Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group

BACKGROUND: Phase II trials of leflunomide, an inhibitor of de-novo pyrimidine synthesis, have shown efficacy in rheumatoid arthritis. This double-blind randomised trial compared leflunomide with placebo and sulphasalazine in active rheumatoid arthritis. METHODS: 358 patients were randomly assigned leflunomide (100 mg daily on days 1-3, then 20 mg daily), placebo, or sulphasalazine (0.5 g daily, titrated progressively to 2.0 g daily at week 4). The primary endpoints were tender and swollen joint counts and investigator's and patient's overall assessments. Analyses were by intention to treat. FINDINGS: The mean changes in the leflunomide, placebo, and sulphasalazine groups were -9.7, -4.3, and -8.1 for tender joint count; -7.2, -3.4, and -6.2 for swollen joint count; -1.1, -0.3, and -1.0 for physician's overall assessment; and -1.1, -0.4, and -1.1 for patient's overall assessment. Leflunomide and sulphasalazine were significantly superior to placebo (p=0.0001 for joint counts; p<0.001 for assessments). Radiographic disease progression was significantly slower with leflunomide and sulphasalazine than with placebo (p<0.01). Most common adverse events with leflunomide were diarrhoea (17%), nausea (10%), alopecia (8%), and rash (10%). Transiently abnormal liver function was seen in three leflunomide-group patients and five sulphasalazine-group patients. There were two cases of reversible agranulocytosis in the sulphasalazine group. INTERPRETATION: Leflunomide was more effective than placebo in treatment of rheumatoid arthritis and showed similar efficacy to sulphasalazine. Leflunomide was well tolerated. This drug may be a useful option as a disease-modifying antirheumatic drug.     

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.     

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 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.     

A proposed 30-45 minute 4 page standard protocol to evaluate rheumatoid arthritis (SPERA) that includes measures of inflammatory activity, joint damage, and longterm outcomes

A proposed 4 page, 30-45 minute standard protocol to assess rheumatoid arthritis (SPERA) is described that includes all relevant measures of inflammatory activity such as joint swelling, measures of joint damage such as joint deformity, and outcomes such as joint replacement surgery, to monitor patients in longterm observational studies. Forms are included: (1) a patient self-report modified health assessment questionnaire (MHAQ) to assess function, pain, fatigue, psychological distress, symptoms, and drugs used; (2) assessor-completed forms: "RA clinical features" --criteria for RA, functional class, family history, extraarticular disease, comorbidities, joint surgery, radiographic score, and laboratory findings. (3) A 32 joint count with 5 variables: (a) a "shorthand" normal/abnormal so that normal joints require no further detailed assessment; (b) tenderness or pain on motion; (c) swelling; (d) limited motion or deformity; (e) previous surgeries; physical measures of function, i.e., grip strength, walk time, and button test. (4) Medication review of previous disease modifying antirheumatic drugs (DMARD), work history, and years of education. The forms allow cost effective acquisition of all relevant measures of activity, damage, and outcomes in routine clinical care, and allow recognition that measures of activity may show similar or improved values over 5-10 years, while measures of damage and outcomes indicate severe progression in the same patients. The SPERA is feasible to acquire most known relevant measures of activity, damage, and outcomes in RA in 30-45 min in usual clinical settings, to provide a complete database for analyses of longterm outcomes.     

The long-term outcomes of rheumatoid arthritis: a 23-year prospective, longitudinal study of total joint replacement and its predictors in 1,600 patients with rheumatoid arthritis

OBJECTIVE: Although total joint arthroplasty (TJA) is a common procedure and an important outcome in rheumatoid arthritis (RA), little is known about its prevalence, failure rate, or predictors over the course of the illness. The current study evaluated these factors in 1,600 consecutive RA patients seen during a period of observation that extended 23 years. METHODS: Beginning in 1974, data from 34,040 RA patient visits were entered prospectively into a computer databank. Data consisted of laboratory, radiographic, physical examination, and self-report questionnaires. At each assessment, we also noted a complete surgical history. Patients were also followed up by questionnaires that were mailed at 6-month intervals. RESULTS: Kaplan-Meier life-table estimates indicated that 25% of RA patients will undergo total joint arthroplasty (TJA) within 21.8 years of disease onset. For patients with 1 TJA, 25% had a TJA in a different joint within 0.92 years and 50% within 7.0 years. Ten years after TJA, approximately 6% of implanted knees and 4% of implanted hips had been replaced with a second TJA, and 12% and 13% of the joints had either a second TJA or a TJA-related operation, respectively. In Cox regressions, a large series of clinical and laboratory variables, which primarily reflected disease activity, predicted TJA. Smoking, either past or present, had a protective effect. Patients with highly abnormal values on the Health Assessment Questionnaire Disability Scale, global severity, and erythrocyte sedimentation rate had a 3-6 times increased risk of TJA. CONCLUSION: TJA, a marker of joint failure and of RA outcome, is predicted by self-report assessments of severity and function, and by a series of laboratory, radiographic, and clinical variables. Prediction improves with the extent of observation, and 2-year observations approach full-study observations in their accuracy. Most TJAs survive for a long time in RA.     

