Differential cytotoxic activity of chemotherapy agents on colony-forming cells from human tumors and normal bone marrow in vitro.

We have compared the in vitro differential killing efficacy of doxorubicin, 5-fluorouracil, cis-platinum, etoposide, and bleomycin on human tumor cells in a new adhesive tumor cell culture system (ATCCS), and on normal bone marrow granulocyte-macrophage colony-forming units (GM-CFUC) in culture. All of the above chemotherapy agents were tested with continuous exposure against tumor cells and GM-CFUC. In addition, bleomycin was also tested with a short (60 min) exposure against GM-CFUC. In order to determine chemosensitivity against all five drugs, 48 tumor specimens from patients with heterogeneous tumor types were tested in the ATCCS. Each drug was tested at three different concentrations corresponding to their lethal doses against GM-CFUC. Our results show that all five drugs exhibited a dose-response relationship against tumor cells and GM-CFUC. Bleomycin also showed a pronounced GM-CFUC-sparing quality with 60-min exposure even at very high concentrations (86% survival of GM-CFUC at 10 micrograms/ml and 48% at 50 micrograms/ml). In addition, it has a high tumor response rate with continuous exposure at low concentrations (67% at GM-CFUC LD5 and 91% at LD40). These data suggest that the comparison of differential cytotoxicity of chemotherapy drugs between tumor cells and bone marrow cells may serve as a model to select agents suitable for in vitro chemotherapy of bone marrow for the purpose of autologous bone marrow transplantation. In particular, bleomycin appears very attractive and deserves further investigation.

Primary oligoarthritis in a parent of a child with meningococcal group B sepsis and meningitis.

The mother of an eight-month-old child with meningitis presented with petechiae on her trunk and lower extremities, fever, and oligoarthritis. Although pathogens were never revealed by Gram stain nor cultured from the aspirated joint fluid, the diagnosis was primary meningococcal arthritis. This diagnosis was based on the simultaneous occurrence of Neisseria meningitidis group B infection in her son and the clinical presentation.

[Musculoskeletal symptoms often incorrectly attributed to Lyme disease]. / Musculoskeletale klachten vaak ten onrechte aan Lyme-ziekte toegeschreven.

OBJECTIVE: To establish, in patients referred with persisting noninflammatory musculoskeletal complaints. diagnosed elsewhere with Lyme disease, whether Lyme disease was present. SETTING: Outpatient Clinic for Rheumatology. Eemland Hospital Amersfoort and University Hospital Utrecht, the Netherlands. DESIGN: Descriptive, prospective. METHOD: Patients were classified as having had Lyme disease in the past, having ongoing Lyme disease of no Lyme disease at all, on the basis of clinical history, physical examination, and classification criteria for Lyme disease. RESULTS: In a two-year period 37 consecutive patients (mean age 50 years) were examined, 20 (54%) of whom had (a history of) Lyme disease. Of these 20, two suffered from erythema migrans, one of synovitis of the knee, and one of acrodermatitis chronica atrophicans (these four had not been treated). while one had persistent chronic oligoarthritis. Seventeen patients did not have Lyme disease, but were suffering from aspecific, noninflammatory musculoskeletal problems. CONCLUSION: In this patient group with persisting musculo-skeletal complaints, 'Lyme disease' had been diagnosed correctly as often as incorrectly.

[Pharmacotherapy of patients with (early) rheumatoid arthritis]. / Medicamenteuze behandeling van patiënten met (beginnende) reumatoïde artritis.

As soon as the diagnosis 'early rheumatoid arthritis (RA)' is made, a disease-modifying antirheumatic drug (DMARD) should be prescribed without delay. Methotrexate in dosages up to 30 mg once weekly is being used more frequently than in the past, also in early RA. Combination therapy with DMARDs is indicated in case of insufficient effect of a single DMARD. Combinations with methotrexate appear to be especially effective, like methotrexate and cyclosporin. A novel effective DMARD is leflunomide. In the near future promising biologicals will probably be applied in clinical daily practice, presumably in combination with conventional DMARDs. New non-steroidal anti-inflammatory drugs (NSAIDs) have been developed that are probably safer than conventional NSAIDs. If the recent finding that glucocorticoids are able to inhibit joint damage in (early) RA will be confirmed, prednisone might be used more often in (early) RA. Bone marrow transplantation in RA is still experimental.

