In addition to a skin rash, many eczema sufferers also experience chronic itching, but sometimes that itching can become torturous. Worse, antihistamines – the standard treatment for itching and allergy – often don’t help.
New research from Washington University School of Medicine in St. Louis indicates that allergens in the environment often are to blame for episodes of acute itch in eczema patients, and that the itching often doesn’t respond to antihistamines because the itch signals are being carried to the brain along a previously unrecognized pathway that current drugs don’t target.
The new findings, published Jan. 14 in the journal Cell, point to a possible new target and strategy to help eczema patients cope with those episodes of acute, severe itch.
“Years ago, we used to think that itch and pain were carried along the same subway lines in the nerves to the brain, but it turned out they weren’t, and these new findings show there’s another pathway entirely that’s causing these episodes of acute itching in eczema patients,” said principal investigator Brian S. Kim, MD, a dermatologist and an associate professor of medicine.
“The itch can be maddening. Patients may rate their chronic itch at around a 5 on a scale of 10, but that goes up to 10 during acute itch flares.
Now that we know those acute flares are being transmitted in an entirely different way, we can target that pathway, and maybe we can help those patients.”
The typical pathway for itching in eczema patients involves cells in the skin that are activated and then release histamine, which can be inhibited with antihistamine drugs. But with this acute itching, a different type of cell in the bloodstream transmits itch signals to the nerves.
Those cells produce too much of another non-histamine substance that triggers itch; therefore, antihistamines don’t work in response to such signals.
“We’ve connected acute itching in eczema to allergic reactions transmitted by an entirely different population of cells,” said Kim, also the co-director of the Center for the Study of Itch & Sensory Disorders. “In patients who experience episodes of acute itching, their bodies react in the same way as in people with acute allergy.
If we can block this pathway with drugs, it might represent a strategy for treating not only itch but other problems, including perhaps hay fever and asthma.”
In recent years, several clinical studies have tested a strategy that involves blocking Immunoglobulin E (IgE), a substance produced by the immune system in response to allergens. Patients with allergies produce IgE, causing allergic reactions, but its role in itch has been unclear.
Reviewing data from clinical studies of drugs aimed at treating chronic itching, Kim found a pattern in which patients reported episodes of acute itching, often after exposure to environmental allergens.
“Environmental allergens actually promote this type of itch,” he explained. “Say a patient with eczema goes to Grandma’s house, where there’s a cat, and that person’s itching just goes crazy. It’s likely cat dander is activating IgE, and IgE is activating itch.”
Kim’s team took these observations to the laboratory, where his team made a mouse model of eczema. Studying the animals, they found that when the mice made IgE, they began to itch.
But unlike standard itch signals, in which cells in the skin called mast cells release histamine, the IgE in mice with eczema activated a type of white blood cell called a basophil. Those cells then activated an entirely different set of nerve cells than the cells that carry itch signals that respond to antihistamines.
The discovery that acute itching in eczema is linked to exposure to allergens may help them avoid things that make them itch intensely, including animals, dust, mold or certain foods.
Meanwhile, it also offers drug companies new targets for treating itch in eczema patients, including proteins and molecules Kim’s team has identified along this newly identified neuro-immune pathway.
In the late 17th century, German physician Samuel Hafenreffer defined pruritus, or itch, as an “unpleasant sensation that elicits the desire or reflex to scratch.”1 In the short term, scratching in response to itch may provide protection against noxious environmental stimuli and insects.
However, chronic itch, or itch that lasts greater than 6 weeks, is highly pathologic, affects approximately 15% of the population, and has a profoundly negative effect on sleep, mental health, and overall quality of life.2, 3, 4, 5, 6, 7 Although often considered a single symptom, chronic itch underlies many different medical disorders, including primary dermatologic disorders, such as atopic dermatitis (AD) or eczema, allergic contact dermatitis, chronic urticaria, and prurigo nodularis (PN).
