Identifying patients with rheumatoid arthritis with moderate disease activity at risk of significant radiographic progression despite methotrexate treatment.

OBJECTIVES: To determine the baseline factors predictive of significant radiographic progression (SRP) in patients with moderately active rheumatoid arthritis (RA) despite receiving methotrexate (MTX). METHODS: Patients from the MTX arm of the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) trial with sustained moderate RA (defined as ≥3.2 mean disease activity score in 28 joints ≤5.1 during the last 6 months of the first year) were analysed for SRP (mTSS >3.0 overall) after 2 and 3 years. Baseline predictors for SRP were identified by univariate and multivariate analyses. All variables shown to be significantly associated with SRP were categorised based on clinically relevant cut-offs and tertiles and were included in a matrix risk model. RESULTS: 228 patients were assigned MTX treatment, 210 patients were in the radiographic intention-to-treat population, and 96 of these had sustained moderate RA. SRP occurred in 25 (26%) and 33 (34%) patients after 2 and 3 years of MTX treatment, respectively. Univariate and multivariate analyses found that C reactive protein (CRP) and rheumatoid factor (RF) positivity at baseline were predictive of SRP after 2 and 3 years (p<0.05 for all). The matrix risk model showed that RF positivity and CRP levels >40 mg/L at baseline were significantly associated with SRP after 2 (p<0.05 for both; R(2)=0.24) and 3 years (p<0.05 for both; R(2)=0.22). The baseline erosion score was not found to be predictive of SRP. CONCLUSIONS: Patients with sustained moderate RA despite receiving MTX treatment are at risk of SRP, with both RF positivity and high CRP levels shown to be predictive of this.

Efficacy and safety of combination etanercept and methotrexate versus etanercept alone in patients with rheumatoid arthritis with an inadequate response to methotrexate: the ADORE study.

OBJECTIVE: To evaluate the efficacy and safety of etanercept (ETN) monotherapy compared with combination ETN and methotrexate (MTX) treatment in patients with rheumatoid arthritis who had an inadequate response to MTX monotherapy. (The response was defined by the presence of Disease Activity Score-28 joint count (DAS28) >or=3.2 or a combination of >or=5 swollen joints, >or=5 painful joints and erythrocyte sedimentation rate >or=10 mm/h.) METHODS: Patients with active rheumatoid arthritis taking MTX >or=12.5 mg/week for >or=3 months were included in this 16 week, randomised, open-label study. Patients were randomly assigned to either ETN (25 mg subcutaneous injection twice weekly) added to the baseline dose of MTX or ETN monotherapy. RESULTS: 315 patients were randomised to ETN (n = 160) or ETN plus MTX (n = 155). The primary end point, DAS28 (4) improvement of >1.2 units, was achieved by 72.8% and 75.2% of patients treated with ETN and those treated with ETN plus MTX, respectively, with no significant difference (p = 0.658) between the two groups. The European League Against Rheumatism response criteria of good or moderate response was attained by 80.0% of patients in the ETN group and by 82.4% of patients in the ETN plus MTX group. American College of Rheumatology 20%, 50% and 70% response rates achieved by both groups were also similar: 71.0% v 67.1%, 41.9% v 40.1% and 17.4% v 18.4%, respectively. The rates of adverse and serious adverse events were similar between the treatment groups. CONCLUSION: Both the addition of ETN to MTX and the substitution of ETN for MTX in patients with rheumatoid arthritis who had an inadequate response to MTX resulted in substantial improvements in clinical signs and symptoms and were generally well-tolerated treatment strategies for improving clinical signs and symptoms of rheumatoid arthritis.

Fluoroquinolone use and the change in incidence of tendon ruptures in the Netherlands.

