Wiley
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Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen‐induced arthritis Abstract Objective Mesenchymal stem cells (MSCs) are precursors of tissue of mesenchymal origin, but they also have the capacity to regulate the immune response by suppressing T and B lymphocyte proliferation in a non–major histocompatibility complex–restricted manner. Use of MSCs as immunosuppressant agents in autoimmune diseases has been proposed and successfully tested in animal models. We explored the feasibility of using allogeneic MSCs as therapy for collagen‐induced arthritis, a mouse model for human rheumatoid arthritis. Methods DBA/1 mice were immunized with type II collagen in Freund's complete adjuvant, and some of the animals received an intraperitoneal injection of allogeneic MSCs. Results A single injection of MSCs prevented the occurrence of severe, irreversible damage to bone and cartilage. MSCs induced hyporesponsiveness of T lymphocytes as evidenced by a reduction in active proliferation, and modulated the expression of inflammatory cytokines. In particular, the serum concentration of tumor necrosis factor α was significantly decreased. MSCs exerted their immunomodulatory function by educating antigen‐specific Tregs. Conclusion Our results suggest an effective new therapeutic approach to target the pathogenic mechanism of autoimmune arthritis using allogeneic MSCs. However, further studies are required before these results can be translated to clinical settings.
Wiley - Tập 56 Số 4 - Trang 1175-1186 - 2007
Cysteine Proteinase Inhibitors Decrease Articular Cartilage and Bone Destruction in Chronic Inflammatory Arthritis Abstract Objective . To determine the effects of peptidyl fluoromethyl ketones on the in vitro activity of purified cathepsins B and L, on tissue cysteine proteinase activity, and on cartilage and bone destruction in experimental arthritis.Methods . The effects of the fluoroketones on cathepsins B and L in vitro and the effects of oral administration of fluoroketones on ex vivo cysteine proteinase activity in tissue homogenates were determined by measuring the inhibition of fluorogenic substrate cleavage. To determine the effects on arthritis, animals were injected with adjuvant or type II collagen, treated orally with the fluoroketones, and the severity of arthritis was assessed by clinical, histologic, and radiologic methods.Results . All of the fluoroketones tested were potent inhibitors of purified cathepsins B and L activity. Oral administration of the fluoroketones reduced tissue cysteine proteinase activity by up to 77%. In addition, fluoroketone treatment significantly reduced the severity of clinical joint disease and decreased the destruction of articular cartilage and bone. Quantitative analysis of radiographic images indicated that treatment significantly reduced soft tissue changes, periosteal proliferation, and bone erosion, but only partially reduced juxtaarticular osteoporosis.Conclusion . These studies suggest that cysteine proteinase inhibitors may limit tissue destruction in diseases such as rheumatoid arthritis.
Wiley - Tập 37 Số 2 - Trang 236-247 - 1994
Association of the PD‐1.3A allele of the <i>PDCD1</i> gene in patients with rheumatoid arthritis negative for rheumatoid factor and the shared epitope Abstract Objective To study the frequency of allele A of polymorphism PD‐1.3 of the PDCD1 gene in patients with rheumatoid arthritis (RA) and its subsets, based on the presence of rheumatoid factor (RF) and the shared epitope (SE) alleles. Methods A total of 1,175 patients with RA and 3,404 controls were genotyped for the PD‐1.3 A/G polymorphism, which previously was identified as being involved in susceptibility to systemic lupus erythematosus (SLE) in patients of European descent. Results We first detected a trend for association of allele A of the single‐nucleotide polymorphism PD‐1.3 with RA (P = 0.053, odds ratio [OR] 1.18, 95% confidence interval [95% CI] 0.99–1.41). To further clarify the nature of this association, patients with RA were divided into 4 groups according to the presence of RF and the SE alleles. Association was found only in the group of patients negative for both RF and the SE alleles (P = 0.0054 [corrected P = 0.015], OR 1.75, 95% CI 1.15–2.65). Conclusion Patients negative for both RF and the SE alleles showed association with the same allele that we previously identified as being involved in susceptibility to SLE. These results provide the first evidence of the involvement of the human PDCD1 gene in arthritis.
