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Management of Psoriasis Vulgaris with Methotrexate 0.25% in a Hydrophilic Gel: A Placebo-Controlled, Double-Blind Study
Abstract
Background
Methotrexate has been used as one of the first and systemic therapies for psoriasis. In general, 70% of patients with psoriasis prefer topical therapy as the treatment of choice.
Objective
The purpose of this placebo-controlled double-blind study was to evaluate the clinical efficacy and tolerability of methotrexate 0.25% incorporated in a hydrophilic gel (hydroxyethylcellulose 1%) to treat patients afflicted with psoriasis vulgaris.
Methods
Sixty patients (37M/23F) ranging between 18 and 70 years of age, with slight to moderate chronic plaque-type psoriasis and PASI (Psoriasis Area and Severity Index) scores between 5.3 and 17.5 joined the study. The mean duration of the disease at entry was 9.6 years (range 1–24 years). The diagnosis of psoriasis was established by clinical and histopathologic methods. Patients were sequentially randomized into two parallel groups. Each patient was allocated a precoded 100-g tube (active or placebo) with instructions on how to self-administer the trial medication topically (without occlusion) to their lesions two times daily for 5 consecutive days per week. The study lasted for 12 weeks with 4 weeks of active treatment. Patients were examined on a weekly basis and those showing total clearing or remission of lesions were considered effectively treated.
Results
By the end of the treatment, breaking the code disclosed that methotrexate 0.25% gel had significantly treated more patients than placebo (83.3% vs. 6.7%; p < 0.0001), reduced the PASI score to a mean of 2.2, and cleared more plaques (82.2% vs. 4.3%; p < 0.0001). Laboratory evaluations, including CBC with differential and platelet count, renal function, liver chemistry [SGOT (aspartate transaminase) and SGPT (alanine transaminase)], and serum creatinine, were within the normal limits. The treatment was well-tolerated by all the patients, with no adverse drug-related symptoms and no dropouts. The study was followed up for 12 months from the first day of the treatment; two cured patients had relapsed after 8 months.
Conclusion
The findings of this study demonstrate that methotrexate 0.25% in a hydrophilic gel is well tolerated and significantly more effective than placebo as a patient-applied topical medication to treat psoriasis vulgaris.
... Ten of those related to topical MTX in an aqueous gel or cream, or with chemical enhancers (Table 1). [9][10][11][12][13][14][15][16][17][18] Nineteen related to topical MTX with nanotechnology, supramolecular hydrogels, protein transduction domains and liquid crystalline systems ( Table 2). 8,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] Seven related to topical MTX with physical enhancers/laser/photodynamic therapy (Table 3). ...
... Table 1 summarises 6 studies related to topical plain MTX in psoriasis. [10][11][12][13]15,17 Three of those showed promising results: 1 case series; 1 randomized controlled trial (RCT); and 1 single-blind, placebo-controlled study. 10,12,17 The remaining three showed ineffective results (1 intra-individual comparison, 1 RCT and 1 case series). ...
... [10][11][12][13]15,17 Three of those showed promising results: 1 case series; 1 randomized controlled trial (RCT); and 1 single-blind, placebo-controlled study. 10,12,17 The remaining three showed ineffective results (1 intra-individual comparison, 1 RCT and 1 case series). 11,13,15 Fry et al and Stewart et al reported a small case series of topical plain MTX in patients with plaque psoriasis in years 1967 (n = 9) and 1972 (n = 9), respectively. ...
Methotrexate (MTX) has long been considered the first-line oral systemic pharmacotherapy for psoriasis. The drug has several well-known systemic side effects, such as bone marrow suppression and hepatotoxicity. To avoid them, the use of topical or intralesional administrations of MTX has become an interesting option. With the advent of novel drug delivery systems, especially nanocarriers, the usage of a high-efficacy and safe topical MTX for psoriasis has nearly been attained. This review examined the development, anti-psoriatic efficacy and adverse effects of topical forms of MTX (plain MTX; MTX with chemical enhancer; MTX using nanotechnology; MTX with protein transduction domains; MTX with liquid crystalline systems; and MTX with physical enhancer/laser) and intralesional MTX in psoriasis patients and psoriasis-induced animals. The efficacy of topical MTX varied with the drug delivery technology employed. Nevertheless, the overall safety profile of the topical forms was favourable. A 25 mg/mL MTX solution injected intralesionally at the nail matrix worked well for nail psoriasis recalcitrant to topical treatment. To improve the standard of care for patients with psoriasis, randomized controlled trials that establish the most effective MTX-delivery system are needed.
... Unlike oral MXT, topical preparations of the drug, that was adapted for the treatment of localized lesions, showed nonsignificant related hepatotoxic and hematologic adverse effects (Sutton, Swinehart, Cato, & Kaplan, 2001;Syed, Hadi, Qureshi, & Ali, 2001;Weinstein, McCullough, & Olsen, 1989). ...
Vitiligo is quite a common hypopigmentary disorder, which may affect both children and adults with important psychological effects due to the well-known leopard skin-like appearance. Even if asymptomatic and not life threatening, vitiligo has to be increasingly studied and treated. Hitherto, the efficacy of topical methotrexate in treatment of vitiligo has not been reported. We herein reporting our preliminary observation on the promising efficacy of topical methotrexate in 1 patient with stable vitiligo. The patient applied topical methotrexate 1% gel twice daily for 12 weeks. Significant improvement of the lesion with no local or systemic side effects were noted during the course of therapy. We propose that this well-tolerated drug can be used for vitiligo therapy; however, further investigations should be performed to ascertain the exact topically effective dose. This article is protected by copyright. All rights reserved.
... Results have varied from little effect in some studies 2 to a beneficial effect in others. [5][6][7] Topical methotrexate in palmoplantar psoriasis was tried in two studies, one showing a beneficial result. 8 In second study, methotrexate 0.25% in a hydrophilic gel was used an d it was found that was well tolerated but not very effective in controlling the lesions of psoriasis on the palms and soles. ...
Background:
Palmoplantar psoriasis is often disabling and refractory to conventional therapy. Systemic drugs are indicated in its severe form, but side effects are a concern with their use. Methotrexate is one such systemic drug which is effective and cheap. To reduce systemic toxicity, methotrexate has been tried topically but results have been inconsistent due to poor drug penetration into the skin by passive diffusion. Iontophoresis may enhance its absorption and efficacy.
