Maternal and neonatal antibody levels on pertussis vaccination in pregnant women on immune-modulating therapy for rheumatic disease.

OBJECTIVES: While protection against pertussis following maternal tetanus-diphtheria-and-acellular-pertussis (Tdap) vaccination was demonstrated in healthy term-born infants, no evidence is available on Tdap vaccination in combination with immune-modulating therapy during pregnancy. In this pilot study, we explored whether treatment with tumour necrosis factor alpha inhibitors (TNFis) in pregnant patients with rheumatic disease interferes with Tdap vaccine responses and affects maternal anti-pertussis IgG antibody levels in newborns. METHODS: Patients were included by a rheumatologist during pregnancy in case they received maternal Tdap vaccination in the late-second or early-third trimester of pregnancy. Blood samples were obtained from mothers during the first pregnancy trimester, 3 months after delivery and from the umbilical cord. IgG antibody levels against Tdap-included antigens were measured using a bead-based multiplex immunoassay. Findings on patients exposed to TNFis were compared with those from TNFi-unexposed patients and with data from a historical comparator study among healthy Tdap vaccinated mother-infant pairs (n=53). RESULTS: 66 patients (46 exposed and 20 unexposed to TNFIs) were enrolled. No major differences in IgG antibody levels were observed between TNFi-exposed and unexposed mothers before maternal Tdap vaccination and 3 months after delivery. In cord sera, however, antibody levels against pertussis toxin were significantly lower after TNFi-treatment (35.94 IU/mL, 95% CI 20.68 to 62.45) compared with no TNFi-treatment of mothers with rheumatic disease (94.61 IU/mL, 95% CI 48.89 to 183.07) and lower compared with a cohort of healthy mothers (125.12 IU/mL, 95% CI 90.75 to 172.50). We observed similar differences for filamentous haemagglutinin, pertactin, tetanus toxoid and diphtheria toxoid. CONCLUSION: These preliminary data indicate no major differences in IgG antibody levels on maternal Tdap vaccination in pregnant women with or without immune-modulating treatment, although our findings suggest that TNFis during pregnancy induce lower maternal anti-pertussis-specific protective antibody levels in newborns.

Is methotrexate safe for men with an immune-mediated inflammatory disease and an active desire to become a father? Results of a prospective cohort study (iFAME-MTX).

INTRODUCTION: Current scientific evidence guiding the decision whether men with an active desire to become a father should be treated with methotrexate (MTX) remains controversial. We aimed to prospectively evaluate the testicular toxicity profile of MTX focusing on several markers of male fertility, including semen parameters and sperm DNA fragmentation index (sDFI). As a secondary outcome, we aimed to evaluate whether MTX-polyglutamates can be detected in spermatozoa and seminal plasma and to evaluate the enzymatic activity in spermatozoa of folylpolyglutamate synthetase (FPGS). METHODS: In a prospective cohort study, men ≥18 years who started therapy with MTX were invited to participate (MTX-starters). Participants were instructed to produce two semen samples (a pre-exposure and a post-exposure sample after 13 weeks). Healthy men ≥18 years were invited to participate as controls. Conventional semen analyses, male reproductive endocrine axis and sDFI were compared between groups. FPGS enzymatic activity and MTX-PG1-5 concentrations were determined by mass spectrometry analytical methods. RESULTS: In total, 20 MTX-starters and 25 controls were included. The pre-exposure and postexposure semen parameters of MTX-starters were not statistically significant different. Compared with healthy controls, the conventional semen parameters and the sDFI of MTX-starters were not statistically significant different. These data were corroborated by the marginal accumulation of MTX-PGs in spermatozoa, consistent with the very low FPGS enzymatic activity associated with the expression of an alternative FPGS splice-variant. DISCUSSION: Treatment with MTX is not associated with testicular toxicity, consistent with the very low concentration of intracellular MTX-PG. Therefore, therapy with MTX can be safely started or continued in men and with a wish to become a father.

Tumour necrosis factor inhibitor use during pregnancy is associated with increased birth weight of rheumatoid arthritis patients' offspring.