INTRODUCTION: Shortly after their introduction, fluoroquinolones were associated with reports of tendinitis and tendon rupture. During the past years, the number of reports has risen, possibly because of an increased use of fluoroquinolones. In this study, we describe the use of fluoroquinolones in the Dutch community and the possible public health effects of an association between fluoroquinolone use and tendon ruptures. METHODS: In the PHARMO drug database we identified all prescriptions for fluoroquinolones in the period 1991-1996. The incidence of fluoroquinolone use was expressed as the number of fluoroquinolone episodes per 1000 inhabitants in one year, and extrapolated to the Dutch population after standardisation on age and gender. The annual incidence of non-traumatic tendon ruptures in the period 1991-1996 was calculated with data from the nation-wide hospital registry. The expected number of fluoroquinolone attributable tendon ruptures was calculated on the basis of the use of fluoroquinolones, the number of non-traumatic tendon ruptures and an assumed relative risk of 1.5-10. RESULTS: In 1996, approximately 251,000 patients experienced 318,000 episodes of fluoroquinolone use in the Netherlands. Females used more often fluoroquinolones than males, and the number of episodes increased exponentially with age. In the period 1991 through 1996, the absolute number of fluoroquinolone episodes increased by 160%, from 122,000 to 318,000. The absolute number of hospitalised tendon ruptures increased with 28%, from 768 in 1991 to 984 in 1996. Assuming a relative risk of 1.5 to 10.0, 1 to 15 tendon ruptures could be attributed to fluoroquinolone use in 1996. Only 7% of the observed increase could be attributed to the increased use of fluoroquinolones. If the total increase of hospitalised non-traumatic tendon ruptures would be attributable to the increase in fluoroquinolone use, this would mean that the risk of non traumatic tendon ruptures to fluoroquinolones would be more than 250 times the risk during non-use. CONCLUSION: In the Netherlands, a large simultaneous increase in non-traumatic tendon ruptures and fluoroquinolone use was observed in the period between 1991 to 1996. Assuming a relative risk of 1.5 to 10.0 for tendon ruptures during fluoroquinolone use, only 0.5 to 7% of the increase in non-traumatic tendon ruptures could be attributed to the increased fluoroquinolone use. The increase in the incidence of non-traumatic hospitalised tendon ruptures in the Netherlands is not likely to be explained solely by the increased use of fluoroquinolones.

Achilles tendinitis associated with fluoroquinolones.

AIMS: To determine whether there is an association between use of fluoroquinolones and tendinitis in a large population under everyday circumstances. METHODS: A retrospective cohort study was carried out in a dynamic population. Data came from the IPCI-database which consists of all data on consultations, morbidity, prescriptions and other interventions, as registered by GPs in a source population of approximately 250 000 persons. For this study data were collected from 41 general practices in the period from January 1st, 1995 through December 31st, 1996. All persons treated with either fluoroquinolones, amoxicillin, trimethoprim, cotrimoxazole or nitrofurantoin were followed from the first day of treatment until the outcome of interest, death, transfer to another practice, or end of the study period, whichever came first. The risk window was defined as the legend duration +1 month. Potential cases were defined as a registration of a tendinitis or tendon rupture. Patients with a history of tendinitis or tendon rupture, preceding trauma or inadequate diagnoses were excluded on the basis of a review of the patient profiles and additional clinical data, blinded as to the exposure status. Results were adjusted for age, gender, concurrent corticosteroid exposure and number of GP visits. RESULTS: There were 1841 users of fluoroquinolones and 9406 users of the other antibacterial drugs with an average duration of 9 and 7 days, respectively. Tendinitis or tendon rupture was registered in 97 profiles, but after review only 22 complied with the case definition. The adjusted relative risk of tendinitis to fluoroquinolones was 3. 7 (95%CI: 0.9-15.1) for Achilles tendinitis and 1.3 (95%CI: 0.4-4.7) for other types of tendinitis. Achilles tendinitis to ofloxacin had a relative risk of 10.1 (95%CI: 2.2-46.0) and an excess risk of 15 cases per 100 000 exposure days. CONCLUSIONS: Although the numbers in our study are small, our results suggest that some fluoroquinolones may increase the risk of Achilles tendinitis, and that this risk increase is highest for ofloxacin.

Do non-specific minimal signs in a biennial mammographic breast cancer screening programme need further diagnostic assessment?

