Authors: SK Shahriar Ahmed, Yashpal Manchanda, Abhishek De, Sudip Das, Rajesh Kumar
Categories: Symposium Article
Source: Indian Journal of Dermatology
Psoriasis is a chronic condition that progresses in remitting and relapsing phases. Most of these patients have mild-to-moderate illness, which can be managed with topical medications or could be thought of as continuing therapy after remission. Potential therapeutic efficacy is offered, and systemic treatment's negative side effects are constrained. Topical therapies have recently advanced in tandem with recent advancements in our understanding of psoriasis. To improve the quality of life of patients, appropriate knowledge and application of these topical agents are crucial.
Key Words: Psoriasis, symposium, Topical medicines
Psoriasis is a chronic disorder with relapsing and remitting courses. The majority of these patients have mild-to-moderate disease and can be treated with topical agents or can be considered as continuation therapy after remission. It provides potential therapeutic efficacy and limits the adverse effects of systemic treatment. Recent advances in the understanding of psoriasis have provided parallel advances in topical treatments. Appropriate knowledge and proper use of these topical agents are essential to improve the quality of life of patients.
Host factor
Topical or local therapy is the mainstay of treatment in limited cutaneous psoriasis. It is the treatment of choice in patients with psoriasis involving <10% body surface area (BSA).[1]
It can also be used for nail psoriasis, scalp psoriasis, palmoplantar psoriasis and psoriasis in children and in immunocompromised patients and affecting sensitive areas such as the face, flexures and genitals. Topical agents can also be used as an adjuvant for psoriasis affecting >10% BSA (moderate/severe psoriasis) on systemic medications.
Emollients form the cornerstone of therapy for psoriasis and act as adjuvants to other topical/systemic medications.
Emollients help in loosening the adherent hyperkeratotic scales and improve penetration of other drugs. They hydrate the stratum corneum and prevent transepidermal water loss. Emollients moisturise dry skin, reduce scaling, relieve itching and improve cracks.[2]
Emollients have no benefit over placebo as monotherapy[3] but as an adjuvant to topical/systemic therapy. However, it improves the penetration of topical corticosteroids (TCS) and also is useful as a steroid-sparing agent and in continuation phase.[4] There is no study available that proves that it can prevent frequent relapse or not in localised plaque psoriasis.
No side effects except occasional folliculitis.
Low efficacy.
Topically applied corticosteroids form the cornerstone of the treatment of psoriasis.[5] Potent and very potent TCS are the most effective topical therapies and are also recommended by the National Institute for Health and Care Excellence (NICE) as a first-line topical treatment on cost-effectiveness grounds.[6] The combination of a potent TCS with calcipotriol provides the most effective strategy for topical treatment of limited plaque psoriasis over a short period of time and then topical calcipotriol as a continuation therapy.[7]
Corticosteroids bind to intracellular corticosteroid receptor and regulate gene transcription of numerous genes, particularly those that code for pro-inflammatory cytokines. They act as vasoconstrictive, antiproliferative, anti-inflammatory and immunosuppressive.
While selecting the potency of corticosteroids and their vehicle, one should take into consideration the disease severity, the site being treated, the age of the patient and patient preference. Penetration correlates inversely with the thickness of the stratum corneum.[8] Several potencies are available, ranging from class 1 (highest potency) to class 7 [Table 1].[9] Mild-to-moderate potency corticosteroids are mainly used on the face and neck, flexures and genitalia and are also used in unstable, erythrodermic and generalised pustular psoriasis. Potent and very potent corticosteroids are suitable for scalp psoriasis and plaque psoriasis at sites of thick skin such as the palms and soles. Intralesional corticosteroid infiltrated intradermally into localised lesions of resistant plaques of psoriasis, for instance, on the backs of the hands and knuckles.[10]
The maximum dose of topical superpotent topical steroid should not exceed 45 grams/week.
The clinical efficacy of class I TCS such as clobetasol and halobetasol is well documented in the treatment of plaque psoriasis.[11,12] Dosing is done generally twice a day for approximately 2 weeks followed by an intermittent dosing regimen to preserve remission as maintenance therapy. Three consecutive applications (12 h apart) once-a-week therapy with betamethasone dipropionate (BMD) ointment have been used for maintenance of remission.[13] Another maintenance regimen of clobetasol propionate twice weekly achieved remission for an average of 4 months in 75% of treated patients.[14] Similarly, mid-potent TCS such as fluticasone propionate has also been found to be effective in plaque psoriasis. TCS in the form of lotions, solutions and foams are effective in scalp psoriasis. Potent topical steroids can be used for the treatment of psoriasis involving a nail bed and/or nail matrix.[15]
Easy to apply, cosmetically accepted, efficacious and nonirritant, with occlusion effect.
