Incidence data by age of new episodes of influenza-like illness reported by sentinel general
practice networks in England and Wales and in The Netherlands over a 10-year period were
examined to ...provide estimates of the consulting population during influenza epidemic periods.
Baseline levels of recording in each age group were calculated from weeks in which influenza
viruses were not circulating and the excess over baseline calculated to provide the population
estimates during influenza epidemics. Influenza A/H3N2 epidemics were associated with higher population estimates for
consultations than influenza B, especially in the age groups 0–4 and 65 years and over. In the
intervening age groups, population estimates were more consistent regardless of the virus type.
Both networks reported simultaneous peaking of incidence rates in all of the age groups. There
were substantial increases in the number of persons reporting other respiratory illnesses during
influenza epidemics. Population estimates of the consulting population provide the only secure basis for which
health services resource utilization during influenza epidemics can be estimated.
Background: A substantial proportion of patients with rheumatoid arthritis (RA) do not respond, or lose initial response, to adalimumab treatment. One explanation for non-response is that patients ...develop anti-adalimumab antibodies. Objectives: To evaluate the incidence of formation of antibody against adalimumab and the association with serum adalimumab concentrations and clinical response. Methods: In a cohort of 121 consecutive patients with RA treated with adalimumab, serum adalimumab concentrations and antibodies against adalimumab were measured together with clinical response variables before and up to 28 weeks after the start of treatment. Results: Anti-adalimumab antibodies were detected in 21 patients (17%) during 28 weeks of treatment. EULAR non-responders had antibodies significantly more often than good responders (34% vs 5%; p = 0.032). Patients with antibodies showed less improvement in disease activity (mean (SD) delta DAS28 0.65 (1.35)) than patients without antibodies (mean delta DAS28 1.70 (1.35)) (p = 0.001). Patients with antibodies during follow-up had lower serum adalimumab concentrations at 28 weeks than patients without antibodies (median 1.2 mg/l, range 0.0–5.6 vs median 11.0 mg/l, range 2.0–33.0, respectively; p<0.001). Good responders had higher serum adalimumab concentrations than moderate responders (p = 0.021) and non-responders (p = 0.001). Concomitant methotrexate use was lower in the group with anti-adalimumab antibodies (52%) than in the group without antibodies (84%) (p = 0.003). Conclusions: Serum antibodies against adalimumab are associated with lower serum adalimumab concentrations and non-response to adalimumab treatment.
Objective The aim of this study was to test the hypothesis that the reason for non-response (caused by immunogenicity or not) to a first tumour necrosis factor (TNF) inhibitor defines whether a ...second TNF inhibitor will be effective. Methods This cohort study consisted of 292 consecutive patients with rheumatoid arthritis (RA), all treated with etanercept. A total of 89 patients (30%) were treated previously with infliximab or adalimumab (‘switchers’), and the remaining 203 (70%) were anti-TNF naive. All switchers were divided into two groups: with and without antibodies against the previous biological. Differences in clinical response to etanercept between switchers with and without antibodies and patients who were anti-TNF naive were assessed after 28 weeks of treatment using changes in Disease Activity Score in 28 joints (DAS28). Results After 28 weeks of treatment, response to etanercept did not differ between patients who were anti-TNF naive and switchers with anti-drug antibodies (ΔDAS28=2.1±1.3 vs ΔDAS28=2.0±1.3; p=0.743). In contrast, switchers without anti-drug antibodies had a diminished response to etanercept treatment compared to patients who were TNF naive (ΔDAS28=1.2±1.3 vs ΔDAS28=2.1±1.3; p=0.001) and switchers with antibodies (ΔDAS28=1.2±1.3 vs ΔDAS28=2.0±1.3; p=0.017). Conclusion Patients with RA with an immunogenic response against a first TNF-blocking agent had a better clinical response to a subsequent TNF blocker compared to patients with RA without anti-drug antibodies. Hence, determining immunogenicity can be helpful in deciding in which patient switching could be beneficial and can be part of a personalised treatment regimen.
