The pharmacokinetics of ¹²4I-rituximab in patients with rheumatoid arthritis.

Rheumatoid arthritis is a destructive inflammatory joint disorder. Pre- and mature B-cells, characterized by CD20 antigen expression, play an important role in the inflammatory process. Rituximab, a chimeric monoclonal antibody against the CD20 antigen, has been approved since 2006 for the treatment of patients with rheumatoid arthritis. However, not all patients benefit from this treatment. Persistent activity of the disease has been reported despite treatment with rituximab. Imaging of radiolabeled rituximab can be used to monitor the biodistribution of rituximab, and potentially to predict the efficacy of the treatment. In this study, rituximab was radiolabeled with ¹²4Iodine for positron emission tomography (PET) imaging. The aim of this study was to investigate the pharmacokinetics and biodistribution of ¹²4I-rituximab in patients with rheumatoid arthritis, to establish the optimal procedure for PET imaging. Eligible patients received 50 MBq ¹²4I-rituximab, corresponding to approximately 1.5 mg rituximab. Wholebody PET/CT imaging was performed at 10 min, 24 hrs, and 48 hrs post injection. The total body activity, radioactivity in whole blood, and rituximab serum levels were determined. ¹²4I-rituximab has favorable pharmacokinetics for targeting of (pathological) B cells and imaging over several days, but only after pre-treatment with unlabeled rituximab. In addition, protection of the thyroid is recommended to prevent uptake of released ¹²4I.

CD20 antigen imaging with ¹²4I-rituximab PET/CT in patients with rheumatoid arthritis.

INTRODUCTION: Visualization of the CD20-antigen expression could provide a tool to localize sites of inflammation and could be of additive value in the diagnosis, and subsequently, in the treatment follow-up of patients with rheumatoid arthritis. In this study, an anti-CD20 monoclonal antibody, rituximab (Mabthera®), was radiolabeled with ¹²4Iodine. We report the first results of I¹²4-rituximab PET/CT in patients with rheumatoid arthritis. METHODS: Eligible patients received 50 MBq ¹²4I-rituximab. Wholebody PET/CT imaging was performed at 10 min, 24 h, 48 h and 72-96 h post injection. Images were evaluated primarily on a visual basis and were correlated with disease activity as determined by physical examination and clinical measures. RESULTS: Joints with visually detectable targeting of ¹²4I-rituximab were observed in 4 out of 5 evaluable patients. Only the images at 24 h and later showed accumulation in joints, indicating that the visualized signal represented active targeting of rituximab to the CD20 antigen. Several images showed CD20 positive B-cell infiltration in joints which were clinically normal, while a few clinically diagnosed arthritis localizations were not visualized. This discrepancy suggests that infiltration of CD20 positive B-cells in synovium is a phenomenon that is at least partially independent of clinical inflammation. The level of uptake in joints was generally low, representing less than 0.5% of the injected dose. CONCLUSION: We have shown the feasibility of CD20 antigen imaging using ¹²4I-rituximab in patients with rheumatoid arthritis. Further research is needed to elucidate the clinical significance of demonstrated B-cell infiltration in rheumatic joints.

Differential influence of p38 mitogen activated protein kinase (MAPK) inhibition on acute phase protein synthesis in human hepatoma cell lines.

BACKGROUND: Inhibition of intracellular signal transduction is considered to be an interesting target for treatment in inflammation. p38 MAPK inhibitors, especially, have been developed and are now in phase II clinical trials for rheumatoid arthritis (RA). OBJECTIVE: To investigate the influence of p38 MAPK inhibition on acute phase protein (APP) production, which is dependent on both JAK/STAT and p38 MAPK pathways. METHODS: The effects of p38 MAPK inhibition on APP production and mRNA expression in four human hepatoma cell lines was investigated, after stimulation with interleukin (IL)6 and/or IL1beta or tumour necrosis factor alpha. RESULTS: Two out of four cell lines produced C reactive protein (CRP), especially after combined IL6 and IL1beta stimulation. CRP production was significantly inhibited by the p38 MAPK specific inhibitor RWJ 67657 at 1 micromol/l, which is pharmacologically relevant. Fibrinogen production was also inhibited at 1 micromol/l in all cell lines. Serum amyloid A (SAA) was produced in all four lines. In contrast with CRP, SAA production was not inhibited by RWJ 67657 at 1 micromol/l. CONCLUSION: Production and mRNA expression of CRP and fibrinogen, but not SAA production and mRNA expression, were significantly inhibited by p38 MAPK specific inhibitor in hepatoma cell lines. For p38 MAPK inhibitor treatment in RA SAA might be a better marker of disease activity than CRP and fibrinogen, because SAA is not directly affected by p38 MAPK inhibition.