Aim:
To evaluate the efficacy and safety of topical methotrexate iontophoresis in comparison with coal tar ointment in the treatment of palmoplantar psoriasis.
Methods:
Thirty-one patients with palmar and/or plantar psoriasis were selected for the study and 28 patients completed it. The side having more severe involvement was treated while the other palm/sole served as a control. Iontophoresis using methotrexate solution was carried out on the study palm/sole with the injectable preparation of methotrexate (50 mg/2 ml) once a week for the first 4 weeks and subsequently every two weeks, for a total of six sittings. The control palm/sole was treated with coal tar ointment on other days. Erythema, scaling, induration and fissuring scores were noted in both groups before and after treatment.
Results:
Both study and control groups showed decreases in scores but the reduction was more in the study group, the difference being statistically significant.
Limitations:
Drawbacks of our study include the small sample size and the lack of follow-up. The study and control arms were not exactly matched and the study was not blinded.
Conclusion:
Methotrexate iontophoresis was safe and more effective than coal tar ointmentin palmoplantarpsoriasis.
... Therapeutic guidelines and recommendations have been available from time to time for monitoring methotrexate induced hepatotoxicity (Tables 4 and 5) [94][95][96] . Unfortunately, the potential efficacy of a topical methotrexate preparation in palmoplantar or plaque psoriasis remains unexploited [97][98][99] . Drugs like hydroxycarbamide, azathioprine, leflunamide, 5-fluorouracil, paclitaxel, and MMF too have been used infrequently in spite of limited therapeutic benefit vs methotrexate. ...
... The finding of reduced markers of proliferation may suggest that the resolution of psoriasis is associated with reduced proliferation, though not necessarily a direct result of methotrexate exposure. Reports of clinical efficacy achieved with reformulated versions of topical methotrexate are emerging [52,53]. The clinical efficacy of topical methotrexate may stimulate renewed interest in the effects of methotrexate on keratinocytes. ...
Background: For decades methotrexate has been used in the treatment of psoriasis with well-established efficacy. Although many theories regarding methotrexate's mechanism of action in psoriasis were suggested, the exact the mechanism of action is still not very well understood. This paper reviews the published literature on methotrexate mechanism of action in psoriasis. Articles published with English abstracts between January 1970 and December 2008 identified in MEDLINE were reviewed. It is likely that methotrexate interferes with the inflammatory pathways critical to psoriasis pathogenesis by multiple mechanisms. Current evidence suggests that methotrexate, as an immunomodulatory agent and anti-metabolite, decreases T-cell-mediated inflammation at multiple steps and that explains its efficacy in treating various inflammatory diseases including psoriasis.
... The molar ratios of lipid materials were selected based on our preliminary study and those reported by other research studies (Coderch et al., 2000;El Maghraby et al., 2000a,b;Stuhne-sekalec and Stanacev, 1989;Taylor et al., 1990). The concentrations of MTX entrapped were selected based on those clinically tested for the psoriasis treatment reported elsewhere, although the different routes of MTX administration were applied (Wienstein and Olsen, 1989;Eskicirak et al., 2006;Lakshmi et al., 2007;Syed et al., 2001). ...
This study aimed to investigate the physico-chemical characteristics and in vitro permeability of methotrexate (MTX)-entrapped deformable liposomes prepared from phosphatidylcholine (PC) and oleic acid (OA), comparing with those of MTX-entrapped conventional liposomes prepared from PC and cholesterol (CH). Two formulations of MTX-entrapped PC2:CH1 and PC9:CH1 liposomes and one formulation of MTX-entrapped PC2.5:OA1 liposomes were prepared. The size, size distribution, zeta potential, thermal properties, entrapment efficiency, stability, and in vitro permeability across a porcine skin of the MTX-entrapped liposomes were evaluated. All liposome formulations showed a narrow size distribution with the size range of 80-140 nm which is appropriate for the skin permeability. The percentage of MTX loading, entrapment efficiency and the stability of MTX-entrapped PC2:CH1 and PC9:CH1 liposomes were slightly higher than those of MTX-entrapped PC2.5:OA1 liposomes. However, the MTX-entrapped PC2.5:OA1 liposomes enhanced the skin permeability characterized by the higher concentration and flux of MTX diffused across or accumulated in the epidermis and dermis layers of porcine skin. The enhanced permeability of MTX-entrapped PC2.5:OA1 liposomes was explained by 2 mechanisms: (1) the deformable and elasticity characteristics of OA-containing liposomes and (2) a property as a skin penetration enhancer of OA. This suggested that the PC2.5:OA1 deformable liposome was one of promising candidates to enhance the permeability of MTX for the treatment of psoriasis.
... Earlier formulations of MTX as cream and ointments [8][9][10][11] were ineffective leading to the hypothesis that MTX acts on psoriasis throughout a systemic mechanism. Lately, the formulation of MTX in hydrophilic gels with/ without penetration enhancers [12 -17] showed some promising clinical results [18,19]. Alvarez-Figueroa et al. [16,17] also demonstrated in vitro that MTX can be successfully delivered by iontophoresis. ...
The pharmacokinetics of methotrexate (MTX) in rabbit's skin and plasma after iv-bolus and iontophoretic delivery at different current densities was studied. Linear microdialysis probes were introduced into the upper dorsal shaved skin of tranquilized rabbits. Commercially available patches were used to deliver MTX for 1 h at different current densities (100, 200, and 300 microA/cm2) on different occasions. Iv-boluses (10 mg/kg) of MTX were also administered. Retrodialysis was performed at the end of the experiments to estimate probe recovery. Plasma and microdialysis samples were analyzed using a validated HPLC assay. Following iv-bolus, MTX showed a bi-exponential decay both in plasma and in skin. Cmax in skin occurred with a delay of 22 min compared with plasma. No quantifiable concentration of MTX was detected in the skin on passive drug delivery. Systemic exposure to MTX (AUC) and Cmax increased linearly with current density. Nevertheless, exposure to MTX in the skin did not increase linearly with current density, whereas Cmax did. In conclusion, iontophoresis remarkably improved the dermal delivery of MTX over passive diffusion. However, total exposure did not increase with current density in the skin, suggesting that for local applications lower current densities may achieve the same effects with minimal systemic exposure.