OBJECTIVES: To study pregnancy outcomes in a closely monitored, well-defined cohort of women with rheumatoid arthritis (RA). In particular, pregnancy outcomes of women that used a TNFi during pregnancy. METHODS: Patients were derived from a prospective study on pregnancy and RA (Preconception Counseling in Active RA study) and treated according to a treatment protocol aimed at minimal disease activity. Multivariate linear regression analysis was used to describe which variables influenced birth weight. RESULTS: 188 patients were included, 92 (48.9%) patients with RA used a TNFi during pregnancy. Disease Activity Score in 28 joints C reactive protein (DAS28CRP) was low at all time points during pregnancy (DAS28CRP in the third trimester: 2.17 (SD 0.73). TNFi use was not associated with an increase of adverse pregnancy outcomes such as low birth weight (<2500 g), (emergency) caesarian section, hypertensive disorders or congenital malformations. TNFi use resulted in less children born small-for-gestational age (p=0.05), however, did not increase the risk of large-for-gestational age (p=0.73). Mean birth weight was 173 g higher in women that used a TNFi during pregnancy (3.344 kg vs 3.171 kg, p=0.03). In the multivariate analysis, maternal age (ß -0.023, 95% CI -0.040 to -0.0065, p=0.007), TNFi use (ß 0.20, 95% CI 0.066, 0.34, p=0.004), diabetes mellitus (ß 0.37, 95% CI 0.12, 0.63, p=0.004) and gestational age (ß 0.18, 95% CI 0.15, 0.2, p<0.001) were statistically significant associated with birth weight. CONCLUSIONS: This is the first study to show that TNFi use during pregnancy is associated with increased birth weight of offspring of women with well-controlled RA. The underlying mechanism of TNF-inhibition on birth weight and the long-term consequences for the offspring should be explored in future research.

Paternal inflammatory arthritis is associated with a higher risk of miscarriage: results of a large multicentre study (iFAME-Fertility).

OBJECTIVES: Paternal preconception health is recognized as an important contributor to pregnancy outcomes. Nonetheless, pregnancy outcomes of partners of men with inflammatory arthritis (IA) have never been studied. Our objective was to describe the pregnancy outcomes of partners of men diagnosed with IA. METHODS: We performed a multicentre cross-sectional retrospective study conducted in the Netherlands. Men with IA who were over 40 years old that reported at least one positive pregnancy test were included. To analyse the impact of IA on pregnancy outcomes, pregnancies were classified into two groups: pregnancies conceived after the diagnosis of IA and before the diagnosis of IA. RESULTS: In total, 408 male participants diagnosed with IA reported 897 singleton pregnancies that resulted in 794 live births. Pregnancies conceived after the diagnosis of IA had higher rate of miscarriage (12.27 vs 7.53%, P = <0.05). This increased risk was still present after adjusting for confounders [OR 2.03 (95% CI 1.12, 3.69) P = 0.015]. CONCLUSIONS: This is the largest study to describe the pregnancy outcomes of partners of men diagnosed with IA and the first to demonstrate that paternal IA is associated with a higher risk of miscarriage. Notwithstanding, the overall rate of miscarriage reported in our study could be comparable to previously reported population estimates.

It is not just about sex: viewpoints of men with inflammatory arthritis on the overall impact of the disease on their sexual health.

OBJECTIVES: Sexual health is defined as a state of physical, emotional, mental and social well-being in relation to sexuality. The impact of inflammatory arthritis (IA) on male sexual health has been mainly studied focusing on erectile function, one of the physical components of sexual health. Our objective was to describe the viewpoints among men with IA in the Netherlands on the overall impact of IA on their sexual health. METHODS: Q-methodology, a mixed methods approach to systematically study subjectivity was used. Adult men diagnosed with IA ranked 34 opinion statements about potential impacts of IA on their sexual health and were interviewed. By-person factor analysis was used to identify common patterns in the rankings, which were interpreted as viewpoints. Data from the interviews were used to verify and adjust the interpretations. RESULTS: 30 men (22-77 years) with IA were included. The analysis revealed three viewpoints. Men with the viewpoint 'Arthritis negatively affects my sexual health' experience a dramatic impact on all components of sexual health. In viewpoint 'I am keeping up appearances', IA negatively impacts sexual health but a distinguishing coping mechanism could mask a more serious negative impact. Men with the viewpoint 'I am satisfied with my sexual health'' experience no significant impact of IA on their sexual health. CONCLUSIONS: We identified three viewpoints on the impact of IA on male sexual health, two revealed a negative influence that goes beyond the physical act of sex. IA can severely affect the emotional, mental and social components of sexual health.

Impaired fertility in men diagnosed with inflammatory arthritis: results of a large multicentre study (iFAME-Fertility).

