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Monday, February 8, 2016

Sublingual grass and ragweed immunotherapy: Clinical considerations—a PRACTALL consensus report

In early 2014, the Food and Drug Administration approved three sublingual allergen immunotherapy (SLIT) products for use in the United States: a 5-grass tablet, a timothy grass tablet, and a ragweed tablet. The approval was based on multicenter clinical trials with large patient populations and supported by decades of real-life use in Europe. Li et al. have provided a consensus report of the experts of the American Academy of Allergy, Asthma and Immunology (AAAAI) and European Academy of Allergy and Clinical Immunology (EAACI) for the prescribing clinician (J Allergy Clin Immunol 2016; 137(2): 369-376).

The decision to use SLIT depends on practical considerations, cost, convenience, and patient preference. Within the current therapeutic options for allergic rhinitis, SLIT offers a therapy that can be self-administered at home and has the potential to permanently alter the course of allergic disease. In addition to those patients who prefer a disease-modifying approach, SLIT may work well for those with disease that does not respond to standard pharmacotherapy. While preliminary studies suggest it has a beneficial effect on asthma, asthma alone is not a clinical indication.

There is currently insufficient evidence to make a meaningful comparison between SLIT and subcutaneous immunotherapy (SCIT), but the current data suggests both routes reduce symptom scores and rescue medication use. Systemic reviews and meta-analyses suggest the clinical effect size may be greater for SCIT than SLIT, but the findings are not definitive. There have also been no head-to-head comparisons of SLIT with as-needed medications such as second generation antihistamine or nasal corticosteroids, but indirect comparisons suggest SLIT’s efficacy can be as good as SCIT. An important addition is that SLIT can provide sustained benefits for up to two years after discontinuation of three years of treatment as previously observed for SCIT.

The most common adverse events associated with SLIT are local reactions, such as gastrointestinal symptoms, which affect up to 75% of patients. Most occur shortly after treatment initiation and cease without medical intervention. Patients often also experience irritation in the lips, tongue, or throat. The incidence rate of fatal and near-fatal systemic reactions is low, likely lower than that of SCIT; and severe anaphylaxis is rare. Data from three large, pivotal European trials have indicated SLIT is efficacious and safe for children. Evidence also suggests that in children with allergic rhinitis, SLIT may decrease the rate of future asthma development.


Predictive value of nonspecific bronchial responsiveness in occupational asthma

The diagnosis of occupational asthma (OA) poses challenges to the clinician and requires a stepwise approach. The American College of Chest Physicians has recently published a consensus on this approach, also providing guidelines that indicate “the absence of airway hyper-responsiveness on challenge testing has a fairly high negative predictive value (NPV) for current symptomatic asthma, and can generally be used to rule out active disease.” Pralong et al. have verified this statement, evaluating the sensitivity, specificity, and positive and negative predictive values of the methacholine challenge in the diagnosis of occupational asthma (J Allergy Clin Immunol 2016; 137(2): 412-416).

The authors used a Canadian database to review 1012 cases of workers who, between the years of 1983 and 2011, were referred for suspicion of having occupational asthma and who underwent a specific inhalation challenge (SIC). SIC is considered the gold standard for diagnosing OA. It entails a first day of testing during which a patient is exposed to a control substance followed by a methacholine challenge. The patient is then exposed to the suspected causative occupational agent and undergoes another methcholine challenge. Among the 1012 patients reviewed, the median exposure duration was seven years, the median symptom duration was one year, and the median delay between exposure cessation and testing was two months. SIC confirmed OA in 27.5% of the cases.


Results presented here are the first to confirm two current recommendations. First, a negative methacholine challenge during the time in which the patient is still working at the exposure site makes the diagnosis of OA highly unlikely, as the negative predictive value (NPV) of the test in this population while at the workplace was 95.2%. Second, the NPV rose to 97.7% when considering all patients who had undergone a methacholine challenge at least once while at work at the exposure site, and it fell to 82.2% among patients who were tested off-site. The data demonstrate the utility of the methacholine challenge and indicates that, when possible, an OA diagnostic workup is best done when the patient is still working at the location of exposure.

Tuesday, January 12, 2016

Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology

Mastocytosis is a condition characterized by expansion of clonal mast cells in various organ systems, often in association with activating KIT mutations. The organs most frequently affected are the skin and bone marrow. Traditionally, the disease is divided in cutaneous mastocytosis (CM) and systemic mastocytosis (SM). CM is further divided into maculopapular cutaneous mastocytosis (MPCM), also known as urticaria pigmentosa, diffuse cutaneous mastocytosis (DCM), and mastocytoma of skin. Children with mastocytosis usually have CM, whereas the majority of adults are diagnosed with SM. Both children and adults usually present with typical cutaneous (red or brown) lesions.

