Maintenance and tolerability of infliximab in a cohort of 152 patients with rheumatoid arthritis.

OBJECTIVE: To determine the maintenance, tolerability and safety of infliximab in an unselected cohort of patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: One hundred and fifty-two RA patients receiving at least one course of infliximab between 2000 and 2003 were included in this study. Response to treatment and safety were assessed through recording adverse events, physical examinations and standard laboratory tests. The dosage of infliximab was patient specifically modified, when therapeutic response was judged inadequate by the assessment of a physician. RESULTS: The mean duration of follow-up was 401 days (85-1221). One hundred and twenty-two patients (78%) continued to receive infliximab after one year. 40 patients (26.3%) stopped infliximab therapy: 14 (9.2%) for inefficacy, 21 (13.8%) for adverse events. Fifty nine patients (38.8%) required an increase of the dosage (n=23, 15%) or a shortening of the interval between the infusions (n=20, 13.2%), or both (n=16, 10.5%) for symptomatic control. Infliximab discontinuation tended to be more frequent in smokers (p=0.055). Ninety-four patients (62%) reported at least one adverse event during the study: 64 infections (43%), 35 infusion reaction events (23%) which led to a discontinuation for 10 patients. Infusion reactions were more frequent in patients with a history of allergy. Three cases of tuberculosis and 1 breast carcinoma were reported during the study. CONCLUSIONS: Adjustments in the treatment of RA patients treated with recommended doses of infliximab were common (38.8% of the treated patients). Furthermore, the observed rate of infections (43%), including three cases of tuberculosis, should alert physicians to be vigilant in the routine care of patients treated with infliximab.

Long-term effects of infliximab on bone and cartilage turnover markers in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is associated with systemic bone loss, subchondral bone erosion and cartilage degradation under the control of pro-inflammatory cytokines, including tumour necrosis factor alpha (TNFalpha). Therefore, we tested the hypothesis that administration of infliximab, an anti-TNFalpha drug in the treatment of RA, would modulate systemic and local bone resorption and reduce cartilage degradation. METHODS: We performed a prospective study of a multicentric cohort of 48 women, mean (SD) age 54.2 (12.1) years old, with severe RA for 11.4 (7.8) years, who started infliximab after failure of other disease-modifying antirheumatic drugs. At baseline and 6, 22 and 54 weeks after initiating Infliximab therapy we measured the following biochemical markers: pro-collagen serum type I N-terminal propeptide (PINP), a marker of bone formation; serum C-terminal cross-linked telopeptide of type I collagen (CTX-I), a marker of cathepsin K-mediated bone collagen degradation believed to reflect systemic bone resorption; serum C-terminal cross-linked telopeptide of type I collagen (ICTP), an index of matrix metalloprotease (MMP) mediated type I collagen degradation reflecting preferential joint metabolism; and urinary CTX-II a biochemical markers of cartilage degradation. Total hip and lumbar spine bone mineral density (BMD) was assessed at baseline, and after 6 and 12 months by dual-energy x-ray absorptiometry (DXA). No patient received bisphosphonates while 77% were under oral glucocorticoids. RESULTS: BMD remained stable over 1 year. Serum CTX-I levels rapidly decreased by 19% and 28% at week 6 and week 22, respectively (analysis of variance (ANOVA) p = 0.032) values returning to pre-treatment level at week 54. By contrast, ICTP levels progressively declined with a maximal 25% decrease at week 54 (ANOVA p = 0.028). By contrast, PINP levels remained stable over time, which led to a 30 to 40% improvement in bone remodelling balance, as assessed by the ratios PINP/CTX and PINP/ICTP (p<0.05). There was no significant change of urinary CTX-II in the whole population, but a slight decrease (ANOVA p = 0.041) in those with pre-treatment levels above the upper limit of normal range. CONCLUSIONS: In summary, the improvement in the formation/resorption marker ratio suggests beneficial systemic and local bone effects of infliximab in patients with RA.

Efficacy and safety of combination etanercept and methotrexate versus etanercept alone in patients with rheumatoid arthritis with an inadequate response to methotrexate: the ADORE study.