OBJECTIVES: The impact of inflammatory arthritis (IA) on male fertility remains unexplored. Our objective was to evaluate the impact of IA on several male fertility outcomes; fertility rate (number of biological children per man), family planning, childlessness and fertility problems. METHODS: We performed a multicentre cross-sectional study (iFAME-Fertility). Men with IA 40 years or older who indicated that their family size was complete were invited to participate. Participants completed a questionnaire that included demographic, medical and fertility-related questions. To analyse the impact of IA on fertility rate, patients were divided into groups according to the age at the time of their diagnosis: ≤30 years (before the peak of reproductive age), between 31 and 40 years (during the peak) and ≥41 years (after the peak). RESULTS: In total 628 participants diagnosed with IA were included. Men diagnosed ≤30 years had a lower mean number of children (1.32 (SD 1.14)) than men diagnosed between 31 and 40 years (1.60 (SD 1.35)) and men diagnosed ≥41 years (1.88 (SD 1.14)).This was statistically significant (p=0.0004).The percentages of men diagnosed ≤30 and 31-40 years who were involuntary childless (12.03% vs 10.34% vs 3.98%, p=0.001) and who reported having received medical evaluations for fertility problems (20.61%, 20.69% and 11.36%, p=0.027) were statistically significant higher than men diagnosed ≥41 years. CONCLUSIONS: This is the first study that shows that IA can impair male fertility. Men diagnosed with IA before and during the peak of reproductive age had a lower fertility rate, higher childlessness rate and more fertility problems. Increased awareness and more research into the causes behind this association are urgently needed.

Modern treatment approach results in low disease activity in 90% of pregnant rheumatoid arthritis patients: the PreCARA study.

OBJECTIVES: In patients with rheumatoid arthritis (RA), high disease activity impairs fertility outcomes and increases the risk of adverse pregnancy outcomes. The aim of this study was to determine the feasibility of a modern treatment approach, including treat-to-target (T2T) and the prescription of tumour necrosis factor (TNF) inhibitors, in patients with RA with a wish to conceive or who are pregnant. METHODS: Patients were derived from the Preconception Counseling in Active RA (PreCARA) cohort. Patients with a wish to conceive or who are pregnant were treated according to a modified T2T approach, in which the obvious restrictions of pregnancy were taken into account. Results of the PreCARA study were compared with results of the Pregnancy-induced Amelioration of Rheumatoid Arthritis (PARA) study, a historic reference cohort on RA during pregnancy. Patients in the PARA cohort were treated according to the standards of that time (2002-2010). Differences in disease activity over time between the two cohorts were tested using a linear mixed model. RESULTS: 309 patients with RA were included in the PreCARA study, 188 children were born. 47.3% of the patients used a TNF inhibitor at any time during pregnancy. Mean disease activity over time in the PreCARA cohort was lower than in the reference cohort (p<0.001). In the PreCARA cohort, 75.4% of the patients were in low disease activity (LDA) or remission before pregnancy increasing to 90.4% in the third trimester, whereas in the PARA cohort, these percentages were 33.2% and 47.3%, respectively. CONCLUSIONS: This first study on a modern treatment approach in pregnant patients with RA shows that LDA and remission are an attainable goal during pregnancy, with 90.4% of patients achieving this in the third trimester.

Parenting problems postpartum can be detected early in pregnancy in patients with rheumatoid arthritis.

OBJECTIVE: To describe parenting disability postpartum in patients with rheumatoid arthritis (RA) using the Parenting Disability Index and to determine early in pregnancy which patients will face parenting problems postpartum. METHODS: Data were collected from a prospective study on pregnancy and RA (Pregnancy induced Amelioration of Rheumatoid Arthritis study). Postpartum visits were performed at 6, 12 and 26 weeks after delivery. Domains causing parenting difficulties were identified. A multivariate logistic regression model to identify which patients develop parenting disabilities postpartum with patient characteristics in the first trimester as covariates was performed. RESULTS: 148 patients were eligible for this study. The domains carrying, hygiene, feeding, getting up and down, and household/shopping were frequently scored as difficult. Maintaining discipline, taking care of the children when sick, listening and having other children over caused the least problems. 30.1% of patients with RA report low parenting disability, 30.9% reports intermediate disability and 39.0% reports high disability. Patients with a low Health Assessment Questionnaire (HAQ)-score in the first trimester (OR 9.2, 95% CI 3.0 to 27.7, p<0.001) and low disease activity in the first trimester (Disease Activity Score 28-joint count C reactive protein<3.2) (OR 4.8, 95% CI 1.8 to 12.9, p=0.002) were likely to report low parenting disability postpartum. Patients with a longer disease duration (OR 0.87, 95% CI 0.79 to 0.95, p=0.003) were less likely to report low parenting disability postpartum. A high HAQ-score in the first trimester (OR 4.54, 95% CI 1.99 to 10.34, p<0.001) and erosive disease (OR 2.32, 95% CI 1.00 to 5.35, p=0.049) increased the risk of high parenting disability postpartum. CONCLUSION: Physical domains of parenting postpartum are most commonly affected in patients with RA. When counselling patients with RA, a HAQ-score in the first trimester is the most reliable marker to identify patients that develop parenting disability after delivery.

