Early radiological progression remains associated with long-term joint damage in real-world rheumatoid arthritis patients treated to the target of remission.

OBJECTIVE: To evaluate radiological damage and to explore characteristics associated with radiological progression in rheumatoid arthritis (RA) treated to the target of remission in a real-world setting. METHODS: Baseline to 6 year follow-up data were used from an observational early RA cohort. Radiographs of hands and feet at baseline, 6 months, and 1, 3, and 6 years were scored using the modified Sharp/van der Heijde score (SHS). The threshold for rapid radiological progression (RRP) after 6 months was based on the calculated smallest detectable change of 3.95. Negative binomial generalized linear mixed model and logistic regression analyses were performed to examine which variables were associated with RRP and 6 year radiological progression. RESULTS: Most radiological damage occurred in the first year of treatment [median 2.0 interquartile range (IQR) 1.0-4.0 SHS points] compared to the subsequent 5 years of follow-up (median 3.0 IQR 1.0-5.0 SHS points). While low disease activity was achieved within 6 months on average, 18.8% of the patients developed RRP. Anti-cyclic citrullinated peptide (anti-CCP) positivity [incidence rate ratio (IRR) 1.42, p = 0.03], baseline erosive disease (IRR 1.60, p = 0.02), and RRP (IRR 3.28, p < 0.001) were associated with 6 year radiological progression. Erosive disease was the strongest predictor of RRP (odds ratio 8.8, p < 0.001). CONCLUSION: Long-term radiological outcome is limited in most real-world RA patients treated to the target of remission, but RRP still occurs. Anti-CCP positivity, baseline erosive disease, and RRP remain associated with long-term radiological outcome.

Acute effects of cigarette smoking on pulmonary function.

INTRODUCTION: Chronic smoking related changes in pulmonary function are reflected as accelerated decrease in FEV1 although histologic changes occur in the peripheral bronchi earlier. More sensitive pulmonary function parameters might mirror those early changes and might show a dose response. METHODS: In a randomized three-period cross-over design 57 male adult conventional cigarette (CC)-smokers (age: 45.1+/-7.1 years) smoked either CC (tar:11 mg, nicotine:0.8 mg, carbon monoxide:11 mg [Federal Trade Commission (FTC)]), or used as a potential reduced-exposure product the electrically heated smoking system (EHCSS) (tar:5 mg, nicotine:0.3 mg, carbon monoxide:0.45 mg (FTC)) or did not smoke (NS). After each 3-day exposure period, hematology and exposure parameters were determined preceding body plethysmography. RESULTS: Cigarette smoke exposure was significantly (p<0.0001) higher in CC than in EHCSS and in NS: (carboxyhemoglobin: CC: 6.4+/-1.9%; EHCSS: 1.3+/-0.6%; NS: 0.5+/-0.3%; serum nicotine: CC: 18.9+/-7.4 ng/ml; EHCSS: 8.4+/-4.3 ng/ml; NS: 1.2+/-1.6 ng/ml). Significantly lower in CC than in EHCSS and NS were specific airway conductance (0.22+/-0.09; 0.25+/-0.12; 0.25+/-0.1 1/cmH(2)O x s; CC vs EHCSS: p<0.05; CC vs NS: p<0.01), forced expiratory flow 25% (7.6+/-1.7; 7.8+/-1.7; 7.9+/-1.7 L/s; CC vs EHCSS or NS: p<0.01). Thoracic gas volume (5.1+/-1; 5+/-1.1; 5+/-1.1L/min) changed insignificantly. CONCLUSION: The data indicate acute and reversible effects of cigarette smoke exposures and no-smoking on mid to small size pulmonary airways in a dose dependent manner.

Pharmacovigilance of drug allergy and hypersensitivity using the ENDA-DAHD database and the GALEN platform. The Galenda project.

