Complications and features after joint surgery in rheumatoid arthritis patients treated with tumour necrosis factor-alpha blockers: perioperative interruption of tumour necrosis factor-alpha blockers decreases complications?

OBJECTIVE: TNF-alpha blockers reportedly increase the risk of complications in rheumatic patients following surgery. Whereas deep venous thrombosis (DVT) is a significant complication after orthopaedic surgery of the lower limbs, the risk for DVT in RA patients receiving TNF blockers remains unclear. The aim of this study was to identify complications that can be attributed to the use of TNF-alpha blocker therapy. METHODS: In a retrospective 1:1 pair-matched case-control study, 64 anti-TNF-treated RA surgeries (TNF group) and 64 surgeries treated with conventional DMARDs (DMARDS group) were evaluated for surgical site infection (SSI), DVT and recurrence of arthritis (flare-up). Multivariate logistic regression analysis was performed to test the association of SSI or DVT with the putative risk factors. RESULTS: Regression analysis identified the use of TNF blockers as a risk factor for SSI [P = 0.036; odds ratio (OR) = 21.80] and development of DVT (P = 0.03; OR = 2.83) after major orthopaedic surgery: 12.5% (8/64) of the patients in the TNF group had SSI, whereas 2% (1/64) of those in the DMARDs group had SSI. Fifty-one per cent (23/45) of the TNF group, but only 26% (12/45) of the DMARDs group was DVT positive. Flare-ups during the perioperative period were found in 17.2% (11/64) of all patients, and no delay in wound healing occurred in either group. CONCLUSIONS: These data suggest that the use of TNF blockers is a likely cause of SSI and DVT development in RA patients following major orthopaedic surgery.

Tumour necrosis factor alpha-stimulated gene-6 inhibits osteoblastic differentiation of human mesenchymal stem cells induced by osteogenic differentiation medium and BMP-2.

To better understand the molecular pathogenesis of OPLL (ossification of the posterior longitudinal ligament) of the spine, an ectopic bone formation disease, we performed cDNA microarray analysis on cultured ligament cells from OPLL patients. We found that TSG-6 (tumour necrosis factor alpha-stimulated gene-6) is down-regulated during osteoblastic differentiation. Adenovirus vector-mediated overexpression of TSG-6 inhibited osteoblastic differentiation of human mesenchymal stem cells induced by BMP (bone morphogenetic protein)-2 or OS (osteogenic differentiation medium). TSG-6 suppressed phosphorylation and nuclear accumulation of Smad 1/5 induced by BMP-2, probably by inhibiting binding of the ligand to the receptor, since interaction between TSG-6 and BMP-2 was observed in vitro. TSG-6 has two functional domains, a Link domain (a hyaluronan binding domain) and a CUB domain implicated in protein interaction. The inhibitory effect on osteoblastic differentiation was completely lost with exogenously added Link domain-truncated TSG-6, while partial inhibition was retained by the CUB domain-truncated protein. In addition, the inhibitory action of TSG-6 and the in vitro interaction of TSG-6 with BMP-2 were abolished by the addition of hyaluronan. Thus, TSG-6, identified as a down-regulated gene during osteoblastic differentiation, suppresses osteoblastic differentiation induced by both BMP-2 and OS and is a plausible target for therapeutic intervention in OPLL.

Spontaneous multiple insufficiency fractures after pelvic abscess and sepsis in a rheumatoid arthritis patient treated with high-load corticosteroid therapy: a case report.

We report the unique occurrence and treatment of spontaneous multiple insufficiency fractures after sepsis in a patient with rheumatoid arthritis (RA). The patient was a 53-year-old woman with a 13-year history of RA. Her disease activity was not influenced by a disease-modifying antirheumatic drug (DMARD) regimen that included bucillamine, D-penicillamine, gold, sulfasalazine, and methotrexate. Due to an increased disease activity, her DMARD treatment regimen was changed to leflunomide. She had also undergone corticosteroid therapy with prednisolone ranging from 10 to 15 mg daily over the previous 8 years. She first presented with a wound infection at the surgical site of resection arthroplasty on her left foot, which had caused hematogenous dissemination that led to pelvic abscess and sepsis. For the next 2 years, she experienced multiple insufficiency fractures in parts of the ilium, sacral body, sacral ala, three thoraco-lumbar vertebral bodies (T12, L1, and L2), and subcapital femoral neck without low energy trauma. Postmenopausal osteoporosis, pelvic abscess, sepsis, decreasing daily activity, high RA disease activity, and high-load corticosteroid therapy were considered to be the causes of these fractures. Nonspecific symptoms such as low back pain and fever delayed diagnosis, which may have led to secondary fractures. Although her course after treatment was satisfactory during the study period, we recommend taking repetitive radiographs to detect insufficiency fracture for RA patients with continuing pain and reducing the corticosteroid dose to prevent infection and fracture.

