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ABSTRACT: The aim of this study was to investigate immunohistological changes in mitogen-activated protein kinases (MAPKs) in the synovium following treatment with golimumab, compared with methotrexate (MTX). We assessed synovial tissues for 13 different molecules to detect cytokine levels histologically from 10 methotrexate (MTX)-treated rheumatoid arthritis (RA) patients as controls and 10 golimumab plus MTX-treated RA patients. Synovium samples from both groups were assessed by hematoxylin and eosin (HE) staining and analyzed for expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), CD4 (T cells), CD8 (T cells), CD20 (B cells), CD68 (macrophages), receptor activator of nuclear (kappa) B ligand (RANKL), bromodeoxyuridine (BrdU), CD29 (β-1 integrin), phospho-p38 MAPK (Tyr180/Tyr182), phospho-p44/42 MAPK (ERK1/ERK2), and phospho-c-Jun N-terminal kinase (JNK), by an immunohistological examination. HE staining showed that there was a significant decrease in cell proliferation in the synovium in RA patients who received golimumab compared with the controls. TNF-α, IL-6, MMP3, BrdU, p38, and ERK were not seen at significant levels in either group. On the other hand, CD4, CD8, CD20, CD29, CD68, RANKL, and JNK were significantly decreased in the golimumab group compared with the control. Based on a histological analysis of the synovium, it appears that the efficacy of the treatment with golimumab may involve the inhibition of cell proliferation, with decreases in T cells, B cells, macrophages, β-1 integrin, RANKL, and JNK in the synovium, compared with MTX treatment, in RA.
Rheumatology International 01/2013; · 1.88 Impact Factor
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ABSTRACT: An artificial patch can be used in open and arthroscopic surgery in a massive rotator cuff tear but there is no evidence of biological attachment between the artificial patch and the cuff or bone tissue. We used an artificial polytetrafluoroethylene (PTFE) patch for the arthroscopic treatment for a massive rotator cuff tear. One year after surgery, we could undertake second-look arthroscopy to evaluate whether the PTFE patch was attached to cuff tissue and humeral bone with regard to histological features. We found a tight connection between the PTFE patch and bone, and also recognized smooth attachment to cuff tissue without proliferation of inflammatory cells in the synovium. We assessed the outcome of surgery using the American Shoulder and Elbow Surgeons (ASES) scale and range of motion before and after surgery: A score of 24 before surgery improved to 75 after surgery. MRI after surgery showed continuous low intensity from the PTFE patch to cuff and bone. This is the first report to describe the histological findings of PTFE patch reconstruction of massive rotator cuff tear after 1 year: A major biological reaction was not observed in this respect.
European Journal of Orthopaedic Surgery & Traumatology 12/2012; · 0.10 Impact Factor
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ABSTRACT: The aim of this study was to investigate the histological changes following the treatment with abatacept compared with methotrexate (MTX) by an immunohistological examination of synovial tissue for eleven different molecules to detect the expression patterns of cytokines. We histologically assessed the synovial tissues from 10 methotrexate (MTX)-treated RA patients as controls and 5 abatacept plus MTX-treated RA patients. The synovium samples from both group were assessed by hematoxylin and eosin (HE) staining and analyzed for their expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), CD20, CD68, vascular endothelial growth factor (VEGF), CD4, CD8, CD28, CD80, and CD86 by an immunohistological examination. HE staining showed that there was a decrease in cell proliferation in the synovium of the RA patients who received abatacept compared with the controls. TNF-α, IL-6, and VEGF were not significantly different in either of the groups. On the other hand, MMP-3, CD68, CD4, CD8, CD20, CD80, and CD86 were significantly decreased in the abatacept group compared with the control (P < 0.05). Based on the histological analysis of the synovium, it appears that the efficacy of the treatment with abatacept may involve the inhibition of cell proliferation, with decreases in the expression of MMP-3, CD68, CD4, CD8, CD20, CD80, and CD86 in the synovium. These findings indicate inhibition of not only T cells but also B cells and macrophages, which likely plays a role in the efficacy of abatacept in RA patients.
Rheumatology International 01/2012; · 1.88 Impact Factor
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ABSTRACT: In order to investigate the histological change in the secondary non-responder cases of adalimumab compared with methotrexate (MTX) treatment, we performed immunohistochemical examination of synovial tissue by seven different molecules to detect expression patterns of cytokines.
