New Treatments and Validations for Atopic Dermatitis in Humans after Comparative Approach with Canine Models

Abstract

This chapter aims to open doors to novel treatments of human Atopic Dermatitis (AD) after validation of successful response in canine AD. Dogs are currently the best model for the human disease and research in this species can benefit people. Interestingly, treatment options used in dogs (e.g., Allergen-specific immunotherapy, oral Janus Kinase Inhibitor and of a biologic targeting Interleukin-31) have equivalents in human medicine. Areas of interest for the future should focus on increasing the efficacy of allergen-specific immunotherapy, modulating non-specific immune response, restoring of cutaneous and gut microbiome by topical application or fecal transplant, and using stem cell therapy. The overall goal is to find treatments that are safe and sustainable to avoid broad spectrum immunosuppressive medications and repair bacterial imbalances in order to minimize the use of antibiotics in these patients.

1. Introduction

Canine atopic dermatitis (AD) has many similarities with the human counterpart both clinically and immunologically. For this reason, canine AD has been considered the best current model for the human disease [1] and many treatments used to treat canine patients are either used in human medicine or have great potential to be considered for people [2]. Dogs, like people, develop a chronic pruritic inflammatory disease that affects specific areas of the body and are prone to Staphylococcal infections which further aggravate the severity of pruritus. The disease in dogs is chronic progressive and it is associated in most cases with allergic sensitization to either foods or environmental allergens. The main route of sensitization in dogs is epicutaneous as the skin barrier function in atopic dogs is altered [3], similar to what is the case in people [4, 5]. Skin barrier defects have been documented in atopic dogs [6] and play an important role in disease development, as they do in humans [7, 8]. Since inflammation worsens skin barrier, these changes are progressive and promote additional sensitization in the lifetime of the patient [9]. Canine atopic patients undergo frequent course of antibiotics and are frequently affected by resistant infections. Thus, control of the disease is critical for both the quality of life of the animal and the owners, as well as to minimize the development and transmission of multidrug resistant bacteria.

As it is in people, the canine disease is multifactorial and the result of a combination of genetic and environmental factors. Atopic dermatitis in dogs has become increasingly common in westernized countries in the last few decades either because of increased awareness or because of changed life-style conditions. Processed foods, excessive exposure to indoor environments with dust mites, and decreased exposure to outdoor farm environments have been considered risk factors in dogs [10] as they are considered for people [11].

Similarly to humans, atopic dogs have less biodiversity in their cutaneous [12, 13] and gut microbiome [14, 15]. Skin microbiome dysbiosis in atopic dogs is particularly exacerbated during allergen induced flares [16]. Dysbiosis is also a hallmark of human AD [17] leading to a prominent Th2 response and a decreased regulatory response [18]. Significant efforts have been devoted to increase biodiversity and normalize the immune response, by either application of beneficial bacteria on the skin [19] or by fecal transplant [20, 21]. The latter has recently been tried in clinical patients in human medicine with encouraging results [22]. Since all these factors (diet, microbiome, skin barrier, sensitization to environmental allergens) are all interconnected, the approach to address canine AD has been multimodal and has relied on a variety of strategies ranging from symptomatic control of the inflammation, to skin barrier repair strategies, and allergen specific immunotherapy to address sensitization developed by the patient and promote tolerance.

Interestingly some treatments have been available first in veterinary medicine (e.g., oral Janus Kinase inhibitor for AD and biologic targeting IL-31) before an equivalent was approved in human medicine while for other medications, the opposite has been true. The advantage of testing treatment in dogs is that approval of studies is, on average, faster and easier and useful information can be obtained that can benefit both canine and human patients. As many atopic humans are children, testing of new strategies in dogs first is an appealing approach.

1.1 Currently approved treatments for canine AD

The clinical approach to canine AD includes short-term strategies to decrease pruritus and inflammation as well as long-term strategies to decrease the need of rescue medications and the severity of flares. Under the short-term strategies are the medications that rapidly and primarily address allergic cytokines. In this category, the most commonly used are glucocorticoids (either topically or systemically) and oclacitinib, a Janus Kinase (JAK) inhibitor.