These cutaneous lesions are highly heterogeneous, encompassing local and disseminated forms. Overall there is a need for a better definition and a clinically meaningful classification of cutaneous lesions detectable in CM and SM. To address this need, an international task force of experts from the European Competence Network on Mastocytosis, the American Academy of Allergy, Asthma, and Immunology, and the European Academy of Allergology and Clinical Immunology met several times between 2010 and 2014. The resulting task force report published by Hartmann et al. in the current issue includes updated criteria for CM, a revised classification of cutaneous lesions, and related recommendations for daily practice (J Allergy Clin Immunol 2016; 137(1): 35-45).

Among other recommendations, the authors indicate that maculopapular cutaneous mastocytosis (urticaria pigmentosa) lesions should be subdivided into two distinct variants: a monomorphic variant characterized by small monomorphic maculopapular lesions that are typically found in adult patients, and a polymorphic variant with larger lesions of varying shape and size that are almost only detectable in children. Clinical experience suggests that the lesions of the monomorphic variant, when detected in children, always persist into adulthood, whereas the polymorphic lesions – when seen – usually fade away and disappear until puberty.

These observations highlight the prognostic value of a detailed inspection and subsequent classification of skin lesions in UP, and the related clinical implication for the management of patients in daily practice. Another recommendation of the task force group is that the Darier’s sign should be regarded as standard method for the evaluation and diagnosis of adult patients with mastocytosis with skin involvement.

Friday, January 8, 2016

Autoimmunity of the lung and oral mucosa in a multisystem inflammatory disease: the spark that lights the fire in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a systemic autoimmune disease that primarily manifests in synovial joints, such as those in the hands and feet. It can appear at any age in life and affects up to 1% of the population. While it is classified based on the presence of articular inflammation, a growing body of evidence indicates that RA autoimmunity begins outside of the joint. Circulating rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), anti-peptidylarginine deiminases (anti-PAD4), and anti-carbamylated proteins (anti-CarP) have been detected in many people years prior to the development of joint symptoms and an RA diagnosis. Several lines of investigation have implicated mucosal tissues of the lung and oral cavity as possible sites of initial autoantibody generation and inflammation. Mikuls et al. review the recent reports of this line of investigation (J Allergy Clin Immunol 2016; 137(1): 28-34).

In addition to harboring host inflammatory cells, mucosal tissues support a rich and diverse microbiome, which is increasingly understood to contribute to host immunity and autoimmunity. Mucosal tissues provide the first line of defense against environmental challenges such as invading pathogens and cigarette smoke. Both of these have been shown to be RA risk factors. Approximately one in six new cases of RA are attributable to smoking, with the risk highest among those who carry the HLA-DRB1 shared epitope. Disease-related autoantibodies in RA include IgA isotypes; the mucosal immune system and the ectopic lymphoid tissues that can develop at mucosal surfaces show dense infiltration by IgA-producing plasma cells.

Patients with RA often have extra-articular, pulmonary complications, and a number of reports of pulmonary involvement preceding joint symptoms in seropositive patients underscore the possibility that RA may be initiated in the lung. Disease-related antibodies have been detected in sputum, and in higher levels than in sera. Those with RA are also prone to disorders characterized by chronic oral inflammation, and the authors have recently found such patients showed a 50% greater prevalence of chronic periodontitis (PD) than those with osteoarthritis. The association was strongest among patients with ACPA-positive disease. 

The evolving evidence presented here suggests the lung and periodontium can be producers or reservoirs of RA-related auto-antigens. Much remains to be elucidated. Such questions include: a) What are the mechanisms through which this autoimmunity leads to the development of an articular disease? b) Does the same occur in other mucosal surfaces? c) Might the initiating site vary across individuals? 

The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects

Autoimmunity and immunodeficiency represent two sides of the same coin. Whether the human body’s defenses attack its own healthy cells or its ability to fight off disease is compromised, both result in a dysfunctional immune system. In their review article, Grimbacher et al. discuss the contribution of various immune system genes to common polygenic autoimmune disorders, as well as the pathophysiological pathways and clinical features of monogenic defects that result in autoimmune disease (J Allergy Clin Immunol 2016; 137(1): 3-17).

