Response to methotrexate predicts long-term mortality of patients with rheumatoid arthritis independent of the degree of response: results of a re-evaluation 30 years after baseline.

OBJECTIVES: To assess if there is a correlation between the degree of response to treatment with methotrexate (MTX) and long-term mortality in a cohort of patients with rheumatoid arthritis (RA) established in Germany in the early eighties. METHODS: RA patients who had started MTX treatment between 1980 and 1987 were included. One year after baseline, the treatment response was evaluated. Responders were defined as patients with at least 20% decline in the swollen joint count (out of 32 joints) and the ESR with a prednisone dosage <5 mg/day. Thereafter, assessments were performed at 10, 18, and 30 years after baseline. Standardised mortality ratios (SMR) were calculated, Cox regression and logistic regression were performed. RESULTS: The cohort comprised 271 patients. In 2015, about 30 years after the initiation of MTX therapy, 185 patients (68%) were deceased, 52 (19%) lost to follow-up and 34 alive. The response after the first year of MTX treatment was the strongest predictor of survival with a hazard ratio of 0.44 (95% confidence interval [CI]: 0.30-0.65). However, even responders still had an SMR of 1.37 (95% CI 1.31-1.65), but this was much worse for non-responders who had an SMR of 4.22 (95% CI 3.13-5.56). Using Cox regression analysis no difference was detected between responders with more than 50% improvement (38% of all patients) and those with 20-50% improvement (28%). CONCLUSIONS: The predictive value of a response to one year of MTX therapy for long-term mortality of RA patients is independent of the degree of response.

Response to methotrexate predicts long-term patient-related outcomes in rheumatoid arthritis.

This study was conducted to investigate the predictive value of the initial response to methotrexate (MTX) on long-term patient-related outcomes (PROs) in rheumatoid arthritis (RA). All RA patients starting MTX treatment between 1980 and 1987 in our department were enrolled in a prospective observational study. After an average of 18 years, patient-related outcomes were assessed in three dimensions according to the International Classification of Functioning, Disability and Health (ICF). Statistical analyses employed multivariable models with baseline values for age, gender, disease duration, rheumatoid factor positivity, disease activity, response to MTX after 1 year and continuous use of MTX as covariates. The 271 patients enrolled had a mean disease duration of 8.5 years, a mean number of swollen joints of 18 (out of 32), and a mean erythrocyte sedimentation rate of 55 mm/h. After 18 years, PRO was available in 89 patients (33 %). A clinical improvement of at least 20 % 1 year after the initiation of MTX was associated with a favourable outcome in all three dimensions of the ICF, independent of continuation of MTX (p < 0.05). The initial response to MTX is an independent predictor of PRO in RA as assessed after an average of 18 years.

Radiologic damage at baseline predicts patient-related outcomes 18 years after the initiation of methotrexate therapy in patients with severe rheumatoid arthritis.

OBJECTIVES: We aimed to assess the association of the degree of radiologic damage at baseline with long-term patient-related outcomes (PRO) in patients with severe rheumatoid arthritis (RA). METHODS: This prospective observational single-centre study (Ratingen, Germany) included all RA patients starting treatment with methotrexate (MTX) between 1980 and 1987. Standardised clinical evaluations and radiographs of hands and feet were obtained at baseline and during the following years. About 18 years later, patients were invited for a re-assessment. PRO were assessed in three dimensions according to the International Classification of Functioning and Disability (ICF). Statistical analyses comprised multivariable models using baseline values for radiologic damage of hands and feet, age, gender, disease duration, rheumatoid factor positivity, measures of disease activity, and response to MTX as covariates. RESULTS: At baseline, the mean disease duration was 8.5 years. The disease was active with a mean number of swollen joints of 18 (out of 32) and a mean erythrocyte sedimentation rate of 55 mm/hour. Radiologic damage was present in 95% of the patients. After 18 years, patient-related outcomes could be assessed in 78/271 patients (29%). Among chosen covariates, only the degree of baseline radiologic damage as measured by the Ratingen score was predictive of all long-term PRO (p<0.016). CONCLUSIONS: In this cohort including patients with severe RA, baseline radiologic damage was a good long-term predictor of PRO related to all three ICF dimensions.

Expert agreement confirms that negative changes in hand and foot radiographs are a surrogate for repair in patients with rheumatoid arthritis.

The objective of the present study was to test the hypothesis that experts recognize repair of erosions and, if so, to determine which, if any, morphologic features permitted them to recognize the repair. We also tested whether scoring by a standard method detected repair. Seven experienced readers of radiographs in rheumatoid arthritis were presented with 64 sets of single joints-of-interest at two time points, randomized and blinded for the correct sequence. The readers assessed which joint was better, and recorded whether any of six specific features were seen. Two independent readers, experienced in scoring by the van der Heijde-modified Sharp method who were not on the expert panel, then scored the complete films that included the joint-of-interest. The panel agreed very well on which of two joints was better, and, even though they did not know the true sequence, the panel accurately assigned a sequence slightly better than chance alone (58%) but worse than their agreement on which image was 'better or worse' (78%). The readers therefore indirectly assigned repair by choosing the second film as the best. Putative repair features were seen in cases of both repair and progression, and were not discriminatory. Similar results were obtained when the experts were presented with the entire hand or foot containing the joint-of-interest. In the third repair exercise, two independent readers who scored whole hands and feet using a standard method found a mean negative score in 22/60 joints-of-interest. All 22 joints were also scored as repair by the panel. Repair was detected reliably by a majority of the panel on viewing paired images based on a better/worse decision and assigning sequence in a set of images that were blinded for sequence by an independent project manager. In this test set of images, repair was manifested by a reduction in the size of erosion in many cases. Size was one feature that aided the experts to detect repair but cannot be the only one; the experts had to find other features to determine whether a smaller erosion was the first in a sequence of radiographs in a patient with progressive damage or was the second film in a patient exhibiting repair. The change in size of erosion was also picked up by independent readers applying the van der Heijde-modified Sharp scoring method and was reflected in their scores.