Mammographic features such as small vague densities, indefinable microcalcifications, subtle architectural distortions, alone or in combination, are non-specific appearances for breast cancer. These features sometimes precede malignancy and a decisive strategy on how to deal with non-specific minimal signs in a breast cancer screening programme is therefore desirable. After studying the prevalence of these signs in a Dutch Breast Cancer Screening Centre and estimating the risk of participants with these signs acquiring breast cancer within 2 years, we have developed such a strategy. Non-specific minimal signs were seen on the mammograms of 53 of 500 (10.6%) participants, aged 50-70 years, in this programme. After retrospective analysis of the mammograms of 254 patients with screen-detected or interval carcinoma, non-specific minimal signs were detected in 77 cases. Combining the incidence of breast cancer with the difference between the expected number of non-specific minimal signs in the screening programme and its actual occurrence in previous mammograms of patients with breast cancer, the risk of cancer in women with these signs, additional to that of screened women in general (additional risk), is calculated as being 0.5%. Invasive breast cancer in women with previously detected non-specific minimal signs demonstrated a favourable stage at diagnosis (axillary metastasis in 23% vs 37% in cancers without these previous signs, p < or = 0.05). Our strategy for follow-up in case of non-specific minimal signs remains unchanged because of the low additional risk and favourable staging, and is restricted to an invitation for the next screening round in 2 years time.

Comparison of breast-conserving therapy with mastectomy for treatment of early breast cancer in community hospitals.

Although the results of clinical trials support breast-conserving therapy as a replacement for mastectomy in early breast cancer, the question remains whether these results apply in routine clinical practice. In the present analysis the breast cancer-specific survival and recurrence-free survival of 464 consecutive patients with breast tumors < or = 3 cm across undergoing breast-conserving therapy were compared with a group of 459 patients with similar extent of disease and period of diagnosis undergoing mastectomy. All patients were treated in community hospitals in the south-eastern Netherlands. Median follow-up of both treatment groups was 6.2 years. After adjustment for the prognostic effects of age, tumour size, axillary nodal status and adjuvant systemic therapy, neither breast cancer-specific survival nor recurrence-free survival differed significantly between the breast-conserving therapy group and the mastectomy group. This finding indicates that in routine clinical practice breast-conserving therapy may be as effective as mastectomy.

Striking changes in smoking behaviour and lung cancer incidence by histological type in south-east Netherlands, 1960-1991.

Changes in lung cancer incidence in south-east Netherlands between 1960 and 1991 were analysed, using data from the Eindhoven Cancer Registry, and related to previous changes in smoking habits. Male lung cancer incidence rates increased markedly from birth cohorts 1890-1899 to 1910-1919, followed by a decline. The peak incidences for both squamous cell carcinoma and small cell carcinoma were reached in 1978, while for adenocarcinoma it was 1985. A rising trend in female lung cancer incidence up to 1988 was found for each successive birth cohort and for every histological type. These changes in lung cancer incidence rates are most likely related to the pattern of past smoking habits: the percentage of male adult smokers in the southern part of the Netherlands decreased from 95% in 1960 to 40% in 1981 and the percentage of female adult smokers increased from 27% in 1960 to 40% in 1967, slightly decreasing only after 1979. In view of the trends in smoking behaviour, the incidence rates for male lung cancer will decline further, whereas female lung cancer incidence may decrease after the year 2000.

Long-term prognosis of breast cancer: an analysis of 462 patients in a general hospital in south east Netherlands.

In this study the long-term prognosis was analysed of all 462 consecutive female breast cancer patients who were diagnosed and carefully staged between 1970 and 1980 in a 600-bed community hospital in Eindhoven, south east Netherlands. Follow-up of recurrence and causes of death was obtained until 1 January 1993. Observed survival rates at 5, 10 and 20 years were 66%, 45% and 32%, respectively, and the corresponding breast cancer-specific survival rates were 71%, 54% and 44%. The yearly risk for a recurrence of breast cancer after treatment steadily decreased from 10% the first year to 1% after 10 years. In a multivariate survival analysis both tumour size and nodal status appeared to be equally important prognostic factors in the first 5 years after diagnosis. After 5 years only tumour size had independent prognostic value, which was not significant any more after 10 years. In patients with a tumour size < or = 2 cm and without lymph node involvement at diagnosis, the risk for a recurrence was found to be negligible after 10 years. Those patients may be considered cured, although a search for early diagnosis of a second primary breast cancer in this group is still advisable.

