RESUMO
BACKGROUND: According to the conventional postoperative procedure after total ankle arthroplasty (TAA) against end-stage osteoarthritis (OA) and rheumatoid arthritis (RA), mobilization and weight-bearing is currently started after completion of wound healing. Recently, early mobilization for dorsiflexion after TAA with modified antero-lateral approach was reported to be feasible and safe. To investigate the further possibility of expediting rehabilitation, this study evaluated the feasibility and safety of early full weight-bearing and gait exercise after cemented TAA utilizing a modified antero-lateral approach. MATERIALS AND METHODS: This retrospective, observational study investigated 23 consecutive ankles (OA: 14 ankles, RA: 9 ankles) that had received cemented TAA with a modified antero-lateral approach. These ankles were divided into three groups [1. conventional postoperative protocol: 8 ankles, 2. early dorsiflexion protocol: 7 ankles, 3. early dorsiflexion+full weight-bearing protocol: 8 ankles]. In group 3, after early dorsiflexion mobilization (day 3), full weight-bearing/gait exercise was started from 7 days after surgery (10 days after if malleolar osteotomy was added). Postoperative wound complications were observed and recorded. Number of days for hospitalization was also evaluated. Range of motion (ROM) of dorsiflexion/plantar flexion was measured. Patients also completed a self-administered foot evaluation questionnaire (SAFE-Q) and the scale of Japanese Society for Surgery of the Foot (JSSF) ankle/hindfoot score preoperatively and at final follow-up. RESULTS: No postoperative complications related to wound healing were observed even after early full weight-bearing and gait exercise. Days for hospitalization was significantly shortened in early full weight-bearing and gait exercise group (group 3) from 35-38 days to 24 days. ROM for both dorsiflexion and plantar flexion significantly increased in group 3, furthermore all indices of SAFE-Q score also showed stronger significant improvement in group 3. JSSF score improved significantly after TAA in all groups. CONCLUSION: Within this small number of cases, early full weight-bearing and gait exercise from 7 days after cemented TAA was feasible and safe with the modified antero-lateral approach. Combination of early dorsiflexion mobilization and weight-bearing/gait exercise contributed to shortening the hospitalization day, and improving ROM for both dorsiflexion and plantar flexion after surgery. Innovations in postoperative procedures for rehabilitation after TAA can be expected.
RESUMO
OBJECTIVE: In this study, we examine how advancements in novel antirheumatic drugs affect the clinicopathologic features of lymphoproliferative disorder (LPD) in patients with rheumatoid arthritis (RA). METHODS: In this multicenter study across 53 hospitals in Japan, we characterized patients with RA who developed LPDs and visited the hospitals between January 1999 and March 2021. The statistical tools used included Fisher's exact test, the Mann-Whitney U-test, the log-rank test, logistic regression analysis, and Cox proportional hazards models. RESULTS: Overall, 752 patients with RA-associated LPD (RA-LPD) and 770 with sporadic LPD were included in the study. We observed significant differences in the clinicopathologic features between patients with RA-LPD and those with sporadic LPD. Histopathological analysis revealed a high frequency of LPD-associated immunosuppressive conditions. Furthermore, patients with RA-LPD were evaluated based on the antirheumatic drugs administered. The methotrexate (MTX) plus tacrolimus and MTX plus tumor necrosis factor inhibitor (TNFi) groups had different affected site frequencies and histologic subtypes than the MTX-only group. Moreover, MTX and TNFi may synergistically affect susceptibility to Epstein-Barr virus infection. In case of antirheumatic drugs administered after LPD onset, tocilizumab (TCZ)-only therapy was associated with lower frequency of regrowth after spontaneous regression than other regimens. CONCLUSION: Antirheumatic drugs administered before LPD onset may influence the clinicopathologic features of RA-LPD, with patterns changing over time. Furthermore, TCZ-only regimens are recommended after LPD onset.
