Simon Francis Thomsen

Heredity in sarcoidosis: a registry-based twin study.

Background: Sarcoidosis is a multiorgan granulomatous inflammatory disease of unknown aetiology. Familial clustering of cases and ethnic variation in the epidemiology suggests a genetic influence on susceptibility to the disease. This paper reports twin concordance and heritability estimates of sarcoidosis in order to assess the overall contribution of genetic factors to the disease susceptibility. Methods: Monozygotic and dizygotic twins enrolled in the Danish and the Finnish population-based national twin cohorts (61 662 pairs in total) were linked to diagnostic information on sarcoidosis obtained from the Danish National Patient Registry or the Social Insurance Institution, Finland registry of reimbursed medication using the 8th and 10th editions of the International Classification of Diseases. The Fisher exact test was used to compare probandwise concordance rates in different zygosity groups. Heritability was estimated based on a multifactorial threshold liability model. Results: A total of 210 twin pairs with at least one proband with a diagnosis of sarcoidosis were identified. The probandwise concordance rate was higher in monozygotic than in dizygotic twins (0.148 vs 0.012). Compared with the general population there was an 80-fold increased risk of developing sarcoidosis in co-twins of affected monozygotic brothers or sisters. The increased risk in dizygotic twins was only 7-fold. Aetiological model fitting gave a heritability of sarcoidosis of 0.66 (95% CI 0.45 to 0.80). Conclusions: This study suggests that genetic factors play an important role in the susceptibility to sarcoidosis. This result should encourage the search for molecular genetic markers of susceptibility to the disease.

Atopic Dermatitis: Natural History, Diagnosis, and Treatment

Atopic dermatitis is an inflammatory skin disease with early onset and with a lifetime prevalence of approximately 20%. The aetiology of atopic dermatitis is unknown, but the recent discovery of filaggrin mutations holds promise that the progression of atopic dermatitis to asthma in later childhood may be halted. Atopic dermatitis is not always easily manageable and every physician should be familiar with the fundamental aspects of treatment. This paper gives an overview of the natural history, clinical features, and treatment of atopic dermatitis.

Increased concordance of severe respiratory syncytial virus infection in identical twins

OBJECTIVE. We estimated differences in the severity of respiratory syncytial virus infection attributable to genetic and environmental factors. METHODS. Record linkage data on hospitalizations attributable to respiratory syncytial virus infection were gathered on all twins (12346 pairs) born in Denmark between 1994 and 2003. Latent-factor models of genetic and environmental effects were fitted to the observed data by using maximal likelihood methods. RESULTS. Identical twins resembled each other significantly more than did fraternal twins for respiratory syncytial virus hospitalization (concordance rate: 0.66 vs 0.53), which suggests genetic influences on disease severity. Genetic factors accounted for 16%, family environment for 73%, and nonshared environment for 11% of the individual susceptibility to develop severe respiratory syncytial virus infection. CONCLUSIONS. The severity of respiratory syncytial virus infection is determined partly by genetic factors. This result should stimulate the search for genetic markers of disease severity.

Epidemiology and natural history of atopic diseases

The atopic diseases – atopic dermatitis, asthma, and hay fever – pose a great burden to the individual and society, not least, since these diseases have reached epidemic proportions during the past decades in industrialized and, more recently, in developing countries. Whereas the prevalence of the atopic diseases now seems to have reached a plateau in many Western countries, they are still on the increase in the developing world. This emphasizes continuing research aimed at identifying the causes, risk factors, and natural history of these diseases. Herein, the fundamental aspects of the natural history and epidemiology of the atopic diseases are reviewed.

