Calculating radiological progression in rheumatoid arthritis

We examined two methods of calculating radiological progression in rheumatoid arthritis using hand and wrist radiographs scored by Larsen's method. Progression over 12 months was calculated in two ways: absolute change in score; relative change in score. The two methods of scoring progression were investigated in two studies. In the first 173 patients with rheumatoid arthritis treated with a variety of non-steroidal and slow-acting anti-rheumatic drugs were evaluated. There were different results using absolute and relative changes in score. Relative changes gave more meaningful results. The second study looked at 80 rheumatoid patients treated with slow-acting drugs for 6 months; patients with a persistently high ESR had significantly more progression assessed by relative change but not by absolute change. Evaluating the progression of joint damage by methods employing a scoring system must be interpreted with caution. Relative change may provide a more valuable measure than absolute change.     

Course of chronic polyarthritis

The great variety of rheumatoid arthritis is well known. By means of exemplary cases subgroups are described, which show more homogeneity in relation to onset and course than rheumatoid arthritis as defined by the ARA-criteria. As a result of treatment clinical signs of inflammation as joint pain and swelling and laboratory findings as ESR and Hb may improve, but there is no change in radiological progression. There are correlations between clinical and laboratory measurements but not to radiological findings. It is considered that inflammation and joint destruction may result from independent pathomechanisms. The conclusion is that the pathognomonic process of rheumatoid arthritis, i.e. destruction, shown by radiological progression, is not influenced by treatment and is reflecting the natural course of the disease.     

Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: role of antibodies to citrullinated peptides (anti-CCP)

OBJECTIVE: To investigate the role of anti-cyclic citrullinated peptide antibody (anti-CCP) for the prediction of radiological outcome in patients with early rheumatoid arthritis. METHODS: Anti-CCP was assessed at baseline in 379 patients with early rheumatoid arthritis (disease duration <1 year). Radiological joint damage and progression were assessed by Larsen score after two years of follow up (end point) and used as outcome variables. The prognostic value of anti-CCP and other demographic and disease related baseline variables were assessed by univariate and multivariate analyses, including calculation of odds ratios (OR), predictive values, and multiple logistic regression models. RESULTS: The presence of anti-CCP was associated with significantly higher Larsen score both at baseline and at end point. Univariate predictor analysis showed that anti-CCP had the highest significant OR for radiological joint damage and progression after baseline Larsen score, followed by rheumatoid factor, erythrocyte sedimentation rate (ESR), C reactive protein, age, smoking status, and sex. In stepwise multiple regression analyses, baseline Larsen score, anti-CCP, and ESR were selected as significant independent predictors of the radiological outcomes. CONCLUSIONS: There is good evidence for an association of anti-CCP with radiological joint changes in rheumatoid arthritis. Anti-CCP is an independent predictor of radiological damage and progression. Though prediction in early rheumatoid arthritis is still far from perfect, the use of anti-CCP in clinical practice should make it easier for rheumatologists to reach judicious treatment decisions.     

Clinical significance of interleukin-6 measurement in early rheumatoid arthritis: relation with laboratory and clinical variables and radiological progression in a three year prospective study.

OBJECTIVE--To evaluate the clinical significance of interleukin-6 (IL-6) measurements in relation to laboratory and clinical measures of disease activity and radiological progression in early rheumatoid arthritis (RA). METHODS--A prospective study was performed in 51 patients with early RA during the first three years of the disease, with monthly clinical and laboratory assessments and biannual radiographs of the hands and feet. IL-6 was measured by enzyme linked immunosorbent assay (ELISA). Cross sectional (n = 51) and longitudinal (n = 20) correlations between plasma IL-6 concentrations and values of C reactive protein (CRP), serum amyloid A protein (SAA), erythrocyte sedimentation rate (ESR), haemoglobin (Hb), platelets, and joint scores were calculated, and correlations made between time integrated values of IL-6, CRP and ESR, and radiological progression over three years (n = 20). RESULTS--Significant correlations were found between IL-6 and the acute phase response and platelets, but variable results were obtained for the correlation between IL-6 and Hb. In contrast to a significant correlation between time integrated values of CRP or ESR and radiological progression, time integrated values of IL-6 did not correlate with radiological progression over three years follow up. CONCLUSION--The course of disease activity and the radiological progression of joint damage are better reflected by CRP, SAA, and ESR values than by plasma IL-6 concentrations, particularly in stages of low disease activity.     