Effects of RWJ 67657, a p38 mitogen activated protein kinase (MAPK) inhibitor, on the production of inflammatory mediators by rheumatoid synovial fibroblasts.

OBJECTIVE: To investigate the effect of the p38 mitogen activated protein kinase (MAPK) inhibitor RWJ 67657 on inflammatory mediator production by rheumatoid synovial fibroblasts (RSF). METHODS: RSF were pretreated with RWJ 67657 and stimulated with TNF alpha and/or IL-1 beta. Protein levels and mRNA expression of MMP-1, MMP-3, TIMP-1, IL-6, and IL-8 were determined, as was mRNA expression of COX-2 and ADAMTS-4. RESULTS: MMP-3 production was significantly inhibited at 1 microM RWJ 67657 and MMP-1 production at 10 microM, while TIMP-1 production was not inhibited. Inhibition of IL-6 and IL-8 protein production was seen at 0.1 microM RWJ 67657. Expression profiles of mRNA were in accordance with protein production. Inhibition of COX-2 mRNA expression occurred at 0.01 microM RWJ 67657. CONCLUSIONS: RWJ 67657 inhibits major proinflammatory mediator production in stimulated RSF at pharmacologically relevant concentrations. These findings could have important relevance for the treatment of rheumatoid arthritis.

Functional ability, social support, and depression in rheumatoid arthritis.

OBJECTIVE: First, to investigate the patterns of functional ability, depressive feelings, and social support in early stage rheumatoid arthritis (RA) patients. Second, to demonstrate the stress buffering effect of social support. Social support is thought to reduce the impact of chronic stress on psychological well-being; for patients without social support the impact of functional ability on depressive feelings will be stronger. METHODS: In 4 waves with an intervening period of 1 year, longitudinal data was collected of 264 Dutch RA patients, of which 65% was female. At T1, the mean age of these patients was 53 years, while their mean disease duration was 22 months. In an interview at the patients' homes, data was collected on functional ability, social support en psychological well-being. The buffering effect of social support was examined by testing the significance of the (computed) stressor by social support interaction term in a regression analysis on depressive feelings. RESULTS: Although large differences between subjects existed, the mean scores on functional ability, social support, and depressive feelings barely changed from year to year. Patients who deteriorated in functional ability during one year had the best chances to improve next year, and visa versa. Furthermore, the stress by support interaction terms had no significant effect on depressive feelings in a regression analysis. CONCLUSIONS: This study demonstrated clearly the fluctuating pattern of RA in the first years after onset. The patients' level of depressive feelings was linearly related to the level of functional ability. Like many other studies, also this study could not provide evidence for the stress buffering effect of social support.

Diagnostic and therapeutic approach of systemic amyloidosis.

Amyloidosis is a group of diseases, all characterised by deposition of protein fibrils with a beta-sheet structure. This structure generates affinity of amyloid for Congo red dye and is resistant to proteolysis. Three types of systemic amyloidosis are important for the clinician: AA (related to underlying chronic inflammation), AL (related to underlying monoclonal light chain production) and ATTR amyloidosis (related to old age or underlying hereditary mutations of transthyretin). Signs and symptoms vary considerably among the three types and the choice of treatment differs completely. A stepwise approach in diagnosis and therapy is presented. When amyloidosis is suspected the first step is histological proof of amyloid and the second is proof of systemic involvement. The next two steps are determination of the type of amyloid followed by detection of the precursor protein. The fifth step is a thoughtful clinical evaluation, necessary for assessment of prognosis and therapy. Subsequently, the choice of therapy is based on the 'precursor-product' concept. In the final step, the effects of therapy on the underlying disease as well as on the amyloidosis are assessed during follow-up. In this evaluation serum amyloid P component (SAP) scintigraphy helps to show organ involvement and therapy response.

Serum amyloid P component levels are not decreased in patients with systemic lupus erythematosus and do not rise during an acute phase reaction.