We histologically assessed synovial tissues from five MTX-treated rheumatoid arthritis (RA) patients as controls and five adalimumab plus MTX-treated RA patients after arthroscopic synovectomy in the knee joints. The synovium of both groups were assessed by hematoxylin and eosin (H&E) and analyzed the positive expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), B-cell precursor and mature B-cell transmembrane protein, CD20, macrophage marker, CD68, vascular endothelial growth factor (VEGF), receptor activator of nuclear (kappa) B ligand (RANKL) by immunohistochemical examination.
H&E staining showed the increase of vascular and cell proliferations in the synovium of the RA patients who received adalimumab compared with the controls. TNF-α, IL-6 and CD20 were not significantly different in either group. On the other hand, MMP-3 and CD68 showed a significant decrease in the adalimumab group compared with controls (P < 0.05). VEGF and RANKL were weakly positive in both groups.
Based on the histological analysis of synovium, the effect attenuation of adalimumab may be involved in vascular and cell proliferations; however, there was inhibition of the expression of CD68 and MMP-3 in synovium. These findings indicate CD68 and MMP-3 may have key roles in the mechanism of efficacy of adalimumab.
International Journal of Rheumatic Diseases 08/2011; 14(3):261-6. · 0.81 Impact Factor
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ABSTRACT: To determine what clinical factors relating to efficacy besides complications of orthopedic surgery for patients treated with anti-tumor necrosis factor (TNF)-α therapy (infliximab), we analyzed the clinical data of 52 cases of orthopedic surgery, such as total hip arthroplasy (THA), total knee arthroplasty (TKA), total shoulder arthroplasy (TSA), total elbow arthroplasty (TEA), arthroscopic synovectomy, foot arthroplasty, spine surgery, hand surgery and fracture.
We analyzed clinical factors including age, disease duration, preoperative C-reactive protein (CRP), disease activity score (DAS)-28, matrix metalloproteinase (MMP)-3, and rheumatoid arthritis particle-agglutination (RAPA) in 52 cases of rheumatoid arthritis (RA) undergoing orthopedic surgery. For complications of orthopedic surgery, signs of postoperative infection were recorded, including rubor, discharge, systemic infection and frequencies of wound dehiscence, as well as the incidence of any surgical complication requiring a secondary revision procedure were measured.
Signs of infection or surgical complications occurred in two of 52 patients (3.8%). There is significant correlation between RAPA and improvement of CRP 3 months after surgery; however, there is no correlation between infection and clinical factors including age, disease duration, preoperative CRP, MMP-3, RAPA and the period until surgery after infliximab infusion.
Infliximab did not increase the risk of either infections or surgical complications occurring in patients with RA within 1 year of orthopedic surgery. Improvement of CRP after surgery is likely to be due to infliximab for high RAPA in RA patients.
International Journal of Rheumatic Diseases 02/2011; 14(1):31-6. · 0.81 Impact Factor
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ABSTRACT: Fluvastatin (Fluv) is reported to induce apoptosis in rheumatoid arthritis (RA) synoviocytes through the blocking of protein geranylgeranylation. We report here our investigation of whether geranylgeranylacetone (GGA) induces cell death in RA synoviocytes. Synovial tissues were obtained from patients with RA at the time of total knee arthroplasty. Fibroblast-like synoviocytes (FLS) cultured in three passages were used for the experiments. The FLS were then cultured for 48 h in 48-well flat-bottomed plates containing various concentrations of GGA (0.1-4.0 microg/ml) and either 0.1 or 0.5 microM Fluv. We also examined the effect of GGA and Fluv in human fibroblasts from normal skin (CCD-25SK) and FLS from patients with osteoarthritis (OA). Cells demonstrating cell death were counted following trypan blue staining. In the absence of GGA, there was no apparent cell death, as evidence by trypan blue staining. Concentrations of GGA between 0.1 and 4.0 microg/ml induced cell death in RA FLS, but not in skin fibroblasts (CCD-25SK) nor OA FLS. The number of synoviocytes demonstrating cell death induced by 0.1 or 0.5 microM Fluv was significantly higher than that by the medium alone. In summary, we found that GGA induced cell death in RA FLS, suggesting that GGA may be a potential new therapeutic agent for RA as well as osteoporosis.
Modern Rheumatology 07/2009; 19(4):379-83. · 1.58 Impact Factor
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ABSTRACT: In order to investigate the histological change in effect attenuation cases of etanercept compared with methotrexate (MTX), we performed immunohistochemical examination by seven different molecules.
