Thursday, June 28, 2012
Exciting – and surprising – results from a clinical trial for psoriasis are presented in this month’s issue by Krueger et al (J Allergy Clin Immunol 2012;130:145-154.e9). The authors report on a randomized trial of a new humanized IgG4 monoclonal antibody, ixekizumab. It would be fair to say the results from their phase I trial are near astonishing.
Based on published evidence that psoriasis is a TH17-mediated disease, the authors postulate that IL-17 acts as a “gatekeeping” cytokine in the pathogenesis of psoriasis, noting that much of the evidence from animal studies points to IL-22. They point out that IL-22 in humans is produced from a different T cell subset, TH22 cells, unlike mice where TH17 cell produce both.
Their speculation paid off. Krueger et al. report dose-dependent, significant improvement in both pathophysiology and clinical presentation of psoriasis subjects after only 2 weeks of ixekizumab treatment. Skin biopsies from subjects demonstrated rapid improvements in keratinocyte proliferation, hyperplasia, epidermal thickness, T cell and dendritic cell infiltration of the dermis and significantly suppressed expression of innate immunity peptides. After 6 weeks of treatment, the authors report that subjects’ skin appeared normal. Interestingly, 100% of subjects in the 150mg dosing group no longer presented clinically with psoriasis at 6 weeks of therapy. Krueger et al. comment that the effectiveness of ixekizumab at 2 and 6 weeks was surprising since other antibody therapies typically require 12 weeks to demonstrate efficacy. They also note that the adverse effects profile is agreeable and the drug well-tolerated.
Noting that many genes associated with psoriasis are co-regulated by IL-17 and TNF-α, Krueger et al. show that IL-17 blockade with ixekizumab is far more effective in suppressing the co-regulated genes than TNF-α blockade by etanercept. They suggest that their evidence shows that IL-17 is a pivotal cytokine in the pathology of psoriasis, affecting many effector functions of other T cell subsets.
The consistent observation that developing countries have very low frequencies of atopy and allergic diseases has been correlated with environmental exposure to helminth infection. The hygiene hypothesis has been proffered to account for these observations as it has to explain protective effects of living on traditional farms. Small numbers of pilot and proof-of-concept trials have been looking at the nematode-allergy connection as possible therapy for a number of diseases.
This month’s issue presents a review by Jouvin and Kinet (J Allergy Clin Immunol 2012;130:3-10) of this pioneering research and the preliminary results that suggest that certain helminths may be human symbionts rather than parasites.
Jouvin and Kinet begin with an overview of current research into nematode therapy for inflammatory bowel and autoimmune diseases, employing Trichurus suis ova (TSO), or pig whipworm, to treat patients with Crohn’s Disease (CD), ulcerative colitis (UC) and multiple sclerosis (MS). The trials were very small, from 4 subjects to 54 subjects, with safety and tolerability as the endpoints. There were no AEs reported in the CD and UC trials, and mild GI distress and transient eosinophilia in the MS trial that resolved without subjects dropping out from the studies. Stool specimens collected were all negative for ova and parasites, except an isolated sample in the MS trial. These limited safety results were sufficient for FDA to approve an open-label efficacy study of TSO in MS.
Jouvin and Kinet review the basics of the hygiene hypothesis and discuss the epidemiological and animal evidence for immunomodulatory effects of helminths, as well as limited results of helminth treatment in Western countries. The authors also cover the logic supporting the choice of TSO, in particular because it is not a known human pathogen.
They summarize the safety findings of published research and note their own experience with TSO in the treatment of peanut or tree nut allergy, which was consistent with other reports of transient, mild GI side effects and eosinophilia. Secondary efficacy reports are also included, with some preliminary findings being promising: in a study of CD, 70% of subjects attained remission at the end of the study; in a UC trial, 43% in the treatment group had improved disease compared to 17% in the control group; and in an MS study, a lower rate of appearance of new lesions imaged by MRI was observed during active treatment. The authors also present an interesting single case report on nematode treatment for autism.