Improved prognosis of breast cancer since 1970 in south-eastern Netherlands.

Despite many new advances in breast cancer therapy since the 1970s, there are only few reports on improved prognosis in a general population. A follow-up of more than 10 years is rarely reported, and a differentiation according to stage of the disease or between follow-up intervals is seldom made. Our purpose was to assess whether prognosis of primary breast cancer improved in patients diagnosed between 1970 and 1984 in south-eastern Netherlands, and to distinguish between different stages and follow-up intervals. Data from 4,467 breast cancer patients diagnosed between 1970 and 1984 were derived from the population-based Eindhoven Cancer Registry. Follow-up was attained up to 1 July 1991. Relative survival rates, as the ratio of the observed to the expected rates, were calculated. In a multivariate analysis a change in prognosis over time was computed with adjustment for age and stage; this was done separately for 5 year follow-up intervals. The relative survival rates were 69% after 5 years, 55% after 10 years and 50% after 20 years. Relative survival, after adjustment for age, was strongly related to the stage of the disease in the first 5 years of follow-up, less markedly between 5 and 10 years, and to a small, borderline significant, extent after 10 years of follow-up. Relative survival rates increased markedly over time, during the whole interval of follow-up. This increase was apparent in all age groups and in all stages, except for those with distant disease at diagnosis. The observed improvement in survival is unlikely to be explained by the increased use of adjuvant chemo- and hormonal therapy. Other factors, such as a change in the natural history of the disease in this period, cannot be ruled out.

Changes in long term prognosis for breast cancer in a Dutch cancer registry.

OBJECTIVES: To assess whether the long term survival of patients with breast cancer has changed with time. DESIGN: Population based descriptive study. SETTING: Eindhoven Cancer Registry in south east Netherlands. SUBJECTS: 2052 patients with first primary breast cancer diagnosed between 1955 and 1974. MAIN OUTCOME MEASURES: Overall survival and relative survival. RESULTS: Overall survival was 35% (727 patients) after 10 years, 21% (267) after 20 years, and 15% (25) after 30 years. The corresponding relative survival rates were 43%, 34%, and 34%, respectively. Survival improved from 1955 onwards for all ages and all tumour stages. Improvement was observed in both overall and relative survival. Prognosis was strongly related to the stage at diagnosis in the first 10 years of follow up but independent of stage after 10 years. Survival of patients still alive after 19 years became similar to that of the general female population. CONCLUSIONS: Both short and long term survival improved considerably in all age groups. This improvement was most marked for patients who were diagnosed with a localised tumour. Patients who survive for 19 years may be considered cured.

Is the peak in breast cancer incidence in sight? A study conducted in the southeastern Netherlands.

Breast cancer is the most frequent malignancy in the western world, and increases in the incidence have been observed worldwide. We investigated temporal trends in breast cancer incidence in the southeastern Netherlands between 1960 and 1989 by birth cohort analysis, using data of the Eindhoven Cancer Registry. An overall time-trend in incidence rate was estimated, based on age and year of diagnosis. Rate ratios were calculated, as the ratio of the observed versus the expected incidence rates, which was based on the estimated time-trend. In this unscreened population the age-specific incidence increased for every successive birth cohort in the period 1880-1949. Women born between 1940 and 1949 had the highest age-specific incidence rates with an excess of 10% (relative risk 1.10, 95% confidence interval 1.01-1.22). The incidence rates in women born after 1949 declined and were 21% lower than expected by the estimated secular trend (relative risk 0.79, 95% confidence interval 0.64-0.96). This decrease in incidence for women aged under 40 suggests that the peak in incidence of female breast cancer may be in sight. It remains unclear which risk factors are responsible for this changing trend.