Nonallergic hypersensitivity and allergic reactions are part of the many different types of adverse drug reactions (ADRs). Databases exist for the collection of ADRs. Spontaneous reporting makes up the core data-generating system of pharmacovigilance, but there is a large under-estimation of allergy/hypersensitivity drug reactions. A specific database is therefore required for drug allergy and hypersensitivity using standard operating procedures (SOPs), as the diagnosis of drug allergy/hypersensitivity is difficult and current pharmacovigilance algorithms are insufficient. Although difficult, the diagnosis of drug allergy/hypersensitivity has been standardized by the European Network for Drug Allergy (ENDA) under the aegis of the European Academy of Allergology and Clinical Immunology and SOPs have been published. Based on ENDA and Global Allergy and Asthma European Network (GA(2)LEN, EU Framework Programme 6) SOPs, a Drug Allergy and Hypersensitivity Database (DAHD((R))) has been established under FileMaker((R)) Pro 9. It is already available online in many different languages and can be accessed using a personal login. GA(2)LEN is a European network of 27 partners (16 countries) and 59 collaborating centres (26 countries), which can coordinate and implement the DAHD across Europe. The GA(2)LEN-ENDA-DAHD platform interacting with a pharmacovigilance network appears to be of great interest for the reporting of allergy/hypersensitivity ADRs in conjunction with other pharmacovigilance instruments.

The effect of anti-tumour necrosis factor alpha treatment on the antibody response to influenza vaccination.

OBJECTIVES: The effect of anti-tumour necrosis factor (TNF) therapy on the antibody responses to vaccines is the subject of ongoing debate. Therefore, we investigated the effect of the three currently available anti-TNF agents on influenza vaccination outcomes in a patient population with long-standing disease. METHODS: In a prospective cohort study, we assessed the antibody response upon influenza vaccination in 112 patients with long-standing autoimmune disease treated with immunosuppressive medication either with anti-TNF (etanercept, adalimumab or infliximab; n = 64) or without anti-TNF (n = 48) and a control group of 18 healthy individuals. Antibody responses were determined by haemagglutination inhibition assay, before and 4 weeks after vaccination. RESULTS: The proportion of individuals with a protective titre (>or=40) after vaccination was large (80-94%) and did not significantly differ between the three groups. Post-vaccination geometric mean antibody titres against influenza (A/H3N2 and B) were significantly lower in the 64 patients treated with anti-TNF compared with the 48 patients not receiving anti-TNF, and the healthy controls. CONCLUSIONS: The antibody response to influenza vaccination in patients treated with anti-TNF is only modestly impaired. The proportion of patients that achieves a protective titre is not significantly diminished by the use of TNF blocking therapies.

[Three patients with a fracture during methotrexate use, possibly due to methotrexate osteopathy]. / Drie patiënten met een botfractuur tijdens het gebruik van methotrexaat, mogelijk door methotrexaatosteopathie.

Three female patients, aged 76, 64 and 74 years old, who were treated with low-dose methotrexate due to an inflammatory joint disorder, developed severe pain in a lower extremity. The pain increased on weight bearing and could not be explained by arthritis. Conventional x-ray investigation showed a fracture in the second patient. In the other two patients insufficiency fractures were visualized by MRI and bone scan. Because methotrexate osteopathy was suspected, treatment with methotrexate was stopped. All three patients made a rapid recovery after discontinuation. Methotrexate osteopathy is characterized by pain, osteoporosis and microfractures, and was first reported in children treated with high-dose methotrexate for a malignancy. Similar clinical features are reported in the literature in patients with chronic joint inflammation treated with low-dose methotrexate. The causal relationship between the insufficiency fractures and the use of methotrexate is still under debate. Although the clinical picture fits with methotrexate osteopathy, these patients often also have other risk factors for osteoporotic insufficiency fractures.

Long-term disease and patient-reported outcomes of a continuous treat-to-target approach in patients with early rheumatoid arthritis in daily clinical practice.

Patients in real life may differ from those in clinical trials. The aim of this study is to report 5-year outcomes of a continuous treat-to-target (T2T) approach in patients with rheumatoid arthritis (RA) in daily clinical practice. In the Dutch RhEumatoid Arthritis Monitoring cohort, all patients with a clinical diagnosis of RA were treated according to a protocolled T2T strategy, aimed at 28-joint Disease Activity Score (DAS28) < 2.6. Outcomes were percentages of patients in distinct levels of disease activity, mean course of DAS28 and prevalence of sustained (drug-free) remission. Also, data on functional disability (Health Assessment Questionnaire) and health-related quality of life (Short-Form 36) were examined. Mean DAS28 improved from 4.93 (95% CI 4.81-5.05) at baseline to 2.49 (95% CI 2.35-2.63) after 12 months and remained stable thereafter. Percentages of patients at 12 months with DAS28 < 2.6 (remission), DAS28 ≥ 2.6 and ≤ 3.2 (low disease activity), DAS28 > 3.2 and ≤ 5.1 (moderate disease activity) and DAS28 > 5.1 (high disease activity) were 63, 16, 18 and 3%, respectively. Sustained remission (DAS28 < 2.6 during ≥ 6 months) was observed at least once in 84% of the patients and drug-free remission (DAS28 < 2.6 during ≥ 6 months after withdrawal of all disease-modifying anti-rheumatic drugs) in 36% of the patients. Functional disability and health-related quality of life significantly improved during the first 24 weeks. Continuous application of T2T in real-life RA patients leads to favourable disease- and patient-related outcomes.

