tRNA-guanine transglycosylase from Escherichia coli: recognition of full-length ''queuine-cognate'' tRNAs

OBJECTIVE: To determine clinical variables useful in predicting the prognosis of patients with early rheumatoid arthritis (RA) by investigating the relationship between clinical variables and radiological progression. METHODS: One hundred eighteen patients with early RA whose symptoms developed within the previous year were enrolled in a prospective study. Data from the 98 patients who completed the 2 year study were analyzed, using the number of erosive joints and Larsen's score as the outcome of RA. RESULTS: Increases in the number of erosive joints at 12 months after entry into the study were significantly correlated with the number of swollen joints (r = 0.510), erythrocyte sedimentation rate (ESR) (r = 0.404), and C-reactive protein (CRP) (r = 0.487) at 6 months. The same results were seen using Larsen's score as the measure of outcome. The average number of erosive joints or mean Larsen's score at 12 months was higher in patients whose levels of CRP were high at 6 months and suppressed by 12 months, but increased much less in patients whose levels of CRP were successfully suppressed by 6 months. More joint erosions were noted in patients with positive rheumatoid factor (RF) than in RF negative patients. CONCLUSION: Joint erosions appeared with a certain time lag after active synovitis. Earlier introduction of effective treatment is recommended for the prevention of RA joint damage. The presence of RF, number of swollen joints, ESR, and levels of CRP at 6 months after starting therapy are the most useful variables to predict radiological progression in patients with early RA.     

Only high disease activity and positive rheumatoid factor indicate poor prognosis in patients with early rheumatoid arthritis treated with "sawtooth" strategy

OBJECTIVES: To investigate the prognostic significance of clinical and genetic markers on the outcome of patients with recent-onset rheumatoid arthritis (RA) treated actively with slow acting antirheumatic drugs (SAARDs). METHODS: A total of 142 consecutive patients with early RA (median disease duration of 7 months) were treated according to the "sawtooth" strategy and prospectively followed up for an average of 6.2 years. Several clinical parameters at start as well as genetic markers were related to the functional outcome (ARA Functional class and HAQ disability score) and radiographic joint damage (Larsen's score) at the latest visit. RESULTS: In logistic regression analysis only Mallya score (including morning stiffness, pain scale, grip strength, Ritchie's articular index, haemoglobin, and erythrocyte sedimentation rate) at baseline, and Mallya score and rheumatoid factor (RF) positivity at one year were found to be of significance with respect to the radiographic outcome of the patients. Furthermore, at the latest visit HAQ score was related to radiographic score. At baseline the mean ages of the DR4 positive patients and the patients with RA associated DR alleles were statistically significantly lower than those without the above mentioned risk factors (44 v 49, p = 0.03 and 41 v 53, p = 0.04, respectively). However, these genetic markers had no prognostic significance on the functional or radiographic outcome of the patients. CONCLUSION: High clinical disease activity at baseline and RF positivity especially at one year after the institution of SAARD treatment are the best predictors of poor prognosis in early RA. However, from the clinical point of view, the disease outcome of an individual patient with early RA, cannot be predicted accurately enough by present means.     

Radiographic outcome of recent-onset rheumatoid arthritis: a 19-year study of radiographic progression

OBJECTIVE: To describe the longitudinal radiographic course of rheumatoid arthritis (RA), and to identify and quantitate predictors of radiographic progression. METHODS: This prospective, longitudinal study of radiographic progression and clinical predictors of RA involved 256 patients with RA who were seen within the first 2 years of disease (mean 0.77 years) and were followed up for up to 19 years. Participants underwent a total of 6,278 clinical assessments (mean 24.5) and 934 paired radiographs (mean 3.1, range 2-6). Clinical assessments at every visit included determination of the erythrocyte sedimentation rate (ESR), grip strength, pain scores, tender joint counts, and anxiety and depression measurements. Regression analyses utilized time-integrated predictors. RESULTS: Overall, radiographic progression rates, as measured by the summary Sharp scores, appeared constant over the course of RA. The strongest correlate of progression was the time-integrated ESR (rho=0.53). This association grew stronger with time. At 0-5 years, 5-10 years, 10-15 years, and 15-20 years, correlations were 0.40, 0.50, 0.65, and 0.74, respectively, and for the period 10-20 years, the correlation was 0.67. In multivariate models, the mean ESR, mean grip strength, rheumatoid factor positivity, and tender joint count were independent predictors of radiographic progression. CONCLUSION: Radiographic damage occurs at a constant rate in RA, and is not greater early in RA or reduced later in the course of the illness. Acute-phase reactants are, by far, the strongest determinants of progression.     