We histologically assessed synovial tissue from five MTX-treated rheumatoid arthritis (RA) patients as control and six etanercept and MTX-treated RA patients after synovectomy by arthroscopy. The synovium of both groups were assessed by hematoxylin and eosin (HE) and we also analysed the expression of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), B-cell precursors and mature B-cell transmembrane protein, CD20, macrophage marker, CD68, bromodeoxyuridine (BrdU) and vascular endothelial growth factor (VEGF) by immunohistochemistry.
HE staining showed vascular and cell proliferations of the synovium of the RA patients who received etanercept compared with the control MTX group. TNF-alpha and IL-6 were expressed in both groups.MMP-3 and CD68 expressed less significantly in the etanercept group compared with the control (P < 0.05). CD20 strongly expressed in the etanercept group significantly (P < 0.05). BrdU expressed in the synovium in the etanercept group significantly (P < 0.05). VEGF was not found overall in both group.
Based on the histological change of synovium, treatment by etanercept may be involved in vascular and cell proliferations with inhibition of the expression of CD68 and MMP-3 in synovium of RA patients. These findings indicate immunohistochemical change of synovium with etanercept is one of the mechanism of efficacy of etanercept.
International Journal of Rheumatic Diseases 04/2009; 12(1):7-13. · 0.81 Impact Factor
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Minako Murata,
Kazuo Yudo,
Hiroshi Nakamura, Junji Chiba,
Kazuki Okamoto,
Naoya Suematsu,
Kusuki Nishioka,
Moroe Beppu,
Kazuhiko Inoue,
Tomohiro Kato,
Kayo Masuko
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ABSTRACT: The objective of this article was to investigate the role and expression of a novel adipocytokine, angiopoietin-like-4 (ANGPTL4), in arthropathy. Human chondrocytes were obtained from articular cartilage of patients with rheumatoid arthritis (RA) and osteoarthritis (OA), who underwent total knee or hip arthroplasty. Isolated chondrocytes were cultured under hypoxic (95% N(2), 5% CO(2)) or normoxic conditions. The effects of hypoxia on ANGPTL4 expression were determined by real-time reverse transcription polymerase chain reaction and Western blot analysis. We examined the role of ANGPTL4 using small interference RNA or by stimulating chondrocytes with recombinant ANGPTL4 protein. ANGPTL4 expression in the articular cartilage specimens was examined by immunohistochemistry. Hypoxia induced a significant increase in ANGPTL4 production (p < 0.05). Incubation of chondrocytes in vitro with recombinant ANGPTL4 enhanced the expression of matrix metalloproteinase (MMP)-1 and MMP-3. Downregulation of ANGPTL4 mRNA expression by siRNA diminished the expression of MMP-1, but not that of MMP-3, suggesting that each proteinase has a distinct response to ANGPTL4. Although the in vitro responses of chondrocytes to hypoxia were similar between RA and OA samples, the in vivo expression of ANGPTL4 had unique disease-specific patterns, suggesting differences in oxygen tension in vivo. Human chondrocytes expressed ANGPTL4 and the expression was enhanced by hypoxia. ANGPTL4 might modulate cartilage metabolism by regulating MMPs.