Pulmonary arterial hypertension (PAH) is a progressive and lethal pulmonary vascular disease (PVD). Although in recent years outcome has improved by new treatments that delay disease progression, a ...cure has not yet been achieved. In PAH associated with congenital heart disease (CHD), remodeling of the pulmonary vasculature reaches an irreversible phenotype similar to all forms of end-stage PAH. In PAH-CHD, however, also an early stage is recognised, which can be completely reversible. This reversible phase has never been recognised in other forms of PAH, most likely because these patients are only diagnosed once advanced disease has developed. We propose that the clinical model of PAH-CHD, with an early reversible and advanced irreversible stage, offers unique opportunities to study pathophysiological and molecular mechanisms that orchestrate the transition from reversible medial hypertrophy into irreversible plexiform lesions. Comprehension of these mechanisms is not only pivotal in clinical assessment of disease progression and operability of patients with PAH-CHD; specific targeting of these mechanisms may also lead to pharmacological interventions that transform 'irreversible' plexiform lesions into a reversible PVD: one that is amenable for a cure. In recent years, significant steps have been made in the strive to 'reverse the irreversible'. This review provides an overview of current clinical and experimental knowledge on the reversibility of PAH, focussing on flow-associated mechanisms, and the near-future potential to advance this field.
Therapeutic monoclonal antibodies have revolutionized the treatment of various inflammatory diseases. Immunogenicity against these antibodies has been shown to be clinically important: it is ...associated with shorter response duration because of diminishing concentrations in the blood and with infusion reactions. Concomitant immunomodulators in the form of methotrexate or azathioprine reduced the immunogenicity of therapeutic antibodies in rheumatoid arthritis, Crohn disease, and juvenile idiopathic arthritis. The occurrence of adverse events does not increase when immunomodulators are added to therapeutic antibodies. The mechanism whereby methotrexate and azathioprine influence immunogenicity remains unclear. Evidence-based consensus on prescribing concomitant immunomodulators is needed.
Pulmonary arterial hypertension (PAH) in congenital heart disease (CHD) can be reversed by early shunt closure, but this potential is lost beyond a certain point of no return. Therefore, it is ...crucial to accurately assess the reversibility of this progressive pulmonary arteriopathy in an early stage. Reversibility assessment is currently based on a combination of clinical symptoms and haemodynamic variables such as pulmonary vascular resistance. These measures, however, are of limited predictive value and leave many patients in the grey zone. This review provides a concise overview of the mechanisms involved in flow-dependent progression of PAH in CHD and evaluates existing and future alternatives to more directly investigate the stage of the pulmonary arteriopathy. Structural quantification of the pulmonary arterial tree using fractal branching algorithms, functional imaging with intravascular ultrasound, nuclear imaging, putative new blood biomarkers, genetic testing and the potential for transcriptomic analysis of circulating endothelial cells and educated platelets are being reviewed.
Objective To investigate how antibodies against anti-tumour necrosis factor (anti-TNF) agents influence response after switching from infliximab to adalimumab in rheumatoid arthritis (RA). Methods ...This cohort study consisted of 235 patients with RA, all treated with adalimumab. At baseline 52 patients (22%) had been previously treated with infliximab (‘switchers’), and 183 (78%) were anti-TNF naive. Disease activity (using the 28-joint count Disease Activity Score (DAS28)) and presence of antibodies against infliximab and adalimumab were assessed. Clinical response to adalimumab was compared between switchers and anti-TNF naive patients and their anti-infliximab and anti-adalimumab antibody status. Results After 28 weeks of adalimumab treatment the decrease in DAS28 (ΔDAS28) for the 235 patients was 1.6±1.5 (mean±SD). Anti-adalimumab antibodies were detected in 46 patients (20%). ΔDAS28 was 1.8±1.4 in patients without anti-adalimumab and 0.6±1.3 in patients with anti-adalimumab (p<0.0001). Thirty-three of the 52 switchers (63%) had anti-infliximab antibodies. Patients with anti-infliximab more often developed anti-adalimumab than anti-TNF naive patients (11 (33%) vs 32 (18%); p=0.039). ΔDAS28 was greater for anti-TNF naive patients (1.7±1.5) than for switchers without anti-infliximab antibodies (ΔDAS28=0.9±1.4) (p=0.009). ΔDAS28 for switchers with anti-infliximab was 1.2±1.3 and did not differ significantly from anti-TNF naive patients (p=0.262). Conclusion Switchers with anti-infliximab antibodies more often develop antibodies against adalimumab than anti-TNF naive patients. Response to adalimumab was limited in switchers without anti-infliximab antibodies, which raises the question whether a second anti-TNF treatment should be offered to patients with RA for whom an initial treatment with an anti-TNF blocker fails, in the absence of anti-biological antibodies.