Early effective suppression of inflammation in rheumatoid arthritis reduces radiographic progression

OBJECTIVE: To evaluate the effect of early 'aggressive' drug treatment on radiographic progression in patients with recent-onset rheumatoid arthritis (RA), compared to conventional stepwise increasing intensity of treatment. DESIGN: Prospective follow-up study with an experimental group and a historical control group both divided into a high-risk subgroup and a low-risk subgroup, based on prognostic factors. The effect of the 'aggressive' and the conventional treatment strategy was compared between both high-risk groups; the low-risk groups, both treated according to the conventional treatment strategy, were used to ensure internal consistency between the experimental and the historical groups. PATIENTS: A total of 228 consecutive patients with recent-onset RA (complaints < 1 yr at study entry). METHODS: The 'aggressive' drug treatment consisted of institution of relatively fast-acting disease-modifying anti-rheumatic drugs (DMARDs) (sulphasalazine, methotrexate) immediately after diagnosis, and rapid adjustment of dosage and/or drug in the case of insufficient response as measured by a change in C-reactive protein (CRP) level. Radiographic damage was assessed according to a modified version of Sharp's method and cumulative disease activity expressed as CRP-area under the curve (CRP-AUC). The occurrence of side-effects was also evaluated. RESULTS: After 2 yr of follow-up, comparison of the two high-risk subgroups showed the radiographic progression in the 'aggressively' treated subgroup to be significantly lower than that in the control group [Sharp score: median (range) 26 (0-100) vs 35 (1-188); P = 0.03]. Cumulative CRP values were also significantly lower than in the control high-risk subgroup [CRP-AUC: median (range) 1963 (212-8515) vs 3025 (46-15 632) mg.week/1; P = 0.002). This was achieved without an increase in the occurrence of side-effects. There was no difference between the two low-risk subgroups with regard to entry characteristics, CRP-AUC values or radiological progression, indicating comparability between the two groups. CONCLUSION: Early 'aggressive' drug treatment, using sulphasalazine and/or methotrexate, aimed at reduction of the CRP level, significantly reduces the (rate of) radiographic progression in RA.     

Long-term treatment of destructive rheumatoid arthritis with methotrexate

OBJECTIVE: To evaluate the tolerability and efficacy of methotrexate (MTX) treatment in patients with longstanding, progressive, active rheumatoid arthritis (RA) who had failed one or more disease modifying antirheumatic drugs (DMARD). METHODS: Two hundred seventy-one consecutive patients with RA in whom MTX treatment was introduced were followed at regular intervals for up to 108 months. Evaluations included the number of swollen joints, grip strength, patient assessment of pain and mobility, erythrocyte sedimentation rate (ESR), and hemoglobin. Radiographs of hands and feet were taken once a year and 32 joints were evaluated according to a modified Larsen score. RESULTS: Of the 271 patients, 269 had prior treatment with one DMARD, primarily parenteral gold, and 58% with 2 or more DMARD. MTX was started parenterally in all patients in doses between 15 and 25 mg weekly and continued by oral medication in most of the cases. Eighty-three percent of patients complained of adverse events. The most common side effects were nausea, hair loss, transaminase increase, and stomatitis. In 45 patients (16.5%), MTX was withdrawn because of side effects, mostly during the first year. Sixteen patients (5.9%) died during followup, mainly due to myocardial infarction, heart failure, stroke, or cancer. After one year, 78.7% and after 5 years 60.3% of the patients were still taking MTX. Number of swollen joints, ESR, grip strength, patient assessment of pain, and mobility improved significantly at all measurement points. Improvement in the swollen joint count and the ESR of over 50% was seen in more than 50% of patients. Inactivation of the disease, defined as < 2 swollen joints, ESR < 20 mm, and no concomitant steroid use, occurred in 8-14% of patients. Steroid intake was significantly reduced. In spite of clinical improvement the modified Larsen score showed a progression in the vast majority of patients. CONCLUSION: Even in patients with longstanding, active, destructive RA who failed one or more DMARD, MTX treatment is well tolerated and improves clinical and biochemical disease activity significantly, while radiographic progression is still present.     

