The positive influence of methotrexate on the mortality of patients with rheumatoid arthritis is partly independent of its effect on disease activity: results of a re-evaluation 18 years after baseline.

OBJECTIVES: Methotrexate (MTX) is the anchor drug in the treatment of patients with rheumatoid arthritis (RA). MTX shows effects on disease activity and mortality. However, it is unclear whether the effect of MTX on mortality depends on its effect on disease activity. METHODS: In a post-hoc analysis we analysed the data of our cohort established in Ratingen, Germany, and included all patients starting treatment with MTX (n=271) between 1980 and 1987. One year after baseline (BL), response to MTX treatment was assessed using a modified ACR 20 response. Follow-up data of 250 patients were available after 10 and 18 years. RESULTS: After 1 year, there were 66% responders and 20% non-responders; only 14% had discontinued MTX treatment due to side effects or lack of efficacy. Most patients continued MTX treatment irrespective of efficacy. Ten years after BL, 61% of the patients were still treated with MTX. After 18 years, the responder-group showed a standardised mortality ratio of 1.6 compared to 3.2 for the group of non-responders. However, when adjusting for age, gender, response to MTX treatment one year after BL, number of swollen joints and comorbidities after 10 years an independent association of continued MTX treatment with lower mortality was found for the period 10 to 18 years after BL (hazard ratio (HR): 0.63, 95% confidence interval: 0.43-0.92, p=0.015). CONCLUSIONS: In this cohort, the mortality lowering effect of continued MTX use was partly independent of its effect on disease activity. This finding may affect treatment decisions concerning RA patients with insufficient response to MTX.

Smokers and non smokers with rheumatoid arthritis have similar clinical status: data from the multinational QUEST-RA database.

OBJECTIVES: To analyse clinical severity/activity of rheumatoid arthritis (RA) according to smoking status. METHODS: The QUEST-RA multinational database reviews patients for Core Data Set measures including 28 swollen and tender joint count, physician global estimate, erythrocyte sedimentation rate (ESR), HAQ-function, pain, and patient global estimate, as well as DAS28, rheumatoid factor (RF), nodules, erosions and number of DMARDs were recorded. Smoking status was assessed by self-report as 'never smoked', 'currently smoking' and 'former smokers'. Patient groups with different smoking status were compared for demographic and RA measures. RESULTS: Among the 7,307 patients with smoking data available, status as 'never smoked,' 'current smoker' and 'former smoker' were reported by 65%, 15% and 20%. Ever smokers were more likely to be RF-positive (OR 1.32;1.17-1.48, p<0.001). Rheumatoid nodules were more frequent in ever smokers (OR 1.41;1.24-1.59, p<0.001). The percentage of patients with erosive arthritis and extra-articular disease was similar in all smoking categories. Mean DAS28 was 4.4 (SD 1.6) in non-smokers vs. 4.0 (SD 1.6) in those who had ever smoked. However, when adjusted by age, sex, disease duration, and country gross domestic product, only ESR remained significantly different among Core Data Set measures (mean 31.7mm in non-smokers vs. 26.8mm in ever smoked category). CONCLUSIONS: RA patients who had ever smoked were more likely to have RF and nodules, but values for other clinical status measures were similar in all smoking categories (never smoked, current smokers and former smokers).

A double-blind comparison of parenteral methotrexate and parenteral gold in the treatment of early erosive rheumatoid arthritis: an interim report on 102 patients after 12 months.