BACKGROUND: Serum amyloid P component (SAP) and acute phase proteins like C-reactive protein contribute to the clearance of apoptotic cells. This response is diminished in systemic lupus erythematosus (SLE). OBJECTIVES: To analyse SAP concentrations in SLE in relation to disease activity, and investigate whether SAP reacts like an acute phase protein. METHODS: SAP was measured in 40 patients with SLE during active and inactive disease and compared with healthy controls and patients with rheumatoid arthritis and Wegener's granulomatosis. Normal SAP values were determined in 120 healthy controls by ELISA. C reactive protein and serum amyloid A (SAA) were measured in all subjects and their levels related to SAP. SAP was also measured serially in 11 patients with breast cancer treated with recombinant human interleukin-6, and in 16 patients with sepsis. RESULTS: In SLE, SAP was unaltered compared with healthy controls and was not influenced by disease activity, in contrast to C reactive protein and SAA, which increased during active disease. SAP increased in Wegener's granulomatosis but not in rheumatoid arthritis. The rise in C reactive protein and SAA was most pronounced in Wegener's granulomatosis with active disease. SAP did not change significantly during an acute phase response. No correlation was found between SAP and C reactive protein or SAA, but there was a correlation between SAA and C reactive protein (r = 0.4989, p = 0.0492). CONCLUSIONS: Patients with SLE have normal circulating SAP levels. In contrast to C reactive protein or SAA, SAP does not act as an acute phase protein.

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.

Screening for amyloid in subcutaneous fat tissue of Egyptian patients with rheumatoid arthritis: clinical and laboratory characteristics.

OBJECTIVE: To screen for amyloid and to assess associated clinical and laboratory characteristics in Egyptian patients with rheumatoid arthritis (RA). METHODS: Abdominal subcutaneous fat aspirates were consecutively collected from 112 patients (103 women, nine men) having RA for five years or more. To detect amyloid, fat smears were stained with Congo red and the concentration of amyloid A protein in fat tissue was measured. Clinical, radiological, and laboratory characteristics of the patients were assessed. RESULTS: Amyloid was detected in eight (7%) of the fat smears stained with Congo red. Compared with the Congo red stain, the sensitivity for detecting amyloid by measurement of amyloid A protein in fat tissue was 75% and the specificity was 100%. The amount of amyloid found was small for both methods. The median disease duration of the eight amyloid patients was significantly longer (17 years) than that of the non-amyloid patients (10 years). Bronchopulmonary disease and constipation were more common, whereas proteinuria and chronic renal insufficiency were not. The number of swollen joints and the number of red blood cells were significantly lower in the amyloid group. CONCLUSIONS: Quantification of amyloid A protein and staining with Congo red are strongly concordant methods of screening for amyloid in fat tissue. The prevalence of amyloid in Egyptian patients with RA is 7%. Proteinuria is not a discriminating feature, whereas long disease duration, constipation, bronchopulmonary symptoms, and a moderate to low number of red blood cells may help to identify the arthritic patients with amyloid.

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.

No increased mortality in patients with rheumatoid arthritis: up to 10 years of follow up from disease onset.

OBJECTIVE: To investigate mortality, functional capacity, and prognostic factors for mortality in an inception cohort of patients with recently diagnosed RA followed up for up to 10 years. METHODS: The observed mortality of this inception cohort with recently diagnosed RA, was analysed in relation to the expected mortality, calculated with the aid of life tables of the general population of the Netherlands (matched for age and sex). Functional capacity was measured by the Health Assessment Questionnaire. Prognostic factors for mortality were analysed multivariately by the Cox proportional hazards model. RESULTS: Between January 1985 and April 1997, 622 patients entered the study, and were included in the analysis of mortality. The death rate in the first 10 years of the disease was not significantly different from that of the general population. Fifty five patients from the study group died (16% up to 10 years of follow up). The most commonly reported causes of death were of cardiovascular and respiratory origin. The other causes of death could be classified into cancer, sepsis, amyloidosis, leukaemia, renal insufficiency of unknown cause, perforation of the oesophagus, probably related to the treatment with non-steroidal anti-inflammatory drugs, and pancytopenia during aurothioglucose treatment. Functional capacity improved significantly during the first six years compared with the value at start. Statistically significant predictors for death were age at the start and male sex. CONCLUSIONS: In contrast with earlier studies performed, no excess mortality in the first 10 years of an inception cohort of patients with RA was seen. In addition, the functional capacity was relatively constant during the first six years after an initial improvement from baseline. Age at start and male sex were the only statistically significant predictors for death.