Assuntos
Antirreumáticos , Artrite Reumatoide , Transtornos Linfoproliferativos , Metotrexato , Inibidores do Fator de Necrose Tumoral , Humanos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/complicações , Antirreumáticos/uso terapêutico , Antirreumáticos/efeitos adversos , Transtornos Linfoproliferativos/induzido quimicamente , Masculino , Feminino , Pessoa de Meia-Idade , Metotrexato/uso terapêutico , Idoso , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Japão , Tacrolimo/uso terapêutico , Tacrolimo/efeitos adversos , Quimioterapia Combinada , Infecções por Vírus Epstein-Barr/complicações , AdultoRESUMO
BACKGROUND: According to the conventional postoperative procedure after total ankle arthroplasty (TAA), mobilization is currently started after completion of wound healing. To investigate the possibility of expediting rehabilitation, this study evaluated the feasibility and safety of early mobilization of dorsiflexion after cemented TAA utilizing a modified antero-lateral approach. MATERIALS AND METHODS: This retrospective, observational study investigated 14 consecutive ankles that had received cemented TAA. Mobilization of dorsiflexion was started from 3 days after surgery. Postoperative wound complications including blister formation, eschar formation, wound dehiscence, peri-incisional decreased sensation were observed and recorded. Range of motion (ROM) of dorsiflexion/plantar flexion was measured. Patients also completed a self-administered foot evaluation questionnaire (SAFE-Q) and the scale of Japanese Society for Surgery of the Foot (JSSF) ankle/hindfoot score preoperatively and at final follow-up. RESULTS: No postoperative complications related to wound healing were observed. ROM for dorsiflexion, SAFE-Q score, and JSSF score improved significantly after TAA. CONCLUSION: Within this small number of cases, early mobilization of dorsiflexion from 3 days after cemented TAA was feasible and safe with the modified antero-lateral approach. Innovations in postoperative procedures for rehabilitation after TAA can be expected.
RESUMO
Level V.
RESUMO
OBJECTIVES: To clarify the effects of follow-on therapy after denosumab (DMAb) discontinuation. METHODS: In this retrospective, multicenter study, postmenopausal patients with osteoporosis who were previously treated by oral bisphosphonates (BP) (n = 26) or teriparatide (TPTD) (n = 27) were switched to DMAb (administered 2.6 times), and then discontinued. Patients (73.1 years, T-scores of the lumbar spine [LS] - 2.7 and femoral neck [FN] - 2.2) were switched to either (1) raloxifene (RAL) (n = 13) or BP [(2) weekly or monthly BP (wmBP) (n = 29) or (3) zoledronate (ZOL) (n = 11)], based on each physician's decision (mean interval after final DMAb administration was 7.2 months). Bone mineral density (BMD) at final DMAb administration were set as baseline. RESULTS: Changes in LS BMD at 1.5 years after final DMAb administration were -2.7% in the RAL, 0.7% in the wmBP, and 1.9% in the ZOL (p = .31 between groups), and in FN BMD were -3.8%, -0.8%, and 1.8%, respectively (p = .02 between the RAL and ZOL; p = .048 between the RAL and BP). Clinical vertebral fracture incidence during 1.5 years after final DMAb administration was 23.1% in the RAL, 3.4% in the wmBP, and 0.0% in the ZOL (p = .048 between the RAL and ZOL; p = .015 between the RAL and BP). No significant differences were observed in these parameters between the wmBP and ZOL. CONCLUSION: These results may contribute to the selection of adequate follow-on therapy after DMAb discontinuation, although further investigations are required.
Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Denosumab/administração & dosagem , Osteoporose Pós-Menopausa/tratamento farmacológico , Idoso , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Denosumab/uso terapêutico , Difosfonatos/administração & dosagem , Difosfonatos/uso terapêutico , Esquema de Medicação , Feminino , Colo do Fêmur/efeitos dos fármacos , Humanos , Vértebras Lombares/efeitos dos fármacos , Pessoa de Meia-Idade , Estudos Retrospectivos , Teriparatida/administração & dosagem , Teriparatida/uso terapêuticoRESUMO
BACKGROUND: When soft tissue balance is not acceptable at total ankle arthroplasty (TAA) for rheumatoid varus deformity, medial malleolar osteotomy has been performed. At the same time, the shape of the ankle joint changes after soft tissue balancing with such an osteotomy, however there is few information for the radiographic findings after the osteotomy. Thus, radiographic changes in the coronal view of such cases were investigated. METHODS: JSSF-RA foot and ankle scale and SAFE-Q scores were determined along with pre/postoperative radiographic parameters of the ankle joint in 70 ankles (65 patients) with rheumatoid arthritis followed for a mean of 7.9 years (range, 2-16 years) after TAA. Seven ankles were excluded because those underwent lateral or lateral/medial malleolar osteotomy. Twenty-seven ankles underwent medial malleolar osteotomy, and compared with 36 ankles without osteotomy. RESULTS: All ankles achieved bone union after medial malleolar osteotomy, and the tibial medial malleolus (TMM) angle was significantly decreased [30.3°-19.1°] following significant valgus correction [TC angle: -2.7° to 0.5°]. The gap due to medial soft tissue tightness was significantly improved by medial malleolar osteotomy [4.95° to 0.7°]. Lateral malleolar fractures sometimes occurred (19%: 5/27 ankles) at valgus correction, but they healed completely without any internal fixation. CONCLUSION: Medial malleolar osteotomy was useful in rheumatoid varus ankle for not only controlling the soft tissue balance, but also providing a stabilized shape of the ankle joint. Lateral malleolar fractures were caused by valgus correction following medial malleolar osteotomy in some cases, but all fractures were completely healed without any internal fixation.
Assuntos
Tornozelo , Artrite Reumatoide , Articulação do Tornozelo/diagnóstico por imagem , Articulação do Tornozelo/cirurgia , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/cirurgia , Artroplastia , Humanos , Osteotomia , Resultado do TratamentoRESUMO
OBJECTIVES: Tocilizumab (TCZ) shows good retention in patients with rheumatoid arthritis (RA), but no previous reports demonstrated hopeful treatment options against inadequate response to TCZ. Tacrolimus (TAC) has proved to show efficacy against inadequate response to tumor necrosis factor alpha inhibitors, yet its add-on effects on TCZ remain unknown. METHODS: Twenty patients with RA (17 women, age 58.6 years, disease duration 12.1 years, prior TCZ duration 2.6 years, 18 intravenous [8 mg/kg/month] and 2 subcutaneous [324 mg/month] TCZ treatments, methotrexate 6.1 mg/week [70.0%]) who showed an inadequate response to TCZ (clinical disease activity index [CDAI] ≥ 5.8, 18 secondary non-responders) were additionally treated with TAC (1.1 mg/day), and enrolled in this 24-week, prospective study. RESULTS: Seventeen patients (85.0%) continued the treatment for 24 weeks. Statistically significant decreases in outcome measures were as follows: disease activity score based on 28 joints with C-reactive protein (DAS28-CRP) from 3.3 at baseline to 2.1 at week 24 (p < 0.001), CDAI from 17.7 to 7.6 (p < 0.001), and serum matrix metalloproteinase-3 levels from 232.8 to 66.2 ng/ml (p < 0.001). About 15 patients (75%) achieved low disease activity or remission (DAS28-CRP ≤2.7 or CDAI ≤10) at week 24. CONCLUSIONS: Adding low-dose TAC to inadequate responders to TCZ may be a promising complementary treatment option.
Assuntos
Anticorpos Monoclonais Humanizados , Artrite Reumatoide , Tacrolimo , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Proteína C-Reativa/análise , Monitoramento de Medicamentos , Feminino , Humanos , Japão , Masculino , Metaloproteinase 3 da Matriz/sangue , Pessoa de Meia-Idade , Gravidade do Paciente , Estudos Prospectivos , Indução de Remissão/métodos , Índice de Gravidade de Doença , Tacrolimo/administração & dosagem , Tacrolimo/efeitos adversos , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Vaccination against Streptococcus pneumoniae is recommended for rheumatoid arthritis (RA) patients receiving immunosuppressive treatments. The objective of this study was to evaluate the humoral response to 23-valent pneumococcal polysaccharide vaccination (PPSV23) in RA patients receiving methotrexate (MTX) alone or in combination with a tumor necrosis factor inhibitor, golimumab (GOM).PPSV23 was given to 114 RA patients, who were classified into three groups: RA control (nâ=â35), MTX alone (nâ=â55), and GOMâ+âMTX (nâ=â24). Before and 4 to 6 weeks after vaccination, concentrations of antibodies against pneumococcal serotypes 6B and 23F were measured using an enzyme-linked immunosorbent assay and antibody functionality was determined using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI).The IgG concentrations and OIs were both significantly increased in all treatment groups in response to PPSV23 vaccination. In the GOMâ+âMTX group, the IgG responses were lower than those in the MTX alone or control groups, whereas the OI responses were similar to those in the other 2 groups. Furthermore, discrepancies between the IgG and OI responses were found in GOMâ+âMTX group. No severe adverse effect was observed in any treatment groups.OI responses indicate that antibody functionality rather than antibody quantity is important. The similarity of these measurements between all 3 groups suggests that RA patients receiving MTXâ+âGOM still benefit from receiving the PPSV23 vaccination, even though they produce less IgG in response to it. These results can help clinicians to better schedule and evaluate pneumococcal vaccination for RA patients.