Breast cancer in the southeastern Netherlands, 1960-1989: trends in incidence and mortality.

Temporal trends in incidence and mortality in breast cancer were examined in the southeastern Netherlands using data from the population-based Eindhoven Cancer Registry. In the period 1960-1989 the incidence rate of first primary breast cancer approximately doubled in all age groups. The increase mainly occurred before 1975 and after 1985, when no screening activities were performed. This trend appeared to be a result of an average yearly increase in incidence of localised and distant tumours with both 4.6%, whereas the incidence of regional tumours did not change. Simultaneously, breast cancer mortality remained unchanged in women aged under 60, and only increased by a yearly average of 0.7% in women aged 60-74 and of 0.9% in women aged 75 and over. These differing trends in incidence and mortality, which can only partially be explained by earlier detection, suggest an improved survival of breast cancer.

[Increased incidence of breast cancer in southeast Netherlands between 1960 and 1989]. / Toegenomen incidentie van borstkanker in Zuidoost-Nederland tussen 1960 en 1989.

Trends in incidence, stage distribution and mortality of breast cancer were determined in the Southeastern Netherlands in 1960-1989. First and second primary breast cancers were analyzed separately. The incidence and mortality rates were age-standardised according to the European Standard Population. The incidence rate of first primary invasive breast cancer increased from 50 per 100,000 women per year in 1960-61 to 96 in 1988-89, and of second primary invasive breast cancer from 3.2 in 1965-66 to 7.8 in 1988-89. The incidence rate of first primary ductal carcinoma in situ (DCIS) increased from 0.3 per 100,000 women per year in 1975-76 to 2.8 in 1988-89 and of second primary DCIS from 0.06 in 1975-79 to 0.4 per 100,000 in 1985-89. The increase in first invasive primaries was observed in all age groups, but mostly at age 75 and over. The percentage with stage I tumours of the patients with a first primary invasive breast cancer increased from 7% in the sixties to 27% in the eighties, whereas the percentage of stage III and IV tumours combined, decreased from 39% in the sixties to 26% in the eighties. While age-adjusted incidence of first primaries almost doubled in the past thirty years, breast cancer mortality rose only slightly. However, breast cancer mortality showed a proportionate increase of total mortality from 4.5% in 1970-71 to 6.3% in 1988-89.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of digital and conventional mammography: a ROC study of 270 mammograms.

Observer performance tests were conducted to study the visibility of malignancies in digital mammography. Detectabilities of tumours and of microcalcifications were studied separately. For this purpose two sets of images were used, one for tumours consisting of 150 mammograms and one for microcalcifications containing 120 mammograms. Images were digitized at a resolution of 2048 x 2048 pixels using a 12-bit CCD camera. Conventional film mammograms were read on a lightbox, whereas digital mammograms were viewed on a high-resolution monitor. Two experienced radiologists read both sets independently, and ranked their judgements about the presence or absence of tumours or microcalcifications on a confidence-rating scale. Results were evaluated using receiver operating characteristic (ROC) analysis. No statistical differences were found between judgements based on conventional and digitized mammography.

[Digital mammography is very useful in mass screening of breast cancer]. / Digitale mammografie is goed bruikbaar in het bevolkingsonderzoek naar borstkanker.

Mammograms made between 1981 and 1989 in the Nijmegen screening programme for breast cancer were retrospectively reviewed. Those made before detection of breast cancer showed signs of tumour growth in the place of the subsequently detected malignancy in 22% of the cases. A work station was set up for image digitization and image processing. Display with optimal contrast and image processing of mammograms is possible. Diagnoses based on digitized mammograms displayed on a monitor were as good as those based on the conventional images on film. Automatic detection of image features has been investigated. A procedure for automatic detection of microcalcifications was developed. This research is important for optimalization of diagnosis in screening and because of the expected introduction of direct digital imaging techniques.