OBJECTIVE: To evaluate the efficacy and safety of etanercept (ETN) monotherapy compared with combination ETN and methotrexate (MTX) treatment in patients with rheumatoid arthritis who had an inadequate response to MTX monotherapy. (The response was defined by the presence of Disease Activity Score-28 joint count (DAS28) >or=3.2 or a combination of >or=5 swollen joints, >or=5 painful joints and erythrocyte sedimentation rate >or=10 mm/h.) METHODS: Patients with active rheumatoid arthritis taking MTX >or=12.5 mg/week for >or=3 months were included in this 16 week, randomised, open-label study. Patients were randomly assigned to either ETN (25 mg subcutaneous injection twice weekly) added to the baseline dose of MTX or ETN monotherapy. RESULTS: 315 patients were randomised to ETN (n = 160) or ETN plus MTX (n = 155). The primary end point, DAS28 (4) improvement of >1.2 units, was achieved by 72.8% and 75.2% of patients treated with ETN and those treated with ETN plus MTX, respectively, with no significant difference (p = 0.658) between the two groups. The European League Against Rheumatism response criteria of good or moderate response was attained by 80.0% of patients in the ETN group and by 82.4% of patients in the ETN plus MTX group. American College of Rheumatology 20%, 50% and 70% response rates achieved by both groups were also similar: 71.0% v 67.1%, 41.9% v 40.1% and 17.4% v 18.4%, respectively. The rates of adverse and serious adverse events were similar between the treatment groups. CONCLUSION: Both the addition of ETN to MTX and the substitution of ETN for MTX in patients with rheumatoid arthritis who had an inadequate response to MTX resulted in substantial improvements in clinical signs and symptoms and were generally well-tolerated treatment strategies for improving clinical signs and symptoms of rheumatoid arthritis.

Study of the tolerance of infliximab infusions with or without betamethasone premedication in patients with active rheumatoid arthritis.

OBJECTIVES: To assess the incidence of infusion reactions in patients with rheumatoid arthritis (RA) receiving infliximab treatment with and without betamethasone premedication. To determine whether patients with an atopic diathesis had a better response to corticosteroid pretreatment than those without, and the course of patients' functional capacity and quality of life. PATIENTS AND METHODS: A prospective, multicentre, randomised, double blind phase 4 study of 355 patients with RA in two groups: group A received betamethasone and group B placebo, before a 36 week infusion treatment with infliximab. Incidence and severity of infusion reactions from infliximab treatment were assessed. RESULTS: The incidence of reactions to infliximab infusion was <5%. More infusion reactions occurred with betamethasone pretreatment than with placebo. Response to infliximab of patients with atopic backgrounds did not differ in the presence or absence of betamethasone from that of non-atopic patients. Mean Health Assessment Questionnaire score improved by 47% at week 24, quality of life assessed by Short Form-36 improved in mental and physical component subscales. CONCLUSIONS: Incidence of infusion reactions with infliximab was low and their severity generally mild, but betamethasone pretreatment did not decrease the incidence and severity of infusion reactions. Betamethasone, therefore, is not recommended as a systematic prophylactic measure, even in atopic patients.

The efficiency of switching from infliximab to etanercept and vice-versa in patients with rheumatoid arthritis.

OBJECTIVE: To determine whether it may be successful to try another TNF-alpha antagonist (infliximab or etanercept) when one has failed due to non response or the development of side effects. METHODS: In a cohort of 282 patients with rheumatoid arthritis treated with infliximab or etanercept, we observed 38 patients who had received both agents. RESULTS: Twenty-four patients received infliximab first and 14 received etanercept first. Discontinuation was due to a lack of efficiency for 29 patients and to the occurence of an adverse effect for 9 patients. For 25 out of the 38 patients, the switch was a success according to the global physician's assessment 3 months after switching. This result was correlated to a significant decrease of DAS 28 measurements and CRP values (p < 0.05). The response after switching was recorded as a success for 18 out of the 24 patients who were treated with infliximab first, and for 12 out of the 14 patients who were treated with etanercept first. There was no statistical difference concerning the response after the switch between the two groups. Among the 29 patients who discontinued the first anti TNF-alpha treatment due to lack of efficiency, only 6 did not respond to the second anti TNF-alpha treatment. Only one out of the 9 patients who stopped a first anti TNF-alpha treatment after developing a side effect underwent an adverse event with the second anti TNF-alpha treatment. CONCLUSION: Our study suggests that switching between TNF-alpha antagonists seems to be relevant, regardless of which one was used first. It is legitimate to try to switch TNF-alpha blockers before contemplating other therapeutic strategies.