... 9 Accordingly, methotrexate, a potent inhibitor of the enzyme dihydrofolate reductase and related to aminopterin, was developed as an antagonist of keratinocyte hyperplasia and its clinical dosing schedule was developed with an understanding of altered proliferation kinetics of keratinocytes in psoriasis lesions. [10][11][12][13] The assumption that methotrexate specifically targeted keratinocyte hyperplasia led to development of other epithelial-targeted therapeutics, e.g. synthetic retinoids and vitamin D derivatives, which (somewhat paradoxically) inhibit or stimulate differentiation of epidermal keratinocytes. ...
Psoriasis is perhaps unique for a disease studied through translational science in that there is not an accepted animal model, yet many rounds of bidirectional translation have taken place that have helped to define disease pathogenesis and to advance therapy. In this review, we illustrate the evolution of new pathogenic concepts and the testing of new therapeutic agents through translational research in humans. We present a current view of disease pathogenesis that stems from research in patients and animal models, but with the perspectives (i) that disease models can advance or hinder the overall translational enterprise and (ii) that the research process must be firmly grounded in the pathophysiology of the actual human condition.
As well as quantifying the burden of skin disease, epidemiology provides a direct method for assessing the causes of skin diseases. Identification of causes is a necessary step in pursuing the ultimate goal of disease prevention. This chapter covers the importance of thinking in terms of population rather than individuals, and provides a summary of the substantial global morbidity caused by skin disease. Risk factors from genetics to environment are outlined, along with describing the natural history and associations of common skin diseases. Finally, there is a description of how the principles and data from epidemiological studies provide the cornerstone to planning appropriate dermatology services. The chapter closes by providing the reader with a glossary of terms and a checklist to help with reading epidemiological studies.
Background:
Psoriasis Vulgaris is a common immune-mediated skin disease. Its high prevalence, disability, chronicity, disfiguration, and associated comorbidities make it a challenge for physicians. Topical agents remain the mainstay of treatment for patients with mild to moderate psoriasis.
Aim:
To evaluate the efficacy and tolerability of topical methotrexate 1% gel (MTX) versus topical calcipotriol 0.005% cream (CPL) in the treatment of localized plaque psoriasis.
Methods:
This prospective comparative study included 40 patients with localized plaque psoriasis instructed to apply MTX to one side (group A) and CPL to the other side lesions (group B) twice daily for 12 weeks. Clinical and dermoscopic evaluations before, weekly during and after 3 months of treatment were done. The immunohistopathological assessment was done for skin biopsies from 10 patients in each group before and after treatment.
Results:
At the end of 12 weeks, there was marked-complete improvement in 97.5% of group A lesions treated with MTX 1% gel compared with 37.5% of group B lesions treated with calcipotriol 0.005% cream (p < 0.001). There was a very high statistically significant improvement in erythema that was cleared totally in 67.5% vs 22.5%, scaling in 75% vs 17.5%, and infiltration in 72.5% vs 27.5% in group A vs B, respectively (p < 0.001). These results were confirmed by dermoscopic and immunohistopathological findings.
Conclusion:
Methotrexate 1% gel is a marvelous promising well-tolerated effective topical agent that can be used safely in the treatment of localized plaque psoriasis.
Psoriasis is an autoimmune, inflammatory and chronic skin disease in which cell growth and proliferation are increased, causing erythema, lesions and skin's peeling. Oral methotrexate (MTX) is the first-choice drug when phototherapy or retinoid treatment are not effective. Topical administration can be advantageous to better orientate the drug's delivery; however, the stratum corneum performs as a barrier for hydrofilic drugs penetration. This study sought to evaluate two different types of vehicles for MTX on the psoriasis treatment - hydrogel and liquid crystal systems (LCs). Lamellar and hexagonal liquid crystalline phases were selected from a ternary phase diagram based on polysorbate 80, isopropyl miristate and water. The hydrogel was based on alkylated carbomer (ACH). Rheological analysis showed ACH was more elastic than lamellar and hexagonal phases. ACH interacted better with pig skin than LCs in bioadhesion assay. Preclinical study revealed the ACH decreased inflammation in mice with induced psoriasis, being as effective as dexamethasone to regulate epidermis thickness, COX-2 and myeloperoxidase activity and TNF-α level, while LCs demonstrated inflammatory effect. Therefore, MTX-loaded hydrogel based platforms are indicated for local treatment of psoriasis and present great potential for further studies.
Psoriasis is a gene and immune-mediated inflammatory skin disease without any improvement and its treatment is completely dependent on symptom control. Presently, it is affecting millions of people worldwide. Hypodermic needles, topical creams, along with transdermal patches have been more frequently used for transdermal administration of medications. Because of the skin layer, Stratum corneum which gives protection towards the drug and/or foreign particles and only some molecules are allowed to access the target, so the effectiveness of most of the transdermal delivery systems is reduced. A modern method of a delivery system termed as ‘microneedles’ enhances the transport of the medication directly into the skin by bypassing the skin barrier layer solve different problems concerning the conventional transdermal delivery systems. The purpose of this review is to explore about MNs used as a transdermal drug delivery system for treating psoriasis. Owing to the range of benefits offered, such as minimal harm, painlessness, comfort, and increased patient compliance, the MNs approach is considered to be far safer in comparison to conventional transdermal delivery systems. The word MNs have inclined much attention by researchers in recent times and the MNs technology is transiently growing. MNs are categorized by scholars into four main types: dissolving microneedles (DMNs), coated microneedles (CMNs), solid microneedles (SMNs), and hollow microneedles (HMNs). As per their exceptional features like shape and usage, each type of MNs possesses distinct advantages. By reviewing the literature, characteristics and geometry of MNs, mechanism of MNs, and commonly used drugs for the microneedle's fabrication were considered. The polymers and methods used for preparing MNs and applications of microneedle technology with prime focus on psoriasis therapy are explained. Evaluation parameters of MNs such as characteristics, dimensional, mechanical, in vitro, and in vivo evaluations, along with the patents filed and marketed products of MNs are reviewed and included in this article. This piece of writing is therefore intended to include a written description of the advancements of the use of MNs in effective psoriasis treatment.