Real-life compliance and persistence among users of subcutaneous and sublingual allergen immunotherapy.

BACKGROUND: Subcutaneous allergen immunotherapy (SCIT) and sublingual allergen immunotherapy (SLIT) are safe and effective treatments of allergic rhinitis, but high levels of compliance and persistence are crucial to achieving the desired clinical effects. OBJECTIVE: Our objective was to assess levels and predictors of compliance and persistence among grass pollen, tree pollen, and house dust mite immunotherapy users in real life and to estimate the costs of premature discontinuation. METHODS: We performed a retrospective analysis of a community pharmacy database from The Netherlands containing data from 6486 patients starting immunotherapy for 1 or more of the allergens of interest between 1994 and 2009. Two thousand seven hundred ninety-six patients received SCIT, and 3690 received SLIT. Time to treatment discontinuation was analyzed and included Cox proportional hazard models with time-dependent covariates, where appropriate. RESULTS: Overall, only 18% of users reached the minimally required duration of treatment of 3 years (SCIT, 23%; SLIT, 7%). Median durations for SCIT and SLIT users were 1.7 and 0.6 years, respectively (P < .001). Other independent predictors of premature discontinuation were prescriber, with patients of general practitioners demonstrating longer persistence than those of allergologists and other medical specialists; single-allergen immunotherapy, lower socioeconomic status; and younger age. Of the persistent patients, 56% were never late in picking up their medication from the pharmacy. Direct medication costs per nonpersistent patient discontinuing in the third year of treatment were €3800, an amount that was largely misspent. CONCLUSION: Real-life persistence is better in SCIT users than in SLIT users, although it is low overall. There is an urgent need for further identification of potential barriers and measures that will enhance persistence and compliance.

Sensitisation patterns and association with age, gender, and clinical symptoms in children with allergic rhinitis in primary care: a cross-sectional study.

BACKGROUND: Polysensitisation is a frequent phenomenon in patients with allergic rhinitis. However, few studies have investigated the characteristics of polysensitised children, especially in primary care. OBJECTIVES: This analysis describes the patterns of sensitisation to common allergens and the association with age, gender, and clinical symptoms in children in primary care diagnosed with allergic rhinitis. METHODS: Cross-sectional data from two randomised double-blind placebo-controlled studies were used to select children aged 6-18 years (n=784) with a doctor's diagnosis of allergic rhinitis or use of relevant medication for allergic rhinitis in primary care. They were assessed for age, gender, specific IgE (type and number of sensitisations), nasal and eye symptom scores. RESULTS: In 699 of the 784 children (89%) with a doctor's diagnosis or relevant medication use, a positive IgE test for one or more allergens was found. Polysensitisation (>2 sensitisations) was found in 69% of all children. Sensitisation was more common in children aged 9-13 than in younger children aged 5-8 years (p=0.03). Monosensitisation and polysensitisation were not significantly different in girls and boys. The severity of clinical symptoms did not differ between polysensitised and monosensitised children, but symptoms were significantly lower in non-sensitised children. CONCLUSIONS: Polysensitisation to multiple allergens occurs frequently in children with allergic rhinitis in general practice. Overall, clinical symptoms are equally severe in polysensitised and monosensitised children. Treatment decisions for allergic rhinitis should be made on the basis of a clinical history and allergy testing.

The relevance of patient-reported outcomes in a grass pollen immunotherapy trial in children and adolescents with rhinoconjunctivitis.