Assuntos
Anticorpos Monoclonais , Formação de Anticorpos/efeitos dos fármacos , Artrite Reumatoide , Metotrexato , Vacinas Pneumocócicas , Pneumonia Pneumocócica/prevenção & controle , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Antirreumáticos/administração & dosagem , Antirreumáticos/imunologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Método Duplo-Cego , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Imunoglobulina G/sangue , Imunossupressores/administração & dosagem , Imunossupressores/imunologia , Masculino , Metotrexato/administração & dosagem , Metotrexato/imunologia , Pessoa de Meia-Idade , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/imunologia , Sorogrupo , Streptococcus pneumoniae/imunologia , Resultado do TratamentoRESUMO
INTRODUCTION: Patients with rheumatoid arthritis (RA) treated with abatacept (ABT) are at increased risk for vaccine-preventable infections. The aim of the present study is to evaluate the humoral response to 23-valent pneumococcal polysaccharide (PPSV23) vaccination in RA patients receiving ABT. METHODS: The immunogenicity study was nested within a randomized, double-blind placebo-controlled study, designed to evaluate the efficacy of the PPSV23. PPSV23 was given to 111 RA patients, who were classified into three groups: RA control (n = 35), methotrexate (MTX) alone (n = 55), and ABT (n = 21). Before and 4-6 weeks after vaccination, we measured the patients' concentrations of antibodies against pneumococcal serotypes 6B and 23F using an enzyme-linked immunosorbent assay and determined their antibody functionality using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI). RESULTS: The pneumococcal serotype-specific IgG concentrations and OIs were both significantly increased in all treatment groups in response to PPSV23 vaccination. In the ABT group, the IgG responses for the 6B serotype were lower compared with those in the MTX alone or control groups, whereas the OI responses were similar to those in the other two groups. In a subgroup analysis, the pneumococcal serotype-specific IgG responses were significantly lower in both serotypes (6B and 23F) in the ABT/MTX group; however, the OI responses in the ABT group were not different from the control group. There was no association between the pneumococcal serotype-specific IgG and OI responses for the 6B serotype in patients receiving ABT in contrast to the control or MTX alone patients. No severe adverse effects were observed in any of the treatment groups. CONCLUSIONS: OI responses indicate antibody functionality rather than simply their amount, so the similarity of these measurements between all three groups suggests that RA patients receiving ABT still benefit from receiving the PPSV23 vaccination, even though they produce less IgG in response to it. The results suggest an influence of ABT on the humoral response to PPSV23 vaccination under MTX treatment; however, preserved opsonin responses are expected in RA patients treated with ABT plus MTX. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry: UMIN000009566. Registered 12 December 2012.