The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis.

OBJECTIVE: To study the predictive value of anticyclic citrullinated peptide antibody (anti-CCP) in patients with recent-onset rheumatoid arthritis (RA). METHODS: Outcome in terms of physical disability (Health Assessment Questionnaire) and radiologic damage (modified Sharp method) over 3-year and 6-year periods was determined in an inception cohort of 273 RA patients who had had disease symptoms for <1 year at study entry. Anti-CCP titers were determined at baseline and considered positive as recently described. Their prognostic value was studied by means of multiple regression analysis, in which anti-CCP positivity, sex, age at study entry, IgM rheumatoid factor (IgM-RF) status, Disease Activity Score (DAS), HLA-DR4 status, and (in a separate group of patients) shared epitope status were used as independent variables, and radiologic damage and functional disability as dependent variables. RESULTS: Patients with anti-CCP had developed significantly more severe radiologic damage after 6 years of followup. In multiple regression analysis, radiologic damage after 6 years followup was significantly predicted by IgM-RF status, radiologic score at entry, and anti-CCP status. Functional disability was significantly predicted by sex, age at entry, IgM-RF status, and DAS. CONCLUSION: Our data show that in almost 70% of RA patients, anti-CCP antibody is present at the early stages of disease. Anti-CCP-positive patients developed significantly more severe radiologic damage than patients who were anti-CCP negative, although in multiple regression analysis the additional predictive value was rather moderate.

Disease associated time consumption in early rheumatoid arthritis.

OBJECTIVE: To quantify the disease associated time consumption of normal activities of daily living and of treatment and monitoring activities in a cohort of patients with early rheumatoid arthritis (RA) with followup of at least 6 years. Comparison was made with a group of patients with asthma and chronic obstructive pulmonary disease (COPD). METHODS: A prospective and retrospective inventory was carried out, by interview and record investigation, of RA related and RA unrelated items covering the period from the start of the disease. Interviews were also performed in a group of patients with asthma and COPD. RESULTS: For patients with RA there was a mean disease associated time consumption of at least 1.9 h/day during the first 6 years of the disease. The time consumption was mainly due to extra time needed for activities of daily living and daily disease related activities. Patients with the greatest progression of radiographic damage, with the most severe disability, and with the greatest cumulative disease activity had the greatest time consumption. For patients with asthma and COPD the consumption of time was comparable. CONCLUSION: RA is a time consuming disease. Recognition of the disease associated time consumption will have implications for work (dis)ability assessments in patients with chronic diseases such as RA.

Serum levels of matrix metalloproteinase-3 in relation to the development of radiological damage in patients with early rheumatoid arthritis.

OBJECTIVE: To evaluate the significance of serum matrix metalloproteinase-3 (MMP-3) levels in relation to the development of radiological damage (X-ray damage) in early rheumatoid arthritis (RA). METHODS: Serum MMP-3 levels were measured in 46 healthy controls (CTRL), 19 osteoarthritis (OA) and 78 RA patients with joint symptoms for <1 yr at presentation (T0): 48 patients without and 30 with X-ray damage at T0. Serum MMP-3, measured by ELISA, and X-ray damage, scored according to Sharp's method, were assessed at 0, 6, 12 and 24 months. RESULTS: MMP-3 levels in CTRL and OA were low or undetectable with no differences between the groups (P=0.19). Levels in RA were higher than in CTRL (P<0.01). Initial MMP-3 levels in patients with X-ray damage at T0 (n=30) were higher than the levels in patients without any X-ray damage during follow-up (n=19) (P<0.01), but were not different from those in patients who developed X-ray damage during the study (n=29) (P=0.11). In the patients without X-ray damage at T0, there was a significant correlation between MMP-3 at T0 and the total X-ray damage after 6 months (r=0.34, P=0.02) and 12 months (r=0.32, P=0.03). This correlation was almost exclusively determined by joint space narrowing in the Sharp score. CONCLUSION: The serum MMP-3 level seems to be an indicator for the development of radiological damage in patients with early RA and appears to be particularly indicative of cartilage degradation.

Transient osteoporosis of the hip: presentation of (a)typical cases and a review of the literature.