BACKGROUND: Patient-reported outcomes (PROs) are the only instruments available to assess the efficacy of an intervention in patients with allergic rhinoconjunctivitis. As allergic rhinoconjunctivitis is a systemic disease, it is now recommended to use not only PROs focusing at classical symptoms, but also health-related quality of life (HRQL) instruments in immunotherapy trials. METHODS: A previously published immunotherapy trial in children and adolescents (6-18 yr) with hay fever provided us with data to assess the relevance of two of these additional outcome measures, the disease-specific rhinoconjunctivitis quality of life questionnaire (RQLQ) and the generic COOP/WONCA-charts (CWC). A PRO was considered relevant if it was responsive to pollen exposure and at least had a moderate correlation with the classical symptoms of allergic rhinoconjunctivitis. Furthermore, we evaluated a post-season PRO, that is, a global assessment of symptoms (GAS). This assessment is used in clinical trials as a tool for selecting participants with sufficient symptoms and in daily practice to evaluate the patient's complaints during the preceding season. We assessed the correlation of this retrospective score with the actual symptoms during the previous pollen season. RESULTS: Data from 36 children and 63 adolescents were analysed. On the basis of the total scores of the paediatric and adolescent version of the RQLQ, both questionnaires were considered relevant as they were responsive to exposure and showed a moderate to strong correlation with the rhinoconjunctivitis symptoms. However, in both children and adolescents, 40% of the RQLQ items were not relevant according to our definition. The CWC as a whole and the separate charts appear less relevant because of the weak correlations with the daily symptom score from the diary. The correlation between our post-season GAS and the in season daily symptom score was weak. CONCLUSION: The paediatric and adolescent RQLQ are relevant, but could be shortened as they contain a substantial number of irrelevant items. The CWC are not relevant in the monitoring of children and adolescents with allergic rhinoconjunctivitis caused by grass pollen. The retrospective GAS does not sufficiently reflect the actual symptoms during the preceding season.

Quantile regression for the statistical analysis of immunological data with many non-detects.

BACKGROUND: Immunological parameters are hard to measure. A well-known problem is the occurrence of values below the detection limit, the non-detects. Non-detects are a nuisance, because classical statistical analyses, like ANOVA and regression, cannot be applied. The more advanced statistical techniques currently available for the analysis of datasets with non-detects can only be used if a small percentage of the data are non-detects. METHODS AND RESULTS: Quantile regression, a generalization of percentiles to regression models, models the median or higher percentiles and tolerates very high numbers of non-detects. We present a non-technical introduction and illustrate it with an implementation to real data from a clinical trial. We show that by using quantile regression, groups can be compared and that meaningful linear trends can be computed, even if more than half of the data consists of non-detects. CONCLUSION: Quantile regression is a valuable addition to the statistical methods that can be used for the analysis of immunological datasets with non-detects.

Sublingual immunotherapy not effective in house dust mite-allergic children in primary care.

BACKGROUND: Sublingual immunotherapy (SLIT) as a therapy for the treatment of allergic rhinitis in children might be acceptable as an alternative for subcutaneous immunotherapy. However, the efficacy of SLIT with house dust mite extract is not well established. OBJECTIVE: To investigate whether SLIT in house dust mite-allergic children recruited in primary care is effective and safe. METHODS: Children aged 6-18 years (n = 251) recruited in primary care with a house dust mite-induced allergic rhinitis received either SLIT or placebo for 2 years. Symptoms and medication use were assessed throughout the study. Primary outcome parameter was the mean total nose symptom score (scales 0-12) during the autumn of the second treatment year. Safety was assessed by recording any adverse event. RESULTS: Overall, the mean nose symptom score ± s.d. after 2 years of treatment showed no significant effect of SLIT (symptom score intervention group 2.26 ± 1.84 vs. placebo group, 2.02 ± 1.67; p = 0.08). There were no significant differences in secondary outcomes, nor in subgroup analyses. The number of patients reporting adverse events was comparable between both groups. CONCLUSIONS: Sublingual immunotherapy with house dust mite allergen was not better than placebo in reducing rhinitis symptoms in house dust mite-allergic children in primary care. SLIT as administered in this study can be considered safe.

Sublingual immunotherapy in children with allergic rhinitis: quality of systematic reviews.