Assessment of disease activity in rheumatoid arthritis using magnetic resonance imaging: quantification of pannus volume in the hands

We attempted to assess whether pannus volume measured by magnetic resonance imaging (MRI) can be used as an indicator of disease activity in rheumatoid arthritis (RA). Eleven women (mean age 46 yr) with uncontrolled RA were studied for 1 yr. Pannus formation in both hands was quantified using MRI at the start of the study, and at 6 and 12 months thereafter. The volume of enhancing pannus (VEP) was compared with changes in the radiological scores, grip strength, joint tenderness counts, joint swelling counts, erythrocyte sedimentation rate (ESR), and serum C-reactive protein (CRP). Patients were classified into three groups based on VEP changes between 0 and 12 months: unchanged (n = 2), decreased (n = 6) and increased (n = 3). VEP at 6 months and at 12 months differed significantly between the three groups. No statistically significant differences were found between the groups in radiographic scores, physical parameters or laboratory parameters despite the fact that some of these parameters changed in the direction indicated by the changes in VEP. VEP can be used as a new indicator to assess disease activity in individual RA patients and, using this parameter, treatment outcome can be assessed in fewer subjects than with traditional measures.     

Radiologic progression in early rheumatoid arthritis treated with methotrexate

OBJECTIVE: To evaluate radiologic progression in patients with early rheumatoid arthritis (RA) receiving methotrexate (MTX) as the first slow acting drug. METHODS: An open, prospective study of 29 patients with RA (21 F, 8 M, mean age 48.5+/-15.4 yrs). The mean duration of RA was 6.6 (2-60) months; and rheumatoid factor was present in 11 cases. Clinical, biological, and radiographic evaluations were done before the start of MTX treatment and after 13+/-3.8 months. Radiographs of hands and wrists were blindly studied by 2 physicians, using Larsen's and modified Sharp's methods. There was a significant correlation for the scores of the 2 physicians evaluated by kappa coefficient. Radiographic evolution was defined as an increase of 15 points in the radiologic score by each method used. RESULTS: Patients showed significant clinical improvement after one year of MTX treatment. Despite clinical and biological improvement, significant mean radiographic progression was noted, with Larsen's method (p = 0.001) and Sharp's method (p = 0.034), without reaching the maximum score. However, using the definition of radiographic progression, the radiologic scores indicated stabilization in 23 patients with Larsen's method and in 24 patients with Sharp's method. CONCLUSION: This study revealed mild radiographic progression in early RA patients treated with MTX for one year. Further controlled studies are needed.     

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.     

Detection of joint pathology by magnetic resonance imaging in patients with early rheumatoid arthritis

Magnetic resonance imaging (MRI) permits the visualization of anatomical structures not appreciated by conventional radiographic imaging, and may assess inflammatory disease and its progression with greater sensitivity than conventional radiography. In this study of 30 patients with early rheumatoid arthritis (RA), which could be considered as a pilot study because of the relatively small number of patients, we compare MRI of the knee and the fifth metatarsophalangeal joint with clinical and radiographic findings. A parallel study of 10 healthy individuals served as a reference group. In all but one of the 30 patients, MRI revealed some kind of joint abnormality, whereas conventional radiography was normal in 14 patients. The present study thus suggests that MRI may detect inflammatory and/or destructive joint changes in patients with early RA, and that these changes may occur in the absence of clinical symptoms or signs and/or radiographic signs in the examined joint. If these data prove to be confirmed in further controlled studies, MRI may be of importance both for the assessment of prognosis and for the decision to treat in the early critical stages of RA.     