Comparison of the combined cortical thickness of the second metacarpal with Sharp's method for scoring hand microradiographs in rheumatoid arthritis

OBJECTIVE: To compare the correlation and specificity of the combined cortical thickness of the second metacarpal (CCT-MC) with Sharp's method (SM) for scoring joint erosions and joint space narrowing in rheumatoid arthritis (RA) and to compare the degree of interobserver agreement between the 2 methods. METHODS: Hand microradiographs of 22 women with RA, functional classes III and IV, were scored independently by 3 rheumatologists using the CCT-MC and the CCT of the middle phalanx and SM. RESULTS: (1) There was a highly significant correlation between the total SM score and the CCT-MC for the 3 observers (r = 0.61, p = 0.0026), but not between the CCT of the middle phalanx and SM (r = 0.15, p = 0.53). There was a lower degree of agreement between the observers for SM erosion scores compared to the CCT-MC (intraclass correlation 0.88 for the CCT-MC and 0.63 for the SM); (2) Both joint space narrowing and erosion scores correlated highly with the CCT-MC (r = -0.60, p = 0.004; and r = -0.51, p = 0.014, respectively); (3) CCT-MC measurements are more closely related to the inner (d) as opposed to the outer (D) diameter of the 2nd metacarpal; (4) The mean time to obtain the CCT-MC score was 3.43 min (SD = 1.38) versus 9.83 min (SD = 3.20) for SM (p = 0.0001); (5) the derivative, (D2-d2)/D2, was significantly correlated with SM (r = -0.72, p = 0.0002) and its erosion and joint space narrowing components (r = -0.63, p = 0.0019; and r = -0.71, p = 0.0002, respectively). CONCLUSION: The CCT-MC is a rapid, practical method with higher agreement among observers compared to SM and correlates highly with SM scores for joint damage in RA. CCT-MC appears to have a higher degree of specificity than other sites for CCT measurement. The CCT-MC is more closely related to the inner diameter than the outer diameter, which supports the notion that the principal site of accelerated bone loss due to RA in the hand occurs at the endosteal surface. The CCT-MC should be further assessed with respect to monitoring radiological progression in RA.     

Bayesian calculation of methotrexate clearance after low dose intramuscular administration in patients with rheumatoid arthritis

OBJECTIVE: To determine a pharmacokinetic procedure (Bayesian method) for estimation of methotrexate (MTX) clearance, using only 2 blood samples, in outpatients with rheumatoid arthritis treated with low dose intramuscular (i.m.) MTX. METHODS: Population pharmacokinetic parameters were obtained by the weighted least squares (WLSQ) method in plasma samples from 14 patients with rheumatoid arthritis (RA). In each patient, 11 samples were measured by fluorescence polarization immunoassay, at Time 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, and 24 h after i.m. administration. These measures were validated by pharmacokinetic studies in 20 other patients with RA. Individual total body clearance of MTX was calculated using only 2 plasma samples (at 0.5 and 2 h after i.m. injection) by the Bayesian method using the population pharmacokinetic parameters. The clearance measures obtained by the Bayesian method were compared with those obtained by the WLSQ method. RESULTS: The pharmacokinetic variables (clearance, half-life, area under the curve) of 14 patients were determined, as well as the covariance and the mean values necessary to apply the Bayesian method. No significant difference was found between clearance values obtained by the Bayesian method compared to the WLSQ method, confirming the validity of the Bayesian values. CONCLUSION: The present population pharmacokinetic parameters allowed the determination of individual clearance of MTX with only 2 plasma samples (0.5 and 2 h after administration) in patients treated with low dose im MTX. Individual clearance is used to modulate MTX administration in patients presenting adverse reactions in spite of good clinical response. Individual determination of MTX pharmacokinetics in patients at risk for adverse MTX reactions could be useful for adjustment of the drug regimen.     