Does second-line therapy affect the radiological progression of rheumatoid arthritis?

The effect of 'second-line' drugs on radiological progression in rheumatoid arthritis is not clear, and previous studies have yielded contradictory results. Sixty-seven patients with rheumatoid arthritis have been followed up clinically and radiologically for approximately 2 years (26 patients were receiving intramuscular gold, 21 penicillamine, 10 levamisole, and there were 10 controls who had consistently refused second-line therapy). Patients on gold and penicillamine showed improvement in erythrocyte sedimentation rate and haemoglobin over 2 years which was not seen in levamisole and control patients, but hand radiograph scores in all 4 groups showed statistically significant deterioration. There was a trend towards slowing of the rate of erosion in the gold and penicillamine groups in comparison with controls, but healing of erosions was extremely unusual.     

Effect of sulphasalazine on the radiological progression of rheumatoid arthritis.

We have investigated the influence of sulphasalazine, a second line antirheumatic drug, on the radiological progression of erosions in rheumatoid arthritis over a two year period in 41 patients. Hand radiograph scores deteriorated significantly over this period, but in a group of 31 patients in whom one year films were also available this deterioration was limited to the first year. This slowing of radiological deterioration was not related to 'normalisation' of the erythrocyte sedimentation rate (ESR). Compared with a 'control' group of 10 patients who had refused offers of second line therapy, sulphasalazine treated patients showed less deterioration over the two year period, and this difference was more marked than in previous studies of gold or penicillamine. No significant change was seen in large joint radiographs in sulphasalazine treated patients over two years, but this probably represents the poor sensitivity of the method of assessment. No significant correlation was seen between changes in inflammatory indices and slowing of radiological deterioration in erosion score. Thus sulphasalazine appears to slow the progression of radiological disease of the hands over the second year of treatment in a representative sample of patients who continue to receive treatment for two years.     

Effect of age on 3 year outcome in early rheumatoid arthritis

OBJECTIVE: To investigate the effect of age on clinical and radiological outcome and on efficacy and tolerance of antirheumatic therapy in early rheumatoid arthritis (RA). METHODS: In a prospective 3 year study 113 patients (83 women, 30 men) were divided into 2 groups according to age at onset of disease: before (n = 55) and after 55 years of age (n = 58). For clinical outcome, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor, Ritchie index, and number of swollen joints were measured. Radiological progression was analyzed by Larsen score. The principles of the "sawtooth" strategy were applied in the treatment of all patients. RESULTS: At baseline, inflammatory activity (ESR, CRP) and the Larsen score for hands were significantly higher in patients with late onset RA (LORA) and they also developed more extraarticular symptoms compared to patients with early onset RA (EORA). However, no differences were found in Ritchie index, number of swollen joints, or CRP values between the groups. Also during the followup there was a trend toward increased inflammatory activity (ESR) among LORA patients. After the initiation of antirheumatic therapy a parallel improvement in clinical activity was observed in the 2 groups. The frequencies of remissions, side effects, and withdrawals due to drug inefficacy did not differ significantly between the 2 groups. The radiological progression was also comparable. CONCLUSION: The onset of RA was more active in patients with LORA. However, the clinical course and the radiological progression were parallel in LORA and EORA patients. The "sawtooth" therapy was equally tolerated in both patient groups.     