Oclacitinib is an oral selective JAK1 inhibitor that targets the signaling of cytokines important for allergic inflammation [23]. The selectivity for JAK1 and the blockage of signaling of cytokines that are important for allergic inflammation rather than for innate immunity and hematopoiesis, are important considerations for the safety profile of oclacitinib. These characteristics make oclacitinib different from many of the initially approved JAK inhibitors in human medicine, drugs that target other JAK/STAT signaling pathways [24].

The speed of action of glucocorticoids and oclacitinib is comparable and measurable within a few hours after administration [25] thus, both strategies are suitable to quick relief from pruritus. Oclacitinib has been shown to significantly improve the quality of life of allergic dogs [26] and is not associated with increased risk of cancer [27]. This is an important difference between the use of JAK inhibitors in human medicine and oclacitinib in veterinary medicine. Many systemic JAK inhibitors in people have been used for the treatment of rheumatoid arthritis, inflammatory bowel disease, transplant rejection, and psoriasis [28]. In humans with rheumatoid arthritis and other autoimmune diseases, independent of the type of treatment, there is a concern for increased risk of certain malignancies [29, 30].

The JAK inhibitors currently considered for AD in people are topicals (e.g., ruxolitinib cream and delgocitinib ointment). Oral options (e.g., baricitinib (JAK1/2), abrocitinib (JAK1-selective), and upadacitinib (JAK1-selective) have been associated with nausea, headache, upper respiratory tract infection, and to a lesser degree, herpes infections [31]. No topical JAK inhibitor is currently available in veterinary medicine.

Another approach to canine AD and pruritus is the use of an injectable biologic, lokivetmab, that specifically targets canine Interleukin 31 (IL-31). IL-31 is a cytokine that has received a lot of interest in recent years for its role in mediating pruritus and allergic inflammation [32, 33]. Lokivetmab is a caninized monoclonal antibody that targets canine IL-31. Lokivetmab takes a few hours to days to work and may not work in all patients, but it is commonly used in clinical practice as either a monotherapy or an adjunctive therapy. In some patients that benefit may be seen in a few hours and duration seems to be dose dependent [34, 35]. Lokivetmab has also shown usefulness as a tool for a proactive control of the disease [36]. A proactive approach is becoming more popular in both veterinary and human medicine since atopic patients are prone to relapses. Treating the disease once the relapse has occurred requires more medications and drugs of a broader spectrum of action to induce remission. Instead, a proactive long-term maintenance regimen leads to increased time to flare and decreased need for rescue medications [37, 38]. In that context, lokivetmab is adopted more and more frequently by veterinarians to keep patients comfortable.

In human medicine, there is currently no approved monoclonal targeting IL-31 but there is an anti-IL-31 receptor α-chain (IL-31RA) monoclonal antibody, nemolizumab [39]. Interestingly, trials for biologics targeting human IL-31 have been registered, but no results have been published at this time; thus, the caninized monoclonal against IL-31 does not have an equivalent in human medicine.

Among treatments that require longer time to work and control canine AD are drugs such as cyclosporine, which may take 3–4 weeks to start working [40]. Cyclosporine is used for long-term symptomatic control of allergic dogs [41] and, prior to the development of oclacitinib and lokivetmab, was one of the most commonly prescribed treatments. Many dogs develop severe gastrointestinal adverse effects [42] and chronic use increases the risk of saprophytic infections [43, 44]. Cyclosporine is also used for severe cases of AD in people although some of the new biologics are decreasing its use [45, 46].

For the long-term control of canine AD, Allergen Specific Immunotherapy (ASIT) is frequently recommended [47]. It requires several months and is considered a long-term approach to reeducate the immune system and halt the progression of the disease. Allergen specific immunotherapy is used for patients with a long season and can be administered by various routes ranging from injectable to sublingual and intralymphatic, depending on formulations of allergens available in the specific country and the preferences of the owners and the clinician. In dogs, in the US, the most commonly used route of administration of the allergen has been subcutaneous while in Europe intralymphatic is done routinely [48, 49]. When the various routes of administration have been compared for efficacy in canine patients, the subcutaneous and the intralymphatic route have shown more efficacy than the sublingual route [50].