Advanced magnetic resonance imaging of the brain in patients treated with TNF-alpha blocking agents.

OBJECTIVE: Neurological symptoms have been reported in patients treated with anti-TNF-alpha. In a pilot study we evaluated the effect of anti-TNF-alpha on cerebral parenchyma using advanced Magnetic Resonance (MR) techniques. METHODS: Seven patients with a systemic inflammatory disease (5 rheumatoid arthritis, 2 psoriatic arthritis) had Magnetization Transfer Imaging, Diffusion Weighted Imaging (DWI) and Magnetic Resonance Spectroscopy (MRS) of the brain before and after administration of anti-TNF-alpha. Four patients were neuropsychologically evaluated. RESULTS: After treatment with TNF-alpha blocking agents the Magnetization Transfer Ratio histogram Peak-heights (MTR-Pht) of the white and gray matter decreased (p < 0.01 and p < 0.05 respectively). The Apparent Diffusion Coefficient for the white and gray matter and the metabolite ratios in the centrum semiovale did not significantly change after therapy. Neuropsychological assessment showed no difference before and after anti-TNF-alpha. CONCLUSION: The decrease of the MTR-Pht after anti-TNF-alpha therapy suggests loss of parenchyma integrity; however, these changes could not be attributed to inflammation or demyelination based on our complementary DWI and MRS data. The decrease of the MTR-Pht did not result in decreased cognitive function.

[Drug-induced systemic lupus erythematosus: reports to The Netherlands Pharmacovigilance Centre Lareb]. / Geneesmiddelgeïnduceerde lupus erythematodes disseminatus: meldingen aan Nederlands Bijwerkingen Centrum Lareb.

Drug-induced SLE and idiopathic SLE differ in a number of important aspects, for example the male/female ratio and the age of the patients. There are also differences in incidence in different populations. The mechanism of drug-induced SLE is still largely unknown. It is generally assumed to be an allergic reaction to the drug. The database of the Netherlands Pharmacovigilance Centre Lareb contains 31 reports of SLE in relation to the use of 24 different drugs. In 3 of these cases, there was aggravation of pre-existent SLE. Infliximab and terbinafine are the most frequently reported in association with drug-induced SLE. Furthermore, the database contains a small number of reports of SLE associated with the use of antibiotics. It is difficult to determine whether all of the reported cases involve true drug-induced SLE, but a number of factors suggest that this is often the case, such as the presence or absence of skin involvement and the number of patients that recover after withdrawal of the drug. During the diagnosis of SLE, healthcare professionals should be aware of the use of drugs that might be associated with the induction of SLE.

[Amyloidosis despite normal ESR]. / Niet-verhoogde BSE, maar toch amyloïdose.

BACKGROUND: Amyloidosis is a clinical picture brought on by extracellular deposits of insoluble, non-degradable proteins. The clinical presentation of amyloidosis depends upon the type of protein and the organ afflicted. CASE DESCRIPTION: A 65-year-old woman had stiffness of the locomotor apparatus, recurrent carpal tunnel syndrome and problems with swallowing. Laboratory and urine investigations initially showed no abnormalities, but histopathological investigation of a synovial biopsy revealed amyloidosis with light-chain deposits. This turned out to be due to multiple myeloma. CONCLUSION: Amyloidosis can present with atypical symptoms, such as stiffness. Normal erythrocyte sedimentation rate (ESR) and normal urine analysis do not exclude this diagnosis. When there are clinical indications of amyloidosis further analysis for free-light chains should be performed, even when ESR is normal.

[A localized reaction to sublingual immunotherapy]. / Een lokale bijwerking van sublinguale immunotherapie.