Transient osteoporosis of the hip (TOH) is a rare disorder affecting primarily middle-aged men and women during the last trimester of pregnancy. The disease is characterized by pain in the involved joint with temporary osteopenia apparent on radiology without joint space narrowing or destruction, in the absence of other recognizable causes of synovitis or osteoporosis. Within a few months the pain as well as radiological abnormalities disappear spontaneously with complete resolution. In this paper the literature is reviewed, with particular focus on the topic of the role of magnetic resonance imaging (MRI) in the diagnostic procedure. Two patients with TOH, a father and daughter, are described. Such a familial appearance has not been reported before. Based on HLA-typing, the existence of an HLA-associated genetic predisposition nevertheless seems unlikely.

Interpreting the clinical significance of the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2.

The International Consensus Meeting on the Mode of Action of COX-2 Inhibition (ICMMAC) brought together 17 international experts in arthritis, gastroenterology and pharmacology on 5 6 December 1997. The meeting was convened to provide a definition of COX-2 specificity and to consider the clinical relevance of COX-2-specific agents. These compounds are a new class of drugs that specifically inhibit the enzyme COX-2 while having no effect on COX-1 across the whole therapeutic dose range. The objectives of the meeting were to review the currently available data regarding the roles and biology of COX-1 and COX-2, and to foster a consensus definition on COX-2 specificity. At the present time, no guidelines exist for the in vitro and in vivo assessment of COX specificity, and it was felt that consensus discussion might clarify some of these issues. The meeting also reviewed recent clinical data on COX-2-specific inhibitors. The following article reflects discussion at this meeting and provides a consensus definition of COX-2-specific inhibitors.

A quantitative method for detecting deposits of amyloid A protein in aspirated fat tissue of patients with arthritis.

OBJECTIVE: To describe a new, quantitative, and reproducible method for detecting deposits of amyloid A protein in aspirated fat tissue and to compare it with smears stained with Congo red. METHODS: After extraction of at least 30 mg of abdominal fat tissue in guanidine, the amyloid A protein concentration was measured by a monoclonal antibody-based sandwich ELISA. RESULTS: The concentrations in 24 patients with arthritis and AA amyloidosis (median 236, range 1.1-8530 ng/mg tissue) were higher (p < 0.001) than in non-arthritic controls, uncomplicated rheumatoid arthritis, and other types of systemic amyloidosis (median 1.1, range 1.1-11.6 ng/mg tissue). Patients with extensive deposits, according to Congo red staining, had higher concentrations than patients with minute deposits. CONCLUSION: This is a new, quantitative, and reproducible method for detecting deposits of amyloid A protein in aspirated fat tissue of patients with arthritis, even when minute deposits are present as detected in smears stained with Congo red.

Influence of a ceiling effect on the assessment of radiographic progression in rheumatoid arthritis during the first 6 years of disease.

OBJECTIVE: To evaluate at what disease duration and to what extent a ceiling effect, due to reaching maximum scores for erosions (E) and/or joint space narrowing (JSN) in separate joints, started to influence the assessment of radiographic progression according to the modified method of Sharp, in patients with recent onset rheumatoid arthritis (RA). METHODS: Prospective followup study of 87 patients with classical or definite RA, joint symptoms <1 year at study entry. Radiographs of hands and feet were made at study entry (Time 0), after 3 (T3), and after 6 years (T6) of followup. Assessment of radiographic progression according to the Van der Heijde modification of Sharp's method. The scores for E and JSN were analyzed separately in the individual groups of joints. Percentages of E joints, of joints with JSN, and of joints with maximum scores were assessed at T0, T3, and T6. The relative risks for the development of radiographic damage and of maximum scores were assessed for the individual joints. An approximation of the magnitude of the ceiling effect was calculated. RESULTS: After a disease duration of 6 years, a significant influence of a ceiling effect on the mean radiographic progression was found. In some individual patients the ceiling effect appeared to occur earlier. After 6 years, the maximum scores were distributed over 50% of the patients, and 20% of the patients had maximum scores in more than 10 joints without preference for specific localization. CONCLUSION: The ceiling effect appeared to be clinically relevant and should be taken into account when interpreting the effects of disease modifying antirheumatic drugs on radiographic progression in RA during the first years of the disease. Furthermore, it must be accounted for when describing the relationship between radiographic progression and process variables.

Early effective suppression of inflammation in rheumatoid arthritis reduces radiographic progression.

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