Serum hyaluronate level as a predictor of radiologic progression in early rheumatoid arthritis

Increased serum levels of hyaluronate (HA) have been found in patients with rheumatoid arthritis (RA). This probably reflects increased leakage of HA from the inflamed joints into the circulation. In a prospective study of 40 patients with early RA, we evaluated the relationship of serum HA to clinical, laboratory, and radiologic parameters of disease activity. The patients were followed for 12 months; all had active disease at study entry. We confirmed the previous finding of higher serum HA concentrations in RA patients compared with healthy controls. At study entry, the patients' serum HA levels correlated positively with clinical and laboratory parameters of acute inflammation. Despite marked clinical improvement during therapy with second-line drugs, the serum HA levels increased during the followup period. At the end of 1 year, these levels correlated with the radiologic progression of joint lesions, whereas they showed a less pronounced correlation with clinical or laboratory parameters of inflammation. We conclude that, in early RA, serum HA levels may reflect ongoing joint destruction and may even predict subsequent joint damage.     

Serum matrix metalloproteinase 3 in early rheumatoid arthritis is correlated with disease activity and radiological progression

OBJECTIVE: To analyze the clinical significance of serial measurements of serum matrix metalloproteinase 3 (MMP-3) levels in relation to markers of disease activity and radiological progression in early rheumatoid arthritis (RA). METHODS: In a 3 year prospective study of 33 patients with early RA (symptoms < 1 year at entry) monthly measurements of serum MMP-3 were transformed into time integrated values for 6 month periods for comparison with other markers of disease activity like swollen joint count (SJC), tender joint count (TJC), Ritchie articular index (RAI), the disease activity score (DAS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and radiological progression, scored according to Sharp's method, in which erosions and joint space narrowing are scored separately and combined to a total Sharp score. RESULTS: Significant correlations were found between serum MMP-3 and SJC, ESR, and CRP during all periods and between 6 and 30 months with the DAS. There were no correlations between serum MMP-3 and TJC or the RAI. During the first 12 months serum MMP-3 was correlated only with the item joint space narrowing of the Sharp score. After 12 months of followup it was also correlated with the total Sharp score and after 18 months it was correlated with all 3 items of the Sharp score. There was a wide interindividual variation in the relation between serum MMP-3 and radiological progression but intraindividually this relation seemed to be rather constant. CONCLUSION: Time integrated values of serum MMP-3 are correlated with time integrated values of other markers of disease activity such as joint swelling, ESR, CRP, and the DAS. Of the radiological scores, as outcome measures, especially joint space narrowing correlated closely with cumulative serum MMP-3.     

SELECTION OF SUITABLE PATIENTS FOR SECONDLINE THERAPY IN RHEUMATOID ARTHRITIS

Investigators studying second-line drugs often try to enrol‘ideal’ patients with a high ESR, short diseaseduration and who have received no previous second-line therapy.In this paper we investigate the influence of gender, diseaseduration, previous second-line therapy, and initial ESR in 150rheumatoid patients with clinically-active disease treated withsulphasalazine. Clinical improvement was seen in all subgroupsand no difference in toxicity could be demonstrated. Haematologicalresponse was absent in patients with an initial low ESR althoughthese patients improved clinically. Thus, patients with clinically-active disease suggesting a needfor second-line drugs should benefit from sulphasalazine therapyirrespective of any of the above variables. The implicationsfor clinical trial design regarding patients with low ESR, however,may be more complex. KEY WORDS: Rheumatoid arthritis, Sulphasalazine, Disease activity, Previous treatment, ESR     

Biannual Radiographic Assessments of Hands and Feet in a Three-Year Prospective Followup of Patients with Early Rheumatoid Arthritis

In a prospective followup study of 147 patients with rheumatoid arthritis of recent onset, we assessed the progression of radiographic evidence of joint damage on films of the patients' hands and feet obtained biannually. Patients were receiving first-line and second-line treatment. Ninety patients were followed up for 3 years, and 57 were followed up for only 2 years. Radiographic damage was determined by a modification of the method described by Sharp, and to ensure comparability of findings, we determined the percentage of damage per joint group (actual score divided by the maximum possible score). After 3 years, radiographic damage was present in 70% of the patients, all of whom could be identified after 1 year of study. Overall, 18—20% of the joints of the hands and feet were affected after 3 years, with relatively little abnormality per joint (˜8% of maximum possible score). During the entire followup, more foot joints than hand joints were affected. The rate of progression in the first year was significantly higher than in the second and third years of study, indicating a flattening of the curve of radiographic progression of joint damage.     

