Leukotriene Antagonists in Dermatology.

Leukotriene antagonists constitute an important group of drugs in the therapeutic armamentarium of all dermatologists. It has been quite valuable in the management of various types of urticaria and atopic dermatitis. Recently, the role of zileuton in the management of acne has been elaborated, and in the near future it could be used as a first-line agent for the same, thereby preventing adverse effects and antibiotic resistance encountered following antibiotic use. This review will throw light on the dermatologic aspects of leukotriene antagonists. Copyright:

Introduction

Leukotrienes (LTs) are potent biological proinflammatory mediators, derived from arachidonic acid through the 5-lipoxygenase pathway. They are broadly divided into two groups based on their chemical structure.

They include those with

Sulfur linkage or cysteinyl (Cys) LTs, such as LTC4, LTD4, and LTE4 and

Non-Cys LTs such as LTB4.

The Cys LTs are more frequently involved in chronic inflammatory responses and exert their actions by binding to two types of activating receptors: a cysteinyl-LT1 (Cys LT1) receptor and cysteinyl-LT2 (Cys LT2) receptors.[12]

Eosinophils, basophils, and mast cells are the most important sources of LTs.[3] Even epidermal cells can transform neutrophil-derived LTA4 into LTB4 and LTC4.[4] Therefore, even the epidermis could pose a significant contribution towards the synthesis of LTs.

LT antagonists used in dermatology include montelukast, zafirlukast, pranlukast, and zileuton.

Mechanism of Action

The mechanism of action of LT antagonists has been lucidly described as a flow chart in Figure 1.

Figure 1

Mechanism of action of leukotriene antagonists

Pharmacokinetics

Montelukast and zafirlukast are well absorbed orally. Both are highly protein bound and metabolized by CYP2C9 (motelukast by CYP3A4 as well). The plasma t1/2 of montelukast and zafirlukast is 3-6 and 8-12 hours respectively. Elimination is via the renal route.

Zileuton is rapidly absorbed following oral administration with plasma concentrations of zileuton being proportional to the dose administered. Zileuton is 93% bound to plasma proteins, primarily albumin. The t1/2 of zileuton is 2.5 h. Metabolism takes place by oxidation in the liver. Kidneys are the major route for zileuton elimination.

Indications

All indications of LT antagonists in dermatology are off label and include the following:

Atopic dermatitis (AD)

Chronic urticaria

Acne vulgaris

Granuloma annulare (GA)

Bullous pemphigoid (BP)

Psoriasis

Pruritus associated with Sjogren-Larrson's syndrome (SLS).

Contraindications

Hypersensitivity to the drug

Patients with active liver disease or persistent alanine aminotransferase elevation of three times or more the upper limit of normal.

Pregnancy prescribing status

Montelukast and zafirlukast: category “B”

Zileuton: category “C”.

Clinical uses

Atopic dermatitis

AD is a chronic eczematous disorder with a relapsing tendency more commonly seen in children.[5]

LTs have been demonstrated to have a proinflammatory role in AD. In patients with AD, activated circulating basophils are present and there is an increased release of LTC4 by these basophils.[6] In fact, an increase in Cys LT release from basophils and eosinophils isolated from patients with AD has been clearly demonstrated when compared with controls.[7]

Furthermore, allergic rhinitis and asthma have demonstrated numerous pathophysiological elements similar to AD and together these three diseases constitute the “atopic triad.” Also, there are pathogenic mechanisms central to both asthma and allergic rhinitis.

Evidence in literature does demonstrate the use of Cys LT receptor blockers in the treatment of AD.[89] However, the exact mechanism of action of LT antagonists in AD has not been clearly elucidated, with suggestions being put forward.

Montelukast has been shown to

Decrease circulating eosinophils by 15%

Reduce eosinophilic protein X levels compared with baseline.[1011]

Moreover, montelukast also suppresses the proliferation of eosinophil hematopoetic progenitor cells thereby antagonizing the effects of LTD4 and proving to be of benefit in patients with AD.[12]

Zafirlukast has been used in AD by its ability to inhibit LTD4 and histamine-mediated vascular permeability.[13]

There has been supportive evidence of the use of montelukst and zafirlukast in AD which has been summarized in Table 1.

