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Cysteine leukotriene receptor 2 appears to be a key player in chronic itch

Eczema, or atopic dermatitis (AD), is sometimes called “the itch that rashes.” Often, the itch begins before the rash appears, and, in many cases, the itchiness of the skin condition never really goes away.

Approximately 9.6 million children and 16.5 million adults in the U.S. have AD, which can have a serious effect on quality of life for patients.

Although much has been learned about the uncomfortable sensation that triggers the desire to scratch, many mysteries remain about chronic itch, making it a challenge to treat.

A paper by authors from Brigham and Women’s Hospital and Harvard Medical School published in The Proceedings of the National Academy of Sciences, offers new clues about the underlying mechanisms of itch.

Findings suggest a key molecular player known as cysteine leukotriene receptor 2 (CysLT2R) that may be a new target for intractable chronic itch.

“In atopic dermatitis, the itching can be horrific and it can aggravate disease,” said co-corresponding author K. Frank Austen, MD, a senior physician in the Division of Allergy and Clinical Immunology at the Brigham. Austen is also the AstraZeneca Professor of Respiratory and Inflammatory Diseases, Emeritus, at Harvard Medical School.

“We began collaborating for two reasons: one is an interest in science — I wandered into the study of what is now the cysteine leukotriene pathway decades ago, and I’ve been pursuing it ever since. The second reason is itch — understanding its cause and connections to neurons.”

Austen and his lab, which focuses on the molecular components that contribute to allergic inflammation, collaborated with Isaac Chiu, PhD, an assistant professor of Immunology at Harvard Medical School. The team also included researchers at the Center for Immunology & Inflammatory Diseases at Massachusetts General Hospital and at the University of Texas at Dallas.

“As a neuro-immunologist, I’m interested in how the nervous system and immune system cross-talk,” said Chiu, co-corresponding author of the study.

“Itch arises from a subset of neurons, and acute itch may be a protective response to help us remove something that’s irritating the skin. However, chronic itch is not protective and can be pathological. The underlying mechanism that activates neurons and causes chronic itch is not well understood and new treatment is needed.”

Chiu, Austen and colleagues set out to elucidate the molecular mechanisms that may trigger chronic itch. To do so, they looked for gene activity in dorsal root ganglia (DRG) neurons linked to itch in mice. They found a striking level of CysLT2R, which was uniquely and highly expressed in these specific neurons. They also found expression of this receptor in human DRG neurons.

This led the researchers to focus their analysis on the receptor’s role in itch signaling. Additional studies showed that activating this receptor induced itching in a mouse model of AD, but not in other mouse models. Mice that lacked CysLT2R showed decrease itching. Collectively, their findings pointed to the receptor’s key role in causing itch and potentially contributing to AD.

Lead author Tiphaine Voisin, PhD, carried out many of the preclinical experiments in mouse models of AD during her time in the Chiu lab at HMS.

“The last ten years or so of research in the field of chronic itch have shown the importance and the complexity of the interactions between the immune system and the nervous system,” said Voisin. “It was very exciting to explore the contribution of cysteine leukotrienes in these neuro-immune cross-talks leading to itch, including in a mouse model of AD.”

Leukotrienes are a class of lipid molecules that originate from white blood cells, such as mast cells, which are involved in allergy and inflammation. Today, the leukotriene inhibitor montelukast, which targets CysLT1R, is used to treat asthma but does not provide relief from itch.

No clinically approved inhibitors of CysLT2R currently exist and, while the researchers have seen evidence of the receptors in humans, until an inhibitor is developed and trialed in humans, it will remain an open question as to whether the new target can lead to a therapy for patients.

While Chiu and Austen are eager to see their findings prompt treatment improvements, Austen, who has been pursuing leukotrienes since the 1970s, also notes the importance of making new discoveries and unexpected connections through research.

“I do believe that science is bottom up, not top down,” said Austen. “The joy of research is doing it for the pleasure of finding out something you didn’t know. The immune system is far more complex than we give it credit for. Understanding the involvement of nerves is an immense step forward — it’s been a missing piece in the study of inflammation. In my view, this is immensely important to connect neuroscience with those of us committed to studying inflammation.”

Funding: Funding for this work was provided by the National Institutes of Health (DP2AT009499, R01AI130019 and NS111929), the Food Allergy Science Initiative, the Burroughs Wellcome Fund, the Brigham and Women’s Hospital Hypersensitivity Fund, the National Institutes of Allergy and Infectious Diseases (K08 AI132723), and the American Academy of Allergy, Asthma & Immunology Foundation Faculty Development Award.


Urticaria (hives) is a condition characterized by superficial skin weals and pruritus. Classically, chronic urticaria is de- fined as the daily, or almost daily, occurrence of urticarial weals for at least 6 weeks, without any physical, allergic, in- fectious, drug-related or vasculitic cause [1,2]. In the past, chronic urticaria was divided into two types, i.e., chronic autoimmune urticaria and chronic idiopathic urticaria [3].