Joint damage in rheumatoid arthritis: radiological assessments and the effects of anti-rheumatic drugs

Summary Joint damage is a major problem in the long-term course of rheumatoid arthritis. It is usually assessed radiologically. In this review the methods of measuring the radiological changes are outlined, and the effects of anti-rheumatic drugs on radiological progression summarised. Two methods of scoring radiographs have become standard techniques; these are the Sharp index and the Larsen index. They both concentrate on cartilage loss and erosive damage in the hands and wrists. Investigations of the effects of drugs upon the radiological progression of rheumatoid arthritis include: indirect studies evaluating the inter-relationships between clinical, laboratory and radiological variables; placebo-controlled studies of slow-acting drugs and similarly controlled studies without a placebo group; open studies evaluating the long-term effects of treatment of slow-acting drugs. Only slow-acting drugs such as gold have been persistently considered to have a possible effect on reducing radiological progression. Unfortunately the therapeutic studies use a wide range of different radiological assessment techniques, and the incomparability is therefore difficult. None of the studies give a good indication that there is a marked reduction in joint damage by slow-acting drugs. On balance studies do suggest minor effects on the process of progression. Instead of debating how strong the evidence of such minor effect really is, it is concluded that rheumatologists should look towards novel therapeutic approaches to induce a major reduction in the rate of damage.     

Relationship of progression of radiographic changes in hands and wrists, clinical features and HLA-DR antigens in rheumatoid arthritis

One hundred and twelve hospital based outpatients with rheumatoid arthritis (mean duration +/- standard error, 10.7 +/- 0.9 years) were studied for radiological progression of the hands and wrists over a mean period of 26.5 +/- 0.5 months. The majority were taking slow acting antirheumatic drugs (SAARD). The rate of radiographic progression was positively and independently associated with the female sex (p less than 0.01), erythrocyte sedimentation rate (ESR, p less than 0.05) and HLA-DR1 (p less than 0.05). There was a negative association with HLA-DR4 (p less than 0.05) but this was no longer significant after adjusting for ESR. There was no relationship between the rate of radiological progression and the presence of rheumatoid factor, rheumatoid nodules and duration of treatment with SAARD.     

Biannual radiographic assessments of hands and feet in a three-year prospective followup of patients with early rheumatoid arthritis.

In a prospective followup study of 147 patients with rheumatoid arthritis of recent onset, we assessed the progression of radiographic evidence of joint damage on films of the patients' hands and feet obtained biannually. Patients were receiving first-line and second-line treatment. Ninety patients were followed up for 3 years, and 57 were followed up for only 2 years. Radiographic damage was determined by a modification of the method described by Sharp, and to ensure comparability of findings, we determined the percentage of damage per joint group (actual score divided by the maximum possible score). After 3 years, radiographic damage was present in 70% of the patients, all of whom could be identified after 1 year of study. Overall, 18-20% of the joints of the hands and feet were affected after 3 years, with relatively little abnormality per joint (approximately 8% of maximum possible score). During the entire followup, more foot joints than hand joints were affected. The rate of progression in the first year was significantly higher than in the second and third years of study, indicating a flattening of the curve of radiographic progression of joint damage.     

Prediction of progressive joint damage in patients with rheumatoid arthritis receiving gold or D-penicillamine therapy.

Seventy two patients with classical or definite rheumatoid arthritis (RA) were randomly allocated to receive gold or D-penicillamine therapy (DPA) in a prospective study designed to evaluate whether it is possible to predict which patients will show radiological progression despite therapy. Forty five patients completed 12 months' treatment. There were no significant demographic or clinical differences between them and the 27 drop outs. Twenty of the 45 patients showed no radiological progression between six and 12 months. These patients had less severe initial radiological damage, lower levels of serum aspartate transaminase (serum AST) and lactic dehydrogenase (LDH), but higher levels of serum cholesterol. Twenty five patients did show progression during the six to 12 month period. This group included all the men with nodules. Of the 43 pretreatment clinical and laboratory variables examined, however, the majority failed to predict whether or not progression would subsequently occur. This included the acute phase response and seropositivity.     