Visceral leishmaniasis infection in a rheumatoid arthritis patient treated with infliximab.

Anti-TNFalpha strategies can result in significant clinical benefits in rheumatoid arthritis (RA), but with an increased rate of opportunistic infections. Visceral leishmaniasis (VL) is a severe disease that can develop in immunocompromised hosts, principally in HIV patients. VL in RA patients treated with TNFalpha antagonists is an extremely rare event, and only one case has been described. Here we report a case of VL, occurring after 9 infusions of infliximab in association with azathioprine, in a patient who developed blood cytopenia, fluctuant fever, and splenomegaly.

[Laparoscopy under local anaesthesia and hypnoanaesthesia about 35 cholecystectomies and 15 inguinal hernia repair]. / Coeliochirurgie sous anesthésie locale et hypnosédation, à propos de 35 cholécystectomies et 15 cures de hernies.

OBJECTIVE: To present hypnosedation and the feasibility of this technique performed for laparoscopic procedure. STUDY DESIGN: Retrospective and descriptive study of feasibility. PATIENTS AND METHODS: Hypnosis can significantly reduce intraoperative requirements of intravenous sedation for surgery under local anaesthesia. Modifications of surgical procedure: laparoscopic surgery under local anaesthesia and hypnosis is performed using a subcutaneous lifting of anterior abdominal wall. Insufflation is only use to push out smoke. If patient or surgical uncomfort happens, moral contract with patient includes convert to general anaesthesia. RESULTS: We performed 35 cholecystectomies; 13 needed convert to general anaesthesia, mainly for peritoneal pain induced by CO(2) insufflation; 22 procedures were completed with patients' satisfaction. Upon 15-hernia repairs, only one patient needed convert to general anaesthesia, for dissection difficulty. CONCLUSION: Probably hypnosis can't be extent to intraperitoneal laparoscopic procedures. On the other hand interest of hypnosis performed for extraperitoneal laparoscopic hernia repair must be explore.

HLA-DMA*0103 and HLA-DMB*0104 alleles as novel prognostic factors in rheumatoid arthritis.

OBJECTIVE: To evaluate HLA-DM alleles as markers for disease severity in rheumatoid arthritis (RA). METHODS: Two distinct cohorts of patients with RA were oligotyped for HLA-DB1 and HLA-DM genes using PCR amplified genomic DNA with sequence specific oligonucleotide probes. Cohort 1 comprised 199 unselected patients with RA (mean (SD) age 45.5 (13.5) years; disease duration 11.9(8.8) years), whose disease severity was assessed using Larsen score on hand and foot radiographs. Cohort 2 comprised 95 patients with severe RA and 70 patients with benign RA according to the Larsen method. RESULTS: In cohort 1, after stratification according to DRB1 genotypes, patients positive for HLA-DMA*0103 and negative for HLA-DRB1*04 tended to have greater articular damage on hands and wrists (p = 0.07 by Mann-Whitney U test) and reached statistical significance for the Larsen score per year (p = 0.05). This association between HLA-DMA*0103 and articular damage was especially observed in patients with HLA-DRB1*01. Similarly, HLA-DMB*0104 positive patients had higher Larsen score on hands and wrists (p = 0.02). This association was even stronger in DRB1*04 positive patients (p = 0.005). In cohort 2, HLA-DMA*0103 was associated with severe RA in patients negative for HLA-DRB1*04 (OD = 5.4; p = 0.014). HLA-DMB*0104 allele frequency tended to be higher in patients with severe RA but without reaching significance. CONCLUSION: This is the first study evaluating the role of HLA-DM genes in the severity of RA. Our results suggest that HLA-DMA*0103 and HLA-DMB*0104 alleles may represent new genetic markers of RA severity. The HLA-DMA*0103 allele tends to be associated with patients with RA negative for DRB1*04 and could predict a more severe form of disease especially in HLA-DRB1*01 positive patients. The HLA-DMB*0104 allele could have an additive effect in HLA-DRB1*04 patients. Combined determination of HLA-DM and HLA-DRB1 alleles could facilitate identification of patients likely to have a poor disease course.