Background: Systemic methotrexate (MTX) is a useful treatment for many dermatologic conditions, however, the risk of adverse events prevents its use in patients with minimal or localized disease. Topical application of MTX may be an option to avoid the systemic adverse effects of oral MTX.
Objective: To assess what is known about the efficacy and safety of topical methotrexate.
Methods: A search on Pubmed was conducted. There were no limits on publication date.
Results: A total of 963 articles were discovered. Using our exclusion criteria, 916 articles were excluded; 47 articles were used for full text assessment. Topical MTX has been used primarily in psoriasis but also in mycosis fungoides, lymphomatoid papulosis, and oral precancerous lesions. Optimal delivery system and formulation for adequate penetration is still under investigation.
Conclusion: The quality of evidence for the utility of topical methotrexate in psoriasis is good, however, for other dermatologic diseases, the quality is poor. Topical MTX with improved delivery methods may be a viable tool against certain localized dermatologic conditions for patients who do not tolerate oral MTX. Further double-blinded randomized controled studies are needed to substantiate the utility of topical methotrexate.
Background/objectives:
Palmoplantar psoriasis is a localised variant of psoriasis. Topical therapy is the preferred treatment modality, but in severe and recalcitrant cases, systemic drugs like methotrexate are prescribed, with potential for significant adverse effects. Iontophoresis is gaining popularity in enhancing the transdermal delivery of drugs in ionic state. This study was undertaken to evaluate and compare the efficacy of topical methotrexate by iontophoresis technique with clobetasol propionate 0.05% ointment in the treatment of palmar psoriasis.
Methods:
This was a prospective randomised controlled study conducted on patients with palmar psoriasis. Group 1 patients (n = 31) were treated with once weekly iontophoretic delivery of methotrexate over 6 sittings, and group 2 patients (n = 31) were treated with clobetasol propionate 0.05% ointment, twice daily for 6 weeks. Severity of palmar psoriasis was assessed by modified Palmoplantar Pustular Psoriasis Area and Severity Index (m-PPPASI), and treatment was considered as satisfactory when there was >50% improvement.
Results:
Sixty two patients were recruited, of which 50 completed the study. Eight out of 25 (32%) patients in group 1 and 12 out of 25 (48%) patients in group 2 showed satisfactory improvement at the end of 6 weeks. However, this difference was statistically not significant (P = 0.25). Burn injury was noted in 12 (48%) group 1 patients with no adverse effects in group 2.
Conclusion:
Iontophoretic delivery of methotrexate is a promising therapeutic modality, the efficacy of which is comparable to that of clobetasol propionate ointment in the treatment of palmar psoriasis.
Background
Long before the advent of the biologic agents, methotrexate was the gold standard for the treatment of moderate to severe psoriasis. Although methotrexate's therapeutic efficacy in the treatment of psoriasis is well-established, the mechanism of action is still poorly understood.
Objective
This paper reviews the published research on methotrexate's mechanism of action in psoriasis.
Methods
Studies published with English abstracts between January 1970 and December 2006 identified in MEDLINE with the keywords methotrexate, psoriasis and mechanism were reviewed.
Results
Methotrexate appears to exert clinical efficacy in psoriasis by interfering with CLA+ T-cell infiltration into lesional skin via multiple mechanisms.
Conclusion
It is likely that methotrexate interferes with the inflammatory pathways critical to psoriasis pathogenesis by multiple mechanisms. Current evidence suggests that methotrexate works by decreasing the number of circulating CLA+ T cells; decreasing inflammatory infiltrate into the dermis and epidermis by downregulating adhesion molecules in endothelial cells; and downregulating the expression of adhesion molecules on T cells.
Dermatologists have the good fortune to work on the most accessible organ of the body. Many inflammatory and neoplastic conditions can be effectively managed using the wide range of locally applied physical or pharmacological modalities that are available. The latter are the subject of this chapter, which reviews the pharmacological treatments used topically, i.e. by application to the surface of the skin. Some of these are time-honoured treatments that have been used for a century or more, whilst others belong to the ever-expanding range of newer and increasingly potent agents constantly being developed and formulated for topical use. Topical treatment offers the potential to achieve high concentrations of a drug in the skin with minimal exposure of other organs. This can greatly increase efficacy and also safety relative to systemic administration. When side effects do occur, they are most likely to take the form of localized reactions.
Non-biologic therapies are useful in psoriasis for intermittent, rotational or combination treatment and in managing "difficult to treat" psoriasis, patients with minimal lesions, or who have achieved recommended cumulative dose or developed side effects/intolerance to conventional drugs, or where co-morbidities pose unusual challenges. Methotrexate, cyclosporine, acitretin, tar, anthralin, corticosteroids or calcipotriol ointments, and phototherapy are well established in psoriasis treatment. Hydroxycarbamide, azathioprine, leflunomide, mycophenolate mofetil, isotretinoin, fumarates, calcineurin inhibitors, peroxisome proliferator-activated receptor agonists, statins, pentoxifylline, sulfasalazine, colchicine, or various physical modalities often mentioned as non-standard therapies. They will remain important until an affordable, safe, effective, and remittiv therapy becomes available.
Early stage mycosis fungoides represents the most common clinical presentation of cutaneous lymphoma, with skin-directed therapies long established in its treatment. These therapies continue to change as new treatment regimens emerge. Other skin-directed treatments include light and radiation therapy. Therapies with higher levels of evidence and less systemic toxicity are usually preferred as first-line treatment. However, even these established therapies, like topical corticosteroids and carmustine, lack randomized clinical trials to establish their efficacy. Research is also needed to further define the role of combination topical therapies and how skin-directed therapies can be used as adjuvants to systemic medications.
Background:
Chronic plaque psoriasis is the most common type of psoriasis, and it is characterised by redness, thickness, and scaling. First-line management of chronic plaque psoriasis is with topical treatments, including vitamin D analogues, topical corticosteroids, tar-based preparations, dithranol, salicylic acid, and topical retinoids.
Objectives:
To compare the effectiveness, tolerability, and safety of topical treatments for chronic plaque psoriasis, relative to placebo, and to similarly compare vitamin D analogues (used alone or in combination) with other topical treatments.