Diagnostic properties of inhaled mannitol in the diagnosis of asthma: A population study

BACKGROUND A new indirect bronchial provocation test measuring airway responsiveness by using inhaled mannitol was recently introduced. OBJECTIVE The aim of this study was to examine the diagnostic properties of airway responsiveness to inhaled mannitol in the assessment of asthma in an unselected sample of young adults. METHODS Two hundred thirty-eight young adults randomly drawn from the nationwide civil registration list were challenged with inhaled, dry-powder mannitol. A respiratory specialist, blind to the test results, classified all 238 subjects with respect to the presence of asthma. The classification was based on respiratory symptoms, spirometric results, atopy, and fraction of exhaled nitric oxide values and response to inhaled beta(2)-agonists. On this basis, sensitivity, specificity, and predictive values were assessed to different cutoff values of the test. A receiver operating characteristic curve was constructed, and the accuracy of the test, defined as the area under the curve, was computed. RESULTS Fifty-one (21.4%) subjects had current asthma. Of 33 subjects with airway hyperresponsiveness to mannitol, 30 had current asthma. The specificity and sensitivity were 98.4% (95% CI, 96.2% to 99.4%) and 58.8% (95% CI, 50.7% to 62.6%), respectively. The positive predictive value (PPV) and negative predictive value (NPV) were 90.9% (95% CI, 78.4% to 96.8%) and 89.8 (95% CI, 87.7% to 90.7%), respectively. The area under the receiver operating characteristic curve was 0.89 (95% CI, 0.83-0.95). CONCLUSIONS In an unselected sample of young adults, bronchial provocation with inhaled dry-powder mannitol had a high diagnostic specificity for the diagnosis of asthma.

Causal direction between respiratory syncytial virus bronchiolitis and asthma studied in monozygotic twins.

BACKGROUND Respiratory syncytial virus (RSV) bronchiolitis has been associated with later development of asthma, wheezing, abnormal pulmonary function, and sensitization. Our aim was to determine the differential effect within monozygotic (MZ) twin pairs discordant for severe RSV bronchiolitis in infancy on the subsequent development of asthma, pulmonary function, and allergy. METHODS Thirty-seven MZ twin pairs discordant for RSV hospitalization in infancy (mean age 10.6 months) were compared at the mean age of 7.6 years for lung function, bronchial responsiveness, fractional exhaled nitric oxide (Feno), asthma diagnosis, use of asthma medication, and skin prick test to common inhalant allergens. RESULTS There were no differences within MZ twin pairs discordant for RSV hospitalization in infancy with respect to pulmonary function, Feno, asthma prevalence, asthma medication use, or sensitization (P > .1 for all comparisons). CONCLUSIONS We found no differential effect from severity of RSV infection on the development of asthma and allergy in MZ twin pairs discordant for RSV hospitalization in infancy. This argues against a specific effect of severe RSV infection in the development of asthma and allergy. Because of the small sample size, this study must be considered as a hypothesis-generating study.

Response to mannitol in asymptomatic subjects with airway hyper‐responsiveness to methacholine

Background Bronchial provocation using methacholine, a cholinergic agonist, causes airway narrowing directly by contraction of bronchial smooth muscle. While methacholine has a high sensitivity for identifying airway hyper‐responsiveness (AHR), it does not have a high specificity to diagnose asthma and false‐positive responses may be observed in non‐asthmatics. Mannitol is an osmotic stimulus that acts indirectly to cause airway narrowing by release of endogenous bronchoconstricting mediators.

Effectiveness and safety of omalizumab in chronic spontaneous or inducible urticaria: evaluation of 154 patients.