Moreover, chronic itch is also associated with a number of other allergic, hepatobiliary, neurologic, renal, and lymphoproliferative disorders.8,9 Emerging evidence indicates that the mechanisms that drive itch are diverse and that there are likely many different kinds of itch.
Despite its widespread nature and high prevalence, effective therapies for chronic itch remain limited. Indeed, a number of different medications, including antihistamines, neuromodulators such as gabapentin, topical and intralesional steroids, and systemic immunosuppressants, are often used with limited efficacy.10
We review a variety of itch mechanisms and disorders that pertain to the broader fields of type 2 immunology and allergy.
The sensation of itch involves complex interactions orchestrated by a variety of factors released from and acting on the skin, immune system, and the sensory nervous system (Fig 1). B
riefly, pruritus begins when itch-inducing factors, or pruritogens, interact with sensory nerve fibers that innervate itch-sensing tissues, including the skin, some mucous membranes, and the cornea. These itch-specific nerve fibers or pruriceptors originate from cell bodies in the dorsal root ganglia and carry signals into the spinal cord and ultimately the brain for itch to be perceived.11
Recent discoveries of itch-specific receptors, including the gastrin-releasing peptide receptor, the Mas-related G protein–coupled receptor family, and natriuretic peptide receptor 1, highlight how heterogeneous pathways underlie itch sensation.12, 13, 14
Indeed, such complexity in itch-sensory pathways may account for the diverse clinical presentations of chronic itch. Furthermore, recent studies have also found that the proinflammatory cytokines interleukin (IL) 4, IL-13, IL-33, and thymic stromal lymphopoietin (TSLP) can function as pruritogens, particularly in the context of AD.15, 16, 17, 18
Encouragingly, recent and emerging therapeutic advances, coupled with our understanding of novel neuroimmune pathways, are driving the rapid development of new treatments for various chronic itch disorders. We review new mechanistic studies and relate them to emerging clinical trials to discuss how various neurotransmitters and cytokines may be targeted for the treatment of chronic itch disorders.
The Immune Response in Cutaneous Inflammation
The skin immune response can be organized into 3 general modules. Type 1 immunity is mainly designed to combat intracellular bacteria and viruses and is characterized by the production of interferon γ and tumor necrosis factor α and underlies allergic contact dermatitis and psoriasis.
Type 2 immunity promotes the expulsion of toxins, environmental pollutants, and macroparasites; is driven by the production of IL-4, IL-5, and IL-13; and drives the atopic march and AD pathologic findings. Type 3 immunity involves group 3 innate lymphoid cells, TH17 cells, and TH22 cells and is specialized for defense against extracellular bacteria and fungi.
It is associated with the production of IL-17A, IL-22, and/or IL-23 and is strongly implicated in the pathogenesis of psoriasis.19,20 In terms of new therapies, understanding the specific pathways that underlie various inflammatory skin disorders have proved critically important for the success of new treatments, especially for AD and psoriasis.11,21
Recent advances in our understanding of the type 2 immune axis have provided deeper insight into different inflammatory disorders, including AD and, in particular, its associated itch. Indeed, although pruritus is a symptom associated with activation of all 3 immune modules, type 2 inflammation seems particularly well equipped to drive chronic itch.
The epithelial cell–derived cytokines IL-33 and TSLP are induced in stressed keratinocytes in the context of barrier dysfunction and potently promote the activation of type 2 immune cells, including basophils, group 2 innate lymphoid cells and TH2 cells. Collectively, these cells produce the effector cytokines IL-4, IL-5, IL-13, and IL-31, which all contribute to the pathogenesis of AD and potentially to other inflammatory skin disorders.
In addition, elevated levels of type 2 cytokines promote production of immunoglobulin E (IgE), activation of mast cells, and release of histamine, which underlie conditions such as urticaria (Fig 1).20 Thus, increasing knowledge of the complex interplay between various effector cells and cytokines represents an opportunity to better understand the association of skin inflammation with itch.