Characteristics of patients with rheumatoid arthritis in France: a study of 1109 patients managed by hospital based rheumatologists.

OBJECTIVE: To describe the characteristics of rheumatoid arthritis in patients managed by hospital based rheumatologists in France. METHODS: All public and non-profit private hospitals in France were invited to participate in a cross sectional study. Clinical data on the day of inclusion and health resources used for rheumatoid arthritis over the previous 12 months (treatments, medical devices, physician visits, examinations, hospital admissions, and other health professional care) were recorded. RESULTS: 1109 patients from 75 centres located throughout the country were included (846 female; mean disease duration, 10.6 years; mean age, 56.7 years). Active disease (swollen joint count > or =6, tender joint count > or =6, and two of: morning stiffness > or =45 min, C reactive protein > or =20 mg/l, erythrocyte sedimentation rate >28 mm/h) was observed in 146 patients (13.2%). Mean (SD) DAS(28) was 4.51 (1.55). Severe extra-articular manifestations were reported in 8.4%. ACR functional status was: class I, 19%; class II, 28%; class III, 31%; class IV, 22%. Comorbidity was observed in 44.9% of cases, particularly chronic pulmonary disease and coronary or peripheral vascular disease. Average AIMS2-SF dimension scores were between 4.56 and 6.18, and mean HAQ was 1.32 (0.77). Disease modifying antirheumatic drugs (DMARDs) were prescribed for 82.1% of the patients. During the previous four weeks, one DMARD was used in 62.5%, and two or more in 19.5%. Corticosteroids were prescribed in 72%. CONCLUSIONS: In a rheumatoid arthritis population managed by hospital based rheumatologists, the disease was active in 13% and severe in more than one third of cases.

Outcomes of a multicentre randomised clinical trial of etanercept to treat ankylosing spondylitis.

OBJECTIVE: A double blind, randomised, placebo controlled study to evaluate the safety and efficacy of etanercept to treat adult patients with ankylosing spondylitis (AS). METHODS: Adult patients with AS at 14 European sites were randomly assigned to 25 mg injections of etanercept or placebo twice weekly for 12 weeks. The primary efficacy end point was an improvement of at least 20% in patient reported symptoms, based on the multicomponent Assessments in Ankylosing Spondylitis (ASAS) response criteria (ASAS 20). Secondary end points included ASAS 50 and ASAS 70 responses and improved scores on individual components of ASAS, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), acute phase reactants, and spinal mobility tests. Safety was evaluated during scheduled visits. RESULTS: Of 84 patients enrolled, 45 received etanercept and 39 received placebo. Significantly more etanercept patients than placebo patients responded at the ASAS 20 level as early as week 2, and sustained differences were evident up to week 12. Significantly more etanercept patients reported ASAS 50 responses at all times and ASAS 70 responses at weeks 2, 4, and 8; reported lower composite and fatigue BASDAI scores; had lower acute phase reactant levels; and had improved spinal flexion. Etanercept was well tolerated. Most adverse events were mild to moderate; the only between-group difference was injection site reactions, which occurred significantly more often in etanercept patients. CONCLUSIONS: Etanercept is a well tolerated and effective treatment for reducing clinical symptoms and signs of AS.

Prognostic factors for remission in early rheumatoid arthritis: a multiparameter prospective study.