The potential side effects of TCS are well known and include cutaneous atrophy, striae formation, telangiectasia, tachyphylaxis, rebound flare and systemic absorption, although there is a lack of data about the magnitude of these risks.[16] Systemic adverse events including hypothalamic–pituitary–ovarian (HPO) axis suppression occur when TCS are used for prolonged periods of time or at doses higher than commonly prescribed. TCS usage in higher doses can lead to pustular psoriasis on their discontinuation.
Pregnancy category C.
Use during lactation—safety is unknown.
Use in children—lower potency should be used.
Vitamin D analogues are later entrants into the treatment of psoriasis. They are also useful in the treatment of nail psoriasis and chronic plaque psoriasis of the scalp.
Topical vitamin D analogues inhibit keratinocyte growth, promote keratinocyte differentiation and decrease inflammation in psoriatic lesions after binding with vitamin D receptors on the nucleus of keratinocytes.[17]
There are three vitamin D analogue preparations available, namely calcipotriene (in the United States), calcipotriol (in Europe), calcitriol and tacalcitol.
It is a synthetic vitamin D analogue available as 0.005% (5 mg/g) cream, ointment and solution. Calcipotriene is more effective than other vitamin D analogues (tacalcitol or calcitriol). It has similar efficacy to class 2 and 3 TCS but has relatively fewer side effects, but calcipotriene has a delayed onset of action, and the maximal response usually requires 2 months when used as monotherapy.[18] However, it provides longer disease-free interval in comparison with TCS.[19] The combination of the calcipotriene and TCS is superior to either agent used alone, so it is better to start with a combination and to continue with calcipotriene alone as it has a lesser side-effect profile.[20] The cream and solution are efficacious at twice-daily application, whereas ointment can be applied once daily.[21] Solutions are effective in scalp psoriasis.
It is a synthetic form of the active metabolite of vitamin D. It is available as an ointment only (3 mg/g).
Multicentre and randomised clinical trials have demonstrated the long-term safety and efficacy of calcitriol.[22] It is less potent than BMD, 0.05%, but induces longer remission than the latter.
It is a synthetic vitamin D analogue available as 4 mg/g ointment and lotion, applied once daily.
Clinical studies have shown tacalcitol ointment to be a safe and more effective long-term treatment for chronic plaque psoriasis with no systemic side effects and good tolerability in sensitive areas.[23] It is, however, less potent than calcipotriene.[24] The combination with clobetasol propionate in lacquer for the treatment of nail psoriasis where tacalcitol ointment under occlusion was applied twice daily on weekdays and the steroid lacquer on weekends has been found to be effective.[15]
Relatively safe and can be used in combination or even for longer duration as monotherapy for a longer duration.
Vitamin D analogues are relatively safe with few side effects. The most common adverse effect is skin irritation on or around the psoriasis plaques.[23] Face and intertriginous areas are especially prone to irritation. Calcitriol and tacalcitol have better tolerability in sensitive areas as compared to calcipotriene and therefore serve as better options in these areas.[23]
Systemic side effects such as hypercalcaemia, hypercalciuria and parathyroid hormone suppression are very rare if the maximum dose is not 100 g/week for calcipotriene, 210 g/week for calcitriol and 70 g/week for tacalcitol.[25]
Calcitriol may have greater effects on serum calcium in comparison with other analogues.[26]
Vitamin D analogues are contraindicated in patients already suffering from hypercalcaemia. Patients with renal impairment need to be observed carefully.
Calcipotriene is a relatively unstable molecule that is inactivated by an acid pH.[27] It can be combined with halobetasol ointment or cream or with 5% tar gel; however, it is degraded when mixed with 6% salicylic acid, 12% ammonium lactate or hydrocortisone 17 valerate ointment.[28]
Treatment with vitamin D analogues during pregnancy is rated category C.[29] Vitamin D analogues have not been found to be teratogenic in animals, although no clinical data on humans have been reported. The use of calcipotriene for the treatment of psoriasis in children is effective, and the dose should not exceed 50 g/week.[30]
Newer vitamin D analogues including maxacalcitol, paricalcitol and becocalcidiol are being studied for the treatment of psoriasis. They appear to be promising drugs for the treatment of plaque psoriasis.[31]
Calcineurin inhibitors though approved for use in mild-to-moderate atopic dermatitis only can be used in psoriasis as an off-label drug.