Journal of Orthopaedic Research 01/2009; 27(1):50-7. · 2.81 Impact Factor
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Minako Murata,
Kazuo Yudo,
Hiroshi Nakamura, Junji Chiba,
Kazuki Okamoto,
Naoya Suematsu,
Kusuki Nishioka,
Moroe Beppu,
Kazuhiko Inoue,
Tomohiro Kato,
Kayo Masuko
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ABSTRACT: The objective of this article was to investigate the role and expression of a novel adipocytokine, angiopoietin-like-4 (ANGPTL4), in arthropathy. Human chondrocytes were obtained from articular cartilage of patients with rheumatoid arthritis (RA) and osteoarthritis (OA), who underwent total knee or hip arthroplasty. Isolated chondrocytes were cultured under hypoxic (95% N2, 5% CO2) or normoxic conditions. The effects of hypoxia on ANGPTL4 expression were determined by real-time reverse transcription polymerase chain reaction and Western blot analysis. We examined the role of ANGPTL4 using small interference RNA or by stimulating chondrocytes with recombinant ANGPTL4 protein. ANGPTL4 expression in the articular cartilage specimens was examined by immunohistochemistry. Hypoxia induced a significant increase in ANGPTL4 production (p < 0.05). Incubation of chondrocytes in vitro with recombinant ANGPTL4 enhanced the expression of matrix metalloproteinase (MMP)-1 and MMP-3. Downregulation of ANGPTL4 mRNA expression by siRNA diminished the expression of MMP-1, but not that of MMP-3, suggesting that each proteinase has a distinct response to ANGPTL4. Although the in vitro responses of chondrocytes to hypoxia were similar between RA and OA samples, the in vivo expression of ANGPTL4 had unique disease-specific patterns, suggesting differences in oxygen tension in vivo. Human chondrocytes expressed ANGPTL4 and the expression was enhanced by hypoxia. ANGPTL4 might modulate cartilage metabolism by regulating MMPs. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:50–57, 2009
Journal of Orthopaedic Research 07/2008; 27(1):50 - 57. · 2.81 Impact Factor
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ABSTRACT: Recent data suggest that vascular endothelial growth factor (VEGF) is involved in the pathogenesis of osteoarthritis (OA). Cartilage is an avascular tissue, leading to a low cartilage O2 level. Thus, in a variety of pathologic or physiologic conditions, VEGF is partly regulated by hypoxic stress. The implications of hypoxia for VEGF expression by OA chondrocytes, however, are not known. We investigated the regulatory system of VEGF in OA chondrocytes under hypoxic conditions. Chondrocytes were obtained from articular cartilage of patients with OA. Cells were cultured and then incubated under hypoxic (95% N2, 5% CO2) or normoxic conditions, with or without interleukin (IL)-1 (10 ng/mL) stimulation. The mitogen activated protein kinase (MAPK) inhibitors were also used. VEGF levels in the culture supernatants were measured using an enzyme-linked immunosorbent assay. Western blot analysis was used to examine the expression of hypoxia inducible factor (HIF)-1alpha. Hypoxia significantly increased VEGF levels (p<0.05). Hypoxia-induced VEGF secretion was abolished by p38MAPK inhibitor, but not by JNK inhibitor. In contrast, IL-1-induced VEGF secretion was blocked by JNK inhibitor, and not by p38MAPK inhibitor. Both hypoxia and IL-1-induced HIF-1alpha were attenuated by p38 MAPK and JNK inhibitors. We demonstrate that hypoxia and IL-1 induce VEGF production in chondrocytes through distinct MAPK signaling pathways, indicating that VEGF is induced in a HIF-1-dependent or -independent manner in chondrocytes.
Journal of Orthopaedic Research 07/2006; 24(7):1544-54. · 2.81 Impact Factor