Wiley - Tập 50 Số 6 - Trang 1770-1773 - 2004
Progression of radiologic damage in patients with rheumatoid arthritis in clinical remission Abstract Objective To assess whether radiologic progression occurs during clinical remission in patients with rheumatoid arthritis (RA). Methods One hundred eighty‐seven patients with RA in clinical remission were followed up clinically and radiologically for 2 years. Clinical remission was defined according to a modification of the American College of Rheumatology criteria (i.e., the criterion of fatigue was omitted, and patients had to fulfill 4 of the 5 remaining criteria). Radiologic joint damage was assessed by the Sharp/van der Heijde method. Results After 2 years of followup, remission persisted in 52% of patients. The median radiologic score for the total group of patients increased from 21 (interquartile range [IQR] 5, 65) at the time of entry to 25 (IQR 7, 72) after 2 years (P < 0.001). The median score for radiologic progression between baseline and 2 years was 0.5 (IQR 0, 2.5). Among patients with an exacerbation of RA (n = 86), the median score for progression over 2 years was 1.0 (IQR 0, 4.5) (P < 0.001), and in patients with a persistent remission (n = 93) it was 0 (IQR −0.5, 2.0) (P < 0.001). Clinically relevant progression of damage was more frequent in patients with exacerbation (23%) than in those with persistent remission (7%) (P = 0.001). However, in 15% of patients with persistent remission, an erosion developed in a previously unaffected joint. In the logistic regression analysis, the area under the curve of the Disease Activity Score, a continuous measure, was related to the chance of radiologic progression, regardless of the absolute disease activity level. Results were similar when other definitions of remission were used. Conclusion Although rare, clinically relevant progression of joint damage does occur in patients with RA in prolonged remission. This suggests the need for markers that predict progression during periods of low disease activity and for drugs that prevent damage that is independent of disease activity.
Wiley - Tập 50 Số 1 - Trang 36-42 - 2004
An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis Abstract Objective Achieving remission is the aim of treatment in rheumatoid arthritis (RA). This should represent minimal arthritis activity and ensure optimal disease outcome. However, we have previously demonstrated a high prevalence of imaging‐detected synovial inflammation in RA patients who were in clinical remission. The purpose of this study was to evaluate the long‐term significance of subclinical synovitis and its relationship to structural outcome. Methods We studied 102 RA patients receiving conventional treatment who had been judged by their consultant rheumatologist to be in remission, as well as 17 normal control subjects. Subjects underwent clinical, laboratory, functional, and quality of life assessments over 12 months. In addition to standard radiography of the hands and feet, imaging of the hands and wrists was performed with musculoskeletal ultrasonography (US) and conventional 1.5T magnetic resonance imaging (MRI) at baseline and 12 months, using validated acquisition and scoring techniques. Results Despite their being in clinical remission, 19% of the patients displayed deterioration in radiographic joint damage over the study period. Scores on musculoskeletal US synovial hypertrophy, power Doppler (PD), and MRI synovitis assessments in individual joints at baseline were significantly associated with progressive radiographic damage (P = 0.032, P < 0.001, and P = 0.002, respectively). Furthermore, there was a significant association between the musculoskeletal US PD score at baseline and structural progression over 12 months in totally asymptomatic metacarpophalangeal joints (P = 0.004) and 12 times higher odds of deterioration in joints with increased PD signal (odds ratio 12.21, P < 0.001). Conclusion Subclinical joint inflammation detected by imaging techniques explains the structural deterioration in RA patients in clinical remission who are receiving conventional therapy. Our findings reinforce the utility of imaging for the accurate evaluation of disease status and the prediction of structural outcome.
Wiley - Tập 58 Số 10 - Trang 2958-2967 - 2008
Predictors of joint damage in patients with early rheumatoid arthritis treated with high‐dose methotrexate with or without concomitant infliximab: Results from the ASPIRE trial Abstract Objective To identify disease characteristics leading to progression of joint damage in patients with early rheumatoid arthritis (RA) treated with methotrexate (MTX) versus those treated with infliximab plus MTX. Methods Patients who had not previously been treated with MTX with active RA were randomly assigned to receive escalating doses of MTX up to 20 mg/week plus placebo or infliximab at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. Radiographic joint damage was assessed using the modified Sharp/van der Heijde score (SHS). The relationship between disease activity measures at baseline and week 14, as well as those averaged over time, were examined in relation to the change in SHS from baseline through week 54. Results C‐reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and swollen joint count were associated with greater joint damage progression in the MTX‐only group, while none of these parameters was associated with progression in the infliximab plus MTX group. Mean changes in SHS among patients in the highest CRP (≥3 mg/dl) and ESR (≥52 mm/hour) tertiles in the MTX‐only group were 5.62 and 5.89, respectively, compared with 0.73 and 1.12 in the infliximab plus MTX group (P < 0.001). Patients with greater joint damage at baseline (SHS ≥10.5) showed less progression with infliximab plus MTX compared with MTX alone (−0.39 versus 4.11; P < 0.001). Patients receiving MTX alone who had persistently active disease at week 14 showed greater radiographic progression of joint damage than those taking MTX plus infliximab. Conclusion High CRP level, high ESR, or persistent disease activity was associated with greater radiographic progression in the group taking MTX alone, while little radiographic progression was seen in patients receiving both MTX and infliximab, regardless of the abnormal levels of these traditional predictors.