There are 4 known histamine receptors: H1R, H2R, H3R, and H4R. Each exhibit distinct tissue distributions and pharmacologic characteristics. Of these, H1R and H4R seem to be relevant therapeutic targets for itch (Fig 2). H1R antagonists are widely used in acute urticaria and are also first-line therapy for chronic spontaneous urticaria (CSU), although their efficacy is often limited.22
Notably, H1R antagonists are ineffective in the treatment of itch secondary to AD and a variety of other chronic inflammatory skin disorders.11 Although most H1-antihistamines have little to no affinity for H4R, H1R and H4R are expressed on sensory neurons in the dorsal root ganglia and directly mediate itch.23,24
In experimental models of histamine-induced itch, dual blockade of H1R and H4R was more effective than either treatment alone, although the effect from H4R appears greater.25 Furthermore, H4R antagonism has both antipruritic and anti-inflammatory effects.26
The anti-inflammatory effects of H4R modulation are likely attributable to the fact that this receptor is expressed in various immune cells, including lymphocytes, eosinophils, and mast cells, where it plays a role in multiple processes, such as chemotaxis and cytokine production.27 For example, H4R activation on TH2 cells leads to induction of the pruritogenic cytokine IL-31.28 H4R is also expressed on keratinocytes, where it drives proliferation.29
Thus, inhibition of H4R on keratinocytes might break a vicious cycle whereby increased epithelial-derived cytokines from histamine-stimulated keratinocytes drives further inflammation in AD. These findings suggest that H4R is an attractive target for anti-itch therapeutics. However, its precise role in itch remains to be clearly defined.
H4-antihistamines are currently in development for potential use in a variety of chronic itch disorders (Table 1).30, 31, 32, 33, 34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57 In 2 recent phase 2 clinical trials in patients with moderate to severe AD, the oral H4R antagonists JNJ-39758979 and ZPL-3893787 had significant reductions in pruritus, although the former study was discontinued prematurely because 2 patients developed neutropenia.30,31
Notably, ZPL-3893787 also had anti-inflammatory effects, inducing a 50% reduction in Eczema Area and Severity Index (EASI) score compared with 27% with placebo.31 Although EASI scores measure excoriations as a part of overall disease severity in AD, it is not considered a tool to measure itch severity. Indeed, EASI and Numerical Rating Scale (NRS) itch scores have poor correlation.58 Notwithstanding these observations, whether antihistamines derive their anti-itch properties by disrupting histamine-neuron interactions or by their activity on other intermediary immune or stromal cells remains to be more formally defined.
Table 1Summary of Selected Systemic Therapeutics for Various Inflammatory Itch Disorders
|Target||Therapeutics||Mechanism||Condition and selected studies|
|H4R||JNJ-39758979||H4R antagonist||AD: phase 230|
|ZPL-3893787||H4R antagonist||AD: phase 231|
|IgE||Omalizumab||Anti-IgE mAb||CSU: phase 332,33|
AD: phase 334
|Ligelizumab||Anti-IgE mAb||CSU: phase 235 (phase 3 under way [NCT03580369])|
|IL-4 and IL-13||Dupilumab||Anti–IL-4Rα mAb (shared receptor for IL-4 and IL-13)||AD: phase 2 and 336, 37, 38|
|IL-13||Tralokinumab||Anti–IL-13 mAb||AD: phase 2 and 3 (NCT03131648, NCT03160885, and NCT03363854)39|
|Lebrikizumab||Anti–IL-13 mAb||AD: phase 240|
|IL-31||Nemolizumab||Anti–IL-31RA mAb||AD: phase 241,42 (phase 3 under way [NCT03985943]); PN: phase 243|
|IL-33||Etokimab||Anti–IL-33 mAB||AD: phase 245 (phase 2 under way [NCT03533751])|
|TSLP||Tezepelumab||Anti-TSLP mAb||AD: phase 244 (phase 2 under way [NCT03809663])|
|JAK||Abrocitinib||JAK1 selective||AD: phase 249 (phase 3 [NCT03575871])|
|Oclacitinib||JAK1 selective||AD: case report46|
|Upadacitinib||JAK1 selective||AD: phase 248 (phase 3 under way [NCT03569293])|
|Baricitinib||JAK1/2 selective||AD: phase 350|
|Tofacitinib||JAK1/3 selective||AD: case series47|
|PDE4||Apremilast||PDE4 antagonist||AD: phase 251|
|Serlopitant||NK1R antagonist||PN: phase 253; phase 3 discontinued|
CPUO: phase 2 discontinued
|Tradipitant||NK1R antagonist||AD: phase 354 (NCT04140695)|
|KOR||Nalfurafine||KOR agonist||Uremic pruritus: phase 355; cholestatic pruritus: phase 356|
|Difelikefalin (CR845)||KOR agonist||Uremic pruritus: phase 357|
Immunoglobulin E Antagonists
Omalizumab is a recombinant humanized anti-IgE monoclonal antibody (mAb) that blocks IgE binding to its receptor FcεRI, thereby preventing activation of basophils and mast cells (Fig 1).