A novel closed-wedge high tibial osteotomy procedure to treat osteoarthritis of the knee: hybrid technique and rehabilitation measures.

High tibial valgus osteotomy (HTO) is an established treatment for medial-compartment osteoarthritis of the knee. We have combined medial open and lateral closed-wedge HTO (hybrid closed-wedge HTO) to overcome the limitations of traditional closed-wedge HTO. Our new hybrid procedure has the following advantages: (1) the bone block removed is smaller in size; (2) the procedure yields optimal geometric characteristics for bone healing; (3) there is no step-off at the lateral osteotomy site; (4) the lateral cortex of the proximal and distal fragments is attached firmly by the oblique osteotomy; and (5) early full weight-bearing walking is possible. This procedure is effective in treating medial-compartment osteoarthritis accompanied by patellofemoral osteoarthritis. The indications for this procedure include a willingness and ability to comply with the postoperative rehabilitation program; a diagnosis of either medial-compartment osteoarthritis or complicated patellofemoral osteoarthritis; and preferably, an age of 70 years or younger, although this is not a strict constraint. Patients are permitted to stand using both legs on the day after surgery and walk with full weight bearing within 2 weeks of undergoing our novel HTO procedure. We describe the details of this surgical technique and the postoperative rehabilitation program for the patients who undergo this treatment.

Association of EMCN with susceptibility to rheumatoid arthritis in a Japanese population.

OBJECTIVE: Endomucin, an endothelial-specific sialomucin, is thought to facilitate "lymphocyte homing" to synovial tissues, resulting in the major histopathologies of rheumatoid arthritis (RA). We examined the association between RA susceptibility and the gene coding endomucin, EMCN. METHODS: Association studies were conducted with 2 DNA sample sets (initial set of 1504 patients, 752 controls; and validation set, 1113 patients, 940 controls) using 6 tag single-nucleotide polymorphisms (SNP) from the Japanese HapMap database. Immunohistochemistry for the expression of endomucin was conducted with synovial tissues from 4 patients with RA during total knee arthroplasty. Electromobility shift assays were performed for the functional study of identified polymorphisms. RESULTS: Within the initial sample set, the strongest evidence of an association with RA susceptibility was SNP rs3775369 (OR 1.20, p = 0.0075). While the subsequent replication study did not initially confirm the observed significant association (OR 1.13, p = 0.062), an in-depth stratified analysis revealed significant association in patients testing positive to anti-cyclic citrullinated peptide (anti-CCP) antibody in the replication data set (OR 1.15, p = 0.044). Investigating 2 sample sets, significant associations were detected in overall and stratified samples with anti-CCP antibody status (OR 1.17, p = 0.0015). Positive staining for endomucin was detected in all patients. The allele associated with RA susceptibility had a higher binding affinity for HEK298-derived nuclear factors compared to the nonsusceptible allelic variant of rs3775369. CONCLUSION: A significant association between EMCN and RA susceptibility was detected in our Japanese study population. The EMCN allele conferring RA susceptibility may also contribute to the pathogenesis of RA.

Iliopsoas bursitis-associated femoral neuropathy exacerbated after internal fixation of an intertrochanteric hip fracture in rheumatoid arthritis: a case report.

We present the case of a 63-year-old woman with a six-year history of rheumatoid arthritis (RA) and a left iliopsoas bursitis. Radiography had detected destructive changes in her hip joint associated with her bursitis, and she had reported some paresthesia along the left anterior distal thigh. Her pain and numbness remained tolerable, and her disease activity was well controlled until she accidentally fell on the floor, which resulted in an unstable intertrochanteric fracture of left femur with displacement of the proximal portion. The fracture was successfully treated with open reduction and internal fixation, but after the surgery, her femoral nerve palsy worsened. She subsequently underwent bursa excision after the failure of conservative treatment. Accordingly, after bursa excision, the postoperative course was uneventful, and her neurological symptoms gradually disappeared. We would recommend that bursa excision be considered even in cases of iliopsoas bursitis associated with mild femoral neuropathy when destructive changes in the hip joint are also present.