OBJECTIVE: To determine prognostic factors for remission in early rheumatoid arthritis. METHODS: 191 patients with rheumatoid arthritis whose disease duration was less than one year were followed up prospectively for five years. Remission, defined by a disease activity score (DAS) of <1.6, was used as the outcome measure. Baseline clinical, laboratory, genetic, and radiographic data (with radiographic scores determined by Sharp's method, modified by van der Heijde) were obtained. RESULTS: 48 patients (25.1%) fulfilled the remission criteria at the three year follow up visit, and 30 (15.7%) at three and five years. On univariate analysis by Fisher's exact test, remission at three years and persistent remission at five years were closely correlated with baseline DAS values, C reactive protein level, Ritchie score, health assessment questionnaire score, duration of morning stiffness, and to a lesser extent baseline total radiological scores and rheumatoid factor negativity. No significant correlation was found with sex, age, extra-articular manifestations, erythrocyte sedimentation rate, anti-cyclic citrullinated protein antibodies, anti-keratin antibodies, anti-HSP 90, anticalpastatin antibodies, antinuclear antibodies, or HLA-DRB1* genotypes. Logistic regression analysis showed that the baseline independent variables predictive of remission were low DAS, Ritchie score, morning stiffness duration, and total radiographic score. CONCLUSIONS: Baseline prognostic factors for remission in early rheumatoid arthritis were mainly clinical markers of disease activity and radiological scores.

Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed.

OBJECTIVE: To evaluate the efficacy and safety of monotherapy with adalimumab in patients with RA for whom previous DMARD treatment has failed. METHODS: In a 26 week, double blind, placebo controlled, phase III trial, 544 patients with RA were randomised to monotherapy with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, 40 mg weekly, or placebo. The primary efficacy end point was > or =20% improvement in the ACR core criteria (ACR20 response). Secondary efficacy end points included ACR50, ACR70, EULAR responses, and the Disability Index of the Health Assessment Questionnaire (HAQ DI). RESULTS: After 26 weeks, patients treated with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, and 40 mg weekly had significantly better response rates than those treated with placebo: ACR20 (35.8%, 39.3%, 46.0%, 53.4%, respectively v 19.1%; p< or =0.01); ACR50 (18.9%, 20.5%, 22.1%, 35.0% v 8.2%; p< or =0.05); ACR70 (8.5%, 9.8%, 12.4%, 18.4% v 1.8%; p< or =0.05). Moderate EULAR response rates were significantly greater with adalimumab than with placebo (41.5%, 48.2%, 55.8%, 63.1% v 26.4%; p< or =0.05). Patients treated with adalimumab achieved better improvements in mean HAQ DI than those receiving placebo (-0.29, -0.39, -0.38, -0.49 v -0.07; p< or =0.01). No significant differences were found between adalimumab and placebo treated patients for serious adverse events, serious infections, or malignancies. Injection site reaction occurred in 10.6% and 0.9% of adalimumab and placebo treated patients, respectively (p< or =0.05). CONCLUSION: Among patients with RA for whom previous DMARD treatment had failed, adalimumab monotherapy achieved significant, rapid, and sustained improvements in disease activity and improved physical function and was safe and well tolerated.

[MRI study before and after extracorporal shock wave therapy in calcifying tendinitis of the shoulder]. / Etude IRM avant et aprEs lithotritie des tendinopathies calcifiantes de l'épaule.

PURPOSE: Extracorporal shock wave therapy has recently been proposed with good results (70%) for treatment of persistent painful calcifying tendinitis of the shoulder. The aim of this study was to evaluate the early impact of shock wave therapy on the anatomic structures of the shoulder. MATERIALS AND METHODS: Eight patients (7 women and 1 man, with mean age of 48 years) were prospectively followed up after undergoing shock wave therapy (1500 pulses with 0.28 mJ/mm2 energy). MRI (T1: 500/12 [TR/TE] and STIR: 7200/60/180/180 [TR/TE/TI/alpha]) were obtained 2 hours before and 15 days after the procedure; in addition for 5 of them one more examination was carried out 6 hours after extracorporal shock wave therapy. RESULTS: There was no significant signal change of the humeral bone or rotator cuff, and the calcification size, when seen (6 times), was unchanged at successive MR examinations. One patient had subcutaneous fat signal change (STIR) next to the zone of impact, which resolved 15 days after the extracorporal shock wave therapy. No bursitis or joint effusion was found. CONCLUSION: Shock wave therapy has no early complications or significant impact on the anatomic structures of the shoulder.