Furthermore, omalizumab also reduces circulating IgE levels and FcϵRI expression and function on target cells.59 In 2 phase 3 clinical trials, omalizumab significantly reduced itch in H1-antihistamine refractory CSU.32,33 Although these findings raise the possibility that omalizumab blocks the release of pruritogens other than histamine, the mechanisms by which omalizumab improves symptoms in CSU are not well understood.
In a recent clinical trial of omalizumab in children with severe AD, there was a statistically significant mean treatment group difference in the EASI score of 6.7 between the omalizumab and placebo groups. Higher doses of omalizumab were used in this trial, and it was the first clinical trial of omalizumab in AD with a positive clinical outcome.
It may be that IgE plays a more significant role in AD in children or that higher doses of omalizumab are required for efficacy in AD.34,60 Notwithstanding these findings, the role of omalizumab in AD remains unclear and controversial.
Ligelizumab, another humanized mAb with higher affinity for IgE than omalizumab, has recently been developed (Table 1).59 In a phase 2 clinical trial in patients with CSU inadequately controlled by H1-antihistamine therapy, ligelizumab had significantly higher efficacy with complete control of urticaria in 51% vs 26% of the patients in the omalizumab group at week 12.
There were similar reductions in pruritus with responses observed as early as week 4.35 A phase 3 trial comparing ligelizumab and omalizumab is under way (NCT03580369). Again, although studies are limited, IgE blockade has little efficacy in AD, suggesting additional and/or distinct itch pathways and mediators may be operative in the pathogenesis of AD compared with CSU.60
Interleukin-4 and Interleukin-13 Antagonists
Both IL-4 and IL-13 act as key promoters of type 2 inflammation by acting on a variety of immune cells and have been implicated in the pathogenesis of AD for years based on multiple preclinical and translational studies.61 More recently, they have been reported to act directly on itch-sensory neurons to promote itch (Fig 2).15,20
Notably, the shared receptor for IL-4 and IL-13 (IL-4 receptor α) is expressed and functionally active on murine and human sensory neurons, and IL-4 promotes neural hypersensitivity to a multitude of other pruritogens, including histamine, chloroquine, IL-31, and TSLP.15
Dupilumab, a fully human mAb that targets IL-4 receptor α (Fig 2 and Table 1), had unprecedented efficacy in phase 2 and phase 3 clinical trials with regard to AD disease severity, quality of life, and itch severity.36, 37, 38 Of note, the marked reduction in pruritus severity was significant after only 2 weeks of treatment compared with the placebo control group.37 In case studies, dupilumab has also been successful in patients with other chronic itch conditions, such as PN, a multifactorial condition characterized by pruritic lichenified nodules, and in other pruritic disorders, such as chronic pruritus of unknown origin, uremic pruritus, lichen planus, and malignancy–associated pruritus.62, 63, 64 Collectively, these clinical findings support the role of IL-4 and IL-13 in a broad array of pruritic disorders.