Search methods:
We updated our searches of the following databases to February 2011: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2011, Issue 2), MEDLINE (from 1948), EMBASE (from 1980), Science Citation Index (from 2008), Conference Proceedings Citation Index - Science (from 2008), BIOSIS (from 1993), Dissertation Abstracts via DialogClassic (all publication years), and Inside Conferences (all publication years).We identified ongoing and unpublished studies from the UK Clinical Research Network Study Portfolio and the metaRegister of Controlled Trials. We checked the bibliographies of published studies and reviews for further references to relevant trials, and we contacted trialists and companies for information about newly published studies.A separate search for adverse effects was undertaken in February 2011 using MEDLINE and EMBASE (from 2005).Final update searches for both RCTs and adverse effects were undertaken in August 2012. Although it has not been possible to incorporate RCTs and adverse effects studies identified through these final searches within this review, we will incorporate these into the next update.
Selection criteria:
Randomised trials comparing active topical treatments against placebo or against vitamin D analogues (used alone or in combination) in people with chronic plaque psoriasis.
Data collection and analysis:
One author extracted study data and assessed study quality. A second author checked these data. We routinely contacted trialists and companies for missing data. We also extracted data on withdrawals and on local and systemic adverse events. We defined long-term trials as those with a duration of at least 24 weeks.
Main results:
This update added 48 trials and provided evidence on 7 new active treatments. In total, the review included 177 randomised controlled trials, with 34,808 participants, including 26 trials of scalp psoriasis and 6 trials of inverse psoriasis, facial psoriasis, or both. The number of included studies counted by Review Manager (RevMan) is higher than these figures (190) because we entered each study reporting a placebo and an active comparison into the 'Characteristics of included studies' table as 2 studies.When used on the body, most vitamin D analogues were significantly more effective than placebo, with the standardised mean difference (SMD) ranging from -0.67 (95% CI -1.04 to -0.30; 1 study, 119 participants) for twice-daily becocalcidiol to SMD -1.66 (95% CI -2.66 to -0.67; 1 study, 11 participants) for once-daily paricalcitol. On a 6-point global improvement scale, these effects translate into 0.8 and 1.9 points, respectively. Most corticosteroids also performed better than placebo; potent corticosteroids (SMD -0.89; 95% CI -1.06 to -0.72; I² statistic = 65.1%; 14 studies, 2011 participants) had smaller benefits than very potent corticosteroids (SMD -1.56; 95% CI -1.87 to -1.26); I² statistic = 81.7%; 10 studies, 1264 participants). On a 6-point improvement scale, these benefits equate to 1.0 and 1.8 points, respectively. Dithranol, combined treatment with vitamin D/corticosteroid, and tazarotene all performed significantly better than placebo.Head-to-head comparisons of vitamin D for psoriasis of the body against potent or very potent corticosteroids had mixed findings. For both body and scalp psoriasis, combined treatment with vitamin D and corticosteroid performed significantly better than vitamin D alone or corticosteroid alone. Vitamin D generally performed better than coal tar, but findings relative to dithranol were mixed. When applied to psoriasis of the scalp, vitamin D was significantly less effective than both potent corticosteroids and very potent corticosteroids. Indirect evidence from placebo-controlled trials supported these findings.For both body and scalp psoriasis, potent corticosteroids were less likely than vitamin D to cause local adverse events, such as burning or irritation. Combined treatment with vitamin D/corticosteroid on either the body or the scalp was tolerated as well as potent corticosteroids, and significantly better than vitamin D alone. Only 25 trials assessed clinical cutaneous dermal atrophy; few cases were detected, but trials reported insufficient information to determine whether assessment methods were robust. Clinical measurements of dermal atrophy are insensitive and detect only the most severe cases. No comparison of topical agents found a significant difference in systemic adverse effects.
Authors' conclusions:
Corticosteroids perform at least as well as vitamin D analogues, and they are associated with a lower incidence of local adverse events. However, for people with chronic plaque psoriasis receiving long-term treatment with corticosteroids, there remains a lack of evidence about the risk of skin dermal atrophy. Further research is required to inform long-term maintenance treatment and provide appropriate safety data.
Prescribing topical treatment Formulation of topical treatment Topical treatments used in the management of skin disease References
Chronic plaque psoriasis is the most common type of psoriasis and is characterised by redness, thickness and scaling. First line management of chronic plaque psoriasis is with topical treatments, including vitamin D analogues, topical corticosteroids, tar-based preparations, dithranol, salicylic acid and topical retinoids.
To compare the effectiveness, tolerability and safety of topical treatments for chronic plaque psoriasis with placebo; to compare vitamin D analogues with other topical treatments.
The Cochrane Skin Group's Trials Register was searched (2004/12). To update an unpublished 2002 review we also searched CENTRAL in The Cochrane Library (Issue 1,2005); MEDLINE (to 2005/02); EMBASE (to 2005/08); Science Citation Index (to 2005); Biosis (to 2005); Dissertation Abstracts (all publication years); Inside Conferences (all publication years); SIGLE (to 2005); National Research Register (all projects with a start date of 2001 to 2005); metaRegister of Current Controlled Trials.
Randomised trials comparing treatments against placebo or against vitamin D analogues in people with chronic plaque psoriasis.
One author extracted study data and assessed study quality. A second author checked these data. We routinely contacted triallists and companies for missing data. We extracted data on withdrawals and adverse events.
The review included 131 RCTs with 21,448 participants. Vitamin D was significantly more effective than placebo, although there was a wide variation in effect size with the standardised mean difference (SMD) ranging from -0.82 (95% CI -1.34 to -0.29) to -1.90 (95% CI -2.09 to -1.71). With one exception, all corticosteroids performed better than placebo, with potent corticosteroids (SMD: -0.95 (95% CI: -1.11 to -0.80; I(2): 61.1%; 17 studies; 2386 participants)) having smaller benefits than very potent corticosteroids (SMD: -1.29 (95% CI: -1.45 to -1.13; I(2): 53.2%; 11 studies; 1571 participants)). Dithranol and tazarotene performed better than placebo. Head-to-head comparisons of vitamin D against potent or very potent corticosteroids found no significant differences. However, combined treatment with vitamin D /corticosteroid performed significantly better than either vitamin D alone or corticosteroid alone. Vitamin D performed better than coal tar, but findings relative to dithranol were mixed. Potent corticosteroids were less likely than vitamin D to cause local adverse events. No comparison of topical agents found a significant difference in systemic adverse effects.