Risk factors for wrist surgery in rheumatoid arthritis.

To assess the risk factors for wrist surgery in a cohort of rheumatoid arthritis (RA) patients recruited and followed prospectively for 6 years. A linked registry study was performed using information from a large observational cohort of RA patients followed at the Institute of Rheumatology, Tokyo Women's Medical University. Baseline routine clinical and laboratory assessments were recorded. The data were analyzed using the multivariate Cox regression model that included variables such as gender, age, disease duration, a visual analog scale (VAS) generated by physicians, a patient-reported VAS for pain (VAS-pain), a VAS for general health, disability level using the Japanese version of the Health Assessment Questionnaire (J-HAQ), erythrocyte sedimentation rate, and serum levels of C-reactive protein and rheumatoid factor as potential risk factors. Of the 5,497 patients registered at baseline, 122 (2.22%) had surgery on one or both wrist joints. Multivariate Cox regression analysis of the variables revealed positive coefficients for J-HAQ and VAS-pain and that advanced age and long RA duration were associated with a reduced risk of wrist surgery. The hazard ratios were: 1.515 for J-HAQ, 1.126 for VAS-pain, 0.985 for age, and 0.964 for RA duration. Advanced age and long RA duration were associated with a decreased risk of wrist surgery, while J-HAQ and VAS-pain were associated with an increased risk. The identification of the risk factors for wrist surgery provides important insights into the course of the disease and its impact on patients, as well as the potential consequences for health care resource utilization planning.

Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Japanese population.

OBJECTIVE: STAT4 encodes a transcriptional factor that transmits signals induced by several key cytokines, and it might be a key molecule in the development of autoimmune diseases. Recently, a STAT4 haplotype was reported to be associated with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in Caucasian populations. This was replicated in a Korean RA population. Interestingly, the degree of risk of RA susceptibility with the STAT4 haplotype was similar in the Caucasian and Korean populations. The present study was undertaken to investigate the effect of STAT4 on susceptibility to RA and SLE in the Japanese. METHODS: We performed an association study using 3 independent Japanese RA case-control populations (total 3,567 cases and 2,199 controls) and 3 independent Japanese SLE populations (total 591 cases). All samples were genotyped using the TaqMan fluorogenic 5' nuclease assay for single-nucleotide polymorphism (SNP) rs7574865, which tags the susceptibility haplotype. The association of the SNP with disease susceptibility in each case-control study was calculated using Fisher's exact test, and the results were combined, using the Mantel-Haenszel method, to obtain combined odds ratios (ORs). RESULTS: We observed a significant association of the STAT4 polymorphism with susceptibility to both RA and SLE. The combined ORs for RA and SLE, respectively, were 1.27 (P = 8.4 x 10(-9)) and 1.61 (P = 2.1 x 10(-11)) for allele frequency distribution; these ORs were quite similar to those previously observed in the Caucasian population. CONCLUSION: We conclude that STAT4 is associated with RA and SLE in the Japanese. Our results indicate that STAT4 is a common genetic risk factor for autoimmune diseases, with similar strength across major racial groups.

A case of Castleman's disease associated with diffuse idiopathic skeletal hyperostosis and ossification of the posterior longitudinal ligament of the spine.

Castleman's disease (CD), diffuse idiopathic skeletal hyperostosis (DISH), and ossification of the posterior longitudinal ligament of the spine (OPLL) are three different entities. Castleman's disease displaying a variety of calcifications in the abdomen and/or pelvis has been reported in some papers. However, there were no reports suggesting an association between CD and ossification/calcification in spine and joints. So far, there has been no case report regarding the coexistence of these diseases in the literature. Herein, we detail a 75-year-old man suffering from CD who demonstrated the features of DISH with coexisting features of OPLL. The cardinal symptoms such as fatigue, high fever, and swollen glands in this case were reduced by corticosteroid therapy. However, it is possible to produce actual symptoms of ossifying/calcified diathesis of entheses and ligaments as a consequence, like the pathology of calcification found in the region of the spleen. In this paper, we describe this patient in order to discuss the association of these diseases.

The serum concentration of infliximab in cases of autologous blood donation for patients with rheumatoid arthritis.