Muscle strength in rheumatoid elbow: quantitative measurement and comparison to Larsen's X-ray grade

Accurate assessment of elbow function is important to determine the total ability of the arm. The purpose of this study was to clarify the relationship between isometric muscle strength of the elbows of patients with rheumatoid arthritis (RA) and Larsen's X-ray evaluation. Fifty-six elbows of 45 RA patients aged 47 to 77 years (mean age, 63 years) were tested. Muscle strength was measured with an isometric torque-cell dynamometer. Test-retest reliability of the dynamometer was proven by measuring 12 elbows of 6 healthy young men. In RA patients, elbow flexion and extension strength decreased in proportion to increases in the severity of Larsen's grades from Grade 1 to 4. However, Grade 5 elbows had greater muscle strength than those in Grade 4. Forearm pronation and supination strength also decreased in proportion to increases in the severity of Larsen's grades from Grade 1 to 5. This quantitative study made it clear that the muscle strength of RA patients' elbows almost completely correlates to X-ray finding according to the grade of Larsen's evaluation based on X-rays. With regard to muscle strength of postoperative elbows, both flexion strength and supination strength after total elbow replacement (TER) were about two times greater than before TER, and after synovectomy it was as great as those in non-operative RA patients of Grade 2.     

Long-term follow-up of 453 rheumatoid arthritis patients treated with methotrexate: an open, retrospective, observational study

A total of 453 rheumatoid arthritis (RA) patients were followed up for 35.2 +/- 27.9 months (range 3-106). The clinical parameters decreased significantly after 6 months. Twenty-eight patients were in remission (6.4%). Rheumatoid factor (RF) positivity was less common in the group of patients in remission, with a higher frequency of visits and methotrexate (MTX) onset after 65 yr. There was a significant degradation of radiographic lesions (n = 60). A total of 101 patients (23.1%) stopped MTX, for toxicity (n = 61) and failure (n = 20). The onset of MTX after 65 yr, a low number of visits and the occurrence of side-effects were predictive of MTX withdrawal. A total of 259 patients (59.3%) had side-effects. A Ritchie's index < or = 10, a lower polymorphonuclear cell count and the absence of RF were predictive of side-effects. The probability of being on MTX at 5 yr was 73%. This study confirms the high efficacy of MTX in RA.     

Radiographic progression in rheumatoid arthritis: a long-term prospective study of 109 patients

OBJECTIVE: To investigate the long-term radiographic course as a mathematical function of disease duration in individual patients and in a group of patients with rheumatoid arthritis (RA). METHODS: In 109 patients with RA, radiographic examinations of 46 diarthrodial joints were performed at regular intervals of 1-3 years, for up to 30 years after disease onset. RESULTS: Five main types of progression were identified: 1) a rare type (<1%), with no radiographic progression at all; 2) a type with a slow or moderate onset, but an increasing progression rate (9% exponential growth type and 30% linear type); 3) a type with a moderate-to-fast onset and a stable progression rate (the square-root type; 11%); 4) a type with a fast onset, but a later decreasing progression rate (the first-order kinetics type, 30%); and 5) a type characterized by slow onset, then acceleration and later deceleration (the sigmoid type, 20%). CONCLUSION: The progression of radiographic damage in RA followed mathematical functions of time. The identification of progression type may be used in the prediction of outcome in patients with RA.     