Corticosteroids perform as well as vitamin D analogues and are associated with a lower incidence of local adverse events. Further research is required to inform long-term maintenance treatment.
A positive correlation between disease severity and the frequency of cutaneous lymphocyte-associated antigen (CLA)-positive T cells in the blood of untreated patients with psoriasis has been previously observed. A dose-dependent inverse relationship between disease severity and the frequency of circulating CLA(+) T cells in psoriasis patients on methotrexate (MTX) treatment is reported. Circulating T cells from a patient with psoriasis were monitored for CLA expression on a daily basis for 5 weeks. A decrease in the intensity and frequency of CLA(+) mononuclear leucocytes was consistently observed in the blood during the first 3-4 days after each MTX intake, but the CLA expression increased thereafter until the next weekly dose was taken. The MTX treatment of this patient was then discontinued for 16 days, and a marked subjective exacerbation was reported within 9 days, which was confirmed objectively (laser Doppler perfusion imaging) after 11 and 16 days. Biopsies taken 4 days after the last MTX intake showed only a few mononuclear leucocytes in lesional skin, but the exacerbation coincided with a marked increase in CLA expression by mononuclear blood leucocytes, followed by an increase in endothelial E-selectin and a striking influx of CLA(+) mononuclear cells into lesional skin. Conversely, a clinical improvement after the patient resumed the MTX treatment was associated with reduction in CLA expression by mononuclear cells in the blood, downregulation of endothelial E-selectin and an approximate threefold decrease in mononuclear leucocyte infiltration of lesional skin. No MTX-associated changes were detected in the expression of very late antigen-4, vascular cell-adhesion molecule-1 nor the late activation marker CD25. It is concluded that MTX decreases the expression of CLA and E-selectin and that this may be a major mechanism for the therapeutic effect of MTX on psoriatic skin lesions.
Palmoplantar psoriasis (PPP) is a chronic, disfiguring condition, and its management is difficult. The systemic side effects of methotrexate can be avoided if it is effective topically. We studied the efficacy and safety of a recently marketed topical methotrexate (0.25%) preparation in a hydrogel base in patients with palmoplantar lesions. A total of 14 adult patients diagnosed clinically as plaque type of palmoplantar psoriasis (>30% of the palm and/or sole areas involved) were included in the study. Topical methotrexate 0.25% in a hydroxygel base was applied twice daily to the lesions for twelve weeks. The lesions were assessed for degree of erythema, scaling, induration and fissuring (ESIF) and were scored on a severity score of 0-3 (0--clear, 1--mild, 2--moderate, 3--severe) every two weeks. The most severe condition was given 12 points; 0 denoted no disease. The response at the end of the study was graded as minimal if there was up to 25% reduction in the EISF score, mild as 26-50% reduction, moderate improvement as 51-75% reduction in score, and marked improvement as >75% reduction in score. The average age of the 11 male and female patients was 41.5 years (18-57 years) with the duration of the disease varying from 2 months to 15 years. Ten patients had both palmar and plantar lesions; two each had only palmar lesions or plantar lesions. The ESI score at baseline was 5.8 +/- 0.9 for the palms and 6.8 +/- 0.5 for the soles. The scores at the end of the study were 3.5 +/- 0.7 for palms and 4.8 +/- 0.2 for the soles. The average time taken for improvement was at least six weeks. None of the patients had complete clearance of lesions. The drug was well tolerated by all patients. Methotrexate 0.25% in a hydrophilic gel is well tolerated but is not very effective in controlling the lesions of psoriasis on the palms and soles. A higher concentration in a different base with better penetration could possibly provide better results.
In general, 70% of patients with psoriasis prefer topical therapy as the treatment of choice.
To evaluate the efficacy and tolerability of 1% topical methotrexate gel vs. placebo (vaseline ointment) as treatment for psoriasis.
Forty patients (20 females and 20 males) with chronic plaque-type psoriasis joined the study. Each patient was allocated to apply 1% methotrexate gel and placebo topically to their two target lesions, equal in area and disease severity, twice daily for 8 weeks. Lesions were scored at baseline and after 2, 4, 6, and 8 weeks of treatment for erythema, scale, and infiltration. The global improvement and histopathologic features were also assessed after methotrexate treatment.
At the end of treatment, erythema was cleared totally in 47.5% of patients treated with methotrexate vs. 7.5% of those treated with placebo, and infiltration in 22% of patients treated with methotrexate vs. 2.5% of those treated with placebo (P<0.01). Clinical improvement was almost the same for the two groups with regard to scale (P<0.5). The global improvement was 97% for patients treated with methotrexate vs. 60% for those treated with placebo, and a significant difference was found between the groups (P<0.01). Histopathologic improvement was achieved in the methotrexate group (P<0.01). No side-effects were observed.
The findings of this study suggest that methotrexate 1% in a hydrophilic gel is well tolerated and significantly more effective than placebo as a topical medication for the treatment of psoriasis vulgaris.
The aim of this study was to investigate the transdermal iontophoretic delivery of methotrexate, alone or in combination with microneedles, in-vitro and in-vivo using intracutaneous microdialysis in the hairless rat. The average depth of the microdialysis probe in the skin was found to be 0.54 mm. Methotrexate was stable in the presence of an applied electric field as determined by cyclic voltammetry. A current density of 0.4 mA cm(-2) applied for 60 min was used in combination with maltose microneedles to enhance delivery of methotrexate across the skin. Delivery was enhanced by iontophoresis and microneedles, both in-vitro and in-vivo. A synergistic 25-fold enhancement of delivery was observed in-vivo when a combination of microneedles and ionto- phoresis was used compared with either modality alone.
As a chronic condition affecting about 2% of the European population, psoriasis has a substantial economic impact. Several studies on the economic impact of psoriasis have previously been reported. Increased pressure on health care budgets in most countries has emphasized the need for economic evaluation studies of drugs and treatments. It is not easy to calculate exactly the costs and outcomes of treatments. One has to be careful of the pitfalls and avoid making wrong interpretations. Results from different countries cannot be extrapolated and are not easily compared. Psoriasis also causes significant psychosocial morbidity. Improvement in the quality of life has to be a major concern in economic considerations. Physicians and patients are becoming aware through these economic studies of the cost of treatment which is important in this period of budget restrictions. Providing that they are correctly interpreted, the results of the studies can help in management decision-making, in using resources more rationally, and in ruling out ineffective and expensive treatments.