Our aim was to determine whether the use of infliximab for rheumatoid arthritis (RA) patients is associated with an increased rate of postoperative complications. In this study we evaluated the serum concentration of infliximab to study the influence of autologous blood donation (AB donation) in patients who were administered infliximab and underwent total knee replacement (TKR). We examined five RA patients. Infliximab combined with methotrexate was administered at 3 mg/kg every 8 weeks for all patients. We carried out the TKR operation in the middle of the 8-week interval in which infliximab was administered. The AB donation consisted of 400 ml pooled AB drawn at one point 2 weeks following the final administration of infliximab. Serum infliximab levels were measured using an enzyme-linked immunosorbent assay. Mean serum infliximab levels were 5.46 +/- 5.62 microg/ml 2 weeks after the final administration of infliximab, 2.02 +/- 1.66 microg/ml just before the operation, and 1.48 +/- 1.31 microg/ml 1 day post operation. Moreover, the mean serum level in an autologous blood bag sampled just before AB donation was 5.02 +/- 4.79 microg/ml. This study indicated the serum level of infliximab in the stored blood remained at almost the same level as the collected autologous blood. However, even after autotransfusion those levels were decreased compared with levels measured just before the operation. Therefore, we conclude that there is little influence of AB donation on the risks of infliximab.

Disturbances of the symphysis pubis in rheumatoid arthritis: report of two cases.

We present two rheumatoid arthritis (RA) patients suffering from disturbances of the symphysis pubis. Radiography revealed one with pelvic ring disruption with symphysis pubis diastasis, and the other with osteolysis at both pubic rami and disruption of the superior aspect of the symphysis pubis. Both cases had received long-term corticosteroid therapy, including pulse therapy. We recommend reducing the corticosteroid dose to prevent disturbances of the symphysis pubis especially in RA patients on long-term steroid therapy.

Risk factors for total knee arthroplasty in rheumatoid arthritis.

We conducted a study to assess the predictive factors for total knee arthroplasty (TKA) in a cohort of rheumatoid arthritis (RA) patients recruited and followed prospectively for 5 years. A linked registry study using information from a large observational cohort of RA patients followed at the Institute of Rheumatology, Tokyo Women's Medical University (IORRA) was done. Baseline routine clinical and laboratory assessments were recorded. The data were analyzed using the multivariate piecewise-linear Cox (PL-Cox) regression model; the model initially included variables such as gender, age, duration of the disease, visual analog scale (VAS) generated by physicians (VAS-physician), patient-reported VAS for pain (VAS-pain), VAS for general health (VAS-GH), disability level using the Japanese version of the Health Assessment Questionnaire (J-HAQ), C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor (RF), and hemoglobin. Of the 3945 patients registered at baseline, 955 (24.2%) had pain or tenderness in their knee joints, and 114 (11.9%) had TKA surgery in one or both knee joints. On PL-Cox regression, the variables with positive coefficients were J-HAQ, VAS-pain, VAS-physician, and RF positive; advanced age was associated with a reduced risk of TKA. The hazard ratios were: 0.920 for age >60 years; 2.64 for J-HAQ <1.5; 1.01 for J-HAQ >1.5; 1.47 for VAS-pain >6 (cm); 1.20 for VAS-physician >4 (cm); and 2.08 for RF positive. The consistently predictive factors for TKA in RA were age, J-HAQ, VAS-pain, VAS-physician, and RF positive. Age greater than 60 years was associated with a decreased risk of TKA, while J-HAQ from 0 to 1.5, VAS-pain >6 (cm), and VAS-physician >4 (cm) were associated with an increased risk for TKA surgery. These results suggest that, when treating RA patients, physicians should pay particular attention to pain complaints, the patient's daily activity level, and the RF factor status.

Current topics in pharmacological research on bone metabolism: Promyelotic leukemia zinc finger (PLZF) and tumor necrosis factor-alpha-stimulated gene 6 (TSG-6) identified by gene expression analysis play roles in the pathogenesis of ossification of the posterior longitudinal ligament.