One hundred two patients with active erosive rheumatoid arthritis (RA) without malalignment or deformities (median disease duration, 14 months) entered a double-blind, randomized study to compare the effects of 50 mg gold sodium thiomalate (GST) with 15 mg methotrexate (MTX) administered intramuscularly for 12 months. Roentgenograms of hands, wrists, and forefeet were taken at baseline and after 6 and 12 months, and 32 joints were evaluated according to Larsen. Sixteen of 50 patients in the MTX group were withdrawn; one patient in the MTX group died of cerebral bleeding that was not related to treatment. Thirty-four GST patients and 44 MTX patients were evaluated for efficacy. Thirty-eight joints were counted. The number oftender and swollen joints, the Lansbury articular index, morning stiffness, activities of daily living (ADL) score, and erythrocyte sedimentation rate improved significantly in both groups without statistical intergroup differences. After 12 months, there was a significant deterioration of the mean Larsen index and the number of joints with erosions without intergroup difference. However, the radiological progression was retarded significantly during the second 6-month period in the gold group, whereas this effect was less pronounced in the MTX group. At 12 months, the progression rate was the same in both groups.

Benefit and risk of methotrexate treatment in rheumatoid arthritis.

This is a literature review on the efficacy and toxicity of low dose weekly methotrexate treatment in rheumatoid arthritis. Personal recommendations on dosing and monitoring (of) the drug are given.

Healing of erosive changes in rheumatoid arthritis.

This is an overview over the history and present state of knowledge of radiographic signs of erosion healing. The existence of healing or repair has been confirmed; different observers agree in the identification of healing; it may be identified without knowing the sequence of the films. As healing indicates that inflammation has discontinued for several months in an individual joint, it might represent a good additional outcome measure in RA clinical trials.

Thrombocytopenia in patients with rheumatoid arthritis on long-term treatment with low dose methotrexate.

We reviewed the records of 315 patients with rheumatoid arthritis (RA) treated with low-dose methotrexate (MTX) and evaluated the conditions contributing to thrombocytopenia. Thirteen out of 315 patients with RA presented with low platelet counts (< or = 100,000/mm3). The age of these patients (51 +/- 12.6 years) did not correlate with thrombocytopenia (r = 0.211, p > 0.05). Thrombocytopenia resulted from coadministration of MTX and NSAID or multiple drug interactions. We observed a significant (r = 0.48, p < 0.05) increase of discontinuation of NSAID's but not of MTX therapy (r = 0.42, p > 0.05) with a mounting weekly dosage of MTX (12.5 +/- 5 mg orally). There was a significant correlation between this weekly dosage of MTX coadministered on the same day with NSAID and thrombocytopenia (r = 0.6, p < 0.05). In most cases (9/13) MTX was not or just temporarily withdrawn. Three of the remaining patients had multiple drug interactions. Reintroduction of low dose MTX treatment in patients having had thrombocytopenia could be performed safely, if thrombocytopenia occurred as a result of concomitant application of MTX and NSAID and no other multiple drug interactions. Preferably, MTX and NSAID should be given to these risk patients on separate days or intervals considering half time clearance of NSAIDs. This procedure has prevented the reoccurrence of thrombocytopenia and controlled further drug interactions of NSAIDs and MTX in our patients.

Thrombocytopenia in patients with rheumatoid arthritis on long-term treatment with low dose methotrexate.

We reviewed the records of 315 patients with rheumatoid arthritis (RA) treated with low-dose methotrexate (MTX) and evaluated the conditions contributing to thrombocytopenia. Thirteen out of 315 patients with RA presented with low platelet counts (< or = 100.000/mm3). The age of these patients (51 +/- 12.6 years) did not correlate with thrombocytopenia (r = 0.211, p > 0.05). Thrombocytopenia resulted from coadministration of MTX and NSAID or multiple drug interactions. We observed a significant (r = 0.48, p < 0.05) increase of discontinuation of NSAID's but not of MTX therapy (r = 0.42, p > 0.05) with a mounting weekly dosage of MTX (12.5 +/- 5 mg orally). There was a significant correlation between this weekly dosage of MTX coadministered on the same day with NSAID and thrombocytopenia (r = 0.6, p < 0.05). In most cases (9/13) MTX was not or just temporarily withdrawn. Three of the remaining patients had multiple drug interactions. Reintroduction of low dose MTX treatment in patients having had thrombocytopenia could be performed safely, if thrombocytopenia occurred as a result of concomitant application of MTX and NSAID and no other multiple drug interactions. Preferably, MTX and NSAID should be given to these risk patients on separate days or intervals considering half time clearance of NSAIDs. This procedure has avoided the reoccurrence of thrombocytopenia and controlled further drug interactions of NSAIDs and MTX in our patients.