Multiple single gene defects have been shown to result in rare diseases that show features of both autoimmunity and immunodeficiency. Nearly 300 monogenic traits have been associated with various forms of primary immunodeficiency diseases and auto-inflammatory syndromes. It is likely that more common autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) result from a polygenic inheritance. Genes implicated in single gene disorders have also been linked to polygenetic disorders thus confirming the intricate connections and overlays between autoimmunity and immune deficiency,

In the case of SLE, genome-wide association studies and their follow-up studies have identified more than 50 robust loci associated with susceptibility, suggesting polygenic disease development. There are also emerging monogenic SLE disease models, as factors such as early disease onset, familial SLE, and syndromal lupus likely involve monogenic defects. The authors outline nine pathophysiological pathways, which, if impaired, inevitably lead to serious disease and ultimately to autoimmunity.

Different pathways can lead to the development of a given disease.. Autoimmunity is one of these etiopathologies, and recent and continued advancement in detection methods, in particular next generation sequencing, has led to the identification of genetic defects associated with autoimmune phenotypes. The monogenic defects explored here all interrupt the equilibrium of the immune system, and they have already begun to influence and change our patients’ management. 

This review thus emphasizes of looking at immune dysfunction as a whole rather than breaking it down into silos of immunodeficiency and autoimmunity

Monday, December 7, 2015

Efficacy of baked milk oral immunotherapy in baked milk-reactive allergic patients

Oral immunotherapy (OIT) has shown overall benefit in desensitizing many patients with persistent IgE-mediated food allergy. Still, the treatment is not without adverse reactions. In a large OIT milk treatment program conducted in Israel, approximately 15% of patients were unable to follow it to completion because of IgE-mediated reactions. Some patients with allergy to unheated milk or egg tolerate such foods when they are heated, as heating likely induces conformational changes to a number of the epitopes responsible for IgE binding.

Goldberg et al present a study of 14 children who failed unheated- or unbaked-milk OIT who received OIT with baked milk testing the hypothesis that this might result in desensitization to to unheated milk as well (J Allergy Clin Immunol 2015; 136(6): 1601-1606). Only three of the children tolerated the primary outcome dose of 1.3 g of baked milk protein, and eight out of the other 11 experienced IgE-mediated reactions, including two patients with anaphylactic episodes requiring intramuscular epinephrine. The three children who reached the 1.3 g baked milk dose were able to tolerate up to 900 mg of unheated milk at the end of the study, and all patients remaining in the program through 12 months demonstrated an increase in tolerance to unheated milk The authors also provide evidence that a basophil activation test, comparing patient reactivity to heated or unheated milk, could prospectively distinguish between patients succeeding or failing to complete the program.

The study contributes to our understanding of the benefits and risks of OIT, which continue to be under close scrutiny. The results indicate caution is required, and more work must be done before baked milk OIT is used freely in milk-reactive patients. 

Friday, December 4, 2015

Randomized controlled trial of primary prevention of atopy using house dust mite oral immunotherapy in early childhood

The epidemic proportion of atopic diseases in the last 30 years has resulted in major health and economic effects. Atopy is believed to be due to a genetic propensity to produce IgE antibodies in response to an allergen; such propensity is due to an imbalance between various lymphocyte subsets,TH1, TH2 and T regulatory (Treg) cells in particular. In the absence of early intervention, children born with atopic diathesis are likely to develop allergic disease. Zolkipli et al. report the results of a house dust mite allergy prevention study conducted in infants (J Allergy Clin Immunol 2015; 136(6): 1541-1547). 

Overcoming maturation deficiencies in the developing immune system and countering TH2 bias requires a very early strong and adequate immune stimulation. In the first 18 months of life, the gut is the primary site of Treg cells stimulation in response to antigens, suggesting oral exposure is likely the most effective in inducing tolerance. The authors hypothesized that exposure to a ubiquitous allergen, such as house dust mite (HDM), would result in both HDM-allergen-specific and a more generalized desensitization effect preventing the atopic march. One hundred eleven infants less than one year of age who had two or more first-degree relatives with allergic disease received an oral administration of HDM extract twice daily for 12 months.

The authors found that HDM-allergen extract induced a significant reduction in sensitization to any common allergen as compared to placebo. There was, interestingly, no significant difference in the cumulative proportion of infants who developed HDM-specific sensitization between the active and placebo groups, nor did HDM-allergen extract impact the number who developed eczema, wheeze, or food allergy. The intervention was well-tolerated, with no differences between the two groups in relevant adverse events.


This early proof-of-concept study points to a feasible, safe, and effective preventive measure. High-dose HDM-allergen extract appears to exert a prophylactic effect on the development of atopy, as defined by skin prick test response to any common allergen. Preventive reduction in allergen sensitization in early childhood may translate into a reduction of asthma, eczema, rhinoconjunctivitis, and food allergy as children at risk for these diseases grow up.