Similar to dupilumab, the anti–IL-13 mAbs tralokinumab and lebrikizumab (Fig 1 and Table 1) disrupt type 2 immune signaling and have produced promising results in patients with AD. Although not yet published, in 3 recently completed phase 3 clinical trials for the treatment of moderate to severe AD in adults as monotherapy and in combination with topical corticosteroids, tralokinumab met all primary and secondary end points, including reduction in pruritus on the NRS itch score (NCT03131648, NCT03160885, and NCT03363854).39
In a recent phase 2 clinical trial, lebrikizumab significantly reduced skin lesions and pruritus with reductions in itch observed by day 2 of treatment for adults with moderate to severe AD.40 Future studies will likely better characterize the efficacy of IL-13 blockade vs dual IL-4/IL-13 blockade, particularly with regard to itch symptoms.
IL-31 was the first pruritogenic cytokine found to directly stimulate sensory nerves and mediate itch (Fig 1).16 Its heterodimeric receptor is composed of IL-31 receptor α and oncostatin M receptor subunits (Fig 2).65 Increased IL-31 expression was found in lesional and nonlesional skin from patients with AD, and serum levels correlated with disease severity.66,67
Strikingly, lesional skin from patients with PN has shown 50-fold and 4.5-fold higher expression of IL-31 compared with healthy skin and even AD lesions, respectively.66 There is also evidence that IL-31 plays a significant role in other pruritic disorders, such as CSU and bullous pemphigoid.68 However, the broad role of IL-31 in a variety of pruritic disorders remains to be investigated and is an exciting area of clinical investigation.
The humanized anti–IL-31 receptor α mAb nemolizumab (Fig 2 and Table 1) recently demonstrated unique anti-itch properties in phase 2 clinical trials in patients with moderate to severe AD.41,42 In addition, significant reduction in pruritus was observed as early as day 2 of treatment.
One study used mean percentage of improvement from baseline score on the pruritus visual analog scale as the primary outcome measure, with a 63.1% reduction observed with nemolizumab vs 20.9% with placebo.41 A phase 3 clinical trial of nemolizumab in AD is under way (NCT03985943).
Nemolizumab also has efficacy in PN. In a recently published phase 2 clinical trial of nemolizumab in patients with moderate to severe PN, the primary outcome measure of percent change from baseline in the mean peak score for pruritus on the NRS scale at week 4 was met with a 53.0% improvement in the treatment group vs 20.2% with placebo and similar improvement in skin lesions.43 Taken together, these clinical studies indicate that anti–IL-31 mAb may represent not just an anti-inflammatory approach but a direct antipruritic therapeutic strategy.
Interleukin-33 and Thymic Stromal Lymphopoietin Blockade
The epithelial cell–derived cytokines IL-33 and TSLP promote type 2 immunity in the setting of skin barrier disruption through multiple cell types, including TH2 cells, basophils, and group 2 innate lymphoid cells and have been implicated in the pathogenesis of pruritic disorders, such as AD (Fig 2).20 Furthermore, IL-33 and TSLP also act as pruritogens, directly stimulating sensory neurons to mediate itch.17,18
Because the epithelial cell–derived cytokines act upstream of effector cytokines, such as IL-4, IL-13, and IL-31, they are potentially excellent targets in AD and other pruritic disorders (Fig 1).
Tezepelumab, an anti-TSLP mAb (Table 1), was evaluated in a phase 2 clinical trial in patients with moderate to severe AD in combination with class 3 topical corticosteroids. At week 12, 64.7% of patients treated with tezepelumab achieved the primary end point of a 50% or greater reduction in EASI scores vs 48.2% with placebo, although the difference was not statistically significant. Similar, but not statistically significant, improvements in pruritus were also seen at 12 weeks with a 35.5% vs 21.1% mean percent improvement in NRS itch score in the treatment vs placebo groups.44 Another phase 2 clinical trial of tezepelumab in AD is currently under way (NCT03809663). Thus, whether TSLP represents a potent clinical target remains an exciting question.