A modified version of Larsen's scoring method to assess radiologic changes in rheumatoid arthritis.

We describe the development and application of a modified version of the radiologic scoring method proposed by Larsen in patients with rheumatoid arthritis (RA). We modified Larsen's method adding a semiquantitative description of the loss of joint surface area and provide standardized reference films for all stages at different anatomical sites (metacarpophalangeal joints, proximal interphalangeal joints, wrists, metatarsophalangeal joints). To evaluate the method, standard anteroposterior radiographs of hands, wrists and forefeet of 24 patients with early erosive RA taken at baseline (t0) and after 36 months (t1) were read by 2 raters in a blinded fashion. The interrater difference was compared with the interpatient (t0 to t1) difference using a hierarchical analysis of variance. Moreover, the method was applied to patients included in a 2 year clinical trial to evaluate the efficacy of intramuscular methotrexate (MTX) and gold sodium thiomalate (GSTM) with radiographs taken at baseline and after 6, 12, and 24 months. There was a good agreement between the 2 raters and the change could be well documented. The estimation of the intrapatient variance (at t0 and t1) was 8 times higher than the estimation of the interreader variance. The method was easily applicable in 57 patients treated with MTX and 53 patients under treatment with GSTM, showing a slowing of radiologic progression after Month 6 with both drugs. The modification of Larsen's scoring method is a reliable measure to assess baseline status and radiologic progression in patients with RA.

Healing phenomena of erosive changes in rheumatoid arthritis patients undergoing disease-modifying antirheumatic drug therapy.

OBJECTIVE: To describe radiographic healing phenomena and reparative changes of joint destruction in rheumatoid arthritis (RA). METHODS: Serial radiographs of 6 patients with erosive RA undergoing long-term treatment with disease-modifying antirheumatic drugs (DMARDs) were studied. Radiographs showing healing phenomena were reproduced, and examples of single joints are shown. RESULTS: The examples show recortication of erosions, filling in of erosions with new bone, and secondary osteoarthrosis with bone sclerosis and osteophyte formation. Commonly use radiographic scoring methods do not have the capacity to account for these reparative changes. CONCLUSION: Healing phenomena can be observed in RA patients undergoing long-term DMARD treatment. These phenomena can be regarded as clinical end points, and their assessment should be incorporated into existing standardized methods for radiologic evaluation and scoring of RA.

[Development and evaluation of a modified version of the Larsen method for evaluating roentgenologic changes in chronic polyarthritis]. / Entwicklung und Evaluation einer modifizierten Version der Larsen-Methode zur Bewertung röntgenologischer Veränderungen bei chronischer Polyarthritis.