The effects of food on methotrexate absorption

OBJECTIVE: To determine the effects of food on methotrexate (MTX) absorption in patients receiving MTX for the treatment of rheumatoid arthritis (RA). METHODS: Standard pharmacokinetic variables were determined in patients with RA after their usual maintenance dose of MTX, under fasting conditions and after they ate a standard breakfast. RESULTS: No significant differences in area under the serum concentration versus time curve, maximal MTX concentration after dosing (Cmax), time to Cmax), bioavailability, urinary MTX, renal clearance of MTX, or creatinine clearance were observed between the 2 dosing conditions. CONCLUSION: We observed no significant effect of food on MTX absorption or bioavailability. Patients may consume MTX without regard to meals.     

Lymphoma in patients with rheumatoid arthritis: association with the disease state or methotrexate treatment

Although long-term clinical studies have shown no excessive risk of lymphoma in rheumatoid arthritis (RA) patients treated with methotrexate (MTX), an increasing number of reports of this association continue to appear. We describe two cases, review the cases in the world's literature, and summarize their important characteristics. Possible oncogenic mechanisms are discussed. Most lymphoproliferation cases presented here have features of immunosuppression-associated lymphoma. The immunosuppressed state is attributable to a combination of factors, such as RA itself and the actions of MTX. The risk factors for RA patients to develop lymphoma while on MTX include severe disease, intense immunosuppression, genetic predisposition, and an increased frequency of latent infection with prooncogenic viruses such as Epstein-Barr virus (EBV). The spontaneous remission of lymphomas in eight RA patients after MTX was stopped highlights the likely causative role of the drug in the development of these malignancies. If the clinical situation permits, a period of observation for spontaneous remission after MTX is stopped is advisable. The physicians caring for RA patients on MTX should maintain a high surveillance for signs and symptoms suggestive of lymphoma.     

Clinical and radiographic outcomes of rheumatoid arthritis patients not treated with disease-modifying drugs

OBJECTIVE: To compare the radiographic and clinical features of rheumatoid arthritis (RA) patients who were not given disease-modifying antirheumatic drugs (DMARDs) with those of RA patients who were followed up and treated with DMARDs at a rheumatology clinic. METHODS: The population of this case-control study includes a series of RA patients who immigrated to Israel from the previous Union of Soviet Socialist Republics and who were treated only with nonsteroidal antiinflammatory drugs. Control patients who were followed up and treated with DMARDs at our rheumatology clinic were matched by sex, disease duration, number of actively inflamed joints, and the presence of serum rheumatoid factor. The outcome measures were the number of deformed and radiographically damaged joints. Radiographic damage was evaluated by the methods of Steinbrocker and Sharp. RESULTS: The study population consisted of 22 RA patients (15 women, 7 men) who were not treated with DMARDs and 22 patients (15 women, 7 men) who were treated with DMARDs. The mean disease duration was 16.2 years for the study patients and 14.3 years for the controls. Compared with the matched controls, RA patients who were not treated with DMARDs were found to have a significantly higher mean number of deformed joints (13.8 versus 7.2), a higher mean number of damaged joints (24.4 versus 15.5), and a higher overall damage score by the Sharp criteria (146.1 versus 65.7). CONCLUSION: RA patients who were not given DMARDs had a 1.57-fold increased number of radiographically damaged joints and a 2.22-fold increased overall Sharp damage score compared with patients who were treated with second-line agents.     