An otherwise healthy 31-year-old woman with allergic rhinoconjunctivitis developed considerable swelling of the floor of her mouth after sublingual allergen-specific immunotherapy with the hyposensitization product 'Slit One grass pollen'. After discontinuation, complaints disappeared and she was successfully put on a regimen of subcutaneous immunotherapy. Despite a lack of reports of serious adverse reactions in clinical trials, the Inspectorate of Health Care and The Netherlands Pharmacovigilance Centre Lareb received several reports of sometimes serious localized reactions to oral and sublingual allergen-specific immunotherapy. Under-reporting is likely since local reactions are more or less expected. Caution should be exercised with allergen treatment, even in the case of non-invasive administration.

A nasal squamous cell carcinoma complicated by a paraneoplastic syndrome consisting of a myositis and anti-Jo-1 autoantibodies.

We report a female patient with the clinical features of a Jo-1-syndrome as a paraneoplastic phenomenon secondary to a nasal squamous cell carcinoma.

Reproductive and hormonal factors in male and female colon cancer.

We analysed data from a case-control study in the Netherlands in order to investigate whether reproductive events and hormonal factors are similarly related to colon cancer risk in men and women after adjustment for dietary factors. In total, 232 colon cancer cases (102 women, 130 men) and 259 controls (123 women, 136 men) were interviewed about life style, medical conditions and usual dietary patterns, using a structured dietary history technique. In women, age at first childbirth was positively associated with colon cancer risk (odds ratio (OR) age > or = 26 vs < 26 years, 1.7; 95% confidence interval (CI), 0.9-3.3). Women with three or more children were at reduced risk compared with women with one or two children (OR, 0.6; 95% CI, 0.3-1.1). When women had had their first child after the age of 26 years, parity was observed to be important (for one or two children vs > or = three children: OR, 2.8; 95% CI, 1.1-7.0). For men, opposite but non-significant associations were found. Adjustment for dietary patterns and other risk factors did not change the estimates markedly. Of the hormonal factors, late age at menarche decreased risk (OR, 0.5; 95% CI, 0.3-0.9) while late age at natural menopause slightly increased risk. Our study provides additional support for the role of reproductive status in the aetiology of colon cancer in women, independently of dietary factors.

What limits endurance in normal children?

We have compared the results of a standard progressive maximal exercise test to those of an endurance exercise test in 22 healthy school children (13 girls, 9 boys, mean age 14.8 years) in order to examine whether it is possible to extrapolate results from a maximal test to predict their endurance capacity. All children performed a standard progressive maximal exercise test (15 W increments every minute until exhaustion) and an endurance test (individually calculated loads to mimic cycling at 20 km/h against a windforce 5 of Beaufort for 30 minutes) on 2 separate days. In both tests metabolic [oxygen uptake (VO2), CO2 production, blood lactate accumulation], ventilatory [minute ventilation (VE)], and circulatory variables were measured. From the maximal test the threshold of lactate accumulation (LT) was determined. Thirteen children were capable of enduring the 30 minute exercise (Group 1), and 9 could not complete the endurance test (Group 2). These two groups were comparable with respect to age, height, and baseline lung function. Children in Group 2 had a higher mean weight (P < 0.005) than those in Group 1. Eight of the 9 children in Group 2 were girls, whereas Group 1 consisted of 5 girls and 8 boys. There was no significant difference between Group 1 and 2 in the mean values of VO2 max, maximal respiratory exchange ratio (R max), VEmax, LT, oxygen pulse, and other variables obtained during the maximal exercise tests. Lactate accumulation during the endurance test in Group 2 was larger than in Group 1 (P < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Cultivation of free-living stages of Trichostrongylus colubriformis in media without bacteria, animal tissue extract, or serum.

Trichostrongylus colubriformis was cultured from hatched first-stage to third-stage larvae in bacteria-free media in the absence of animal tissue extract or serum. This was achieved for the first time with a nematode, parasitic in vertebrates, whose rhabditiform larvae are food-dependent. The best media contained enzymatic hydrolysed casein (amino nitrogen:total nitrogen ratio 0.39), yeast extract, phosphatidylcholine from soybean, and a number of chemically defined ingredients, which include a salt solution, a sterol, and an iron porphyrin. The yield of third-stage larvae obtained was up to 17% of all the living larval stages present after incubation. When casein hydrolysate with AN:TN ratio of 0.39 was replaced by casein hydrolysate with AN:TN ratio of 0.53, little or no development to third-stage larvae occurred. Development to infective larvae was shown to be possible in media with soy peptone instead of casein hydrolysate, although to a very limited extent. It is proposed that the free-living stages of the parasite require peptides, whose molecular weights all lie within a narrow range.