AIM OF THE STUDY: To develop and evaluate a modification of the Larsen scoring method aimed at a clear definition of the different grades and a better correlation of the numerical scale with the amount of joint destruction. DESCRIPTION OF THE METHOD: While the original method described by Larsen is based on a comparison with standard reference films the modification defines the different grades semiquantitatively by the amount of destruction of the joint surface: grade II is a destruction (erosion) of the joint surface of up to 25%, in grade III it is 26-50%, in grade IV 51-75% and in grade V over 75%. Grade I is characterized by soft tissue swelling and in addition subchondral osteoporosis and remains unchanged compared with the original method. 32 joints of the hands, wrists and forefeet are counted summing up to a total score of 0-160. Examples for different joints are given. EVALUATION OF THE METHOD: Standard ap-x-rays of hands, wrists and forefeet of 24 patients with early erosive rheumatoid arthritis at baseline (T0) and after 36 months (T1) were graded by two investigators (G.H. and R.R.). The difference of the scoring between both observers (inter-observer-difference) was related to the difference between the two timepoints (T0 and T1) in the same patient (intra-patient-difference) by means of a hierarchical analysis of variance (ANOVA). The intra-patient variance (from T0 to T1) was 259.3, which is 8 times greater than the inter-observer-variance of 32.1. The square root of intra-patient-standard deviation (16.1) and inter-observer-standard deviation (5.7) is 2.8. These data show that the progression between T0 and T1 is real. The method was easily applicable to patients in a 2-year-DMARD-trial with x-rays at baseline after 6, 12 and 24 months, showing a slowing of radiologic progression after month 6 under treatment with parenteral gold and methotrexate. CONCLUSION: The modification of Larsen's scoring method is a reliable measure to assess radiologic progression in patients with RA. Possibilities for further improvement are discussed.

Methotrexate treatment in Felty's syndrome.

Felty's syndrome is a rare disorder characterized as a systemic manifestation of severe rheumatoid arthritis associated with granulocytopenia and splenomegaly. We report a retrospective analysis of a series of seven patients treated successfully with low-dose methotrexate. leading to sustained clinical improvement (number of swollen joints) and normalization of the granulocyte count for an observation period of 1 yr. Our cohort is the largest ever published with methotrexate treatment of this rare condition. Our results confirm earlier single case reports suggesting methotrexate to be the first-choice treatment nowadays in Felty's syndrome.

[Is H15 (resin extract of Boswellia serrata, "incense") a useful supplement to established drug therapy of chronic polyarthritis? Results of a double-blind pilot study]. / Ist H15 (Harzextrakt von Boswellia serrata, "Weihrauch") eine sinnvolle Ergänzung zur etablierten medikamentösen Therapie der chronischen Polyarthritis?--Ergebnisse einer doppelblinden Pilotstudie.

BACKGROUND: Leukotrienes and prostaglandines are important mediators of inflammation. While prostaglandine synthesis can be influenced by NSAIDs therapeutical approaches to the 5-lipoxygenase pathway are rare. Resinous extracts of Boswellia serrata (H15, indish incense), known from traditional ayurvedic medicine, decrease leukotriene synthesis in vitro. Case reports suggest a clinical role for that drug. METHODS: Outpatients with active RA have been enrolled into a multicenter controlled trial. Patients received 9 tablets of active drug (3600 mg) or placebo daily in addition to their previous therapy. Doses of NSAIDs could be adjusted on demand. Efficacy parameters, Ritchies Index for swelling and pain, ESR, CRP, pain on VAS and NSAID dose were documented at baseline and 6 and 12 weeks after initiation. Mean values and medians were calculated to compare the groups for significant or clinically relevant change from baseline or difference between both groups at any time point of observation. RESULTS: A total of 78 patients were recruited in 4 centers, the data have been published in abstract form. Only 37 patients (verum 18, placebo 19), enrolled in Ratingen were available for detailed efficacy and safety analysis. All evaluations in these patients were performed by one investigator (G.H.). There was no subjective, clinical or laboratory parameter showing a significant or clinically relevant change from baseline or difference between both groups at any time point of observation. The mean NSAID dose reduction reached levels of 5.8% (H15) and 3.1% (placebo). One patient in each group showed a good response in all parameters but 4 patients in each group worsened. The others showed no alteration of their disease. CONCLUSION: Treatment with H15 showed no measurable efficacy. Controlled studies including a greater patient population are necessary to confirm or reject our results.

Retardation of radiologic progression in rheumatoid arthritis with methotrexate therapy. A controlled study.