• In vitro percutaneous penetration of methotrexate is enhanced with 1-dodecylazacycloheptan-2-one (laurocapram [Azone]). Laurocapram-containing methotrexate formulations provide effective local inhibition of epidermal DNA synthesis in the in vivo hairless mouse and minipig models, providing the biochemical rationale for topical use in the treatment of psoriasis. Topical methotrexate (0.1%, 0.5%, and 1%) in a laurocapram-containing formulation was tested in a two-center double-blind pilot clinical study of 42 patients with plaque psoriasis. Drugs were applied twice a day for six weeks, and lesions were scored weekly for erythema, scale, and elevation. An overall improvement of 50% or more in the combined scores for erythema, scale, and elevation was obtained with 0.1% methotrexate (64% of patients), 0.5% methotrexate (59%), and 1% methotrexate (56%) vs the vehicle alone (25%). These preliminary findings suggest that methotrexate preparations that provide adequate methotrexate taneous absorption may have a beneficial effect in the treatment of psoriasis.
(Arch Dermatol 1989;125:227-230)
Ro 10-9359 is a retinoic acid derivative, selected for study because of a better tolerance than retinoic acid, shown in animal experiments. Doses of 25 mg b.i.d., 25 mg t.i.d. and 50 mg b.i.d. were administered orally to 27 patients suffering from severe chronic generalized psoriasis. The clinical efficacy was evaluated by means of a new index, psoriasis area and severity index (PASI) based on severity and area of psoriatic lesions. At doses of 25 mg t.i.d. or 50 mg b.i.d. Ro 10--9359 proved to be an extremely potent antipsoriatic drug. A more than 90% reduction of psoriatic lesions could be seen in 10 patients out of 20 after 4-8 weeks of treatment. This good effect lasted about 5 weeks after treatment. Side effects were frequent, but mostly mild and completely reversible after termination of treatment.
In vitro percutaneous penetration of methotrexate is enhanced with 1-dodecylazacycloheptan-2-one (laurocapram [Azone]). Laurocapram-containing methotrexate formulations provide effective local inhibition of epidermal DNA synthesis in the in vivo hairless mouse and minipig models, providing the biochemical rationale for topical use in the treatment of psoriasis. Topical methotrexate (0.1%, 0.5%, and 1%) in a laurocapram-containing formulation was tested in a two-center double-blind pilot clinical study of 42 patients with plaque psoriasis. Drugs were applied twice a day for six weeks, and lesions were scored weekly for erythema, scale, and elevation. An overall improvement of 50% or more in the combined scores for erythema, scale, and elevation was obtained with 0.1% methotrexate (64% of patients), 0.5% methotrexate (59%), and 1% methotrexate (56%) vs the vehicle alone (25%). These preliminary findings suggest that methotrexate preparations that provide adequate percutaneous absorption may have a beneficial effect in the treatment of psoriasis.
Alopecia areata is suspected to be an autoimmune disease. We studied 104 consecutive patients with alopecia areata for the presence of autoantibodies and associated autoimmune diseases.
A detailed history and examination was carried out in all patients to look for associated atopy, diabetes mellitus, hypertension, rheumatoid arthritis, vitiligo, lupus erythematosus, and thyroid disorders, etc. in the patients or their family members. Venous blood for estimation of fasting and postprandial blood glucose was collected in 30 patients, especially in those with family history of diabetes mellitus. Antimitochondrial (AMA), antismooth muscle (SMA), antinuclear antibodies (ANA), antiparietal cell antibody (PCA), and antibody against thyroid microsome (TMA) were detected employing indirect immunofluorescence on a composite section of rat liver, stomach, kidney, and human thyroid. Skin biopsy was processed for direct immunofluorescence by a conventional technique.
Disseminated discoid lupus erythematosus, lichen planus, urticaria, psoriasis, and seronegative spondylarthritis were associated with alopecia areata in one case each. Antismooth-muscle-antibodies and PCA were found in 36 (34.6%) and 44 (42.3%) patients respectively, followed by TMA in 8 (7.7%), AMA in 6 (5.7%), antithyroglobulin antibodies in 3 (2.8%), and ANA in 2 (1.9%) patients. The incidence of SMA was higher in men with alopecia areata (P < 0.001). Direct immunofluorescence carried out in 24 patients did not reveal significant findings, except for occasional immunoglobulin deposits around hair follicles and blood vessels.
Alopecia areata in India is associated more often with antismooth muscle and antiparietal cell antibodies.
The hereditary transmission of psoriasis is suggested by epidemiological data and familial association, but remains incompletely defined, not appearing to follow simple autosomal dominant or recessive patterns. The confusion may be due to a multifactorial inheritance, or to inheritance of only a 'predisposition' to disease which requires an environmental stimuli for expression. Recent advances in genetic mapping indicate genetic heterogeneity, and suggest that definition of psoriasis at the level of the gene may soon be possible. Two of the three major pathogenic features of psoriasis--abnormal keratinocyte differentiation and hyperproliferation of keratinocytes--are secondary to altered growth and maturation kinetics related to the normal wound healing process. The third major pathogenic feature--infiltration of inflammatory components into the skin--can be explained by keratinocyte release of a wide variety of cytokines, immune and inflammatory modulators. Three theories have been proposed for the relationship between epidermal keratinocyte and immunocyte activation. The first theory proposes direct activation of epidermal keratinocytes by physical, chemical, or ultraviolet injury, increasing the synthesis and release of cytokines, which trigger T-lymphocyte activation in an antigen-independent fashion. The other two theories propose persistent T-lymphocyte stimulation as a result of either antigen/superantigen presentation by antigen-presenting cells, or as a result of autoreactivity. One or more of these mechanisms may be operative in different patients, at different times, or in response to different environmental stimuli. Also, the genetic heterogeneity of psoriasis suggests that different mechanisms could be linked to different genetic loci. Advances in understanding the aetiology and pathogenesis of psoriasis suggest the possibility of innovative, targeted therapies.