Systematic reviews have gained popularity as a way to combine the increasing amount of research information. This study assessed the quality of systematic reviews and meta-analyses of sublingual immunotherapy (SLIT) for allergic rhinitis in children, published since 2000. Eligible reviews were identified by searching Medline/Pubmed, Embase, and the Cochrane Library, from 2000 through 2008. Methodological quality was assessed using the assessment of multiple systematic reviews instrument. Ten systematic reviews were included, one of which was published in the Cochrane Library. Eight reviews gave some details about the search strategy. None of the reviews included measures to avoid selection bias. In 60% of the reviews, the methodological quality of the included studies was (partly) assessed. Four reviews pooled the results of individual studies, neglecting clinical heterogeneity. Three of the 10 reviews provided information about sources of funding or grants from industry. Of the 10 reviews, the six reviews with the highest overall score scored 5-8 points, indicating moderate quality. Systematic reviews are useful to evaluate the efficacy of SLIT in children. Although more reviews have become available, the methodological quality could be improved. SLIT for children could be promising, but methodological flaws in the reviews and individual studies are too serious to draw definite conclusions.

Randomized double-blind placebo-controlled trial of sublingual immunotherapy in children with house dust mite allergy in primary care: study design and recruitment.

BACKGROUND: For respiratory allergic disorders in children, sublingual immunotherapy has been developed as an alternative to subcutaneous immunotherapy. Sublingual immunotherapy is more convenient, has a good safety profile and might be an attractive option for use in primary care. A randomized double-blind placebo-controlled study was designed to establish the efficacy of sublingual immunotherapy with house dust mite allergen compared to placebo treatment in 6 to 18-year-old children with allergic rhinitis and a proven house dust mite allergy in primary care. Described here are the methodology, recruitment phases, and main characteristics of the recruited children. METHODS: Recruitment took place in September to December of 2005 and 2006. General practitioners (in south-west Netherlands) selected children who had ever been diagnosed with allergic rhinitis. Children and parents could respond to a postal invitation. Children who responded positively were screened by telephone using a nasal symptom score. After this screening, an inclusion visit took place during which a blood sample was taken for the RAST test. RESULTS: A total of 226 general practitioners invited almost 6000 children: of these, 51% was male and 40% <12 years of age. The target sample size was 256 children; 251 patients were finally included. The most frequent reasons given for not participating were: absence or mildness of symptoms, absence of house dust mite allergy, and being allergic to grass pollen or tree pollen only. Asthma symptoms were reported by 37% of the children. Of the enrolled children, 71% was sensitized to both house dust mite and grass pollen. Roughly similar proportions of children were diagnosed as being sensitized to one, two, three or four common inhalant allergens. CONCLUSION: Our study was designed in accordance with recent recommendations for research on establishing the efficacy of sublingual immunotherapy; 98% of the target sample size was achieved. This study is expected to provide useful information on sublingual immunotherapy with house dust mite allergen in primary care. The results on efficacy and safety are expected to be available by 2010. TRIAL REGISTRATION: the trial is registered as ISRCTN91141483 (Dutch Trial Register).

Immunotherapy in children and adolescents with allergic rhinoconjunctivitis: a systematic review.

Allergen-specific immunotherapy is one of the cornerstones of allergic rhinoconjunctivitis treatment. Since the development of non-invasive administration forms with better safety profiles, there is an increasing tendency to prescribe immunotherapy in youngsters. However, no overview is available on the efficacy of immunotherapy in all its different administration forms in youngsters. Therefore, we systematically reviewed randomized controlled trials (RCTs) to evaluate the effect of immunotherapy with inhalant allergens on symptoms and medication use in children and adolescents with allergic rhinoconjunctivitis. Medline, EMBASE, the Cochrane Controlled Clinical Trials Register and reference lists of recent reviews and published trials were searched. RCTs including youngsters aged 0-18 yr with allergic rhinoconjunctivitis and comparing immunotherapy with placebo, symptomatic treatment or a different administration form of immunotherapy were included. Primary outcome measures were rhinoconjunctivitis symptom and/or medication scores. Methodological quality was assessed using the validated Delphi list. A method of best evidence synthesis, a rating system with levels of evidence based on the overall quality and the outcome of the trials, was used to assess efficacy. Six subcutaneous (SCIT), four nasal (LNIT), seven oral (OIT) and 11 sublingual (SLIT) immunotherapy trials, comprising 1619 youngsters, were included. Only 39% of the trials were of high methodological quality. For the SCIT and OIT subgroups the level of evidence for efficacy was conflicting. Moderate evidence of effect was found for LNIT. Analysis of the SLIT subgroup showed no evidence of effect. The evidence for the perennial and seasonal allergen trials within the subgroups varied from moderate evidence of effect to no evidence of effect. In conclusion, there is at present insufficient evidence that immunotherapy in any administration form has a positive effect on symptoms and/or medication use in children and adolescents with allergic rhinoconjunctivitis.