We evaluated the effects of methotrexate (MTX) on radiographic changes of rheumatoid arthritis (RA) in the hands, wrists, and feet of 31 patients who completed at least 24 months of treatment. Radiographs were obtained at baseline and every 1 or 2 years thereafter. MTX was administered for 2-6 years (mean 3.9 years); the total dose was 1,925 mg (range 970-3,810 mg). The mean duration of disease at baseline was 8.1 years (range 1-26 years). Radiographs taken over 1-5 years during previous, clinically ineffective, gold therapy (mean 2.2 years) were available for 24 patients, and the changes over time were compared. During MTX treatment, the mean number of swollen joints decreased from 22.5 to 8.3 (40 joints evaluated), and the mean erythrocyte sedimentation rate decreased from 61.6 mm/hour to 28.4 mm/hour. Thirty-six (19%) of 190 joints with Larsen scores of 0 at baseline progressed to a score of 1 or 2 within 1 year of beginning MTX, whereas with gold, 37 (44%) of 89 joints progressed (P less than 0.001). Of 419 joints with Larsen scores of 1, 12.5% deteriorated within 1 year with MTX treatment, compared with 14.7% of 183 joints during gold therapy (P not significant). There were no between-treatment differences for joints with higher Larsen scores. During gold therapy, the mean Larsen index (score per joint) for the hand and wrist joints (18 joints counted) progressed from 1.45 to 1.82 over a mean of 22.1 months, and during MTX, from 1.82 to 1.97 over a mean of 48.0 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiographic outcome after three years of patients with early erosive rheumatoid arthritis treated with intramuscular methotrexate or parenteral gold. Extension of a one-year double-blind study in 174 patients.

OBJECTIVE: To compare the radiographic outcomes after 36 months in patients with early erosive rheumatoid arthritis (RA) who were treated with methotrexate (MTX) or gold sodium thiomalate (GSTM). METHODS: In a randomized, double-blind fashion, 174 patients from two centres were assigned to receive weekly intramuscular injections of either 15 mg MTX or 50 mg GSTM. After 12 months, the study was continued as an open prospective study for an additional 2 yr, administering the same amount of MTX and half of the GSTM dose. Radiographic outcomes were assessed by standardized methods in all patients at baseline and after 6, 12, 24 and 36 months. RESULTS: Intention-to-treat analysis showed that patients treated with MTX had higher radiographic scores and more erosive joints at all follow-up points. However, there was no statistically significant difference between the two treatment groups. The progression rate was significantly slower during the second and third years of follow-up in both groups. Baseline and time-integrated (area under the curve over 6 months) disease activity parameters were good predictors of radiographic outcome after 3 yr. Seropositivity was not an independent predictor of progression. However, patients who were positive for rheumatoid factor had higher time-integrated disease activity (with less response to treatment) and thus their disease was significantly more progressive. CONCLUSION: Both of the disease-modifying compounds used in this study, MTX and GSTM, were able to reduce the slope of radiographic progression during 3 yr of follow-up. There was some advantage for parenteral gold but no significant intergroup difference.

Comparison of intramuscular methotrexate and gold sodium thiomalate in the treatment of early erosive rheumatoid arthritis: 12 month data of a double-blind parallel study of 174 patients.

The objective was to compare the safety and efficacy of methotrexate (MTX) and gold sodium thiomalate (GSTM) in patients with early erosive rheumatoid arthritis (RA). A total of 174 patients with active early erosive RA without deformities were enrolled in a 12 month, two-centre double-blind randomized trial. They received a weekly i.m. dose of 15 mg MTX (n = 87) or 50 mg GSTM (n = 87), respectively. Clinical and laboratory evaluations were carried out every 3 months in all patients, including the withdrawals. Ten patients (11.5%) in the MTX group and 21 patients (24.1%) in the GSTM group achieved a clinical remission of the disease [no swollen joints, erythrocyte sedimentation rate (ESR) < 20 mm, no steroids] within the study period (P < 0.05). An at least marked improvement (> 50% reduction of the number of swollen and tender joints and the ESR) was assessed in 59/87 (68%) and 66/87 (76%) patients treated with MTX or GSTM, respectively (P > 0.05). Significantly more patients in the GSTM group were withdrawn due to toxicity (six MTX/32 GSTM). A total of 126 patients (73 on MTX and 53 on GSTM) completed 12 months on their original medication. In the completers, a significant improvement of > 50% compared to baseline was noted in all six clinical variables [morning stiffness, joint count of swollen and tender joints, Lansbury index, grip strength and activities of daily living (ADL) score], the ESR and the C-reactive protein, without intergroup differences. The number of patients taking prednisone was reduced from 21 to 7% in the MTX group and from 15 to 4% in the GSTM group. While significantly more patients achieved a clinical remission with GSTM treatment, tolerability was significantly better with MTX.