Adenovirus-mediated gene transfer of urokinase plasminogen inhibitor inhibits angiogenesis in experimental arthritis.

Plasmin is essential for metalloproteases activation, endothelial cell migration and degradation of the extracellular matrix. The process is common to neoangiogenesis pannus formation and cartilage degradation within arthritic joints. Since 80% of synovial cells express urokinase plasminogen activator receptor (uPAR), we investigated the inhibition of plasmin activation in a collagen-induced arthritis (CIA) mice model, by expressing a uPA/uPAR antagonist molecule (ATF) fused to human serum albumin (HSA) to extend its serum half-life. Overexpression was obtained with an adenoviral vector expressing the chimeric murine ATF-HSA. We showed that the genetic coupling did not significantly reduce the ability of the ATF moiety to interact with its receptor uPAR. The chimeric protein was detectable in the sera of injected mice 7 days following Ad-mATF-HSA injection, then decreased in parallel with the anti-HSA titer increase. Systemic Ad-mATF-HSA injection performed on day 25 following CIA induction decreased the incidence of arthritis and the severity of the disease. Moreover, synovial angiogenesis in arthritic paws was decreased after Ad-mATF-HSA gene transfer, as assessed by smooth muscle actin immunostaining. The preventive effect observed on arthritis was related to the decrease in angiogenesis, rather than inhibition of extracellular matrix degradation.

Prognostic factors for radiographic damage in early rheumatoid arthritis: a multiparameter prospective study.

OBJECTIVE: To determine prognostic factors of radiologic damage and radiologic progression in early rheumatoid arthritis (RA). METHODS: A cohort of 191 patients with RA whose disease duration was shorter than 1 year were prospectively followed up for 3 years. Radiologic scores (as determined by Sharp's method, modified by van der Heijde) and radiologic progression were used as outcome measures. Numerous baseline clinical, laboratory, genetic, and radiographic data were obtained. RESULTS: The change in the total radiologic score for the patients followed up over 3 years was a mean +/- SD increase of 6.1 +/- 6.2. Radiologic progression was observed in 71 of the 172 patients for whom there were data at the end of the study. By univariate analysis with Fisher's exact test, radiologic scores and progression at followup were closely correlated with the baseline values of the erythrocyte sedimentation rate (ESR), C-reactive protein level, IgM and IgA rheumatoid factor positivity, antiperinuclear antibody positivity, radiologic scores, duration of morning stiffness, and RA-associated HLA-DRB1*04 genes. No correlation was demonstrated with sex, age, Disease Activity Score, swollen or tender joint counts, extraarticular manifestations, Health Assessment Questionnaire score, Ritchie Articular Index, patient's assessment of pain, positivity for anti-heat-shock protein 90-kd antibodies, anticalpastatin antibodies, anti-RA33 antibodies, antinuclear antibodies, YKL-40, or antikeratin antibodies, and HLA-DRB1*01 genes. The logistic regression analysis revealed that the only baseline values that were predictive of the 3-year radiologic scores were IgM rheumatoid factor positivity, DRB1*04 genes, pain score, and total radiologic score. Progression of joint damage was predicted by the ESR, IgM rheumatoid factor positivity, DRB1*04 genes, and erosions score at baseline. CONCLUSION: Prognostic factors for radiographic damage in early RA were identified. A combination of these baseline values allowed us to draw up a predictive arithmetic score that could be used to predict radiologic damage at 3 years and radiologic progression in individual patients.

WHO Collaborating Centre consensus meeting on anti-cytokine therapy in rheumatoid arthritis.