They bind with the intercellular enzyme calcineurin and decrease the activity of the nuclear factor of activated T cell (NFAT), which eventually blocks the transcription of interleukin (IL)-2, IL-4 and IL-10.[32]
There are two topical preparations of calcineurin inhibitors, namely tacrolimus ointment (0.03% and 0.1%) and pimecrolimus cream (1%).
Few studies showed that calcineurin inhibitors are as effective as the placebo for treating plaque-type psoriasis.[33] This is probably because of their inability to penetrate thick, psoriatic plaques due to their large molecular size. However, the penetration can be enhanced by occlusion[34] or by combining these agents with salicylic acid.
A recent review article has concluded that topical tacrolimus (0.1%) and pimecrolimus (1%) have efficacy in the treatment of psoriasis, especially treating in facial, genital and intertriginous areas, in inverse psoriasis and as a continuation therapy in resolving plaques or as occasional rescue therapy.[35] However, they are less efficacious than 0.005% calcipotriol or 0.1% betamethasone valerate.[36] Newer vehicle and microsomal preparations of calcineurin inhibitors should be developed in the treatment of psoriasis.
Lesser side effects—can be used for a longer duration.
The most common adverse event reported with the use of calcineurin inhibitors is irritation, stinging sensation and burning sensation, which is usually transient.[35] There is a theoretical risk of cancer with long-term use of topical calcipotriol inhibitor (TCI). As a result, new Food and Drug Administration (FDA) recommendations state that topical immunomodulators should not be used as long-term treatment, over large surface areas or in children under the age of 2 years but it is for atopic skin where the skin permeability of topical is high.[37]
Pregnancy category C.
Use during lactation—should be avoided.
New calcineurin inhibitor.
Sirolimus is recently been investigated as a possible treatment for chronic plaque psoriasis.[38]
Tazarotene
The first synthetically developed retinoid indicated for the topical treatment of psoriasis is tazarotene. It is available as a gel or cream at a concentration of 0.1% or 0.05%. The noble indication of tazarotene is in nail psoriasis, which is mostly effective when used under occlusion. In stable plaque psoriasis, it is mostly used in combination with TCS and calcipotriene. It can also be treated as an effective maintenance therapy in psoriasis.
Tazarotene selectively binds to β and γ retinoic acid receptors on the cell surface of keratinocytes and is then transported to the nucleus, ultimately altering the transcription of genes in keratinocytes. This results in reduced epidermal proliferation, normalising keratinocyte differentiation and decreasing inflammation.[39]
However, tazarotene 0.1% and 0.05% cream applied daily for at least 12 weeks was found to be more effective than vehicle in plaque psoriasis irritation is a major concern over thin skin.[40] The better result has been found when used in combination with mometasone and also has less side effect in plaque psoriasis.[41] In a recent observer-blinded, randomised controlled trial (RCT) conducted in India, 0.1% tazarotene cream was found to be as effective as clobetasol propionate exclusively for palmoplantar psoriasis.[42] In nail psoriasis, once daily application of 0.1% tazarotene for 12–24 weeks has been shown to improve onycholysis, hyperkeratosis, pitting and salmon patches.[15]
Beneficial over the thick plaque, over palmoplantar and nail psoriasis.
The most common side effect of tazarotene is localised irritation.[40] To alleviate such symptoms, one should use it in cream form and low concentration, alternate day application and short contact (30–60 min) therapy may help.[43] The use of nanotechnology can help to improve efficacy and to decrease side effect. Combination therapy with TCS or calcipotriol also improves efficacy and minimises symptoms. Tazarotene must not be used in sensitive areas such as the face, flexures and genitals.[44]
The FDA has issued a caution regarding the use of tazarotene and exposure to sunlight, and it should be applied at night and advised to use sunscreens during the daytime.
Pregnancy category of tazarotene—X (the theoretical risk of teratogenicity).[40]
Use during lactation—should be avoided.
Use in children—they tolerate topical retinoids very well.
Bexarotene gel, which acts by selectively binding with nuclear retinoid X receptor, is being studied as a potential treatment for psoriasis. It revealed the efficacy of bexarotene gel 1% in treating mild-to-moderate plaque psoriasis as monotherapy[45] and in combination with narrowband ultraviolet B (UVB) therapy.[46]
Salicylic acid is a beta-hydroxyl acid used as a topical keratolytic agent in psoriasis. Mostly, it is used in combination with TCS and calcineurin inhibitors to increase the penetration of the latter into the psoriatic plaques.