Table 1

Clinical evidence demonstrating the efficacy of montelukast and zafirlukast in atopic dermatitis

Author(s)	Type of study	Duration of treatment	No. of study subjects	Drug used	Outcomes measured	Therapeutic outcome
Carruci et al.[14]	Case series	*Variable	4	Zafirlukast 20 mg Q12H	Extent of erythematous dermatitis	All patients experienced alleviation
		*Approximately 2 weeks
Eustachio et al.[15]	Randomized double-blind study	6 weeks	20	Montelukast 10 mg once daily (no other treatment for atopic dermatitis given)	SCORAD index (Severity scoring of Atopic dermatitis)	Significant reduction in disease activity as measured by SCORAD index
Yanase and David-Bajar[16]	Randomized double-blind placebo-controlled cross-over study	8 weeks	8	Montelukast 10 mg once daily versus placebo.	Six signs of AD	Improvement in all the six features mentioned
					-scaling
					- dryness
				Other adjuncts allowed:	- lichenification
				- emollients	- induration
				- weak topical steroids	- erythema
				-histamine antagonists	- erosion
Capella et al.[11]	Randomized single-blind study	6 weeks	32	Montelukast 10 mg once daily (n=16) versus combined regimen in another 16 patients, with oral cetrizine, clarithromycin, topical steroids and moisturizers	-SCORAD (objective and subjective assessment of severity of AD)	-Similar SCORAD reduction in both groups (P<0.05)
					- ECP	- ECP and EPX levels reduced significantly in both groups
					- EPX
Kagi[3]	Case series	8 months	4	Montelukast 10 mg once daily	-Extent of dermatitis (pruritus, skin changes)	Significant improvement in pruritus and skin changes noted
					- Amount of topical steroids needed
Pei et al.[17]	Randomized double-blind placebo-controlled cross-over study	12 weeks	15	Motelukast 5 mg once daily versus placebo	Impact of eczema on daily living (subjective) and disease extent and severity (objective)	Statistically significant improvement in severity of AD in patients on active treatment compared with placebo
Zabawski et al.[18]	Case series	2–6 weeks	5	Zafirlukast 20 mg Q12H	-Pruritus	Clinical improvement of all parameters in all five subjects
					- Lichenification
					- Erythema
					-Reduction in topical corticosteroid usage

AD: Atopic dermatitis; ECP: Eosinophilic cationic protein; EPX: Eosinophilic protein X

Zileuton, an inhibitor of the enzyme 5-lipoxygenase, prevents the release of not only Cys LTs but also LTB4. As it acts on the 5-lipoxygenase enzyme, production of other metabolites in the arachidonic acid cascade like 5-HETE and 5-oxo-ETE also get blocked. As LTB4 and 5-oxo-ETE are potent chemoattractants for eosinophils, zileuton has a role in AD.[19]

Woodmanse and Simon,[20] in a pilot study using zileuton for severe AD at a dose of 600 mg Q6H for 6 weeks, demonstrated a significant reduction in erythema in 20 body parts examined. However, there was no significant reduction in the subjective report of pruritus.

Urticaria

Urticaria is a common disorder of the skin, affecting between one in four and one in six people, sometimes throughout their lives. Urticarial episodes less than 6 weeks are referred to as acute and that exceeding 6 weeks or longer as chronic.

Rationale for treating urticaria with LT antagonists is as follows:

It has been demonstrated that LTD4 is more potent than histamine in producing a wheal and flare response[21]

LT generated urticaria cannot be blocked by other drugs, except LT antagonists[22]

In the sera of patients with urticaria, LT production has been clearly demonstrated apart from histamine.[23]

There have been a number of case reports and studies depicting the role of LT antagonists for various types of urticaria which is stated lucidly in Table 2.