The anti–IL-33 mAb etokimab (ANB020) produced improvement in a phase 2 proof-of-concept clinical trial in adults with moderate to severe AD (Table 1). Twelve patients received a single dose of etokimab, and at 29 days there were significant improvements in EASI scores, with 83.3% and 33% of patients achieving EASI-50 and EASI-75, respectively, along with significant reductions in pruritus. Of note, there was no placebo group.45 A randomized phase 2 clinical trial of etokimab in AD is currently under way (NCT03533751). Although data are currently limited with regard to the efficacy of these agents in AD-associated itch, they remain exciting therapeutic prospects.
Janus Kinase Inhibitors
Small-molecule Janus kinase (JAK) inhibitors are promising new options for the treatment of pruritus, particularly in AD. JAK inhibitors provide anti-inflammatory effects through disruption of the JAK-STAT signaling pathways used by multiple cytokine receptors, including those for IL-4, IL-13, and IL-31 (Fig 2). Selective targeting of 1 or more of the 4 JAKs (JAK1, JAK2, JAK3, and TYK2) allows for inhibition of multiple cytokine pathways at once.69 JAK inhibitors also likely have itch-specific effects. Of note, JAK1 is selectively expressed in itch-sensory neurons compared with JAK2 and JAK3, and in mouse models of AD-like disease, neuron-specific genetic deletion of JAK1 results in markedly reduced pruritus independent of the level of skin inflammation.15
Taken together, these findings indicate that JAK inhibitors likely have anti-itch neuromodulatory properties.
The oral JAK inhibitor oclacitinib, which is approved by the US Food and Drug Administration for canine AD, potently targets JAK1, and treatment produces reduction of pruritus beginning on day 1 of administration.70
No clinical trials have been conducted in humans, but in a case report, oral oclacitinib led to significant improvement in a patient with AD.46 A case series of 6 patients reported efficacy of oral tofacitinib (JAK1/3 selective) in human AD as well.47,69 A recent phase 2 clinical trial in AD with upadacitinib, another oral JAK1-selective inhibitor, found improvement of itch as early as week 1 of treatment.
The primary end point of percentage improvement in EASI score from baseline at week 16 was 74% for the upadacitinib group vs 23% with placebo.48 A phase 3 clinical trial of upadacitinib in AD is currently under way (NCT03569293). Abrocitinib (JAK1-selective) recently completed a phase 2 clinical trial in patients with moderate to severe AD. The primary outcome measure of the proportion of patients achieving an Investigator Global Assessment of clear or almost clear with an improvement from baseline of 2 grades or more at week 12 was achieved by 43.8% vs 5.8% of patients with placebo.
Furthermore, in patients with a baseline pruritus NRS itch score of 4 or greater, 63.6% vs 25.5% with placebo improved by 4 points or more at week 12, with significant reductions in pruritus observed by day 2 of treatment.49 A phase 3 clinical trial of abrocitinib in AD is currently under way (NCT03575871).
In recent phase 3 clinical trials with oral baricitinib (JAK1/2 selective) in patients with moderate to severe AD, the primary end point of a validated Investigator Global Assessment of clear or almost clear was achieved by 16.8% vs 4.8% with placebo at 16 weeks at the highest dose. Significant reductions in pruritus were seen by week 1 and at all key time points in terms of NRS itch score compared with placebo as well.50,69 Collectively, although the only oral JAK inhibitor approved for AD is available in canines, these studies indicate that there will likely be multiple oral JAK inhibitors approved for moderate to severe AD in the near future.
There are also a number of topical JAK inhibitors in development (Table 2). Topical tofacitinib had promising results in a phase 2 clinical trial in patients with mild to moderate AD with significant reductions in itch achieved starting on day 2 of treatment. In addition, 68% vs 13% of the controls achieved an Investigator Global Assessment score of clear or almost clear and an improvement of 2 or more points from baseline at week 4.71
Similarly JTE-052, a pan-JAK inhibitor now known as delgocitinib and recently approved for AD in Japan, also produced rapid improvement of itch and favorable efficacy in AD in phase 2 clinical trials in adults and children. In both trials, delgocitinib achieved significant reductions in EASI scores, with a mean percentage reduction from baseline of 61.8% in children with 0.5% ointment and 72.9% with 3% ointment vs 4.8% and 12.2% in the vehicle groups, respectively, at week 4.