It dissolves the intercellular cement, thus reducing the intercellular cohesiveness of the keratinocytes, leading to desquamation. Moreover, it increases the hydration and softening of the stratum corneum by reducing the pH.[47]
Most of the studies available regarding the efficacy of salicylic acid are as combination therapy. The efficacy improves significantly when it is used with TCS[48] or with other immunomodulators[49] as it increases penetration with its keratolytic effect. Tiplica et al. found that the combination of mometasone furoate (0.1%) and salicylic acid (5%) was more effective than mometasone furoate (0.1%) alone.[48]
While there are no placebo-controlled studies available, verifying the efficacy and safety of salicylic acid is used alone.[48]
A steroid–salicylic acid combination should be considered as the first-line treatment on thick, scaly plaques and areas with thick stratum corneum including palms, soles and scalp. Its use should be avoided on sensitive skin like over the genitals, the mucous membrane and the eyes.
It can be applied as a paste or in creams, ointments and lotions in the concentration of 2%–6%.
Increases the absorption of other topicals when used in combination.
The most common side effect of salicylic acid is local irritation, burning sensation and erythema. The dreaded effect of salicylic acid is salicylism when it is applied in higher concentration (greater than 10%) over a larger surface area (more than 20% of the BSA). It absorbs through blood and causes intoxication leading to frontal headache, central nervous system symptoms, metabolic acidosis, tinnitus, nausea, vomiting and burning sensation over oral mucosa.[50]
Precaution should be taken when it is applied over large body surfaces, especially in children, as lethal cases are also been reported;[51] If larger surfaces require a salicylic acid treatment for initial keratolysis, a sequential treatment is useful (e.g. affected areas in the upper part of the body at night and the lower part of the body in the morning). Careful clinical monitoring, detection of early symptoms and discontinuation of therapy help to avoid severe salicylic acid intoxication. Haemodialysis is the mainstay of treatment for salicylic acid intoxication.
It should be noted that calcipotriol is inactivated by salicylic acid and should not be used in combination.[52] Salicylic acid blocks ultraviolet (UV) light and therefore should be applied after phototherapy.[53]
Use during pregnancy and lactation—safe
Use in children—should be avoided due to the increased chance of intoxication.
Anthralin is an anthracene derivative and one of the oldest agents to be used in stable plaque psoriasis. It is available in creams, ointment or paste form. Mostly, it is used as a short contact anthralin therapy (SCAT) for the treatment of localised, scaly plaques of psoriasis on the body or the scalp.
Anthralin acts probably through mitochondrial dysfunction by accumulating within it and interferes with the supply of energy to the cell,[54] which eventually reduces deoxyribonucleic acid (DNA) replication and keratinocyte proliferation, prevents T-cell activation and restores cell differentiation. In addition, the production of free radicals also helps its effect.[55] It also reduces elevated levels of cyclic guanosine monophosphate (cGMP).
Earlier anthralin was used as an overnight therapy, but now most of the literature recommends SCAT, in which a high concentration of anthralin, 1% or greater, is applied for approximately 20 min to 1 h before removal,[56] considering its side effects.
In another regimen, a sequential increase in application time of anthralin (1% or greater) by 5 min every other day can be considered till mild irritation appears. The period of application is then maintained until clearing.
There are limited data available on placebo-controlled trial with anthralin. However, a systematic review of topical preparations for the treatment of psoriasis shows that dithranol reduced psoriasis severity scores at 4–8 weeks significantly more than placebo.[57] RCTs between short contact (30 min) and overnight therapy with 1%, 2% and 3% dithranol ointment reveal similar efficacy, but the use of SCAT is more convenient and practical.[58] Anthralin has lower efficacy than more potent TCS or vitamin D derivatives when used as monotherapy.[59] Other RCTs have found that SCAT is equally effective as vitamin D but with lesser tolerability and acceptability.[60] Salicylic acid is frequently added to improve the stability of anthralin and to increase its penetration and efficacy.[61]
Not have many advantages over other topicals available as it has lesser efficacy and more side effects.
The most common side effect of anthralin is skin irritation, which is dose- and duration-dependent. It also stains (yellowish-brown) lesional and adjoining skin, hair, nails, clothing and other objects, with which the patients come into contact.[62] It should be applied with caution to the face and intertriginous areas due to the risk of skin irritation, eczematisation and secondary bacterial infection. No systemic toxicity has been reported even following the long-term application of anthralin.
Pregnancy category C.
Use during lactation—can be used avoiding direct contact of anthralin with baby's mouth.
Use in children—use with caution.