Sublingual immunotherapy with grass pollen is not effective in symptomatic youngsters in primary care.

BACKGROUND: Sublingual immunotherapy (SLIT) is considered safer and more convenient than subcutaneous therapy and therefore has been proposed as especially suitable for children and in primary care. Most efficacy studies in children lack power to be conclusive, and all have been performed in referral centers. OBJECTIVE: To investigate the efficacy of SLIT with grass pollen allergen in children and adolescents with rhinoconjunctivitis in a primary care setting. METHODS: Youngsters aged 6-18 years with hay fever were enrolled from general practices and randomly assigned to receive placebo or grass pollen mix for 2 years. The primary outcome was the mean daily total symptom score (scale 0-15) comprising sneezing, itching nose, watery running nose, nasal blockage, and itching eyes during the months May-August of the second treatment year. RESULTS: Out of 204 youngsters randomized, 168 entered the intention-to-treat analysis (91 verum, 77 placebo). The mean daily total symptom score did not differ between participants allocated to verum and those allocated to placebo (difference for verum minus placebo: -0.08, 95%CI, -0.66-0.50; P = .78). No differences were found for rescue medication-free days, disease-specific quality of life, and overall evaluation of the treatment effect. Local side effects were more frequent in the verum group (39% vs 17% of participants; P = .001). CONCLUSION: Sublingual immunotherapy with grass pollen in a primary care setting is not effective in children and adolescents. CLINICAL IMPLICATIONS: Currently, SLIT cannot be recommended for general practitioners as a therapeutic modality in youngsters with grass pollen allergy.

Dual energy X-ray absorptiometry outcomes in male COPD patients after treatment with different glucocorticoid regimens.

STUDY OBJECTIVES: To compare bone mineral density (BMD) outcomes of patients who received continuous oral systemic glucocorticoids (GCs) with BMD outcomes of patients who received multiple GC courses, oral or IV. DESIGN: Cross-sectional study. PARTICIPANTS: Eighty-six white men with COPD selected from the outpatient clinic for pulmonary diseases. INTERVENTION: Data analysis from medical records, bone densitometry, and pulmonary function tests of consecutive selected patients. Inclusion period into the study was exactly 1 year. MEASUREMENTS AND RESULTS: Ten patients received oral prednisolone daily (group 1). Eleven patients were treated for several exacerbations with multiple systemic prednisolone courses, up to a period of 2 weeks per course, with a cumulative dose of > or = 1,000 mg (group 2). Likewise, 28 patients were treated with multiple systemic prednisolone courses, but with a cumulative dose < 1,000 mg (group 3). Thirty-seven patients were never treated with systemic prednisolone, and partly with inhaled corticosteroids (ICS) [group 4]. All groups were balanced for age and pack-years of smoking. In group 2, body mass index (BMI) and FEV(1) were lowest and hyperinflation was highest. The cumulative systemic prednisolone dose was highest in group 1, irrespective of the additional ICS treatments. Dual energy x-ray absorptiometry scanning of the lumbar spine, total hip, and femoral neck regions revealed a T score < or = 2.5 SD in 27 patients (31%), 31 patients (36%), and 34 patients (40%), respectively. BMD outcomes at any site were lower in patients receiving multiple systemic prednisolone courses > 1,000 mg, cumulatively (group 2), compared to the other groups, and these values were (mean +/- 1 SD) 0.759 +/- 0.238 g/cm(2), 0.683 +/- 0.115 g/cm(2), and 0.686 +/- 0.125 g/cm(2), respectively (p < 0.0001). Multivariate regression analysis revealed a correlation between the cumulative dose of prednisolone in group 2 and BMD of the lumbar spine (adjusted r = 0.48; p < 0.01). At the total hip and femoral neck regions, only a correlation between BMI and BMD was observed (adjusted r = 0.65 and 0.58, respectively; p < 0.0001 for both sites). CONCLUSIONS: Despite a far lower cumulative GC dose in comparison with patients treated with systemic corticosteroids continuously, after adjusting for BMI and lung function, osteoporosis of the lumbar spine was most frequent in patients receiving > 1,000 mg of prednisolone cumulatively, administered in multiple courses for the treatment of exacerbations of COPD.