DEAR EDITOR, Out-of-trial data on long-term safety and predictors of effectiveness of omalizumab (anti-IgE) in chronic urticaria are lacking. We evaluated the outcome of treatment with omalizumab in a large cohort of patients with chronic spontaneous or chronic inducible urticaria (CSU and CINDU, respectively). Data were retrieved via retrospective review of patient records from a tertiary dermatological referral centre (Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark). Complete ascertainment of patient records was possible as the department keeps track of all administered biological therapy. A consultant dermatologist (S.F.T.) verified the urticaria diagnosis and assessed response to treatment. Two authors (M.N.G. and S.F.T.) extracted the data and, in cases of disagreement, consensus was obtained by discussion with all the authors. According to Danish law, scientific ethics approval is not needed for retrospective chart reviews. Approval for the study was obtained from the National Board of Health (to examine patient records) and from the Data Protection Agency (to save patient data on file). All patients diagnosed with CSU or CINDU who had received at least one injection of omalizumab from 30 June 2010 to 31 December 2014 were included in the study. Response to omalizumab treatment was graded according to the degree of relief of symptoms reported by the patient and according to the physician’s assessment. It was possible to score the clinical response to treatment with omalizumab for each patient as a ‘complete or almost complete response’, ‘partial response’ and ‘no/limited response’ after 3–6 months of treatment. This grading is in accordance with the modified physician global assessment used in other dermatological diseases, where a complete or almost complete response corresponds to ≥ 90% reduction of symptoms; partial response is reduction in symptoms of between 30% and 89%; and no response or a limited response is a reduction in symptoms of < 30%. In total, 154 patients were identified; 110 (71 4%) women and 44 (28 6%) men (Table 1). The majority of the patients were diagnosed with CSU (89 0%). Of these, 30 7% had concomitant angioedema, 34 3% had a positive histamine release (HR) test and 22 6% had significant comorbidities, the most common being asthma, diabetes, hypertension and hypothyroidism. The 17 patients with CINDU had delayed-pressure urticaria (n = 5), cold urticaria (n = 5), cholinergic urticaria (n = 4), symptomatic dermographism (n = 2) and solar urticaria (n = 1). The average age at disease onset was significantly

TNF-Alpha Inhibitors for Chronic Urticaria: Experience in 20 Patients

Patients with severe chronic urticaria may not respond to antihistamines, and other systemic treatment options may either be ineffective or associated with unacceptable side effects. We present data on efficacy and safety of adalimumab and etanercept in 20 adult patients with chronic urticaria. Twelve (60%) patients obtained complete or almost complete resolution of urticaria after onset of therapy with either adalimumab or etanercept. Further three patients (15%) experienced partial response. Duration of treatment ranged between 2 and 39 months. Those responding completely or almost completely had a durable response with a mean of 11 months. Six patients (30%) experienced side effects and five patients had mild recurrent upper respiratory infections, whereas one patient experienced severe CNS toxicity that could be related to treatment with TNF-alpha inhibitor. Adalimumab and etanercept may be effective and relatively safe treatment options in a significant proportion of patients with chronic urticaria who do not respond sufficiently to high-dose antihistamines or in whom standard immunosuppressive drugs are ineffective or associated with unacceptable side effects.

Off-label use of TNF-alpha inhibitors in a dermatological university department: retrospective evaluation of 118 patients.

Tumor necrosis factor‐alpha (TNF)‐alpha inhibitors are licensed for patients with severe refractory psoriasis and psoriatic arthritis. However, TNF‐alpha inhibitors have also been used off‐label for various recalcitrant mucocutaneous diseases. This study aimed to evaluate the efficacy and safety of TNF‐alpha inhibitors used for off‐label dermatological indications. We retrospectively evaluated patient records of 118 patients treated off‐label with TNF‐alpha inhibitors in a dermatological university department. Patients presented with severe aphthous stomatitis/genital aphthous lesions (26), chronic urticaria (25), hidradenitis suppurativa (29), acne conglobata (11), dissecting cellulitis of the scalp (two), orofacial granulomatosis (four), sarcoidosis (four), granuloma annulare (two), granulomatous rosacea (one), granuloma faciale (one), subcorneal pustulosis (one), pyoderma gangrenosum (four), Sweets syndrome (four), Wells syndrome (one), benign familial pemphigus (one), lichen planus (one), and folliculitis decalvans (one). A significant number of these patients went into remission during therapy with TNF‐alpha inhibitors. A total of 11 patients (9%) experienced severe adverse effects during therapy. Off‐label therapy with TNF‐alpha inhibitors may be considered for selected patients with severe recalcitrant mucocutaneous diseases. The risk of severe adverse effects signals that a thorough benefit–risk assessment should be performed before initiating off‐label treatment with TNF‐alpha inhibitors for these conditions.