Serum matrix metalloproteinase 3 levels in comparison to C-reactive protein in periods with and without progression of radiological damage in patients with early rheumatoid arthritis

OBJECTIVE: To evaluate serum matrix metalloproteinase 3 (MMP-3) levels in comparison to C-reactive protein (CRP) in periods with and without progression of radiological damage in patients with early rheumatoid arthritis (RA). METHODS: Thirty-two patients with RA and radiological progression (> or = 5 points according to the Sharp/van der Heijde method) during 6 months followed by a 6-month period without radiological progression (< or = 1 point) were selected from a prospective follow-up study of early RA patients. Serum MMP-3 levels, CRP, the erythrocyte sedimentation rate (ESR), disease activity index (DAS), swollen joint count (SJC), tender joint count (TJC), and Ritchie articular index (RAI) were measured monthly and results were transformed into mean values for the 6-month periods. RESULTS: During the period with radiological progression the mean serum MMP-3 correlated significantly with the mean CRP (r = 0.68, p < 0.001), ESR (r = 0.54, p = 0.001) and swollen joint count (r = 0.48, p = 0.006). In the period without radiological progression the mean serum MMP-3 only correlated with the mean CRP (r = 0.44, p = 0.012). Individual changes--expressed in percentages (%)--between the two periods showed a decrease in both the mean serum MMP-3 and CRP in 19 and an increase in 3 patients, in parallel with other markers of disease activity in these patients (69% of cases). The individual change (%) in mean serum MMP-3 or CRP did not correlate with the difference in radiological progression between the two periods. CONCLUSIONS: Serum MMP-3 and CRP are closely related and there seems to be no difference between serum MMP-3 and CRP with regard to the monitoring of the progression of radiological damage.     

Lymphoproliferative malignancy in rheumatoid arthritis: a study of 20 cases.

A series of 20 patients with definite or classical rheumatoid arthritis who subsequently developed a lymphoproliferative malignancy are described. The mean time between the onset of the 2 diseases was 13.2 years. A wide range of types of non-Hodgkin's lymphoma and Hodgkin's disease were found; there were no unusual histological features in the lymphomas. Although many of the patients had had gold, penicillamine, and other second-line drugs, none of them had received cytotoxic drugs, and there was no evidence that therapy was a cause of their malignancies. The likely cause of the association is a predisposition to both diseases.     

Sulphasalazine in the treatment of rheumatoid arthritis

Recent reports have found sulphasalazine to have a disease-modifying effect in patients with rheumatoid arthritis. We report on the results of an open study of this drug. Sulphasalazine was given to 20 patients with active rheumatoid arthritis (definite or classical by ARA criteria) during a period of 6 months. Response to the treatment was assessed by subjective symptoms and objectively by changes in selected clinical and laboratory parameters. After 2 to 6 months' therapy some of these measurements had improved significantly in 18 patients. Three patients went into remission by preliminary ARA criteria. The treatment was discontinued in two patients because of side effects (toxic-allergic cutaneous reactions). From these results we conclude that sulphasalazine may be a useful second-line drug in the treatment of rheumatoid arthritis.     

Outcome of second line therapy in rheumatoid arthritis.

OBJECTIVES--To study the functional outcome in patients with rheumatoid arthritis (RA) who tolerate second line drug therapy for five years. METHODS--We enrolled into prospective controlled trials, 190 patients with rheumatoid arthritis who tolerated 'disease modifying' antirheumatic drug therapy for five years. Demographic data were recorded. Disease activity was measured every six months for two years and annually thereafter, using clinical and laboratory variables. Patient function was measured using the modified Health Assessment Questionnaire. The change in each variable was analysed using paired Wilcoxon tests. RESULTS--Patient function improved significantly compared with baseline. The improvement was maximal after one to two years, and thereafter function started to decline slowly. After five years of treatment the patients' function was still significantly better than before treatment had started. There were highly significant improvements in all variables measured to assess disease activity, which remained well controlled throughout the five year period. CONCLUSION--Good control of disease activity and improved function can be achieved long term in approximately 30% of RA patients treated with injectable gold, sulphasalazine or penicillamine.