[Prevalence of Lyme borreliosis in The Netherlands]. / Prevalentie van Lyme-borreliose in Nederland.

In the autumn of 1989 a seroepidemiological study was carried out among 440 owners of hunting dogs and 1052 blood donors from different regions in the Netherlands. To detect IgG antibodies to Borrelia burgdorferi an enzyme-linked immunosorbent assay was performed. The prevalence of antibodies to B. burgdorferi in owners of hunting dogs was 15%, which was significantly higher than in blood donors (9%). In both groups the prevalence of seropositivity increased with age. There was no difference between men and women. The prevalence of antibodies to B. burgdorferi in blood donors from different regions varied significantly, ranging from 2% to 17%. Only 3% of the owners of hunting dogs could recall having had symptoms most likely to be due to Lyme borreliosis. Of the 68 seropositive hunters 64 (94%) were asymptomatic. The results of this study indicate that in the Netherlands asymptomatic infections with B. burgdorferi are common in individuals highly exposed to ticks and that there is considerable variation in the prevalence of seropositivity in the general population. Hence caution is called for in the clinical interpretation of IgG test results.

[A patient with acute hydroxychloroquine poisoning; recommendation for treatment]. / Een patiënt met acute intoxicatie door hydroxychloroquine; een behandelingsadvies.

We treated a 30-year-old man for whom Plaquenil (hydroxychloroquine) had been prescribed for rheumatoid arthritis, and who had taken 4 g orally to end his life. Symptoms of severe intoxication due to (hydroxy)chloroquine are rapid onset of hypoventilation, cardiovascular collapse with bradycardia, peripheral vasodilation, arrhythmias and convulsions. The lethal dose of chloroquine has been estimated at 3-5 g in adults and at 0.75-I g in young children. Acute intoxication should be treated with aspiration of gastric contents, artificial ventilation in case of hypoventilation and intravenous or intratracheal dopamine, noradrenaline or adrenaline in case of cardiovascular depression and peripheral vasodilation. Arrhythmias and convulsions should be treated symptomatically. The patient in our case survived the intoxication and is now under psychiatric treatment.

[Occurrence of Borrelia burgdorferi in Ixodes ricinus in The Netherlands]. / Voorkomen van Borrelia burgdorferi in Ixodes ricinus in Nederland.

In a 1989 surveillance to study the infection rate of Ixodes ricinus ticks with Borrelia burgdorferi, a total of 1838 nymphal and adult Ixodes ricinus ticks were collected from 20 locations in The Netherlands. By means of a culture method using modified Barbour-Kelly-Stoenner medium nymphs were examined in pools of 4 and adults were examined individually. With 63 out of 75 isolates propagation and serological identification were possible. All of these 63 isolates were identified as Borrelia burgdorferi by means of an indirect immunofluorescence assay. In nymphs the minimal infection rate was 2.4%. The rate of infection for adults was shown to be 14.3%. These results are in agreement with the percentages found by other investigators in West-Europe. In all locations examined Ixodes ricinus were found to be infected with Borrelia burgdorferi, although the infection rate varied. The results indicate that the infection is widespread among ticks in The Netherlands and the potential risk of acquiring Lyme borreliosis after a tick bite is serious.

Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial).

BACKGROUND: To investigate whether intensive treatment with methotrexate (MTX) according to a strict protocol and a computerised decision program is more beneficial compared to conventional treatment with MTX in early rheumatoid arthritis. METHODS: In a two-year multicentre open label strategy trial, 299 patients with early rheumatoid arthritis were randomly assigned to the intensive strategy group or the conventional strategy group. Patients in both groups received MTX, the aim of treatment being remission. Patients in the intensive treatment group came to the outpatient clinic once every month; adjustment of the MTX dosage was tailored to the individual patient on the basis of predefined response criteria, using a computerised decision program. Patients of the conventional strategy group came to the outpatient clinic once every three months; they were treated according to common practice. Cyclosporine was added if patients had an inadequate response to maximal tolerated MTX doses. RESULTS: Seventy six (50%) patients in the intensive strategy group achieved at least one period of remission during the two year trial, versus 55 patients (37%) in the conventional strategy group (p = 0.03). Areas under the curve for nearly all clinical variables were significantly lower-that is, there was a better clinical effect for the intensive treatment group compared with the conventional treatment group. CONCLUSION: The results of this study show that it is possible to substantially enhance the clinical efficacy early in the course of the disease by intensifying treatment with MTX, aiming for remission, tailored to the individual patient. Furthermore, participating rheumatologists indicated that the computerised decision program could be a helpful tool in their daily clinical practice.