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ABSTRACT: Recent data suggest that vascular endothelial growth factor (VEGF) is involved in the pathogenesis of osteoarthritis (OA). Cartilage is an avascular tissue, leading to a low cartilage O2 level. Thus, in a variety of pathologic or physiologic conditions, VEGF is partly regulated by hypoxic stress. The implications of hypoxia for VEGF expression by OA chondrocytes, however, are not known. We investigated the regulatory system of VEGF in OA chondrocytes under hypoxic conditions. Chondrocytes were obtained from articular cartilage of patients with OA. Cells were cultured and then incubated under hypoxic (95% N2, 5% CO2) or normoxic conditions, with or without interleukin (IL)-1 (10 ng/mL) stimulation. The mitogen activated protein kinase (MAPK) inhibitors were also used. VEGF levels in the culture supernatants were measured using an enzyme-linked immunosorbent assay. Western blot analysis was used to examine the expression of hypoxia inducible factor (HIF)-1α. Hypoxia significantly increased VEGF levels (p < 0.05). Hypoxia-induced VEGF secretion was abolished by p38MAPK inhibitor, but not by JNK inhibitor. In contrast, IL-1-induced VEGF secretion was blocked by JNK inhibitor, and not by p38MAPK inhibitor. Both hypoxia and IL-1-induced HIF-1α were attenuated by p38 MAPK and JNK inhibitors. We demonstrate that hypoxia and IL-1 induce VEGF production in chondrocytes through distinct MAPK signaling pathways, indicating that VEGF is induced in a HIF-1-dependent or -independent manner in chondrocytes. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 24:1544–1554, 2006
Journal of Orthopaedic Research 05/2006; 24(7):1544 - 1554. · 2.81 Impact Factor
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ABSTRACT: Aims: To investigate the efficacy and safety of leflunomide, including the side-effects, we assessed 84 rheumatoid arthritis (RA) patients who received leflunomide treatment.Methods: We analyzed the C-reactive protein (CRP), white blood cell count (WBC), KL-6, and visual analogue scale (VAS) scores, modified Stanford Health Assessment Questionnaire (MHAQ) score, American Rheumatism Association score (ACR20 and ACR50) within a time course after treatment with leflunomide. We treated 84 RA patients, 12 male and 72 female from 28 to 81-years-old, with an average age of 63.5 years. The patients were divided into three groups: a group consisting of 38 patients who received 100 mg/day of leflunomide for 3 days followed by 20 mg/day thereafter; a second group of 11 patients who received a no-loading dose of 10 mg/day; and a third group of 35 patients who received a no loading dose of 20 mg/day.Results: The 50% decrease of CRP seen in 2 weeks was 52% of the total of 84 patients. The WBC score did not change significantly after the medication was given. The KL-6 score did not change significantly, either. The VAS pain score improved 4 weeks later, and then further improved 8 weeks later. Therefore, RA patients using leflunomide obtained pain relief 4 weeks after commencing medication. The MHAQ score did not change significantly until 8 weeks after the patients started the medication. ACR20 was 62% and ACR50 was 38% at 8 weeks after treatment. The side-effects of leflunomide observed in our patients were rash, respiratory infection, diarrhea, nausea, alopecia, muscle pain, headache, dizziness and general fatigue. Twenty-three out of 84 patients experienced side-effects (27%), and 48/84 (57%) experienced withdrawal. In our hospital, there were no patients who developed severe interstitial pneumonia (IP) or who died after taking leflunomide; however, the incidence of side-effects of the 100 mg/day loading dose (42.1%) was 2.5 times higher than in the patients who received 20 mg/day (17.1%) of a no-loading dose.Conclusion: Because of this, it is possible that a 100 mg/day loading dose is a relatively high risk dose in terms of causing side-effects, especially for severely ill RA patients with a high CRP level.
APLAR Journal of Rheumatology. 08/2005; 8(2):114 - 118.
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ABSTRACT: 関節リウマチ(RA)の治療において生物学的製剤であるエタネルセプトが近年使用されているが,その効果減弱例に対して関節鏡視下滑膜切除を施行した7例88関節,男性2例,女性5例,平均年齢62(48～75)歳について術前c-reactive protein(CRP)とdisease activity scores(DAS)28を経時的に48週まで調べ,術中採取した滑膜を組織学的にtumor necrosis factor-alpha(TNF-α),interleukin-6(IL-6)およびreceptor activator of nuclear kappa B ligand(RANKL)の発現について調べた.その結果CRPは術前3.8±0.5mg/dlから術後48週で0.7±0.4mg/dlに有意に低下し,DAS28は術前6.3±0.6から術後48週で2.7±0.9に有意に低下した.エタネルセプト効果減弱例の滑膜はリンパ球浸潤,血管増生を示し,滑膜表層に多核の組織球の発現を認めた.免疫組織化学的検討ではTNF-αの発現は滑膜全体の細胞に見られ,IL-6は滑膜細胞は抑制され血管のみ発現していた.破骨細胞の分化を促進するRANKLは滑膜に発現していなかった.