The Relationships Between Pain-Catastrophizing Subcomponents and Multiple Pain-Related Outcomes in Japanese Outpatients with Chronic Pain: A Cross-Sectional Study.

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.

Randomized open-label [corrected] non-inferiority trial of acetaminophen or loxoprofen for patients with acute low back pain.

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.

Multiple subcutaneous xanthogranuloma at juxta-articular sites with bone cystic changes resembling rheumatoid arthritis: A case report.

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.

Hallux valgus deformity after total ankle arthroplasty for rheumatoid arthritis: A case report.

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.

Autoantibodies to IgG/HLA class II complexes are associated with rheumatoid arthritis susceptibility.

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.

Association between preoperative pain intensity of MTP joint callosities of the lesser toes and fore-mid-hindfoot deformities in rheumatoid arthritis cases.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Comparison of a self-administered foot evaluation questionnaire (SAFE-Q) between joint-preserving arthroplasty and resection-replacement arthroplasty in forefoot surgery for patients with rheumatoid arthritis.

OBJECTIVES: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: Joint-preserving arthroplasty resulted in better patient-based outcomes than resection-replacement arthroplasty.

Bruton tyrosine kinase (Btk) suppresses osteoblastic differentiation.

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.

IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro.

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.

Validation of the Japanese version of the pain self-efficacy questionnaire in Japanese patients with chronic pain.

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.

Validity, reliability, and assessment sensitivity of the Japanese version of the short-form McGill pain questionnaire 2 in Japanese patients with neuropathic and non-neuropathic pain.

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.

In vivo kinematics of three-component mobile-bearing total ankle replacement in rheumatoid ankle with talocalcaneal arthrodesis and spontaneous talocalcaneal fusion.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Modified Sauvé-Kapandji procedure for rheumatoid wrists: a long-term study with a minimum follow-up of 5 years.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Prevalence of gastroesophageal reflux disease symptoms and related factors in patients with rheumatoid arthritis.

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.

Vitamin K2 administration is associated with decreased disease activity in patients with rheumatoid arthritis.

OBJECTIVES: 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. METHODS: 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 of >4.5 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. RESULTS: 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). CONCLUSIONS: VitK2 may have the potential to improve disease activity besides osteoporosis in RA.

Discordance of global assessment between the patients and physicians predicts 9-year pain-related outcomes in rheumatoid arthritis patients.

Introduction: Perspectives regarding the disease state often differ between patients with rheumatoid arthritis (RA) and physicians. The aim of the present longitudinal cohort study was to investigate the impact of the discordance in global assessments between patients and physicians on 9-year pain-related outcomes in patients with rheumatoid arthritis. Method: Sixty-eight consecutive outpatients with rheumatoid arthritis on their first visit to a tertiary center were included. Baseline measurements included demographic data, drugs used, disease activity, and a modified Health Assessment Questionnaire (mHAQ). Discordance in global assessment between patients and physicians at baseline was defined as 10 mm higher in the patient global assessment (PGA) than in the physician global assessment. A 9-year follow-up assessment included pain intensity, the European Quality of Life 5 Dimensions 3 Level (EQ-5D-3L) scale, Pain Catastrophizing Scale (PCS), Hospital Anxiety and Depression Scale (HADS), Pain Disability Assessment Scale (PDAS), and Pain Self-Efficacy Questionnaire (PSEQ). Results: The number of patients with discordance was 26 (38%) in 68 patients. Patients with a 10 mm higher PGA than the physician global assessment at baseline measurements had significantly worse pain intensity, PCS score, PSEQ score, and EQ-5D-3L score measurements at the 9-year follow-up than those with concordance. A higher mHAQ score and 10 mm higher PGA at baseline were significantly independently associated with the EQ-5D-3L scale score and pain intensity at the 9-year follow-up. Conclusion: This longitudinal cohort study suggested that discordance in global assessment between patients and physicians modestly predicted worse 9-year pain-related outcomes in patients with rheumatoid arthritis.

Serum level of oxidative stress marker is dramatically low in patients with rheumatoid arthritis treated with tocilizumab.

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.

Nkx3.2-induced suppression of Runx2 is a crucial mediator of hypoxia-dependent maintenance of chondrocyte phenotypes.

Hypoxia is a key factor in the maintenance of chondrocyte identity. However, crucial chondrogenic transcription factors in the Sox families are not activated in this phenomenon, indicating that other pathways are involved. Nkx3.2 is a well-known chondrogenic transcription factor induced by Sonic hedgehog (Shh); it suppresses a key osteogenic transcriptional factor, Runt-related transcription factor 2 (Runx2), to maintain the chondrogenic phenotype in mesenchymal lineages. The purpose of this study was to examine the function of Nkx3.2 in hypoxia-dependent maintenance of chondrocyte identity. C3H10T1/2 pluripotent mesenchymal cells were cultured with rh-BMP2 (300 ng/ml) to induce chondrogenesis under normoxic (20% O(2)) or hypoxic (5% O(2)) conditions. Immunohistological detection of Nkx3.2 in a micromass cell culture system revealed that hypoxia promoted expression of the Nkx3.2 protein. Real-time RT-PCR analysis revealed that hypoxia promoted Nkx3.2 mRNA expression and suppressed Runx2 mRNA expression; however, Sox9 mRNA expression was not altered by oxygen conditions, as previously described. Over-expression of exogenous Nkx3.2 promoted glycosaminoglycan (GAG) production and inhibited Runx2 mRNA expression and, based on a dual luciferase assay, Runx2 promoter activity. Interestingly, downregulation of Nkx3.2 using RNAi abolished hypoxia-dependent GAG production and restored Runx2 mRNA expression and promoter activity. These results demonstrated that Nkx3.2-dependent suppression of Runx2 was a crucial factor in hypoxia-dependent maintenance of chondrocyte identity.