Interestingly, ASIT is frequently used for human patients with asthma and rhinitis and venom hypersensitivity [51], but its use for AD in people is not widespread. In fact, ASIT’s efficacy in human patients with eczema is still questioned [52]. Only recent studies have shown that ASIT is a beneficial adjunctive therapy for AD patients with allergic sensitizations [53] while in dogs its benefit for AD has been long recognized. In veterinary medicine, the dermatologist is also the allergist; thus, facilitating the process of allergy testing and the formulation of a custom-made vaccine. In human medicine, these are two different figures and AD has been considered for decades more of a disease of skin barrier rather than an allergic disease, thus ASIT is not routinely considered as a long-term strategy to decrease severity of skin flares in atopic patients. It is hoped that this strategy is considered in polysensitized human patients with cutaneous disease.

1.2 Areas of research in canine AD

1.2.1 Strategies to improve immunotherapy

The new treatments have provided new tools to help affected patients, however, there are always some dogs that do not respond or develop adverse effects, thus there are unmet needs and the need to exploration other strategies. Areas of interest include ways to improve the success rate of immunotherapy considering different formulations to increase the desired immune response, or using recombinant allergens to ensure standardization of allergens [54, 55]. Faster response and increased safety are important factors that can enhance compliance with immunotherapy.

Currently, there is minimal standardization of allergen extracts and identification of the most effective protocol in veterinary medicine. As a result, there is a wide range of protocols and doses being used without strong evidence to support one over the other. When efficacy and speed to reach effect with allergen specific immunotherapy in dogs, it was found that efficacy was significantly higher with the polymerized allergoids coupled with non-oxidized mannan than for the “classic” aqueous and alum-precipitated subcutaneous IT types [56]. Allergoids improve safety and formulations using nanoparticles or microparticle packed with the allergen are considered with vehicles that protect immunogenicity to be suitable for oral immunotherapy rather than injectable. Adjuvants that enhance the desired immune response have also been considered [57]. They are typically products derived from Gram-negative bacteria and have been shown to increase Th1 cytokine and regulatory cytokines like IL-10 [58, 59]. Liposome-DNA combined with protein or peptide antigens can be used effectively as a vaccine adjuvant and in pilot studies liposome-DNA complexes mixed with allergen had beneficial effect on pruritus [60].

In dogs, several studies have been published using cytosine-phosphate-guanine oligodeoxynucleotides bound to gelatine nanoparticles as immunotherapy for canine AD [61, 62] as strategy to induce gamma Interferon (IFN-γ) and improve clinical efficacy. Cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODN) are short single-stranded synthetic DNA molecules that bind to the Toll-like receptor 9 on antigen presenting cells and promote the release of IFN-γ, TNF, IL-6, and IL-12 and suppress Th2 response.

The question whether immunotherapy needs to be allergen specific is an important one as non-allergen specific strategies could be of great benefit. This approach would typically include inactivated bacterial products aimed to increase a regulatory response. This approach is considered palatable to help patients where owners do not have the resources to do allergy testing which is necessary for a custom made “vaccine”. Injection of killed bacterial products has shown promise in veterinary medicine. In one double-blinded, placebo-controlled study, 64 atopic dogs were allocated to receive intradermal injection of a suspension of heat-killed mycobacterium vaccae or placebo [63]. Dogs with mild to moderate disease showed improvement while it did not help, as monotherapy, more severe cases. Interestingly, when the same strategy was used in children with AD no benefit could be found [64, 65]. Another killed bacterial formulation used in veterinary medicine has been a suspension of Gordonia bronchialis, Rhodococcus coprophilus, or Tsukamurella inchonensis. Injection of two doses, three weeks apart from each other of this mix of Actinomycetales has been effective in decreasing severity of lesions and pruritus in dogs allergic to fleas [66]. This strategy has not been explored yet in human medicine to decrease severity of allergic skin disease.