Day and night pain measurement in rheumatoid arthritis

OBJECTIVE: An attempt was made to see if rheumatoid arthritis (RA) patients can use visual analogue scales (VAS) to distinguish and grade the severity of pain at night, during rest, and on joint movement and to determine if discriminate measurement of these three pain components enhances the value of VAS estimation. METHODS: Two hundred and fifty two consecutive RA patients were evaluated by a single observer using 10 cm VAS for pain at night, at rest during the day, and on movement. Values were correlated against age, disease duration, joint tenderness, swollen joint count, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and Larsen x ray scores. RESULTS: Night pain was recorded by 71 (28%) and this component of pain was lower than VAS scores for daytime rest and movement. However, those with nocturnal pain had significantly more joint tenderness (p < 0.0001), swollen joints (p < 0.0001), and higher ESR and CRP. Age, disease duration, and radiographic scores were similar in those with and without night pain. Correlations of joint tenderness were apparent for all three pain scores but only nocturnal pain correlated with swollen joints (p < 0.001) and CRP (p < 0.005). Age, disease duration, and radiographic severity correlated with daytime rest or movement scores but not nocturnal pain. CONCLUSION: Patients were able to distinguish and estimate the severity of pain at rest, on movement, and at night. The occurrence of night pain characterised those with more active disease and night pain VAS measurement correlated best with measures of joint inflammation whereas daytime pain scores, both at rest and on movement, seemed influenced by the degree of permanent joint damage. Thus, discrete measurement of rest, movement, and nocturnal pain may provide useful information about RA disease status.     

Chronic arthritis and carpo:metacarpal ratio in Japanese patients with adult Still's disease

OBJECTIVE: To characterize Japanese patients having adult Still's disease (ASD) with chronic arthritis (> 6 months) and to examine the association of chronic arthritis with carpo:metacarpal ratio (CMC ratio), an index of radiographic progression in rheumatoid arthritis (RA). METHODS: Twenty-seven patients with ASD (16 women and 11 men, mean age at disease onset 27.7 years) were classified into 2 groups: patients with (chronic articular ASD, 16 patients, 59%) or without (systemic ASD, 11 patients, 41%) chronic arthritis. Clinical and laboratory findings were compared between both groups. CMC ratio was calculated on serial hand radiographs in patients with chronic articular ASD. RESULTS: In our series, serositis was rarely observed in chronic articular ASD. Peripheral arthritis (including transient arthritis), such as metacarpophalangeal, proximal interphalangeal, or ankle joint, was more frequently observed in chronic articular ASD than in systemic ASD (p < 0.05). Wrist arthritis was frequently observed also in systemic ASD; however, joint space narrowing of carpometacarpal or intercarpal joints was recognized only in chronic articular ASD (44%). CMC ratio at the last observation in 14 patients with chronic articular ASD was significantly decreased (0.526 +/- 0.039) compared to that at disease onset (0.553 +/- 0.034) (p < 0.05), while no decrease was observed in 4 with systemic ASD (0.565 +/- 0.062 at disease onset, 0.563 +/- 0.043 at the last observation). CONCLUSION: It is suggested that chronic articular ASD has certain characteristics. CMC ratio may be a quantitative index for assessment of radiographic changes of carpal joints, not only in RA but also in chronic articular ASD.     

Factors associated with the development of vasculitis in rheumatoid arthritis: results of a case-control study

OBJECTIVE: To investigate those characteristics of patients with rheumatoid arthritis (RA) that are associated with the development of rheumatoid vasculitis (RV). METHODS: Demographic and clinical data of 69 patients who had been diagnosed as having RV were compared with those of 138 contemporaneous control patients with RA who were not suspected to have vasculitis. Vasculitis was confirmed histologically in 96% of the subjects with RV. RESULTS: Variables associated with the development of RV were: 1) male gender, presence of increased serum concentrations of rheumatoid factor, joint erosions, subcutaneous nodules, number of disease modifying antirheumatic drugs previously prescribed, treatment (ever) with D-penicillamine or azathioprine; 2) presence of nail fold lesions and any other extrarticular feature one year before the time of diagnosis of RV; 3) treatment with corticosteroids at the time of diagnosis of RV. CONCLUSIONS: The development of RV is associated with male gender, extra-articular features, and a severe course of RA as indicated by the presence of joint destruction and need for intensive treatment with antirheumatic drugs. The strongest association was found with the presence of increased concentrations of rheumatoid factor.     