Assuntos
Anticorpos Antibacterianos/sangue , Artrite Reumatoide/imunologia , Imunidade Humoral/imunologia , Vacinas Pneumocócicas/imunologia , Abatacepte/uso terapêutico , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Pneumonia Pneumocócica/prevenção & controleRESUMO
PURPOSE: To evaluate disease activity, knee function, and walking ability of patients with rheumatoid arthritis (RA) over 10 years after total knee arthroplasty (TKA). METHODS: Four men and 26 women (mean age, 59.9 years) underwent 42 TKAs for RA with a mean duration of 151.3 months and were followed up for a mean of 142.3 months. Preoperatively, disease activity was assessed by C-reactive protein (CRP) level only, and the range of knee motion was recorded. At the final follow-up, tender joint count, swollen joint count, visual analogue scale of RA symptoms, and the Modified Health Assessment Questionnaire (MHAQ) score were assessed. Disease activity was evaluated using CRP, matrix metalloproteinase-3, and Disease Activity Score. Range of motion and Knee Society knee and function scores were also assessed. RESULTS: The use of methotrexate increased from 4 patients preoperatively to 20 patients at the final follow-up (p<0.001), and the mean dose increased from 3.9 to 6.3 mg/week (p<0.001). Among the 30 patients, the mean CRP level decreased from 2.63 mg/dl preoperatively to 0.61 mg/dl at the final follow-up (p<0.001). Disease activity was controlled. At the final follow-up, disease activity was in remission in 10 patients, low in 11, and moderate in 9. The mean Knee Society knee score was excellent (91.0), but the mean function score was poor (57.0) and diverse. Severe walking disability (function score, <40) was noted in 8 patients (11 TKAs). Knee and function scores did not correlate. CONCLUSION: Walking ability in patients with RA after TKA was generally poor. Poor function was associated with a history of spinal or lower extremity fracture surgery and the MHAQ score.
Assuntos
Artrite Reumatoide/cirurgia , Artroplastia do Joelho , Articulação do Joelho/fisiopatologia , Amplitude de Movimento Articular/fisiologia , Caminhada/fisiologia , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/fisiopatologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Articulação do Joelho/cirurgia , Masculino , Pessoa de Meia-Idade , Medição da Dor , Período Pós-Operatório , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
PURPOSE: To evaluate the clinical outcomes of corrective osteotomy and ligament repair for longstanding radial collateral ligament tears of the proximal interphalangeal (PIP) joint. METHODS: We retrospectively evaluated 4 patients with 5 longstanding tears in the radial collateral ligaments of the PIP joints. The average age at the time of surgery was 51 years (range, 40-62 y). The average time from the initial injury to surgery was 31 years (range, 22-40 y). Plain radiographs revealed an ulnar slope at the PIP joint surface with degenerative changes in all fingers. We corrected the slope using a closing wedge osteotomy of the neck of the proximal phalanx secured with a headless screw. We then repaired the radial collateral ligament by overlapping the elongated ligament. Range of motion exercises were started 2 weeks after surgery. To evaluate the results, we compared preoperative and postoperative range of motion, ulnar deviation, instability, pain, and level of satisfaction. Average follow-up was 27 months (range, 18-48 mo). RESULTS: All osteotomies had united at an average of 3 months. We observed no major changes in range of motion, but flexion contracture gradually appeared in 1 high-demand patient. The average preoperative angle of ulnar deviation was 36° and was corrected to a postoperative angle of 2°. The average angle of lateral instability improved after surgery from 22° to 1°. Finger pain disappeared or decreased in 3 low-demand patients but persisted in 1 high-demand patient. Two low-demand patients were very satisfied and 1 low-demand patient was satisfied; however, 1 high-demand patient was dissatisfied with the results of surgery. CONCLUSIONS: Corrective osteotomy and ligament repair can result in a straight and stable joint with a good range of motion in low-demand patients. This method could be a treatment option for carefully selected patients.