Joint surgery in the Utrecht Rheumatoid Arthritis Cohort: the effect of treatment strategy.

OBJECTIVE: To investigate the prevalence and prognostic factors of joint surgery in a large cohort of patients with rheumatoid arthritis, whose treatment, clinical and radiographic data have been assessed at predefined points in time since disease onset. METHODS: Data on surgical interventions were retrospectively obtained from 482 patients with rheumatoid arthritis whose follow-up data for at least 2 years were available, including treatment and response to treatment during the first 2 years. Survival time until the first surgical intervention and until the first major surgical intervention was determined for the total study population by Kaplan-Meier survival curves. Three separate Cox regression analyses were carried out to determine which variables measured at baseline, during the first year and during the first 2 years were predictors for joint surgery. RESULTS: 27% of the patients underwent surgical interventions. Mean survival time until the first surgical intervention was 10.4 years. The percentage of patients with a surgical intervention was 10% lower in the group with response to treatment when compared with the non-response group. Next to a delayed start with disease-modifying antirheumatic drugs, fast radiographic progression during the first year and first 2 years was a predictor of joint surgery in the multivariate regression analyses. CONCLUSION: Treatment with disease-modifying antirheumatic drugs immediately after diagnosis results in less joint surgery when compared with a delayed start. Furthermore, joint surgery is carried out more often in patients who do not respond to treatment.

A good response to early DMARD treatment of patients with rheumatoid arthritis in the first year predicts remission during follow up.

OBJECTIVE: To describe the frequency and duration of remission in the Utrecht rheumatoid arthritis cohort of patients followed since diagnosis, and the clinical and treatment characteristics of patients with remission v those without. METHODS: In 1990 the Utrecht rheumatoid arthritis cohort study group started a clinical trial in which patients with recent onset of rheumatoid arthritis (<1 year) were randomised into four treatment groups: hydroxychloroquine (n = 169); intramuscular gold (n = 163); methotrexate (n = 166); and pyramid (n = 64). After two years, rheumatologists were allowed to prescribe any disease modifying antirheumatic drug. Remission was defined as: duration of morning stiffness < or =15 min, mean VAS pain < or =10 mm, Thompson joint score < or =10, and ESR < or =30 mm/h during at least six months. Cox regression analysis was used to determine baseline clinical, demographic, and treatment predictors of remission. RESULTS: Mean follow up duration was 62 months. Thirty six per cent achieved at least one period of remission. Median duration between diagnosis and the first remission period was 15 months for the intramuscular gold group, 18 months for the methotrexate and hydroxychloroquine groups, and 24 months for the pyramid group (NS). Predictors of remission were early response to initial treatment, less pain, rheumatoid factor negativity, and lower joint score at baseline. CONCLUSIONS: After a mean follow up duration of 62 months, only 36% of the patients had fulfilled the remission criteria at least once. A good response to treatment during the first year seems to be independently associated with remission rather than initial treatment alone.

Clinical evaluation of guidelines and two-test approach for lyme disease.

OBJECTIVE: The diagnosis of Lyme disease should be based on objective clinical signs and symptoms. In a clinical study, we have evaluated whether the recommended two-step approach for serodiagnosis of Lyme disease is useful in daily clinical practice and can influence clinical decision making. METHODS: The signs and symptoms of patients with ongoing musculoskeletal complaints, assumed by their referring physician or themselves to be attributable to active or chronic Lyme disease, and of patients diagnosed as having Lyme disease, were evaluated. On the basis of clinical evaluation only, patients were classified into three groups: previous Lyme disease, active Lyme disease and no Lyme disease. Antibodies to Borrelia burgdorferi were determined by means of an enzyme-linked immunosorbent assay (ELISA), followed, when positive, by immunoblotting. RESULTS: One hundred and three patients (41 males and 62 females, mean age 48.7 yr) participated in the study. Of the 49 patients classified as previous Lyme disease, 25 (51%) had antibodies to B. burgdorferi. All 10 patients with active Lyme disease had positive antibodies and 12 of the 44 patients (27%) classified as no Lyme disease had positive antibodies. No statistically significant differences were found between the percentage of positive immunoblots from patients with previous Lyme disease (72%) and patients with active Lyme disease (100%). In the group of no Lyme disease, five out of 12 patients had a negative immunoblot. Concerning serological testing, immunoblotting could have added additional information. However, immunoblotting did not influence clinical decision making in this group of patients. CONCLUSION: Immunoblotting did not influence clinical decision making for the 47 patients with antibodies to B. burgdorferi in this study.

