal bones (M1/2), and that between the first and fifth (M1/5), measured on standing anteroposterior radiographs, decreased significantly from 49.8 degrees, 16.7 degrees, and 34.4 degrees preoperatively to 10.9 degrees, 8.7 degrees, and 22.2 degrees at the last follow-up, respectively. Union of the corrected first metatarsal bone was recognized in all cases and no such problems as infection, dislocation, or implant fracture were observed. These data suggest that replacement of the first MTP joint with a Swanson implant accompanied with open-wedge osteotomy of the first metatarsal bone can be a useful option for hallux valgus in RA.

Femoral component rollback and tibial rotation were evaluated using lateral radiographs taken during passive knee flexion under fluoroscopy in NexGen Legacy Posterior Stabilized Flex (Zimmer, Warsaw, Ind) total knee arthroplasties (TKAs; 30 with mobile insert and 26 with fixed insert). Measured maximal flexion angle demonstrated no significant differences. Femoral component rollback was observed predominantly in TKAs with fixed insert in more than 45 degrees flexion and correlated with maximal flexion angle in each group. Tibial internal rotation was more significant in TKAs with mobile insert in maximal flexion. However, tibial internal rotation from 90 degrees to maximal flexion, which demonstrated correlation with maximal flexion angle in each group, did not show significant difference. The kinematic differences between 2 inserts seemed to have little relevance to the maximal flexion angle.

Objective. To investigate the morphology and function of multinucleated bone-resorbing giant cells derived from CD14-positive cells in the synovial fluids (SF) of patients with rheumatoid arthritis (RA) or osteoarthritis (OA). Methods. CD14-positive cells were obtained by magnetic-activated cell sorting of primary cultures of mononuclear cells from the SF. Multinucleated bone-resorbing giant cells were induced from the CD14-positive cells in the presence or absence of cytokines. We examined various characteristics, including osteoclast markers, fusion index and bone-resorption activities of the multinucleated giant cells. Results. Multinucleated giant cells were induced from the CD14-positive cells in the SF of the RA and OA patients by the addition of interleukin (IL)-3, IL-5 and IL-7, or granulocyte–macrophage colony-stimulating factor (GM-CSF), respectively. These multinucleated giant cells were positive for tartrate-resistant acid phosphatase (TRAP), carbonic anhydrase II, actin, vitronectin receptor and the calcitonin receptor. However, the average values for the number of nuclei, fusion index and boneresorption functions of the SF cells from the RA patients were significantly higher than those derived from the OA patients. Conclusion. These results suggest that the induction and activities of multinucleated bone-resorbing giant cells may play a pivotal role in bone destruction, and that these processes may be enhanced significantly in RA patients.