以上よりエタネルセプト効果減弱例のRAでは組織学的にTNF-αの発現が見られる滑膜を切除することにより,局所からのサイトカイン産生を抑制する関節鏡視下滑膜切除は有効であり,エタネルセプトの効果を持続できる一つの手段として考えられる. In order to investigate whether arthroscopic synovectomy is effective for rheumatoid arthritis (RA) patients who exhibit an incomplete response to etanercept treatment, we assessed 7 subjects who underwent 8 arthroscopic synovectomies in the knee joint, shoulder joint and elbow joints. We compared c-reactive protein (CRP) and disease activity scores (DAS) 28 before and at 4, 24 and 48 weeks after surgery. Immunohistochemical examination was performed whether tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and receptor activator of nuclear kappa B ligand (RANKL) expressed in synovial cells besides lymphocytes invasion and vascular proliferation occurred in hematoxylin and eosin (HE) staining. After arthroscopic synovectomy we continued etanercept treatment with or without methotrexate (MTX) in a routine manner. We detected synovium proliferation with a vascular increase in the patella femoral (PF) joint, around the meniscus and also on the femoral and tibial side of the anterior cruciate ligament (ACL) in the knee joints. We also found synovium proliferation in the rotator interval (RI) in the glenohumeral joint and fatty change in the subacromial bursa (SAB) in the shoulder. In the elbow joint we found synovium proliferation with white fibrous tissue around the radioulner joint which had developed into bone erosion. The average of CRP at preoperation, 3.8 ± 0.5 mg/dl, was improved to 1.3 ± 0.3 mg/dl at 6 weeks, 0.6 ± 0.2 mg/dl at 24 weeks and 0.7±0.4 mg/dl at 48 weeks after surgery. There were no side effects, not even post surgical infection from arthroscopic synovectomy, during etanercept treatment. DAS28 was improved from 6.3±0.6 to 3.5 ± 1.2 at 6 weeks, 2.8±0.7 at 24 weeks and 2.7±0.9 at 48 weeks after surgery. Histological examination revealed that lymphocyte proliferation, multi-nuclear cells and hyper vascularity emerged in etanercept toleration cases. TNF-α and IL-6 were expressed in the synovium, however RANKL was not expressed. Therefore, it is possible that arthroscopic synovectomy, in order to remove the synovium which produces TNF-α and IL-6, can be an effective method for the continuation of etanercept treatment when its efficacy is decreased in or attenuated for RA patients.
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ABSTRACT: 近年,関節リウマチの治療に対して骨破壊抑制および改善効果のある生物学的製剤の使用により治療が行われている.しかし,すべての症例で骨破壊改善が認められるわけではなく,その詳細については現在不明である.当科でインフリキシマブにより治療し1年以上経過して骨代謝マーカーのデータが詳細にとれた12例について尿中NTxの改善を解析したので報告する.当科でインフリキシマブを使用した12例(男1例,女11例),平均年齢54.7(27～74)歳,平均罹患期間151ヵ月,平均MTX 5.5mg/week,平均Steroid 4.2mg/day,平均BMI31.4であった.投与前と投与後1年の尿中NTxクレアチニン換算値をWilcoxonの符号付き順位検定により比較し,投与後尿中NTxクレアチニン換算値の変化と年齢,罹患期間. steroid投与,リウマチ因子につきカイニ乗分析を行った.インフリキシマブ投与前の尿中NTxクレアチニン換算値は平均41.55±13.5から投与後平均40.77±16.34 n mol BCE/m mol CREであり有意差は認めなかった(p=0.814).投与後尿中NTxクレアチニン換算値の改善はリウマチ因子とステロイド投与に有意に関連した(p=0.038).すなわちリウマチ因子が低い,あるいはステロイド投与なしの症例では尿中NTxクレアチニン換算値は有意に低下を認めた.従って,リウマチ因子の低い,あるいはステロイド非投与の関節リウマチにおけるインフリキシマブ投与による治療は骨破壊改善を有意に導く可能性があると考えられた. In order to investigate which clinical factors are associated with bone improvement by treatment with infliximab in rheumatoid arthritis (RA), twelve cases using concise laboratory data were analyzed in terms of urinary NTx one year before and one year after treatment with infliximab. Urinary NTx changed from 41.55 ± 13.5 (20.9-62.8) (nM BCE/mM Cr) to 40.77 ± 16.34 (15-75.7) (nM BCE/mM Cr) and there was no significant difference between before and after treatment with infliximab (p=0.814). There was a significant correlation between improvement of urinary NTX and steroid or RAPA one year after treatment with infliximab (p=0.038 respectively). At less than 80 times RAPA, urinary NTx significantly decreased from 40.0 ± 15.0 (nM BCE/mM Cr) to 29.98 ± 8.65 (nM BCE/mM Cr) (p=0.043). Therefore, low RAPA and low dose of steroid was associated with improvement of urinary NTx after using infliximab. X-ray examination revealed that bone atrophy improved in 8 cases out of 12 (67%) and erosion improved in 1 case out of 12 (8.3%). MRI of the hand was assessed and synovium proliferation decreased in 1 case. Histological findings of the subchondral bone at the time of total elbow replacement during treatment with infliximab revealed newly formed fibrous woven bone, including osteoid material which filled the space of trabecular bone tissue. Therefore, the rheumatoid factor (RF) may be one of the points which indicates bone healing after using infliximab for RA.