Assessing clinical competence: recognition of case descriptions of rheumatic diseases by general practitioners.

The objective of this study was to detect strengths and weaknesses in the diagnosis of rheumatic diseases by general practitioners in order to set up post-graduate training accordingly and to assess whether open-ended questions give results comparable with multiple choice-type questions. Fifty-one general practitioners were given eight written cases: rheumatoid arthritis (RA), ankylosing spondylitis (AS), reactive arthritis, psoriatic arthritis (PsA), systemic lupus erythematosus (SLE), gout, polymyalgia rheumatica and pseudogout. Only signs and symptoms were provided. All cases were derived from real patients with a definite diagnosis. Each case was presented in both types of question formats. The cases were also presented to 23 rheumatologists. We found that in the open-ended question format 57.1% of the general practitioners gave the correct answers. Cases of RA, AS, gout and PsA were correctly diagnosed by > 70% of the general practitioners. Cases of polymyalgia rheumatica and reactive arthritis were correctly diagnosed by 55 and 39% of the general practitioners, respectively. The cases of pseudogout and SLE were correctly diagnosed by less than 11% of the general practitioners. Fifty-two per cent of the general practitioners gave the correct answers to the multiple choice-type questions. There was no statistical difference in the correct answers between the open-ended questions and the multiple choice-type questions. We concluded that assuming generalization of the results, training of general practitioners should include polymyalgia rheumatica, reactive arthritis, SLE and pseudogout.

Evaluation of nine serological tests for diagnosis of Lyme borreliosis.

Two hundred serum specimens including 13 sera from patients with early Lyme borreliosis, 21 patients with late Lyme borreliosis, 15 rheumatoid factor positive sera, 31 sera from patients with syphilis and 84 sera from healthy controls were used to evaluate the following assays for the detection of antibodies to Borrelia burgdorferi: two in-house enzyme immunoassays (EIAs), two in-house immunofluorescent antibody assays (IFAs), a commercial haemagglutination assay (HA) (Diagast) and four commercial EIAs (Diagast, Dako, Diamedix, Whittaker Bioproducts). In early and late Lyme borreliosis sera sensitivity ranged from 8% to 62% and from 62% to 86% respectively. With the exception of the Dako EIA, which was signifcantly more sensitive in early Lyme borreliosis (62%) than the Diagast HA (8%) (p = 0.05), differences in sensitivity were not significant. In healthy controls the specificity was > or = 95% for all tests. Taking into account sensitivity, specificity, intra-test and inter-test precision, ease of performance and cost, the Dako EIA and Diamedix EIA were shown to be good alternatives to the in-house EIA and in-house IFA. Because of its low sensitivity in diagnosis of both early and late Lyme borreliosis, use of the Diagast HA should be discouraged.

Lyme borreliosis: a very infrequent cause of arthritis of undetermined aetiology in the southern part of The Netherlands.

Seventy-three patients with undiagnosed arthritis of undetermined aetiology, 94 patients with classified arthritis (rheumatoid arthritis, ankylosing spondylitis, etc.) and 70 controls were studied for clinical and serological manifestations of Lyme borreliosis. The patients were recruited from the three rheumatology units in the most southern part of The Netherlands. A clinical diagnosis of possible Lyme borreliosis was made in seven of 73 patients with arthritis of undetermined aetiology, in four of 94 patients with classified arthritis and in one of the controls. A definite diagnosis of Lyme borreliosis could be made in only one patient who belonged to the arthritis of undetermined aetiology group. This patient had erythema migrans, arthritis of the knee joint and showed positive antibodies to B. burgdorferi. In the southern part of The Netherlands, Lyme arthritis does not seem to be a frequent cause of arthritis of undetermined aetiology.