Bacteriotherapy aims to restore diversity in the microbiome of atopic patients and is being explored to decrease severity of allergic skin disease and decrease the need for chronic antibiotic therapy. Skin bacterial transplants have been attempted and results have been encouraging in people [67]. Topical application of benign staphylococcus for example has been shown to displace more pathogenic staphylococcus (e.g., S. aureus) [68]. No similar study has been published in veterinary medicine.

1.2.2 Anti-pruritics that do not target allergic inflammation

New strategies include exploration of medications that target itch in a broader sense rather than simply focusing on allergic inflammation [69, 70]. Under this category, current studies have considered agonists of cannabinoid receptors as a strategy to decrease pruritus. Dogs, like people, have receptor for cannabinoids [71] in the skin and agonists of those receptors have shown promise in decreasing pruritus. For example, in a prospective, randomized, controlled study, a topical endocannabinoid membrane transporter inhibitor (WOL067–531) minimized allergic flares and pruritus in a canine model of AD [72]. In prospective randomized double-blinded controlled study, using privately owned dogs diagnosed with AD, a mix CBD/CBDA was given orally at 2 mg/kg dose and showed a beneficial effect on pruritus but not on skin lesions [73]. There are also reports of case series of canine patients who were treated with CBD-derived products in conjunction with other therapies that shown beneficial effects. In veterinary medicine, there are several reports on this type of approach to decrease allergic pruritus as adjunctive therapy [74]. Interestingly, few studies have considered this approach for human AD although preliminary reports are encouraging in people as well [75]. Beneficial effects of inflammatory skin diseases have been reported but no controlled studies have been published [76, 77, 78].

Similarly, an agonist of K-opioid receptor, asimadoline, has shown promises in a canine study [79] and just recently a synthetic peptide agonist of the kappa opioid receptor has been approved [80]. This medication is for intravenous use, whereas the agonist studied in the canine study was a topical product.

The need to consider different mechanisms and receptors comes from the fact that some pruritic allergic dogs are refractory to commonly used medications. This lack of response may be due to the fact that AD is a clinical syndrome rather than a single disease, and different patients may have different responses to medications, particularly when the mechanism of action is targeted and not broad spectrum.

1.2.3 Modulation of cytokines and administration of recombinant cytokines

The use of biologics to block either a cytokine or a receptor is appealing due to the targeted nature. However, cytokines are pleiotropic, meaning that they can have multiple effects on different processes simultaneously, and they are also redundant, which means that blocking one cytokine may not be sufficient as other cytokines can compensate for the block. As the production of biologics can be challenging and expensive, an alternative approach considered is the actual administration of cytokines to modulate the immune response. Interest in the use of interferons has been expressed in both veterinary and human medicine [81, 82].

In veterinary medicine, most studies have a small number of patients and have used recombinant IFN-γ injectable compared to antihistamine as a positive control and demonstrated more pronounced beneficial effect with the IFN-γ [83]. The effect was found to be dose dependent with the 5000 U/Kg being more effective than 2000 U/kg and several dogs in the higher dose group being in remission for a year after the end of the study [84]. Interferon-omega (IFN-ω) has also been evaluated and its efficacy was found to be comparable to the one of cyclosporine over the course of 6 months in a randomized controlled trial [85]. To overcome the issue of injections, oral administration of IFN has also been considered and compared to injectable when using IFN-ω of a different species (e.g., Feline IFN) [86]. The authors found that both routes of administration led to clinical improvement but significant difference between baseline and end of the study was only achieved in the group that received oral IFN. This consideration is important as oral administration of cytokines although probably degraded in the stomach can still lead to beneficial immune modulation and could increase compliance and access to treatment. No equivalent study has been published in human medicine.

Recombinant human IFN-alfa (IFN-α) was also tested in dogs with AD and the oral route was compared to the subcutaneous route [87]. Although the study was very small, the dogs given IFN orally showed some improvement while injection of IFN was poorly tolerated and needed to be discontinued due to fever, vomiting, and diarrhea.