Wiley - Tập 54 Số 3 - Trang 702-710 - 2006
Interobserver agreement in ultrasonography of the finger and toe joints in rheumatoid arthritis Abstract Objective To evaluate the interobserver agreement of ultrasonographic assessment of finger and toe joints in patients with rheumatoid arthritis (RA) by 2 investigators with different medical backgrounds. Methods Ultrasonography and clinical examination were performed on 150 small joints of 30 patients with active RA. A General Electric LOGIQ 500 ultrasound unit with a 7–13‐MHz linear array transducer was used. In each patient, 5 preselected small joints (second and third metacarpophalangeal, second proximal interphalangeal, first and second metatarsophalangeal) were examined independently on the same day by 2 ultrasound investigators (an experienced musculoskeletal radiologist and a rheumatologist with limited ultrasound training). Joint effusion, synovial thickening, bone erosions, and power Doppler signal were evaluated in accordance with an introduced 4‐grade semiquantitative scoring system, on which the investigators had reached consensus prior to the study. Results Exact agreement between the 2 observers was seen in 91% of the examinations with regard to bone erosions, in 86% with regard to synovitis, in 79% with regard to joint effusions, and in 87% with regard to power Doppler signal assessments. Corresponding intraclass correlation coefficient values were 0.78, 0.81, 0.61, and 0.72, respectively, while unweighted kappa values were 0.68, 0.63, 0.48, and 0.55, respectively. Ultrasonography showed signs of inflammation in 94 joints, while clinical assessment revealed tenderness and/or swelling in 64 joints. Conclusion An experienced radiologist and a rheumatologist with limited ultrasound training achieved high interobserver agreement rates for the identification of synovitis and bone erosions, using an introduced semiquantitative scoring system for ultrasonography of finger and toe joints in RA. Signs of inflammation were more frequently detected with ultrasound than with clinical examination. Ultrasonography may improve the assessment of RA patients by radiologists and rheumatologists.
Wiley - Tập 48 Số 4 - Trang 955-962 - 2003
Power Doppler ultrasound, but not low‐field magnetic resonance imaging, predicts relapse and radiographic disease progression in rheumatoid arthritis patients with low levels of disease activity Abstract Objective Subclinical inflammation and radiographic progression have been described in rheumatoid arthritis (RA) patients whose disease is in remission or is showing a low level of activity. The aim of this study was to compare the ability of ultrasonography and magnetic resonance imaging (MRI) to predict relapse and radiographic progression in these patients. Methods Patients with RA of short or intermediate duration that was either in remission or exhibiting low levels of activity according to the Disease Activity Score (DAS) were included in the study. Over a period of 1 year, patients underwent clinical and biologic assessments every 3 months and radiographic assessments at baseline and 12 months. Radiographs were graded according to the modified Sharp/van der Heijde score (SHS). At baseline, patients underwent ultrasonography and MRI, which were graded using binary and semiquantitative scoring systems. Relapse was defined as a DAS of ≥2.4, and radiographic progression was defined as an increase in the SHS of ≥1. We tested the association of values by multivariate logistic regression. Results A total of 85 RA patients with a mean disease duration of 35.3 months were studied. RA was in remission in 47 of these patients, and 38 had low levels of disease activity. At 1 year, 26 of the 85 patients (30.6%) showed disease relapse, and 9 of the 85 patients (10.6%) showed radiographic progression. The baseline PD synovitis count (i.e., the number of joints at baseline for which the power Doppler [PD] signal indicated synovitis) predicted relapse (adjusted odds ratio [OR] 6.3; 95% confidence interval [95% CI] 2.0–20.3), and the baseline PD synovitis grade predicted disease progression (adjusted OR 1.4 [95% CI 1.1–1.9]). MRI was not predictive of outcomes. Conclusion For RA patients whose disease is in remission or who have low levels of disease activity, PD signals on ultrasonography could predict relapse or radiographic progression and identify those whose disease is adequately controlled, which is especially helpful when considering treatment tapering or interruption.