Comparison of 3 quantitative measures of hand radiographs in patients with rheumatoid arthritis: Steinbrocker stage, Kaye modified Sharp score, and Larsen score

OBJECTIVE: To compare 3 quantitative hand radiograph scores, Steinbrocker stage, Larsen score, and Sharp score modified by Kaye, to one another and to other measures of clinical status in a cross sectional analysis of hand radiographs of 173 patients with rheumatoid arthritis (RA). METHODS: Radiographs were scored and compared to other measures of clinical status according to correlation and cross tabulation analyses. RESULTS: In these cross sectional studies, radiographic scores according to all 3 methods were correlated at high levels (r(s) > 0.5) with one another and duration of disease, as well as with scores for physical joint deformity and limited motion; at lower levels (0.3 < r(s) < 0.5) with physical joint swelling scores, functional status, and age; and at low levels of marginal or no clinical importance (r(s) < 0.3) with physical joint tenderness scores, laboratory data, and pain scores. CONCLUSION: The 3 scoring methods give similar quantitative information concerning hand radiographs of patients with RA. The Larsen and modified Sharp scores are preferred measures, as the detailed information facilitates comparison of different patients and monitoring of individual patients over time.     

Clinical characteristics of patients with rheumatoid arthritis and methotrexate induced pneumonitis

OBJECTIVE: To determine the clinical features of methotrexate (MTX) pneumonitis in patients treated for rheumatoid arthritis (RA). METHODS: The medical records of 284 patients with RA who had been treated with oral MTX (mean followup 33.2 mo) were reviewed retrospectively. RESULTS: MTX induced interstitial pneumonitis developed in 6 patients (2.1%). The affected patients were significantly older than those without MTX pneumonitis (67.3 +/- 9.8 vs 52.4 +/- 12.6 yrs, respectively; p < 0.005). The cumulative MTX dose ranged from 65 to 580 mg at the time pneumonitis developed. Five of the patients (83%) had preexisting interstitial abnormalities, while only 29 of the 278 patients without MTX pneumonitis (10%) had such abnormalities (p < 0.001). The frequency of adverse effects due to previous treatment with disease modifying antirheumatic drugs (DMARD) was 66.7% in MTX pneumonitis patients and 14.3% in the other 278 patients (p < 0.01). CONCLUSION: Advanced age, preexisting interstitial abnormalities, and previous adverse reactions to DMARD may be associated with MTX pneumonitis. Patients with these characteristics require careful monitoring during MTX therapy.     

Lack of interaction between bromfenac and methotrexate in patients with rheumatoid arthritis

OBJECTIVE: To compare the pharmacokinetics of methotrexate (MTX) and bromfenac administered separately or coadministered in patients with rheumatoid arthritis (RA). METHODS: Patients received their usual weekly oral dose of MTX on Days 1 and 8 and bromfenac 50 mg every 8 h from Days 4 to 9. On Days 1 and 8 serial blood and urine samples were collected to study the pharmacokinetics of MTX and 7-hydroxymethotrexate (7-OHMTX). Bromfenac pharmacokinetics were studied on Days 7 and 8. Concentrations of the analytes were assayed using validated high performance liquid chromatography methods. RESULTS: Nine patients, 5 women and 4 men, completed the study. No statistically significant changes were observed in any of the pharmacokinetic variables evaluated for bromfenac with or without MTX. Bromfenac also did not alter the pharmacokinetics of low dose MTX. However, some significant changes were observed in the pharmacokinetics of 7-hydroxymethotrexate: a 30% increase in dose normalized area under the serum concentration time curve (mean +/- SD) to 3102 +/- 1397 micrograms.h/l and a 16% decrease in renal clearance to 10.0 +/- 6.7 ml/h/kg. Eight patients had mild or moderate adverse events: most were considered unrelated to the study drug by the investigator. One patient did not complete the study because of moderate hypertension. No patient had clinically important abnormal laboratory test results. CONCLUSION: No clinically significant changes in MTX pharmacokinetics were detected in patients with RA when bromfenac was added to MTX therapy. Although 7-OHMTX concentrations were elevated, the changes were small and unlikely to be of clinical significance. MTX did not alter the pharmacokinetics of bromfenac.     