Pruritus on the NRS scale was also significantly reduced after 1 week of treatment, with improvement noted within 1 day of treatment.72,73 Another recent phase 2 clinical trial for hand eczema also found favorable tolerability and efficacy with delgocitinib, with 46% vs 15% in the vehicle-only group achieving clear or almost clear with an improvement from baseline of 2 grades or more on the Physician’s Global Assessment of disease severity at week 8.74
In a recent dose-ranging phase 2 clinical trial, topical ruxolitinib (JAK1/2 selective) produced significant reductions in EASI scores of 71.6% vs 15.5% with placebo at 4 weeks. Significant improvements in pruritus occurred within 36 hours on the NRS itch score, and topical ruxolitinib appeared to do remarkably well against its midpotency corticosteroid active comparator.75 Phase 3 clinical trials for topical ruxolitinib in AD are currently under way (NCT03745638 and NCT03745651). Whether in oral or topical form, collectively, these studies found that JAK inhibitors will represent a major new class of therapeutics for AD.
Table 2Summary of Selected Topical Therapeutics for Chronic Inflammatory Itch Disorders
|JAK||Tofacitinib||JAK1/3 selective||AD: phase 271|
|Ruxolitinib||JAK1/2 selective||AD: phase 275; phase 3 (NCT03745638 and NCT03745651)|
|Delgocitinib (JTE-052)||All JAK types||AD: phase 272,73; hand eczema: phase 274|
|PDE4||Crisaborole||PDE4 inhibitor||AD: phase 376|
Phosphodiesterase 4 Inhibitors
Topical and oral phosphodiesterase 4 (PDE4) inhibitors are potential therapies that have also been recently evaluated for pruritus as well (Tables 1 and 2). PDE4 regulates multiple proinflammatory signals by catalyzing the degradation of cyclic adenosine monophosphate in both immune and nonimmune cells, including keratinocytes (Fig 2).77
In patients with mild to moderate AD, phase 3 clinical trials of the topical PDE4 inhibitor crisaborole found significant reductions in pruritus, with 63% of patients vs 53% with vehicle alone achieving a score of 0 or 1 and improvement by 1 or more points on a 4-point itch scale after 29 days of treatment. Of note, reduction in pruritus was significant at the earliest evaluation after 8 days of treatment.76
Apremilast, an oral PDE4 inhibitor, received US Food and Drug Administration approval for psoriasis and psoriatic arthritis in 2014. In the Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis for psoriasis, it led to significant improvements in the secondary end point measure of pruritus visual analog scale score.78
Apremilast is currently undergoing clinical trials in AD. A phase 2 clinical trial in patients with moderate to severe AD found a significant improvement in EASI scores of 31.6% (40-mg twice-daily) vs 11.0% with placebo at week 12. However, improvements in EASI scores were not statistically significant in the 30-mg twice-daily dosing group, and adverse events, including cellulitis, were more frequent, with 40-mg twice-daily dosing leading to discontinuation.
Improvements in pruritus were not statistically significant.51 A small open-label clinical trial in patients with PN found limited improvement in pruritus after 12 weeks of treatment.79 More recently, a phase 2 proof-of-concept trial in chronic pruritus of unknown origin found poor tolerability of apremilast, 30-mg twice-daily, in this population.80 Further studies will likely provide additional information on the efficacy of PDE4 blockade in the treatment of pruritus.
Neurokinin Receptor Antagonists
Substance P is a neuropeptide released from activated cutaneous sensory neurons after scratching and other triggers (Fig 1). In addition to multiple other functions, substance P indirectly induces pruritus by stimulating the release of pruritogens from keratinocytes, endothelial cells, mast cells, and other immune cells by signaling via the neurokinin 1 receptor (Fig 2).