The current classification defines these as chronic spontan- eous urticaria (CSP), characterised by the occurrence of spontaneous weals and/or angio-oedema for longer than
6 weeks [4]. Several chemical mediators such as hista- mines, leukotrienes, prostaglandins and cytokines secreted by mast cells and basophils are involved in the pathogen- esis of urticaria [5]. However, the routine treatment of autoimmune and non-autoimmune chronic urticaria is similar [1,2,6].

A step-wise approach to treatment is currently advo- cated in the EAACI/GA2LEN/EDF/WAO 2009 treatment guidelines [7]. First line therapy is with a non-sedating H1- antihistamine at standard doses. If no response is seen after two weeks, the dose is increased up to four times the standard or licensed dose. The addition of a leukotriene receptor antagonist (LTRA) is recommended as third line treatment.

For severe or resistant cases, immunosuppres- sants such as ciclosporin, dapsone, H2-antihistamines and omalizumab [8] are also used. Short-course systemic steroids are recommended for exacerbations.
Cysteinyl leukotrienes are potent pro-inflammatory mediators whose effect can be blocked by LTRA such as monte- lukast, zafirlukast and pranlukast. The benefit of these drugs in patients suffering from asthma and allergic rhinitis is well established, and current evidence clearly justifies their use in those conditions [9].

Several recent studies have addressed the use of these agents, as monotherapy as well as in combination with other first line therapies, for chronic urticaria. Nonetheless, there is controversy as to the efficacy of LTRA for this indication; a previous review of six randomised clinical trials comparing the use of montelukast either alone or in combination with non-sedating antihista- mines concluded that the presence of contradictory results makes the recommendation of montelukast for treating chronic urticaria not justifiable [10].

Another systematic review on the subject which included several case-series, open-labelled studies and randomised controlled trials also concluded that LTRA are not beneficial alone or in com- bination with antihistamines in patients with idiopathic chronic urticaria, although benefit was seen in patients with food additive hypersensitivity and NSAID-exacerbated chronic urticaria [11].

Evidence from new trials have been published since then. In this context it is timely to evaluate the evidence from randomized control trials on this subject, in order to pro- vide an answer to the clinical question as to whether pre- scribing LTRAs for chronic urticaria is justifiable. Hence, we performed a systematic review of randomized controlled trials examining the efficacy of LTRA either alone or in combination with other drugs, compared with placebo or antihistamines, for the treatment of chronic urticaria.

Conclusions

Our systematic review of randomized controlled trials did not demonstrate strong clinical evidence to refute or accept the practice of prescribing LTRA in patients with chronic urticaria. Reduction in number of hives was seen with LTRAs compared to placebo, although LTRA did not show benefit for any of the other outcomes. Thus, the use of LTRA alone for chronic urticaria is difficult to justify based on current evidence.

Combined therapy of antihistamine with LTRA seems to be beneficial according to most of the studies [14,20,21] although one study gives contradictory re- sults [13]. Head to head comparison of antihistamine versus leukotriene antagonists also gives conflicting data, and no firm conclusion can be made; overall it appears that antihistamines are superior to LTRA. How- ever there is very limited data on this.

The most important difficulty in comparing outcome between the different groups was the wide variability of outcome measures assessed. Even the cumulative scores used to assess overall outcome had wide variation, which is clearly shown in the study by Kosnik et al. [15] where different results were obtained with the two in-house scoring systems compared with the validated UAS. As a result, data pooling for the purpose of meta-analysis was not possible.

We attempted to obtain raw data by contacting the authors, but were not successful despite repeated at- tempts. Another limitation of our review is that because of the wide heterogeneity in study populations, it is difficult to ascertain if LTRA would be more beneficial in patients with more severe, or refractory, chronic urticaria.

Overall, current evidence supports the use of LTRA in combination with antihistamines, and the add-on effect of LTRA in patients currently on antihistamines is likely to be beneficial; this is in agreement with the 2009 treatment guidelines [7]. LTRA cannot, however, be recommended as single therapy for chronic urticaria. LTRA are also significantly more costly, with one month’s treatment with montelukast and zafirlukast costing about GBP 30 and 20 respectively while cetirizine costs just GBP 0.85 and desloratadine costs GBP 7 for the same duration [24].

Importantly, LTRA appeared well tolerated with low side effect profiles; this was demonstrated repeatedly in nearly all trials. Thus, LTRA can be safely recommended in combination with antihistamines in patients with chronic urticaria who show inadequate response to anti- histamines alone.

There is clearly a need for further studies. Future ran- domized controlled studies should stratify patients based on severity of chronic urticaria using standardized criteria. Outcome measures should be carefully chosen, using accepted and validated scales of measurement. Effects on quality of life are an important outcome measure to be considered.

Studies should also be powered sufficiently to evaluate the effect of benefit in subgroups of patients with ASST positivity, food allergy, acetylsalicylic acid and NSAID hypersensitivity. However this may not always be feasible, thus alternately studies should use stringent inclusion criteria to define the type of urticaria clearly, in order to make comparisons and recommendations clearly.

reference link: DOI: 10.1186/1710-1492-10-24


Original Research: Closed access.
The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch” by Isaac Chiu et al. PNAS

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