Cyclosporine A in the treatment of early rheumatoid arthritis. A prospective, randomized 24-month study

OBJECTIVE: To investigate the efficacy, tolerability and safety of cyclosporine A (CSA) in early rheumatoid arthritis (RA) patients. METHODS: Patients with an early diagnosis of RA, a disease duration of less than 3 years, and without prior disease modifying antirheumatic drug (DMARD) treatment were studied. They randomly received oral CSA (3 mg/kg/day) or oral methotrexate (MTX) (0.15 mg/kg/week). In addition, all patients in both groups received oral prednisone (7.5 mg/day). RESULTS: Fifty-two patients were assigned to the CSA group and 51 to the MTX group. After 24 months of treatment, 48 patients from the CSA group and 48 from the MTX group showed significant clinical improvement. This was evaluated by the duration of morning stiffness, grip strength, the total joint count, joint swelling, and joint tenderness and pain, compared to pre-treatment values. The clinical improvement was also associated with a significant decrease in ESR and CRP values in both groups. No significant radiological deterioration was observed in the CSA patients compared to those treated with MTX after 24 months. Four patients from the CSA group dropped out of the study, two because of a synovitis flare, one because of severe hypertrichosis and one because of severe gingival hyperplasia. Three patients from the MTX group withdrew, one because of disease flare-up and two because of gastrointestinal disturbances. CONCLUSION: Early immunointervention in RA patients appears to be crucial to limit the development of joint damage. Cyclosporine A appears to be effective, well tolerated and safe in the long-term treatment of RA and can therefore be used as a first immunomodulatory drug in the armamentarium for the treatment of RA.     

Measuring health status in psoriatic arthritis: the Health Assessment Questionnaire and its modification

OBJECTIVE: The Health Assessment Questionnaire (HAQ) has proven to be a reliable and valid measure of outcome for a variety of arthritides. A recent modification of HAQ for spondyloarthropathy (HAQ-S) has also been reported. Our purpose was to evaluate the HAQ and HAQ-S as outcome measures in the assessment of patients with psoriatic arthritis (PsA). METHODS: The HAQ, including HAQ-S was administered to all patients attending our Psoriatic Arthritis Clinic between June and December, 1993. Clinical and radiological assessments were performed according to a standard protocol that measures disease activity, fibrositic tender points (TP), disease severity and damage. Analysis was performed using SAS for the PC. RESULTS: The patient population included 114 patients, 70 men and 44 women with a mean age of 49.3 years and a mean arthritis duration of 15.1 years. The mean HAQ score was 0.50, while the mean HAQ-S score was 0.53 (scores range 0 to 3 for this instrument). The overall HAQ and HAQ-S disability scores were highly correlated with several clinical measures of function, including grip strength (r = -0.63 and -0.59, respectively). American College of Rheumatology functional class (r = 0.59 and 0.60, respectively), as well as the number of fibrositic TP (r = 0.54 and 0.57, respectively). These disability scores also correlated highly with the overall number of actively inflamed joints (r = 0.49 and 0.50, respectively); however, they correlated only moderately or poorly with other measures of disease activity such as morning stiffness, total number of joint effusions, erythrocyte sedimentation rate (ESR) and the PASI score for psoriasis and with all measures of disease severity. A similar pattern of correlations was found between the individual subscales of the HAQ and HAQ-S and the clinical measures of function, activity, and severity, as well as between the pain scale and the various clinical measures. However, the correlations are generally lower. CONCLUSION: Our data suggest that HAQ and HAQ-S capture clinical measures of function and pain in PsA but do not correlate with disease severity. The HAQ and its modification for spondyloarthropathy may reflect fibromyaglia as a measure of pain and tenderness in these patients. Thus, the clinical assessment of disease activity and both clinical and radiological assessments of joint damage remain important outcome measures in PsA.     

A simple index to assess disease activity in rheumatoid arthritis

Changes in clinical and laboratory measures of disease activity were studied prospectively in 12 European centers. Altogether 282 rheumatoid patients were evaluated during 6 months of therapy with slow-acting drugs. Patients' global assessment was taken to indicate overall response. The number of swollen joints and number of tender joints correlated highly with this. The erythrocyte sedimentation rate (ESR) correlated less well but was more uniform across centers. Grip strength, C-reactive protein and hemoglobin performed poorly between centers. There were cultural and linguistic difficulties using the Health Assessment Questionnaire in a European setting. Physician's global assessments were similar to the patient's global assessments and provided redundant information. The best measures are: the number of swollen joints, the number of tender joints, the ESR, and the patient's global assessment. It may also help to measure articular pain.     

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.     

Clinical improvement and radiological deterioration in rheumatoid arthritis: evidence that the pathogenesis of synovial inflammation and articular erosion may differ

The contrast between clinical improvement and radiological deterioration in rheumatoid arthritis (RA) is striking. We characterized this relationship using serial disease activity measures and radiographs of hands and feet in 40 RA patients observed over 6 yr. All disease activity measures improved, including grip strength, Ritchie index (RI), haemoglobin and erythrocyte sedimentation rate (ESR) (all P < 0.0001). In contrast, articular erosion increased (P < 0.0001). Radiological change during the study correlated with RI (r = 0.49), haemoglobin (r = -0.56) and ESR (r = 0.53). Radiological status at review also correlated with these variables (r = 0.36, -0.44 and 0.36, respectively). Articular erosion continues in RA despite clinical improvement and is accelerated in those with evidence of continuing synovial inflammation, reflected in clinical and laboratory measures of disease activity. Since many therapies in RA suppress inflammation, but not erosion, these findings suggest that the pathogenesis of articular erosion may differ from that of synovial inflammation.     