Preparations available
Coal tar, a thick dark liquid that is a by-product of the production of coke and coal gas from coal, is frequently used in the skin to treat psoriasis and seborrhoeic dermatitis. Its use as a Goeckerman regimen in conjunction with UVB is well recognised.[66]
It suppresses DNA synthesis, thereby reducing the hyperproliferation of keratinocytes.[67]
The patient is exposed to phototherapy (UVB) first. 2% crude coal tar (CCD) is applied over the psoriatic plaques. It is washed off after 4–5 hours. On subsequent days, the strength of tar is increased up to 10% as tolerated by the patient. Salicylic acid can be added with coal tar over the thick plaques. 20% liquid carbonis detergens (LCD) is used for scalp psoriasis.[66]
The efficacy of coal tar has been demonstrated on chronic plaque psoriasis, palmoplantar psoriasis and scalp psoriasis after 1 month of use and patients remain in remission for longer than that with other psoriasis topical treatments.[68] In comparison with the vitamin D analogue, coal tar was found effective as calcipotriol after 12 weeks of treatment; however, calcipotriol was better tolerated and had a faster onset of action.[69] Recently, a Cochrane review supports the use of coal tar products in the treatment of psoriasis, though the level of evidence is not strong enough.[70]
Not have many advantages over other topicals available as it has lesser efficacy and more side effects.
Adverse effects of coal tar include malodor, staining, irritant contact dermatitis, erythema, stinging, burning, folliculitis and even the formation of keratoacanthoma.[71] Though occupational coal tar exposure is a recognised carcinogen, there is no evidence of carcinogenesis reported in patients with psoriasis who have had treatment with coal tar.[72] Treatment with psoralen plus ultraviolet-A radiation (PUVA) and coal tar is not recommended nowadays due to the risk of skin cancer.[73] However, the use of tar has waned due to its poor side-effect profile and superior efficacy of alternative topical therapies.[74]
Pregnancy category C.
Use during lactation—can be used avoiding direct contact with baby's mouth.
Use in children—use with caution.
Recently, new formulations of coal tar, ranging from 1% to 15%, have been developed. They are nonstaining, nonodorous and easily spreadable, and their efficacy is also superior to conventional coal tar preparations and equal to topical ultrapotent steroid preparations.[75,76]
Searching for newer and better topical agents for psoriasis on the basis of small molecules selectively inhibits signalling pathways of pro-inflammatory cytokines, which include inhibitors of phosphodiesterase 4, integrin, Janus kinase (JAK) 1/JAK2 (ruxolitinib and tofacitinib) and tyrosine kinase.[77] Being small molecules, they can easily penetrate the epidermal barrier and hence are used in topical formulations. AN2728, a boron-based phosphodiesterase 4 inhibitor, is administered topically in phase 2 studies to patients with psoriasis.[78] JAK inhibitors such as tofacitinib, a pan-JAK inhibitor with a predominant anti-JAK3 effect, and ruxolitinib, a JAK1/2 inhibitor, have shown their efficacy in the topical treatment of mild-to-moderate psoriasis.[79] T327, a tyrosine kinase A inhibitor when used topically, reduces pruritus significantly. The nano-formulation of topical methotrexate also showed promising results in reducing Psoriasis Area and Severity Index (PASI) score.[80]
Psoriasis, where the skin becomes thick, challenges the permeability of different topical agents. The need for newer and better formulations to improve topical drug delivery is the need of the hour. Failure to choose the appropriate topical formulation for the morphology and site might contribute to poor treatment outcomes.[81] Liposomes, microemulsions, nanoparticles, nanostructured lipid carriers and micelles may have the potential to encapsulate antipsoriatic drugs and deliver them in a better way to improve the efficacy and to decrease the side effects. In addition, techniques such as iontophoresis, electroporation and lasers can be used to enhance penetration of the stratum corneum.[82]
Topical therapies are still the mainstream in the management of mild-to-moderate psoriasis. Even in the severe form of psoriasis, they are used as an adjuvant with systemic therapy. They are safe and well-tolerated. TCS and vitamin D analogues are preferred in modern days among the various topical agents available for psoriasis. TCI can be used as steroid-sparing agents in long-term therapy and on the face and intertriginous areas. Tazarotene can be used as an effective therapy for nail psoriasis.
New formulations such as gels, lotions, solutions, shampoos and foams of different molecules have been tested nowadays to improve the efficacy and side-effect profile and eventually the compliance of the patient. Advancement in nanotechnology has opened the possibility of improving the efficacy of topical agents and minimising their side effects. The emergence of newer molecules and newer drug delivery systems will significantly expand the therapeutic possibilities for the treatment of psoriasis. Target-based topical agents will be developed more as the new horizon opens in the understanding of pathogenesis of psoriasis.
Nil.
There are no conflicts of interest.