Jouvin and Kinet discuss the potential of other nematodes as therapeutic agents then review the biochemistry of helminth extracts, noting that a phosphorylcholine glycoprotein, ES-62, has been isolated as an effector molecule. They comment that ES-62 prevent mast cell activation and modulate TH17 responses. Also, ES-62 has been shown to require TLR4 for its activity.
The authors conclude that TSO as seen from very preliminary data is safe and well tolerated, and limited data suggests it ameliorates certain autoimmune diseases. They urge continued research on the mechanisms and optimal dosing to achieve immunomodulation.
Friday, June 1, 2012
On behalf of the GABRIEL Advanced Studies Group supported by the European Commission, Illi et al. (J Allergy Clin Immunol 2012;129:1470-1477) provide their results from a survey study designed to address the high variability in reported protective effects associated with farm environments on asthma and allergies (pp#). The study group survey was structured into two phases with questions in phase II targeting exposure to specific elements of the farm environment. Farms were placed in one of three categories depending on farm activities and husbandry: farms with no dairy cows or cattle, but other farm animals, and grain cultivation, farms with dairy cows and/or cattle, but no grain cultivation, and finally, farms with dairy cows and/or cattle, and grain cultivation. Survey queries covered exposure in utero to 3 years.
Illi et al. report that protective effects were highest and most broad for children raised on farms with both cows and cattle and agriculture activities. Exposure to cows, cows’ milk and straw had the greatest protective effect for asthma, exposure to fodder storage and manure were most protective on atopic dermatitis. Interestingly, the data collected could not sufficiently account for the protective effect against hay fever and atopic sensitization. Overall single exposure effect was greatest with cows’ milk, which greatly reduced the risk of asthma, hay fever and atopic sensitization. Exposure to straw had the strongest association with asthma protection, though the authors noted that the effects of individual constituents and contaminants in straw, such as manure, grass pollen, and microbial elements, could not be separated out.
Illi et al. comment that protective associations supported different physiological pathways, noting that cow exposure was associated with respiratory disease protection and cows’ milk association with atopic sensitization pointed to gut-mediated immune development.
This month, Rondón et al. (J Allergy Clin Immunol 2012;129:1460-1467) present an important classificatory revision centered on their identification of a new rhinitis phenotype: local allergic rhinitis (LAR). Building on their previous research, the authors characterize LAR as local specific IgE (sIgE), TH2 local tissue response, and positive nasal allergen provocation test (NAPT) results in the absence of clinical indicators of systemic atopy, such as positive skin tests and serum specific-IgE. Patients with LAR are known to respond positively to nasal corticosteroids. In addition, they note that conjunctivitis and/or asthma can be comorbid with LAR.
Rondón et al. effectively argue that the current allergic versus non-allergic rhinitis (AR and NAR, respectively) distinction is not sufficient in light of the findings of localized atopy. They suggest that patients diagnosed with idiopathic rhinitis or non-allergic rhinitis with eosinophilia may in fact have LAR, which would decisively impact clinical management as patients with true idiopathic or non-allergic (vasomotor) rhinitis would not respond to therapy like LAR patients would.
The authors propose a revised rhinitis classification (Table 1, pp#) that splits allergic rhinitis into systemic and local atopy subcategories. They estimate prevalence from European data to be between 47-62% of patients reporting seasonal or perennial allergy symptoms. Their and other early results have shown that house dust mite, grass, and olive pollen are common triggers, though they note that comprehensive findings are needed to refine NAPT specificity.
Rondón et al. review the published pathophysiology evidence as well as the reported clinical presentation. They clearly identify the gaps that future research should fill, such as clinical management overlap between AR and LAR, the need for more practical NAPT testing procedures, the relationship between LAR and atopic march, and mechanisms of localized allergic responses. The authors comment that patients with LAR receiving subcutaneous immunotherapy have increased tolerance upon repeat NAPT and also develop positive skin tests and detectable serum specific-IgE.