Risk factors for progression to new sites of radiographically defined osteoarthritis in women

OBJECTIVE: To describe the association between hormonally related risk factors and the progression to new sites of radiographically defined full body (generalized) osteoarthritis (OA) in a cohort of older women. METHODS: A retrospective cohort design was used to study former radium dial painters over the age of 40 years who had minimal radium exposure. At study entry and at varying followup times, clinical examinations were conducted and full body radiographs were taken. Two followup groups were defined: women with a followup radiograph 1-9 years after baseline (n = 75) and 10-19 years after baseline (n = 53). Fifty-five joints (10 joint groups) were independently graded at baseline and followup for OA by the method of Kellgren and Lawrence, and provided the basis for summary full body OA progression scores. Progression was defined as an increase in the number of sites with OA and in separate analyses as an increase in the number of joint groups with OA. RESULTS: Increasing length of followup and lower baseline OA score were associated with greater OA progression, while age at baseline examination showed no clear relation to progression. Beyond these variables, increasing height and having ever smoked were inversely associated with OA progression, while body mass index (BMI) showed a weak positive association. In multivariable modeling for followup 1-9 years, only lower baseline OA score predicted greater OA progression to new sites (partial r2 = 0.13, p = 0.0009). In followup 10-19 years, baseline OA score (partial r2 = 0.12, p = 0.0011), height (partial r2 = 0.057, p = 0.033), and smoking status (partial r2 = 0.09, p = 0.035) were independent predictors of OA progression to new sites, while greater BMI was a positive, weak, and nonsignificant predictor (partial r2 = 0.031, p = 0.29). History of prior cholecystectomy, hysterectomy, dilation and curetage, number of pregnancies, and change in BMI were not significantly related to progression of OA to new sites. Similar results were found for predictors of OA progression to new joint groups. CONCLUSION: Lower baseline level of OA is associated with greater OA progression to new sites or joint groups independent of age, suggesting a "burnout" phenomenon. In addition, shorter height and having never smoked appear to be independent risk factors that predict the progression of radiographic OA to new sites or joint groups.     

The levels of memory (CD45RA-, RO+) CD4+ and CD8+ peripheral blood T-lymphocytes correlate with IgM rheumatoid factors in rheumatoid arthritis

We investigated whether, in rheumatoid arthritis (RA), the CD45 isoform expression of peripheral blood T-lymphocytes (T-PBL) is related to auto-immune processes (e.g. IgM rheumatoid factors) and to clinical manifestations. By three-colour flow cytometry, we quantified three subsets of CD4+ or CD8+ T-PBL: "naive" CD45RA+,RO-, "transient" CD45RA+,RO+, and "memory" CD45RA-,RO+ cells, in 102 patients with RA and in 41 age- and sex-matched controls. The serum levels of rheumatoid factors (RF) were determined--besides conventional agglutination tests--by ELISA (IgM-RF). Extensive clinical examination was performed at the time of blood sampling. In RA, age, sex and drug therapy did not constitute major influences on the CD45RA/RO patterns. In "healthy" men, higher age significantly' correlated with fewer naive and more memory CD4+ T-PBL (P < 0.01). In RA, distinct correlations between the T-PBL subsets, autoimmune and clinical manifestations became obvious when patients with low and high levels of RF against human IgG Fc fragments, as determined by ELISA, were analysed separately. RA patients with high IgM-RF had elevated proportions of CD45RO+ T-PBL (P < 0.05), that correlated with clinical parameters of disease activity (tender joint count, Ritchie index, P < 0.05) and outcome (Health Assessment Questionnaire, Larsen radiographic scores, P < 0.05). The proportions of memory CD4+ and CD8+ T-PBL correlated strongly (P < 0.001) with the IgM-RF levels. Within 1 year, only three of 34 patients (disease duration of 5-9 years) showed seroconversion from low to high levels of IgM-RF (and positive agglutination tests); this was paralleled by reductions in naive and increases in transient T-PBL (P < 0.02). Thus, in RA, the proportions of memory CD4+ and CD8+ T-PBL correlate with the level of IgM-RF and, together with transient T-PBL, with clinical parameters of disease activity and outcome.