Progression in early erosive rheumatoid arthritis: 12 month results from a randomized controlled trial comparing methotrexate and gold sodium thiomalate.

OBJECTIVE: To compare radiographic outcomes in patients with active early erosive rheumatoid arthritis (RA) who were treated with methotrexate (MTX) and gold sodium thiomalate (GSTM). METHODS: A total of 174 patients from two centres were randomly assigned to receive weekly i.m. injections for 12 months of either 15 mg MTX or 50 mg GSTM in a double-blind fashion. Radiographic evaluations including standardized scoring of 38 joints of the hands, wrists and forefeet, and count of eroded joints, were carried out at baseline and after 6 and 12 months in all patients, including withdrawals. RESULTS: An intention-to-treat analysis revealed no statistically significant difference in the progression of radiographic scores between treatment groups after 6 months (3.4 with MTX vs 2.6 with GSTM, P = 0.66) and after 12 months (6.0 vs 4.8, P = 0.44). A similar pattern was observed for the number of joints with erosions. The slope of radiographic progression was significantly reduced in the second half-year compared to the first 6 months in both groups. Erythrocyte sedimentation rate and C-reactive protein at baseline, and the presence of rheumatoid factor (RF), were the main predictors of progression in bivariate analysis. RF remained as the only predictor for radiographic outcome in multivariable analysis. CONCLUSION: In parallel to clinical improvement, both GSTM and MTX reduce the slope of radiographic progression in patients with active erosive RA.

Prospective six year follow up of patients withdrawn from a randomised study comparing parenteral gold salt and methotrexate.

OBJECTIVE: To confirm the impression of a better outcome of patients withdrawn from parenteral gold salt therapy compared with those withdrawn from methotrexate. METHODS: Patients with early, active, and erosive RA were randomised for a double blind trial to receive either weekly 15 mg intramuscular methotrexate or 50 mg goldsodiumthiomalate. If the drug had to be withdrawn because of side effects treatment was continued with the other drug in still active disease. Patients with insufficient response were treated with a combination of both drugs. All patients were followed up by an extended clinical and radiographic evaluation. RESULTS: 64 patients each were allocated to methotrexate and gold treatment. After 72 months a complete record was available for 88% of patients. Within the first 36 months 38 patients withdrew from gold treatment (95% because of side effects) and 23 patients withdrew from methotrexate (57% because of side effects). A significant 40% to 70% improvement of all parameters (erythrocyte sedimentation rate, C reactive protein, swollen and tender joints, radiological progression) compared with baseline was observed in patients completing their randomised treatment with gold or methotrexate. The same improvement over three years was seen in patients who withdrew from gold treatment, while patients withdrawing from methotrexate experienced a deterioration of their disease. CONCLUSION: Withdrawals represent the majority of patients in long term drug trials. Patients with early RA stopping gold because of side effects show almost the same sustained improvement as patients continuing gold or methotrexate. Patients withdrawn from methotrexate experience a reactivation of their disease.

A method to score radiographic change in psoriatic arthritis.