Severe adult rheumatoid arthritis is a cause of progressive disability and increased mortality across Europe. A cure for the disease remains elusive, but control of symptoms and maintenance of individual independence is possible. Anti-cytokine therapies offer a new approach to disease management. They are effective after the failure of full doses of methotrexate, and are at least as effective as methotrexate in retarding the progression of radiological changes. Until more is known about the long-term safety and efficacy of these drugs they should be reserved for patients with severe disease who are progressing despite adequate doses of methotrexate or other disease-modifying anti-rheumatic drugs. They should be continued until therapeutic failure or intolerance. A comprehensive health economic evaluation is needed to optimally direct the use of these drugs. This should be undertaken when long-term safety and efficacy studies are completed.

Paradoxical effects of tissue inhibitor of metalloproteinases 1 gene transfer in collagen-induced arthritis.

OBJECTIVE: The imbalance between matrix metalloproteinases (MMPs) 1, 3, and 9 and their specific inhibitor, tissue inhibitor of metalloproteinases 1 (TIMP-1), is a critical step in cartilage injury and angiogenesis in arthritis. To explore the therapeutic potential of TIMP-1 gene transfer in erosive arthritis, the effects of an adenoviral vector (Ad-TIMP-1) were assessed in DBA/1 mice with collagen-induced arthritis (CIA). METHODS: DBA/1 mice with CIA received an intravenous injection of replication-deficient adenovirus containing the human TIMP-1 gene or a control LacZ gene on day 28 postimmunization. The efficiency of gene transfer was determined by serum TIMP-1 detection, measurements of paw swelling, as well as radiologic and histologic examination of the paws. RESULTS: A single administration of Ad-TIMP-1 resulted in detectable serum levels of the exogenous protein for at least 13 days. The incidence and onset of arthritis were not statistically modified after human TIMP-1 gene transfer in DBA/1 mice compared with control mice. However, the severity of inflammation was statistically significantly increased in Ad-TIMP-1-treated mice and a similar trend was observed in the histologic and radiologic scores. With regard to the mechanisms of the worsened effect in the Ad-TIMP-1-treated mice, we observed 1) higher serum levels of anti-type II collagen IgG2a, 2) a significant increase in endogenous soluble tumor necrosis factor receptor I (TNFRI) in sera, and 3) increased labeling of mouse tumor necrosis factor alpha and TNFRI within arthritic joints. CONCLUSION: These findings show that overexpression of TIMP-1 does not prevent osteochondral injury in a mouse model of arthritis. Since MMPs have overlapping properties in terms of their roles in extracellular matrix degradation, angiogenesis, and shedding of cell surface adhesion molecules, cytokines, and cytokine receptors, the paradoxical results obtained suggest that TIMP-1 is probably not the main inhibitor to target.

HLA-DRB1 genes and patients with late onset rheumatoid arthritis.

OBJECTIVE: To determine the influence of HLA-DRB*1 genes on susceptibility to and severity of rheumatoid arthritis (RA) in patients with late onset compared with younger onset disease. METHODS: The clinical, biological, and HLA-DRB1 typing characteristics of two groups of patients were studied retrospectively. Group 1 consisted of 262 patients whose disease onset was before or at the age of 60 (young onset RA (YORA)). Group 2 included 60 patients whose illness began after the age of 60 (elderly onset RA (EORA)). RESULTS: The shared epitope level was similarly increased in both groups of patients compared with normal controls (195/262 (74%) in group 1 and 43/60 (72%) in group 2 v 645/1609 (40.1%) in controls). No differences were noted between the two groups of patients for each separate disease related allele. In contrast, when studying all HLA-DRB1*04 RA related alleles as a group, these alleles were underrepresented in EORA compared with YORA (22/60 (37%) v 135/262 (52%); odds ratio 2.0; 95% confidence interval 1.0 to 3.3). An inverse trend was seen for HLA-DRB1*01 alleles. There were no differences in biological characteristics or extra-articular manifestations between the patient groups. The differences noted in radiological evaluation or the number of prescribed disease modifying antirheumatic drugs seemed to be linked with differences in disease duration. CONCLUSION: HLA-DRB1 RA related alleles influence both EORA and YORA. However, HLA-DRB1*04 RA linked alleles are not as closely associated with RA in the elderly as they are in younger patients. This suggests that the importance of these genes in the susceptibility to RA may be lower in elderly patients.