Table 2

Various reports and studies depicting the role of leukotriene antagonists in chronic urticaria

Type of urticaria	No. of patients treated	Drugs used	Details
Severe CU with ASA intolerance[24]	2	Zileuton 600 mg Q6H versus zafirlukast 20mg Q12H	*Zileuton better than zafirlukast
			*Outcome was favorable for both
NSAID-induced exacerbation of CU[25]	1	Montelukast 10 mg once daily	Complete resolution of urticaria, but there was a relapse after a single dose of oral piroxicam
NSAID-induced exacerbation of CU[25]	1	Zafirlikast 20 mg Q12H	Complete resolution of urticaria, without relapse after a course of an injection of piroxicam
ASA-induced urticaria[26]	2	Pranlukast 112.5 mg once daily	*Relapse of urticaria
			*Unfavorable outcome
ASA- and NSAID-induced exacerbation of CU[27]	25	Montelukast 10 mg once daily	Marked improvement in 22 patients
Acquired cold urticaria[28]	2	Zafirlukast 20 mg Q12H versus cetrizine 10 mg once daily versus zafirlukast plus cetrizine	Combination therapy superior to monotherapy
DPU[29]	1	Montelukast 10 mg once daily	Symptom-free under treatment but discontinuation not possible
DPU[30]	20	Loratidine 10 mg once daily alone versus loratidine 20 mg once daily plus montelukast 10 mg once daily	Combination therapy better than loratidine alone
Cold urticaria refractory to H1 blockers[31]	1	Montelukast 10 mg once daily	Improvement of cold urticaria
Dermographism[32]	2	Zafirlikast 20 mg Q12H	Marked improvement
COX-2 selective inhibitors exacerbation of CU[33]	1	Montelukast 10 mg once daily	Marked improvement
Unremitting steroid-dependent urticaria[34]	12	Montelukast 10 mg once daily, zafirlikast 20 mg Q12H	Nearly total remission in some patients
CIU, with majority of patients with a positive ASST[35]	27	Montelukast 10 mg once daily versus fexofenadine 180 mg once a day	Montelukast had better therapeutic effects compared with fexofenadine
CIU[36]	20	Montelukast 10 mg once daily versus cetrizine 10 mg once a day	Cetrizine better than montelukast
CIU[32]	6	Zafirlikast 20 mg Q12H	Marked improvement

CU: Chronic urticaria; ASA: Acetyl salicylic acid; NSAID: Nonsteroidal anti-inflammatory drug; DPU: Delayed pressure urticaria; CIU: Chronic idiopathic urticaria; ASST: Autologous serum skin test

Although LT antagonists demonstrate a good therapeutic outcome in many types of urticaria, they still cannot be considered alternative agents to antihistaminics. Furthermore, in patients with moderate chronic idiopathic urticaria, the role of LTs is rather insignificant.[37]

Although effective in ASA and other nonsteroidal anti-inflammatory drug exacerbated urticaria and in patients with a positive autologous serum skin test, LT antagonists demonstrate lack of advantage in chronic urticaria without an associated cause.

According to the EAACI/GA2LEN/EDF/WAO guidelines for the management of urticaria, the level of evidence for the efficacy of LT antagonists is low, but best for montelukast. However, despite this, even montelukast has not be recommended in patients with chronic urticaria unresponsive to H1 antagonists as per this consensus statement.[38] As far as the consensus statement for the diagnosis and management of urticaria from India goes, a similar conclusion has been derived. However in this guideline, the use of montelukast for select refractory cases as an adjuvant has been permitted.[39]

Acne

Zileuton, an oral 5-lipoxygenase inhibitor, has recently demonstrated promising results for treating inflammatory acne. It has been well established that products of the LT pathway have a role in a number of cutaneous diseases, including acne.[40]

LTB4 is the most potent leukocyte chemotaxis mediator among all LTs.[41] It stimulates the inflammatory responses by

Increasing neutrophil adherence

Stimulating release of lysosomal products from inflammatory cells

Generating superoxide radicals

Activating the complement cascade

Induction of neutrophils to produce interleukins.

As zileuton antagonizes the enzyme 5-lipoxygenase, production of arachidonic acid is blocked wherein LTB4 cannot be produced thereby antagonizing the inflammatory effects of LTB4.

Furthermore, zileuton also inhibits the production of proinflammatory lipids from sebaceous glands potentiating its anti-inflammatory action on acne.[4243] In fact, this capacity of zileuton to reduce sebum secretion in a transient manner is comparable to low-dose treatment with isotretinoin.[39] Also, zileuton is associated with downregulating the inflammatory activity of locally involved macrophages and lymphocytes in acne.[4445]

Zileuton is administered at a dose of 600 mg Q6H in inflammatory acne. By 2 weeks, reduction in acne lesions becomes noticeable with significant improvement at the end of 12 weeks.