QUEST-RA: quantitative clinical assessment of patients with rheumatoid arthritis seen in standard rheumatology care in 15 countries.

OBJECTIVE: To conduct a cross-sectional review of non-selected consecutive outpatients with rheumatoid arthritis (RA) as part of standard clinical care in 15 countries for an overview of the characteristics of patients with RA. METHODS: The review included current disease activity using data from clinical assessment and a patient self-report questionnaire, which was translated into each language. Data on demographic, disease and treatment-related variables were collected and analysed using descriptive statistics. Variation in disease activity on DAS28 (disease activity score on 28-joint count) within and between countries was graphically analysed. A median regression model was applied to analyse differences in disease activity between countries. RESULTS: Between January 2005 and October 2006, the QUEST-RA (Quantitative Patient Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis) project included 4363 patients from 48 sites in 15 countries; 78% were female, >90% Caucasian, mean age was 57 years and mean disease duration was 11.5 years. More than 80% of patients had been treated with methotrexate in all but three countries. Overall, patients had an active disease with a median DAS28 of 4.0, with a significant variation between countries (p<0.001). Among 42 sites with >50 patients included, low disease activity of DAS28 50% of patients had high disease activity of DAS28 >5.1. CONCLUSIONS: This international multicentre cross-sectional database provides an overview of clinical status and treatments of patients with RA in standard clinical care in 2005-6 including countries that are infrequently involved in clinical research projects.

Association of a specific haplotype across the genes MMP1 and MMP3 with radiographic joint destruction in rheumatoid arthritis.

The genetic background of rheumatoid arthritis (RA) is only partly understood, and several genes seem to be involved. The matrix metalloproteinases MMP1 (interstitial collagenase) and MMP3 (stromelysin 1) are thought to be important in destructive joint changes seen in RA. In the present study, functional relevant promoter polymorphisms of MMP1 and MMP3 were genotyped in 308 patients and in 110 controls, to test whether the polymorphisms contribute to the severity of the disease measured by radiographic progression of joint destruction. For comparison, the shared epitope of HLA DR4 and DR1 (SE) was determined by polymerase chain reaction. There was no association of MMP polymorphisms with susceptibility to RA. However, a strong linkage disequilibrium was observed between the 1G/2G (MMP1) and the 5A/6A (MMP3) polymorphisms (P << 10(-6); linkage disequilibrium index D' = 0.46). In factorial regression, the degree of radiographic joint destruction correlated significantly with the 1G-5A haplotype (P = 0.0001) and the interaction term 'estimated number of 1G-5A haplotypes x duration of disease' (P = 0.0007). This association was phasic, indicating that possession of the 1G-5A haplotype has a protective effect over a period of about 15 years of RA, but might be associated with a more pronounced radiographic progression later on. Similar results were also found with the 1G allele of MMP1 alone (P = 0.015) and with the interaction term 'estimated number of 1G alleles x duration of disease' (P = 0.014). The correlation of SE with the Ratingen score was comparable (0.044). The regression model of MMP haplotypes explained 35% of the variance of the radiographic score, whereas the SE explained 29%. The 1G-5A haplotype across the closely linked MMP1 and MMP3 gene loci is a newly described genetic factor strongly associated with the progression of joint damage in RA. Our findings suggest that there are haplotypes in a MMP cluster region that modify the joint destruction in RA in a phasic manner.

Repair of erosions in rheumatoid arthritis does occur. Results from 2 studies by the OMERACT Subcommittee on Healing of Erosions.

The committee was charged with determining whether healing of erosions in rheumatoid arthritis (RA) occurs. Two exercises were performed: The first asked the committee members, as a panel of experts, to express agreement or disagreement with the presence of improvement and features of bone reaction to injury in images submitted by members as examples of healing. The second presented panel members with 28 pairs of serial images, 14 chosen to illustrate progression and 14 chosen to illustrate repair. Agreement was tested on 8 items: global judgment on which image in the pair was better, relative size of the erosion in the 2 images, judgment on which image was first, presence and extent of sclerosis, cortication, filling-in, remodeling, and reconstituting normal structure. Our results showed good agreement, among the 15 respondents, on global assessment of which image was better and which image showed the smaller erosion. Correct assignment of sequence was only slightly better than expected by chance (in 65% of the cases). Agreement was poor regarding the presence of morphologic features of bone repair. A majority of a panel of experts agreed on which 2nd images in a set of paired, serial images represented improvement and which showed progression based on global assessment of which was better and on size of erosion. Features of bone repair were not distinctive and did not enable the panel to deduce the correct sequence of the serial images. This study provides evidence that repair of bone damage in RA does occur, resulting in some degree of improvement, which was recognized by a majority of a panel of experts.