To understand the molecular pathogenesis of ossification of the posterior longitudinal ligament of the spine (OPLL), an ectopic bone formation disease, we performed cDNA microarray analysis on cultured ligament cells from OPLL patients to understand the molecular pathogenesis of OPLL. We identified promyelotic leukemia zinc finger (PLZF) as one of up-regulated genes and tumor necrosis factor-alpha-stimulated gene 6 (TSG-6) as one of down-regulated gene during osteoblastic differentiation. We investigated the roles of PLZF in the regulation of osteoblastic differentiation of human mesenchymal stem cells (hMSCs) and C2C12 cells. siRNA-mediated gene-silencing of PLZF resulted in a reduction of the expression of osteoblast-specific genes such as the alkaline phosphatase, collagen 1A1, Runx2/CBFA1, and osteocalcin genes in the presence of osteogenic differentiation medium (OS) in hMSCs. The overexpression of PLZF induced CBFA1 induction, suggesting that PLZF is an upstream regulator of CBFA1 and thereby participates in promoting the ossification of spinal ligament cells in OPLL patients. Adenovirus-mediated TSG-6 overexpression in hMSCs resulted in suppression of osteoblastic differentiation induced by either BMP-2 or OS. TSG-6 can bind to BMP-2 directly and thereby could inhibit BMP-2 signaling. Taken together, these findings indicate that PLZF and TSG-6 play important roles in early osteoblastic differentiation.

The promyelotic leukemia zinc finger promotes osteoblastic differentiation of human mesenchymal stem cells as an upstream regulator of CBFA1.

Ossification of the posterior longitudinal ligament of the spine (OPLL) is the leading cause of myelopathy in Japan and is diagnosed by ectopic bone formation in the paravertebral ligament. OPLL is a systemic high bone mass disease with a strong genetic background. To detect genes relevant to the pathogenesis of OPLL, we performed a cDNA microarray analysis of systematic gene expression profiles during the osteoblastic differentiation of ligament cells from OPLL patients (OPLL cells), patients with a disorder called ossification of yellow ligament (OYL), and non-OPLL controls together with human mesenchymal stem cells (hMSCs) after stimulating them with osteogenic differentiation medium (OS). Twenty-four genes were up-regulated during osteoblastic differentiation in OPLL cells. Zinc finger protein 145 (promyelotic leukemia zinc finger or PLZF) was one of the highly expressed genes during osteoblastic differentiation in all the cells examined. We investigated the roles of PLZF in the regulation of osteoblastic differentiation of hMSCs and C2C12 cells. Small interfering RNA-mediated gene silencing of PLZF resulted in a reduction in the expression of osteoblast-specific genes such as the alkaline phosphatase, collagen 1A1 (Col1a1), Runx2/core-binding factor 1 (Cbfa1), and osteocalcin genes, even in the presence of OS in hMSCs. The expression of PLZF was unaffected by the addition of bone morphogenetic protein 2 (BMP-2), and the expression of BMP-2 was not affected by PLZF in hMSCs. In C2C12 cells, overexpression of PLZF increased the expression of Cbfa1 and Col1a1; on the other hand, the overexpression of CBFA1 did not affect the expression of Plzf. These findings indicate that PLZF plays important roles in early osteoblastic differentiation as an upstream regulator of CBFA1 and thereby might participate in promoting the ossification of spinal ligament cells in OPLL patients.

COL6A1, the candidate gene for ossification of the posterior longitudinal ligament, is associated with diffuse idiopathic skeletal hyperostosis in Japanese.

STUDY DESIGN: Genetic screening of collagen 6A1 gene (COL6A1) in patients with diffuse idiopathic skeletal hyperostosis (DISH) recruited in Japan and the Czech Republic. OBJECTIVE: To investigate allelic associations between DISH and nucleotide variants of COL6A1. SUMMARY OF BACKGROUND DATA: DISH is a skeletal hyperostotic disease characterized by ligamentous ossification of the anterolateral side of the spine. Ossification of the posterior longitudinal ligament (OPLL) is a related disorder with DISH, and COL6A1 was identified as a susceptibility gene to OPLL. COL6A1 was examined for susceptibility in DISH patients from Japan and the Czech Republic. METHODS: Seven single nucleotide polymorphisms of COL6A1 were genotyped by direct sequencing. The allele frequencies were compared between 97 Japanese DISH patients and 298 Japanese controls, and between 96 Czech DISH patients and 96 Czech controls by chi2 test. RESULTS: The intron 32 (-29) single nucleotide polymorphisms of COL6A1 was significantly associated with the Japanese DISH patients (chi2 = 9.33; P = 0.0022), but not with the Czech DISH patients. CONCLUSIONS: Because COL6A1 could be a susceptibility to the occurrence of DISH and OPLL in the Japanese population, we consider that COL6A1 could be responsible for the hyperostotic state, leading to ectopic bone formation in the spinal ligament.