According to Zouboulis and Bettoli,[46] zileuton may replace systemic antibiotics in the future, especially under the scope of antibiotic resistance prevention.

Granuloma annulare

GA is a noninfectious granulomatous disorder, characterized by small grouped papules that assume annular configurations, often in a symmetrical pattern, commonly involving the extremities. When localized, GA usually is self-limiting. However, in the disseminated variant, lesions tend to persist and are often highly resistant to various therapeutic agents.

Smith et al.[47] demonstrated zileuton (2400 mg/day) along with vitamin E (400 IU/day) to be effective in three patients who had recalcitrant disseminated GA for more than a year. Within 3 months of the above therapy, all of them had complete lesional clearance. This effect was attributed to anti-inflammatory and immune-regulatory properties expressed by both drugs.

Pruritus associated with SLS

SLS is an autosomal recessive neurocutaneous disorder characterized by congenital ichthyosis, mental retardation, and spastic di/tetraplegia.

An association of pruritus in these patients has been associated with elevated levels of LTB4.[48]

Zileuton (400 mg Q6H) has been used for treating pruritus in these cases. However, not all patients responded to zileuton therapy, the cause being unknown.

Nevertheless, it has still been suggested that if at all medical treatment for severe pruritus is required in patients with SLS ≥5 years, a therapeutic trial of zileuton for a period of 4–6 weeks could be considered. In case no benefit is observed, then therapy needs to be discontinued.[49]

Psoriasis

Psoriasis is a chronic inflammatory disorder whose pathogenesis still remains elusive. It has been suggested that LT pathway could play a role in its pathogenesis, by inducing chemotaxis and degranulation of leukocytes and stimulating leukocyte adhesion.[50]

Also, topical application of LTB4 has shown to induce skin inflammation and epidermal proliferation, thereby further advocating its contribution for the same.[5152]

Zemstov et al.[53] in a series of three patients demonstrated zafirlukast (20 mg PO Q12H) to be effective in severe generalized plaque type psoriasis that could not be controlled with other treatment modalities like systemic methotrexate and retinoids. However, it needs to be noted that zafirlukast was not used as monotherapy in this report. Phototherapy and topical steroids and vitamin D3 analogs were also simultaneously used. Within 3 weeks of treatment, reduction in pruritus, flaking, and thickness of psoriatic plaques was noticeable.

Furthermore, the beneficial effects of etalocib (VML 295), a specific LTB4 receptor antagonist, have demonstrated inhibition of LTB4-induced CD11b upregulation of blood neutrophils, LTB4-induced neutrophilic accumulation in skin, trauma-induced hyperproliferation of the epidermis, and regenerative keratinization. A dosing of 200 mg twice daily appeared sufficient enough to demonstrate all the above anti-inflammatory effects.[5455]

However, there are just a few case reports regarding the utility of LT antagonists in psoriasis, demonstrating these drugs to only have an adjunctive role in this setting. Therefore, more studies with a larger number of subjects are warranted to arrive at a better conclusion.

Bullous pemphigoid

BP is a subepidermal blistering autoimmune disease. Peptide LTs have been reported to play a role in blister formation based on their capacity to increase plasma leakage from blood vessels.[56] Furthermore, significant levels of LTC4 have been observed in the blister fluid of patients with pemphigoid.[57]

Nomura et al.[58] have documented a favorable outcome of BP in a 59 year old patient using pranlukast (450mg/day) along with systemic steroids after being tapered to a low dose of prednisolone 7.5 mg/day. This helped in preventing blister recurrence, thereby advocating an inhibitory role of pranlukast in blister formation. As there exists just an individual case report highlighting the beneficial role of LT antagonists for BP, more studies are warranted to substantiate this observation.

Adverse effects

Cutaneous

Drug-induced pemphigus has been reported in an 8-year-old girl who had received montelukast for chronic asthmatic bronchitis[59]

Although LT antagonists are used for treating urticaria, a therapeutic paradox of urticaria developing after montelukast administration has been documented[606162]

Angioedema secondary to montelukast has been described in two isolated reports[6364]

Ecchymosis as an adverse response to montelukast has also been reported.[65]

Neuropsychiatric

Nightmares, hallucinations (auditory and visual), insomnia, somnolence, and night terrors have been reported with montelukast, zafirlukast, and zileuton.[66676869], The Food and Drug Administration recommends that prescribers should consider discontinuing these medications if neuropsychiatric symptoms occur.