1.2.4 Stem cells

Mesenchymal stem cells have been considered in both human [88, 89] and veterinary medicine [90] as a promising new treatment of AD due to their immunoregulatory properties. Mesenchymal stem cells are pluripotent, undifferentiated stem cells found in adult tissues have strong anti-inflammatory and immunomodulatory effects on both B and T cells [91, 92]. In an initial small, non-controlled, pilot study, intravenously administered autogenous adipose-derived stem cells (1.3 million cells/kg, one dose) did not significantly decrease pruritus and severity of dermatitis in atopic dogs [93]. Another group reported that intravenous administration of the allogenic canine adipose-derived mesenchymal stem cells (1.5 million cells/kg bodyweight, one dose) to 26 dogs with refractory AD resulted in the remission of clinical signs [94]. Twenty-two animals completed the study. Pruritus and dermatitis scores decreased significantly after one week or month of treatment, respectively, and remained stable for six months. No adverse effects were reported. Multiple intravenous administrations (2 million cells/kg, every 21 days for 3 times) showed beneficial effects in severity of pruritus and dermatitis [95]. All these initial studies lacked a placebo control group.

A more recent study was a double-blinded, placebo-controlled study on the efficacy of adipose-derived allogenic canine mesenchymal stem cells [96] for canine AD. In that study a normal dog was used as a donor and stem cells were injected at 30-day interval for 3 times in multiple body locations in atopic dogs. Severity of disease was monitored for 180 days. The authors reported that the treatment decreased the degree of pruritus and associated signs but that repeated injections may be needed on a monthly basis to maintain clinical benefits. Intramuscular route was investigated as well. In one study, multidose intramuscular allogeneic adipose stem cells (0.5 million per dose) decreased severity of disease and no adverse reactions were observed at the site of injection [97].

Currently, in the USA, there are no stem cell products approved in people as the belief is that stem cells require the destruction of a life. Most of the studies in veterinary medicine have used stem cells derived by adipose tissue either from the same patient or a healthy donor. Yet, the approval of stem cell products is a challenge, thus interest is shifting toward alternative options with similar properties. To overcome the issue of administration of cells, the concept of exosomes has drawn attention. Exosomes are nano-sized vesicles that can travel between cells and deliver their contents. These extracellular vesicles represent an alternative mechanism used by mesenchymal stem cells with strong anti-inflammatory properties [98]. This approach has been tried in mouse models and has resulted in clinical improvement of signs of AD [99]. No studies have been published using atopic dogs.

2. Conclusions

Much progress has been made in the treatment of AD in the past few years, both in human and veterinary medicine. Despite the development of new therapies, there is still the need to identify more options since some patients are unresponsive to currently available choices. Additionally, we need treatments that do not simply mask the clinical signs but that can safely reshape the immune response. In that context, allergen specific immunotherapy is the prime example of a strategy that could be utilized more frequently in human medicine. Although this approach requires months and is not a quick fix, it can halt the progression of the disease and decrease the sensitizations that a patient develops over the course of a life time. While this concept is well accepted for respiratory disease in people, the recommendation of allergen specific immunotherapy for skin disease is underutilized. Based on the experience in veterinary medicine, this approach is very beneficial.

JAK inhibitors that are JAK1selective are another appealing option, either topically or systemically. The experience in veterinary medicine with oclacitinib has been very encouraging and shows that this category of medication can provide great improvement in the quality of life of patients.

Exploration of anti-pruritic that targets non-allergic pruritus is also needed. Studies in human medicine on CBD-derived products is encouraging and it is believed that controlled prospective studies are also done in human medicine to provide more science-based recommendations for clinicians. As many products are available now, it is critical to assess and standardize them to provide sound advice to patients.

Lastly, with the current epidemic of inflammatory and autoimmune diseases, future exploration of anti-inflammatory/immunomodulatory broad strategies like the one of exosomes and stem cells is warranted. It may turn-out that our own bodies are the source of the most powerful weapons that we have to counteract allergies and autoimmunity. Standardized exploration of this approach may dramatically change how we treat chronic inflammatory diseases, not just AD. An open-minded approach on the lessons learned in other species is important for progress. As clinicians we treat diseases and the more we learn, the more we realize how similar these conditions are across species and how we can benefit from these parallels.

Conflict of interest

The authors declare no conflict of interest.

Notes/thanks/other declarations

The author would like to thank Dr. Perlstein for reviewing this manuscript.