Retrospective surveys of patients with subarachnoid haemorrhage suggest that minor episodes with sudden headache (warning leaks) may precede rupture of an aneurysm, and that early recognition and ...surgery might lead to improved outcome. We studied 148 patients with sudden and severe headache (possible sentinel headache) seen by 252 general practitioners in a 5-year period in the Netherlands. Subarachnoid haemorrhage was the cause in 37 patients (25%) (proven aneurysm in 21, negative angiogram in 6, no angiogram done in 6, sudden headache followed by death in 4). 103 patients had headache as the only symptom, 12 of whom proved to have subarachnoid haemorrhage (6 with a ruptured aneurysm). Previous bouts of sudden headache had occurred in only 2. Other serious neurological conditions were diagnosed in 18. In the remaining 93, no underlying cause of headache was found; follow-up over 1 year showed no subsequent subarachnoid haemorrhage or sudden death. In this cohort, acute, severe headache in general practice indicated a serious neurological disorder in 37% (95% Cl 29-45%), and subarachnoid haemorrhage in 25% (18-32%). 12% (5-18%) of those with headache as the only symptom. The notion of warning leaks as a less serious variant of subarachnoid haemorrhage is not supported by this study. Early recognition of subarachnoid haemorrhage is important but will probably have only limited impact on the outcome in the general population.
The prevalence and mechanism of erythromycin resistance in commensal throat streptococci was determined from October 2000 until December 2002 as part of an ongoing study of the NIVEL in general ...practice patients (
N
=
678). Resistance prevalence for 1
mg/L and 16
mg/L erythromycin was 57% and 20%, respectively. The percentage of total commensal flora resistant within each patient ranged from 1% to 100% (median, 1%).
mefA was predominantly found among isolates on the 1
mg/L plates, and
ermB was found in 64% of the isolates on the 16
mg/L plates. Erythromycin resistance was transferred from a commensal isolate to
Streptococcus pneumoniae with a frequency of 1
×
10
−9. Commensal streptococci of general practice patients in The Netherlands form a large reservoir of transferable erythromycin resistance (genes) for potential pathogenic microorganisms.
CONTEXT Short-term data on the immunogenicity of monoclonal antibodies showed associations between the development of antidrug antibodies and diminished serum drug levels, and a diminished treatment ...response. Little is known about the clinical relevance of antidrug antibodies against these drugs during long-term follow-up. OBJECTIVE To examine the course of antidrug antibody formation against fully human monoclonal antibody adalimumab and its clinical relevance during long-term (3-year) follow-up of patients with rheumatoid arthritis (RA). DESIGN, SETTING, AND PATIENTS Prospective cohort study February 2004-September 2008; end of follow-up was September 2010. All 272 patients were diagnosed with RA and started treatment with adalimumab in an outpatient clinic. MAIN OUTCOME MEASURES Disease activity was monitored and trough serum samples were obtained at baseline and 8 time points to 156 weeks. Serum adalimumab concentrations and antiadalimumab antibody titers were determined after follow-up. Treatment discontinuation, minimal disease activity, and clinical remission were compared for patients with and without antiadalimumab antibodies. RESULTS After 3 years, 76 of 272 patients (28%) developed antiadalimumab antibodies—51 of these (67%) during the first 28 weeks of treatment. Patients without antiadalimumab antibodies had much higher adalimumab concentrations (median, 12 mg/L; IQR, 9-16 mg/L) compared with patients with antibody titers from 13 to 100 AU/mL (median, 5 mg/L; IQR, 3-9 mg/L; regression coefficient, −4.5; 95% CI, −6.0 to −2.9; P < .001) and also those greater than 100 AU/mL (median, 0 mg/L; IQR, 0-3 mg/L; regression coefficient, −7.1; 95% CI, −8.4 to −5.8; P < .001). Patients with antiadalimumab antibodies more often discontinued participation due to treatment failure (n = 29 38%; hazard ratio HR, 3.0; 95% CI, 1.6-5.5; P < .001) compared with antiadalimumab antibody–negative ones (n = 28 14%). Ninety-five of 196 patients (48%) without antiadalimumab antibodies had minimal disease activity vs 10 of 76 patients (13%) with antiadalimumab antibodies; patients with antiadalimumab antibodies less often had sustained minimal disease activity score in 28 joints (DAS28) (< 3.2; HR, 3.6; 95% CI, 1.8-7.2; P < .001) compared with antiadalimumab antibody–negative ones. Three of 76 patients (4%) with antiadalimumab antibodies achieved sustained remission compared with 67 of 196 (34%) antiadalimumab antibody–negative ones; patients with antiadalimumab antibodies less often achieved remission (DAS28 < 2.6; HR, 7.1; 95% CI, 2.1-23.4; P < .001) compared with antiadalimumab antibody–negative ones. CONCLUSION Among outpatients with RA in whom adalimumab was started over 3 years, the development of antidrug antibodies was associated with lower adalimumab concentration and lower likelihood of minimal disease activity or clinical remission.
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