Low-dose methotrexate (MTX) is approved for the treatment of recalcitrant rheumatoid arthritis (RA). The objective of this study was to determine the effect of vehicles and penetration enhancers on the percutaneous absorption of MTX and its analog edatrexate (EDAM), and develop transdermal (TD) delivery systems of the drugs for the treatment of RA.
From previously published pharmacokinetic parameters with low-dose MTX therapy, and considering a 50 cm2 diffusional area, the target steady state in vitro TD flux for MTX was calculated to be 35 micrograms/cm2/hr. Modified Franz diffusion chambers and hairless mouse skin were used for in vitro skin permeation studies. Hairless mice were used for in vivo studies. Delivered amounts of MTX and EDAM were determined by assaying the receiver phase fluid (or blood) with validated reversed phase HPLC methods.
Intrinsic partition coefficient of MTX was low (log P = -1.2). Target MTX fluxes of > or = 35 micrograms/cm2/hr were achievable only with 1-15% (v/v) Azone in propylene glycol (PG). Flux of EDAM (85 micrograms/cm2/hr) was higher than MTX from an isopropyl alcohol (IPA)-5% (v/v) Azone system. Clinically significant steady state in vivo blood concentration of MTX and EDAM was achieved using delivery systems containing > or = 2.5% Azone in PG. Area under the drug concentration-time curves (AUC0-24 hr) for MTX were 2379 and 3534 ng*hr/ml from PG-2.5% Azone and PG-7.5% Azone systems respectively. AUC0-24 hr of EDAM was 6893 ng*hr/ml using a PG-2.5% Azone system.
Results of this study show the feasibility of using a transdermal delivery system of MTX and EDAM for the treatment of rheumatoid arthritis.
Cyclosporine has been in worldwide use for 15 years for patients who have undergone transplantation operations and is now being used to control inflammatory reactions in other organs (eg, joints, bowel, and skin). Neoral, a more consistently absorbed form of cyclosporine, has recently been approved by the Food and Drug Administration for the treatment of psoriasis. This report outlines the indications, contraindications, dosage recommendations, monitoring requirements, adverse events, drug interactions, interactions with other psoriasis treatments, and suggestions for cyclosporine's use in rotational therapy.
Weekend therapy with superpotent topical corticosteroids has been used for the long-term treatment of psoriasis. Recently, calcipotriene ointment has been added to this regimen for use on weekdays, but there are no long-term studies of that combination.
The purpose of this study was to determine whether the addition of weekday calcipotriene to a pulse therapy regimen of weekend superpotent corticosteroids results in a longer duration of remission of plaque psoriasis.
This was a double-blind, placebo-controlled, parallel-group study. Forty-four patients with mild to moderate psoriasis were treated with calcipotriene ointment in the morning and halobetasol ointment in the evening for 2 weeks. Thereafter, 40 patients who were at least moderately (50% or greater) improved were randomized to 2 treatment groups. After 2 weeks of treatment with calcipotriene ointment in the morning and halobetasol ointment in the evening, 20 patients were randomized to receive halobetasol ointment twice daily on weekends and calcipotriene ointment twice daily on weekdays, and 20 patients were randomized to receive halobetasol ointment twice daily on weekends and placebo ointment twice daily on weekdays.
Seventy-six percent of patients applying halobetasol ointments on weekends and calcipotriene ointment on weekdays were able to maintain remission for 6 months compared with 40% of patients applying halobetasol ointment on weekends only with the vehicle on weekdays.
The addition of calcipotriene ointment applied on weekdays to a weekend pulse therapy regimen of superpotent corticosteroids can increase the duration of remission of psoriasis.
The armamentarium of therapies for psoriasis continues to expand with drugs such as tazarotene, calcipotriene, and acitretin approved in recent years. New forms of old treatments such as cyclosporine and anthralin have also been introduced. Frequently, inadequate attention is devoted to duration of remission. The purpose of this article is to examine the duration of remission reported with many therapies currently used for psoriasis. Studies examining duration of remission are included. Among our conclusions were the following: the definitions of remission/relapse used in various studies differ, duration of remission is influenced by the natural history of each patient's disease, among topical monotherapies anthralin and tazarotene appear to induce longer remissions than calcipotriene and corticosteroids, among systemic agents longer remissions occur with etretinate than cyclosporine or methotrexate but compared with the remission rate of phototherapeutic modalities, especially Goeckerman and PUVA therapy, the remission rates are much less.
1alpha, 25-Dihydroxy-22-oxacalcitriol (maxacalcitol) is a vitamin D3 analogue which displays approximately 10 times greater efficacy at suppressing keratinocyte proliferation in vitro than calcipotriol and tacalcitol. To determine clinical efficacy, a phase II double-blind, randomized, left vs. right, concentration-response study was performed with once-daily topical maxacalcitol in patients with mild to moderate chronic plaque psoriasis. Primary efficacy parameters were psoriasis severity index (PSI) based on sum of scores for erythema, scaling and induration and investigators' overall assessment of patients' response to therapy at 8 weeks of treatment. One hundred and forty-four patients participated. All concentrations of maxacalcitol ointment (6, 12.5, 25 and 50 microg/g) were significantly more effective at reducing PSI than placebo (P < 0.01), with greatest effect noted for maxacalcitol 25 microg/g. Calcipotriol ointment 50 microg/g once daily as active comparator had a similar effect. Marked improvement or clearance of psoriasis was greatest for maxacalcitol 25 microg/g (55% of subjects) which compared favourably with calcipotriol (46%). Improvement continued throughout the study period, with no plateau at week 8. Investigators' and patients' side preference (secondary efficacy parameters) rated maxacalcitol more effective than placebo and 25 microg/g maxacalcitol better than calcipotriol (P < 0.05 for investigators' assessment). Twelve patients withdrew from the study due to adverse events, of which four were judged to be due to study medication. This study indicates that once-daily maxacalcitol ointment is effective in the management of plaque psoriasis, with greatest effect noted at 25 microg/g. As no response plateau was noted at 8 weeks, these data suggest that further benefit might be obtained if maxacalcitol ointment were applied for longer. Finally, investigators' overall assessment and side preference suggest that maxacalcitol 25 microg/g may be more effective than once-daily calcipotriol.
Epidemiology and heredity
- Naldi L
- Cainelli T
- Dubertret L