Up-regulation of neuropeptide Y-Y2 receptors in an animal model of temporal lobe epilepsy

OBJECTIVE: To clarify the incidence and background of clinical relapse (escape phenomenon) during low-dose methotrexate therapy for rheumatoid arthritis. METHODS: Seventy one patients with rheumatoid arthritis (RA) were analyzed. They were started on therapy with methotrexate (MTX) between April 1, 1991 and May 30, 1995. Among them, 60 patients showed clinical improvement within 6 months after the start of the therapy and were subjected to the analysis for clinical relapse (escape phenomenon). RESULTS: Twelve patients showed an initial improvement followed by a relapse with increased serum CRP and number of painful joints despite the MTX therapy was continued. Two types of the relapses were seen; (1) early, escape (relapse after an initial brief improvement) in 7 patients, and (2) late escape (relapse after a long-term improvement with MTX therapy) in 5 patients. The early escape was seen at 9.0 +/- 0.7 months after the start of therapy while the late escape was seen at 23.3 +/- 4.8 months. Patients with both types of escape phenomenon had the longer duration of the disease and more advanced stage. There was no relationship between clinical relapse and age, baseline RA activity, MTX dose, or concurrent use of corticosteroids and other disease modifying anti-rheumatic drugs. The efficacy of MTX for RA was restored by increasing dose of MTX in 11 patients. CONCLUSION: These results suggest that clinical relapse is not rare in RA patients during low-dose methotrexate therapy, but could be improved by increasing dose.     

A T cell receptor beta chain variable region polymorphism associated with radiographic progression in rheumatoid arthritis

OBJECTIVE: In rheumatoid arthritis (RA) genetic factors influence susceptibility to disease and progression. Identifying these genetic factors may give more insight into the aetiology and pathogenesis of this disease. Furthermore, if these genetic markers can predict progression in an early stage of disease, timely institution of more aggressive treatment in patients with a bad prognosis may help to prevent joint damage. Several studies have shown that HLA-DRB1 alleles are associated with RA, whereas others have indicated that genes not linked to the HLA complex are also involved. Candidates for such genes are the T cell receptor (TCR) alpha/beta genes. METHODS: The association of a polymorphism in a TCR beta chain variable region gene (TCR-V beta 8) with both risk for RA and radiographic progression of joint disease was analysed after a three year follow up. A cohort of 118 white patients with a duration of disease shorter than one year at entry, and 110 white controls were typed for this (BamHI) TCR-V beta 8 polymorphism. RESULTS: The distribution of the two alleles, 2.0 and 23.0 kb, was identical in patients and controls. Radiographic progression (modified Sharp method) after a three year follow up, studied in 111 patients, was significantly less in the group possessing the 2.0 kb allele (p = 0.03). CONCLUSION: This does not confirm the reported association of the (BamHI) TCR-V beta 8 2.0 kb allele with RA. By contrast with previous findings in smaller studies, in the present study this 2.0 kb allele was protective against radiographic progression. Because well known prognostic variables in RA were corrected for, the findings indicate that the TCR-V beta 8 polymorphism studied is a new prognostic marker for this disease.     

Tumor necrosis factor-alpha stimulates human Clara cell secretory protein production by human airway epithelial cells

OBJECTIVE: Low serum levels of mannan binding lectin (MBL) are associated with increased risk of recurrent infections. We determined whether there was an association between serum MBL levels and the course and prognosis of rheumatoid arthritis (RA). METHODS: MBL was analyzed in sera from 99 patients with RA who were included in a longterm prospective study. RESULTS: Compared with controls, a high fraction of patients lacked detectable MBL in serum (11 vs 3%; p = 0.025). Comparing patients with MBL serum levels above and below the median revealed that those with levels below the median were younger at onset of RA (p = 0.043) and had higher erythrocyte sedimentation rate (p = 0.006), joint swelling score (p = 0.019), limitation of joint motion score (p = 0.027), and annual increase in radiographic destruction score (p = 0.053). CONCLUSION: MBL insufficiency may be a contributing pathogenetic factor in RA.