INTRODUCTION: Radiographic features of psoriatic arthritis (PsA) are very characteristic and differ from those observed in rheumatoid arthritis, especially in two aspects: 1) the distribution of affected joints (i.e. DIP joints), 2) the presence of destructive changes and bone proliferation at the same time. A scoring method for PsA, therefore, has to account for these characteristics of PsA. OBJECTIVE: To develop, describe and validate a method for scoring radiographic changes in patients with PsA. DESCRIPTION OF THE METHOD: Forty joints of the hands and feet are scored for destruction and proliferation. In the destruction score (DS) grading on a 0-5 scale is based on the amount of joint surface destruction: 0 = normal, 1 = one or more erosions with an interruption of the cortical plate of > 1 mm with destruction of the total joint surface up to 10%, 2 = 11-25%, 3 = 26-50%, 4 = 51-75%, 5 = > 75% joint surface destruction. The proliferation score (PS) sums up any kind of bony proliferation typical for PsA; graded 0-4: 0 = normal, 1 = bony proliferation of 1-2 mm or bone growth < 25% of the original size (diameter), 2 = bony proliferation 2-3 mm or bone growth 25-50%, 3 = bony proliferation > 3 mm or bone growth > 50%, 4 = bony ankylosis. The DS (0-200) and the PS (0-160) can be summed up to the total score (0-360). VALIDATION OF THE METHOD: To validate the method x-rays of 20 patients with active PsA taken 3 years apart were read twice in pairs, knowing the chronological order but not knowing demographic, clinical or laboratory data of the patients. The data were analyzed with a hierarchical analysis of variance model. RESULTS: There was good agreement between the first and the second reading of the same rater and between the two raters regarding the destruction score. The agreement regarding the proliferation score was lower but still acceptable. The reliability of the method to describe change over time--relation of progression (intra-patient variance) to the measurement error (inter-rater variance)--was 3.9 for the DS, 2.8 for the PS and 4.1 for the total score. The minimal detectable change when the readings of two raters were compared (inter-rater MDC) was 5.8, 5.0 and 4.6%, respectively of the maximum possible score for the destruction, the proliferation and the total score. These data compare very well with the results of standard scoring methods in rheumatoid arthritis. CONCLUSION: We propose a method for scoring radiographic change in psoriatic arthritis which reliably quantifies the progression of the disease seen on radiographs.

Response to methotrexate treatment is associated with reduced mortality in patients with severe rheumatoid arthritis.

OBJECTIVE: This study investigated whether efficacious methotrexate (MTX) treatment has an impact on mortality of patients with severe rheumatoid arthritis (RA). METHODS: In this prospective, observational, one-center study, patients with severe RA refractory to other disease-modifying antirheumatic drugs started MTX treatment between 1980 and 1987. Patients were divided into 4 different groups according to their response to MTX treatment after 1 year (>50% improvement [n = 99], 20-50% improvement [n = 70], no improvement [n = 52], and discontinued treatment [n = 35]). After a followup of 7.5-15.3 years (mean 10 years), the numbers of deaths were assessed in the different groups. Standardized mortality ratios (SMR) were calculated by comparing the number of observed deaths in the study with the number of expected deaths in an age- and sex-matched sample of the general population. RESULTS: Two hundred seventy-one patients entered the study between 1980 and 1987. In 1995/1996, outcomes for 256 patients (94.5%) could be documented; 88 patients (34.4%) had died. In patients with >50% improvement after 1 year, the SMR was 1.47, while in patients with 20-50% improvement, the SMR was 1.85. In both groups combined, the SMR was 1.64 (95% confidence interval [95% CI] 1.11-2.17), compared with 4.11 (95% CI 2.56-5.66) in patients without improvement. Patients who had discontinued MTX treatment during the first year had an SMR of 5.56 (95% CI 3.29-7.83). CONCLUSION: Patients with severe RA who do not respond to MTX treatment have a poor prognosis, with >4-fold increased mortality compared with the general population, while RA patients who respond to MTX treatment have only a moderately increased mortality rate.