Assuntos
Ligamentos Colaterais/lesões , Ligamentos Colaterais/cirurgia , Traumatismos dos Dedos/cirurgia , Articulações dos Dedos/cirurgia , Osteotomia , Procedimentos de Cirurgia Plástica/métodos , Adulto , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Amplitude de Movimento Articular , Estudos Retrospectivos , Fatores de TempoRESUMO
We report a case of sudden onset of late infection after TKA inflamed by anti-TNFalpha therapy, Infliximab, in a 54-year-old woman with RA. Infliximab therapy was started 3 years and 8 months after TKAs as a result of multiple arthritides showing high inflammation of RA. One week after the third administration of Infliximab, the patient suffered sudden knee pain and infectious clinical symptoms, and bacteria (MSSA) were detected by joint effusion culture. She was successfully treated by open debridement with antibiotics-loaded calcium phosphate bone paste and cement and the prostheses were retained. Early diagnosis and operative treatment might be the key to controlling infected TKA without removing the implant. This present case might indicate a serious risk of immunosuppressive effects caused by Infliximab.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Artrite Reumatoide/cirurgia , Artroplastia do Joelho/efeitos adversos , Articulação do Joelho/fisiopatologia , Infecções Relacionadas à Prótese/induzido quimicamente , Infecção da Ferida Cirúrgica/induzido quimicamente , Antibacterianos/uso terapêutico , Antirreumáticos/efeitos adversos , Artrite Reumatoide/imunologia , Artrite Reumatoide/fisiopatologia , Cimentos Ósseos/uso terapêutico , Diagnóstico Precoce , Feminino , Humanos , Doença Iatrogênica/prevenção & controle , Hospedeiro Imunocomprometido/efeitos dos fármacos , Hospedeiro Imunocomprometido/imunologia , Terapia de Imunossupressão/efeitos adversos , Infliximab , Articulação do Joelho/imunologia , Articulação do Joelho/microbiologia , Pessoa de Meia-Idade , Implantação de Prótese/efeitos adversos , Infecções Relacionadas à Prótese/imunologia , Infecções Relacionadas à Prótese/microbiologia , Infecção da Ferida Cirúrgica/imunologia , Infecção da Ferida Cirúrgica/microbiologia , Fatores de Tempo , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
FR167653 is a potent inhibitor of p38 MAP Kinase and inhibits TNF-alpha and IL-1beta production in inflammatory cells. In this study we investigated the effect of FR167653 on CIA. CIA rats were subcutaneously injected with FR167653 (32 mg/kg/day) starting on the day of the booster injection and after the onset of arthritis in the prophylactic and therapeutic treatment groups, respectively. The hind paw swelling, radiolographic and histologic scores, and osteoclast number were evaluated. Serum and tissue cytokine levels were assessed by ELISA. Flow cytometric analysis of T-lymphocytes from bone marrow was also performed. The effect of FR167653 on in vitro osteoclast formation induced by sRANKL and TNF-alpha was examined. Hind paw swelling occurred in CIA rats but not in the prophylactic treatment group. Therapeutic treatment also significantly reduced the paw swelling. The mean radiographic, histologic score, and osteoclast number of the treatment group were significantly lower than those of CIA rats without treatment. FR167653 treatment reduced serum TNF-alpha and IL-1beta levels, ankle IL-1beta concentration, and CD4-CD8a+ T-cell population in bone marrow. Furthermore, FR167653 inhibited the osteoclast-like cell differentiation induced by both sRANKL and TNF-alpha in vitro. FR167653 prevented the onset of arthritis in a prophylactic treatment model and suppresses the progression of joint destruction in a therapeutic treatment model, suggesting that p38 MAP Kinase is a potential therapeutic target for rheumatoid arthritis.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/prevenção & controle , RatosRESUMO
OBJECTIVE: FR167653 is a potent inhibitor of p38 mitogen-activated protein kinase (MAPK) and inhibits tumor necrosis factor alpha (TNFalpha) and interleukin-1 beta (IL-1 beta) production in inflammatory cells. In this study we investigated the effect of FR167653 on collagen-induced arthritis (CIA). METHODS: Rats with CIA were subcutaneously injected with FR167653 (32 mg/kg/day) starting on the day of the booster injection (day 7) in the prophylactic treatment group and after the onset of arthritis (day 21) in the therapeutic treatment group. Hind-paw swelling, body weight, radiographic and histologic scores, and osteoclast number were evaluated. Cytokine levels in the serum and tissue were assessed by enzyme-linked immunosorbent assays. Flow cytometric analysis of T lymphocytes from bone marrow was performed. The effect of FR167653 on in vitro osteoclast formation induced by soluble receptor activator of nuclear factor kappa B ligand (sRANKL) and TNFalpha was examined. RESULTS: Swelling of hind paws and loss of weight occurred in the CIA rats, but this was not evident in the prophylactic treatment group. Therapeutic treatment also significantly reduced paw swelling. The mean radiographic and histologic scores as well as the osteoclast numbers were significantly lower in the treatment group than in the CIA rats without treatment. FR167653 treatment reduced the serum levels of TNFalpha and IL-1 beta, lowered the IL-1 beta concentration in the ankle joints, and decreased the CD4-,CD8a+ T cell population in bone marrow. Furthermore, FR167653 inhibited the osteoclast-like cell differentiation induced by both sRANKL and TNFalpha in vitro. CONCLUSION: FR167653 prevents the onset of arthritis in a prophylactic treatment model and suppresses the progression of joint destruction in a therapeutic treatment model, suggesting that p38 MAPK is a potential therapeutic target for rheumatoid arthritis.
Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/prevenção & controle , Inibidores Enzimáticos/farmacologia , Imunossupressores/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Pirazóis/farmacologia , Piridinas/farmacologia , Animais , Articulação do Tornozelo/diagnóstico por imagem , Articulação do Tornozelo/metabolismo , Antineoplásicos/farmacologia , Artrite Experimental/diagnóstico por imagem , Células da Medula Óssea/citologia , Relação CD4-CD8 , Proteínas de Transporte/farmacologia , Diferenciação Celular/efeitos dos fármacos , Citocinas/sangue , Progressão da Doença , Inibidores Enzimáticos/química , Feminino , Imunossupressores/química , Injeções Subcutâneas , Fator Estimulador de Colônias de Macrófagos/farmacologia , Glicoproteínas de Membrana/farmacologia , Osteoclastos/citologia , Pirazóis/química , Piridinas/química , Ligante RANK , Radiografia , Ratos , Ratos Endogâmicos Lew , Fator de Necrose Tumoral alfa/farmacologia , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
Nurse-like stromal cell lines from the synovial tissue of patients with rheumatoid arthritis (RA-SNC) produce, on coculture with lymphocytes, large amounts of proinflammatory cytokines. In the present paper, we analyze the molecular events necessary for the induction of cytokine release from RA-SNC cells, and particularly the roles played by cell adhesion and the transmigration (also known as pseudoemperipolesis) of lymphocytes. For this purpose, the effects of various mAbs on the binding and transmigration of a human B-cell line, MC/car, were examined using a cloned RA-SNC line, RA-SNC77. To analyze the role of lymphocyte binding and transmigration on upregulated cytokine production by the RA-SNC77 cells, we used C3 exoenzyme-treated MC/car cells, which could bind to RA-SNC77 cells but could not transmigrate. Treatment with anti-CD29 or anti-CD49d mAb significantly reduced binding and transmigration of the MC/car cells. In contrast, the neutralizing anti-CD106/vascular cell adhesion molecule 1 mAb did not show any inhibitory effect. Likewise, none of the neutralizing mAbs against CD11a, CD18, CD44, CD49e, or CD54 showed significant effects. Binding of C3-treated or untreated MC/car cells to RA-SNC77 cells induced comparable levels of IL-6 and IL-8 production. In addition, the enhanced cytokine production by RA-SNC77 cells required direct lymphocyte contact via a very late antigen-4 (VLA-4)-independent adhesion pathway. These results indicate that, although both the VLA-4-dependent/vascular cell adhesion molecule 1-independent and the VLA4-independent adhesion pathways are involved in MC/car binding and subsequent transmigration, only the VLA4-independent adhesion pathway is necessary and sufficient for the enhanced proinflammatory cytokine production by RA-SNC77 cells. The transmigration process, which is dependent on Rho-GTPase, is not a prerequisite for this phenomenon.
Assuntos
Artrite Reumatoide/metabolismo , Integrina alfa4beta1/fisiologia , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Membrana Sinovial/metabolismo , Anticorpos Monoclonais/farmacologia , Artrite Reumatoide/patologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Adesão Celular , Movimento Celular , Células Cultivadas , Técnicas de Cocultura , Humanos , Integrina alfa4/imunologia , Integrina alfa4/farmacologia , Integrina beta1/imunologia , Integrina beta1/farmacologia , Células Estromais/imunologia , Células Estromais/metabolismo , Células Estromais/patologia , Membrana Sinovial/imunologia , Membrana Sinovial/patologiaRESUMO
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.