Wiley - Tập 64 Số 1 - Trang 67-76 - 2012
Elevated expression of interleukin‐7 receptor in inflamed joints mediates interleukin‐7–induced immune activation in rheumatoid arthritis Abstract Objective To evaluate the expression and functional ability of the high‐affinity interleukin‐7 receptor (IL‐7Rα) in patients with rheumatoid arthritis (RA). Methods Expression of IL‐7Rα and IL‐7 was determined in synovial tissue from RA patients and was compared with that in synovial tissue from patients with undifferentiated arthritis (UA) and osteoarthritis (OA). IL‐7Rα expression on CD4 T cells, CD19 B cells, and CD14 monocyte/macrophages from RA synovial tissue, synovial fluid, and peripheral blood was also assessed. The proliferative capacity of IL‐7Rαbright and IL‐7Rαdim/− T cells was measured. In addition, we examined IL‐7R blockade with soluble human IL‐7Rα (hIL‐7Rα) in the prevention of immune activation of peripheral blood mononuclear cells. Results We found significantly higher IL‐7Rα expression in RA and UA synovial tissue than in OA synovial tissue, and the level of IL‐7Rα expression correlated significantly with the levels of CD3 and IL‐7 expression. CD4 T cells from RA synovial fluid and synovial tissue strongly expressed IL‐7Rα. A substantial percentage of B cells and macrophages from RA synovial fluid and synovial tissue also expressed IL‐7Rα, although less prominently than T cells. We found that peripheral blood IL‐7Rαbright T cells that did not express FoxP3 were highly proliferative as compared with IL‐7Rαdim/− T cells that did express high levels of FoxP3. Soluble hIL‐7Rα inhibited IL‐7–induced proliferation and interferon‐γ production by mononuclear cells from RA patients. Conclusion Our data suggest that enhanced expression of IL‐7Rα and IL‐7 in RA patients contributes significantly to the joint inflammation by activating T cells, B cells, and macrophages. The inhibition of IL‐7R–mediated immune activation by soluble hIL‐7Rα further indicates an important role of IL‐7Rα in inflammatory responses in RA, suggesting IL‐7Rα as a therapeutic target for immunotherapy in RA.
Wiley - Tập 60 Số 9 - Trang 2595-2605 - 2009
Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: A two‐year prospective study (the DAMAGE study cohort) Abstract Objective The primary aim of this prospective 2‐year study was to explain the wide variability in joint damage progression in patients with rheumatoid arthritis (RA) from measures of pathologic changes in the synovial membrane. Methods Patients underwent clinical measurements and joint damage assessments by magnetic resonance imaging (MRI) and radiography at enrollment and at year 2. Synovial membrane was obtained by knee biopsy and assessed histologically by hematoxylin and eosin staining. Interleukin‐1β (IL‐1β), IL‐10, IL‐16, IL‐17, RANKL, tumor necrosis factor α (TNFα), and interferon‐γ (IFNγ) messenger RNA (mRNA) expression was determined by quantitative reverse transcription–polymerase chain reaction. The relationship of synovial measurements to joint damage progression was determined by multivariate analysis. Results Sixty patients were enrolled. Histologic features had no relationship to damage progression. Multivariate analysis by several different methods consistently demonstrated that synovial membrane mRNA levels of IL‐1β, TNFα, IL‐17, and IL‐10 were predictive of damage progression. IL‐17 was synergistic with TNFα. TNFα and IL‐17 effects were most pronounced with shorter disease duration, and IL‐1β effects were most pronounced with longer disease duration. IFNγ was protective. These factors explained 57% of the MRI joint damage progression over 2 years. Conclusion We have demonstrated for the first time in a prospective study that synovial membrane cytokine mRNA expression is predictive of joint damage progression in RA. The findings for IL‐1β and TNFα are consistent with results of previous clinical research, but the protective role of IFNγ, the differing effects of disease duration, and IL‐17–cytokine interactions had only been demonstrated previously by animal and in vitro research. These findings explain some of the variability of joint damage in RA and identify new targets for therapy.
Wiley - Tập 54 Số 4 - Trang 1122-1131 - 2006
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