An increased density of cutaneous nerve fibers staining for substance P has been reported in both AD and PN lesions.11 The small-molecule neurokinin 1 receptor antagonists aprepitant, serlopitant, and tradipitant hold potential to treat pruritus of multiple origins.
Aprepitant is currently approved for use as an antiemetic and has potential in many chronic pruritic disorders, such as lymphoma-associated pruritus in case studies.52 In phase 2 clinical trials for PN and chronic pruritus, serlopitant led to significant reductions in pruritus; however, phase 2 clinical trials for chronic pruritus of unknown origin and phase 3 clinical trials for PN did not meet primary end points, and thus serlopitant use was recently discontinued for these indications.53,81, 82, 83
In a phase 3 clinical trial in AD, tradipitant did not achieve the primary end point; however, subgroup analysis in the mild AD group found significant improvement in the worst itch NRS, and another phase 3 clinical trial is under way (NCT04140695).54 Additional clinical trials will likely further delineate the role of targeting neuroinflammatory processes in the treatment of chronic pruritus.
It is thought that imbalance in μ- and κ-opioid receptor activity in the peripheral and central nervous systems may contribute to chronic itch.55 Opioid-induced pruritus is a known adverse effect of morphine and other μ-opioid receptor agonists, and μ-opioid receptor antagonists, such as naloxone and naltrexone, are reported to suppress cholestatic and uremic pruritus in certain cases.84
Opioid receptors also play a role in inflammation, and in vitro studies found that κ-opioid receptor activation down-regulates cytokines and chemokines in human inflammatory cells (Fig 2).85 Furthermore, κ-opioid receptor expression is decreased in lesional skin from patients with AD.84 The κ-opioid receptor agonists nalfurafine and difelikefalin (CR845) have shown promise in the treatment of chronic pruritus. Nalfurafine was efficacious in treating uremic and cholestatic pruritus, as found in phase 3 clinical trials, and is approved for use in uremic pruritus in Japan.55,56
Nalfurafine also reduced itch in an AD mouse model and is a potential treatment for patients with AD.86 In a recent phase 3 clinical trial in uremic pruritus in the United States, difelikefalin (CR845), a peripherally restricted κ-opioid receptor agonist, produced significant reductions in pruritus, with 51.9% vs 30.9% in the placebo group achieving a decrease of at least 3 points from baseline in the weekly mean score on the worst intensity itch NRS at week 12.57
Phase 2 clinical trials of difelikefalin (CR845) in AD and cholestatic pruritus are currently under way (NCT04018027 and NCT03995212). In addition, clinical trials evaluating the use of the κ-opioid receptor agonist and μ-opioid receptor antagonist/partial agonist nalbuphine in PN are currently under way (NCT03497975). Overall, modulation of opioid receptor activity shows promise in the treatment of a variety of chronic pruritic conditions.
Chronic pruritus, defined as itch lasting more than 6 weeks, is common and highly pathologic with a profoundly negative effect on quality of life. Although many primary dermatologic disorders, such as AD and chronic urticaria, are characterized by itch, numerous other allergic, hepatobiliary, neurologic, renal, and lymphoproliferative disorders are also associated with intractable pruritus.
The sensation of itch involves complex interactions orchestrated by a variety of factors released from and acting on the skin, immune system, and the sensory nervous system. Novel topicals, oral medications, and biologics are revolutionizing the treatment of itch. Specifically, in AD, mAbs that target type 2 associated cytokines have produced striking results. Furthermore, topical and oral JAK inhibitors exhibit unique anti-itch effects and target multiple cytokine pathways. Novel targets also include H4R, PDE4, neurokinin 1 receptor, and κ-opioid receptor.
Advancements in our understanding of the pathophysiology of chronic pruritus have led to the development of new therapeutic targets and completion of clinical trials at a rapid pace. However, despite these remarkable advancements, chronic itch continues to be an area of great unmet need.
reference link : https://www.annallergy.org/article/S1081-1206(20)30391-4/fulltext
More information: Fang Wang et al, A basophil-neuronal axis promotes itch, Cell (2021). DOI: 10.1016/j.cell.2020.12.033