Hepatobiliary

Cases of life-threatening liver failure have been reported in patients receiving montelukast, zafirlukast, and zileuton. Clinically, these patients usually present with abdominal pain, nausea, fatigue, and vomiting. Laboratory evaluation in these patients reveals hypertriglyceridemia and altered levels of hepatic transaminases[707172]

An isolated case report of acute pancreatitis secondary to montilukast has been described in literature.[73]

Renal

An isolated report of montelukast-induced hematuria has been documented by Xie et al.,[74] which returned to normal 2 weeks after discontinuing the drug. Hematuria and glomerulonephritis could be considered one aspect of an unexpected immune response triggered by the intake of montelukast and resembling subclinical Churg–Strauss syndrome (CSS).

Churg–Strauss syndrome

CSS is a rare form of eosinophilic vasculitis associated with asthma. Several case reports and series have described the onset of CSS in patients receiving montelukast for the management of moderate to severe resistant asthma. Montelukast-induced CSS presents with a wide range of clinical features that include fever, malaise, arthralgias, clinical jaundice, peripheral blood eosinophilia, eosinophilic hepatitis, scleritis, and arthritis.[7576777879] This adverse reaction is more commonly observed in asthma patients treated with montelukast.

Drug monitoring

Guidelines mention assessment of alanine aminotranferase levels before initiation of treatment, once a month for the first 3 months and then once every 2–3 months for the remainder of the first year and periodically thereafter in all patients receiving long-term zileuton therapy.

However, as hepatotoxic side effects are also documented with other LT antagonists, it would be worthwhile following this monitoring guideline for them as well.

Drug interactions

Various drug interactions of LT antagonists are elaborated in Table 3.

Table 3

Drug interactions of leukotriene antagonists

Drug	Zileuton	Zafirlukast	Montelukast
Warfarin	Zileuton reduces warfarin clearance by 15% and increases the serum concentration of warfarin by 22%, thereby resulting in significant prolongation of the prothrombin time	Zafirlukast increases the t1/2 of warfarin and mean prothrombin time by 3.5%	-
	The mechanism of this interaction is thought to result secondary to competitive inhibition of CYP1A2 and CYP2C9 isoenzymes by zileuton[80]	When both drugs are administered simultaneously, monitoring of prothrombin time/INR and for symptoms and signs of bleeding is strongly recommended[69]
	When treatment requires both these drugs, monitoring of prothrombin time/INR and for signs and symptoms of bleeding is strongly recommended
Theophylline	When zileuton and theophylline are administered together, both the peak and trough levels of theophylline increase by 75%–125% with an increase in the serum half-life of theophylline by around 24%	Theophylline reduces mean plasma levels of zafirlukast by 30%[69]	-
	The mechanism of this increase could be secondary to competitive inhibition of isoenzymes CYP1A and CYP3A by zileuton
	Therefore, when both drugs are given together, the dose of theophylline should be halved[81]
Propranolol	Zileuton increases the concentration and t1/2 of propranolol, thereby potentiating bradycardia	-	-
	Dosing of propranolol therefore needs to be reduced when simultaneously used with zileuton[81]
Terfenadine	Zileuton reduces the clearance of terfenadine, thereby increasing its bioavailability	-	-
	Concomitant use of both drugs is not recommended[81]
Aspirin	-	Aspirin increases plasma levels of zafirlukast by 45%	-
		Dosing of zafirlukast may need to be halved when aspirin is given along with it[82]
Erythromycin	-	Erythromycin reduces plasma levels of zafirlukast by 40%	-
		In case reduced clinical response to zafirlukast is noted, then an escalation of its dosing may need consideration[69]
Cytochrome P450 enzyme inducers like rifampicin and phenobarbital	-	-	These drugs may reduce montelukast levels
			It may be essential therefore to monitor for a reduced clinical response from montelukast when these drugs are simultaneously administered with montelukast[69]

INR: International normalized ratio

Conclusion

LT antagonists have proven to be a safe and viable option in patients with CU and AD. With the discovery of the favorable properties of zileuton for inflammatory acne, its usage for this indication could become more common in the years to come. Furthermore, there have been reports suggesting LT antagonists to be effective in disseminated GA, psoriasis, and BP.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.82