[Prevalence of IgE-mediated allergy to natural rubber latex in operation room personnel of Rotterdam]. / Prevalentie van IgE-gemedieerde allergie voor natuurrubberlatex op Rotterdamse operatiekamers.

OBJECTIVE: To determine the prevalence of IgE-mediated latex allergy in workers in an operation room (OR) complex. DESIGN: Descriptive. METHOD: Regular OR staff members of Rotterdam University Hospital were tested in May-July 1998 for latex allergy and cross-reacting allergens. Questionnaires, serologic testing and skin prick tests with different extracts were used. RESULTS: The study group comprised 163 persons (response: 70%), 30 men and 133 women, with a mean age of 38 years (range: 18-60). Twenty-three persons (14.1%) had specific IgE antibodies against latex. Persons with an atopic constitution ran an increased risk of latex sensitization (odds ratio: 4.3; 95% confidence interval: 1.6-11.4). Of these 23 persons, 16 showed symptoms of urticaria, angio-oedema, rhinoconjunctivitis and/or dyspnoea. CONCLUSION: IgE-mediated allergy to natural rubber latex was prevalent in 23/163 (14.1%) of the OR personnel.

Sustained beneficial effects of a protocolized treat-to-target strategy in very early rheumatoid arthritis: three-year results of the Dutch Rheumatoid Arthritis Monitoring remission induction cohort.

OBJECTIVE: Treat-to-target (T2T) leads to improved clinical outcomes in early rheumatoid arthritis (RA). The question is whether these results sustain in the long term. Our objective was to investigate the 3-year results of a protocolized T2T strategy in daily clinical practice. METHODS: In the Dutch Rheumatoid Arthritis Monitoring remission induction cohort, patients newly diagnosed with RA were treated according to a T2T strategy aimed at remission (Disease Activity Score in 28 joints [DAS28] <2.6). Patients were treated with methotrexate, followed by the addition of sulfasalazine, and exchange of sulfasalazine with anti-tumor necrosis factor α agents in case of failure. Primary outcomes were disease activity, Health Assessment Questionnaire (HAQ) score, Short Form 36 physical component summary (PCS) and mental component summary (MCS) scores, and the Sharp/van der Heijde score (SHS) after 3 years. Secondary outcomes were sustained DAS28 remission (≥6 months) and remission according to the provisional American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) definition. RESULTS: After 3 years (n = 342), 61.7% of patients were in DAS28 remission and 25.3% met the provisional ACR/EULAR definition of remission. Sustained remission was experienced by 70.5%, which in the majority was achieved with conventional disease-modifying antirheumatic drugs only. The median scores were 0.4 (interquartile range [IQR] 0.0-1.0) for the HAQ, 45.0 (IQR 38.4-53.2) for the PCS, 53.1 (IQR 43.2-60.8) for the MCS, and 6.0 (IQR 3.0-13.0) for the total SHS. CONCLUSION: In very early RA, T2T leads to high (sustained) remission rates, improved physical function and health-related quality of life, and limited radiographic damage after 3 years in daily clinical practice.

Efficacy of intraarticular infliximab in patients with chronic or recurrent gonarthritis: a clinical randomized trial.

OBJECTIVE: To evaluate the efficacy and safety of intraarticular infliximab compared with intraarticular methylprednisolone in patients with gonarthritis. METHODS: In 23 patients with recurrent gonarthritis despite previous intraarticular corticosteroid therapy, a total of 41 intraarticular injections (20 infliximab and 21 methylprednisolone) were performed in 28 knees. Initial therapy was randomly assigned, and crossover therapy was eligible within 3 months. The clinical effect was assessed during 6 months of followup. The primary outcome was event-free survival, defined as the time after treatment until local retreatment was performed and/or nonimprovement of the knee joint score. Adverse effects were recorded during followup. RESULTS: All patients treated with intraarticular infliximab had an insufficient response. In contrast, 8 of the 21 intraarticular methylprednisolone injections were effective (P = 0.004). Between groups, no differences in the patients' age, disease duration, number of disease-modifying antirheumatic drugs, or previous intraarticular methylprednisolone were observed. Reported adverse effects were not related to therapy. CONCLUSION: Treatment with intraarticular infliximab injection was not effective in patients with a chronically inflamed knee joint. Intraarticular injection with methylprednisolone was superior despite previous intraarticular corticosteroid therapy. Further investigation is needed to provide these patients with a better alternative.