INTRODUCTION:

Animal models are essential tools for pharmaceutical research. Any drug molecule with a potential to treat the disease has to go through the preclinical studies before tested clinically. Hence animal model has a crucial role in the progress of 'lead molecule' into well established 'pharmaceutical product.' Apart from serving as a tool for testing the drugs, animal models also have a vital role in understanding the pathophysiology of the disease.

Psoriasis is a chronic, inflammatory, immune-mediated disease. Though the exact cause of the disease has not identified it is considered to arise as the result of genetic predisposition, external stimuli, and immune dysregulation. The disease is characterized by epidermal hyperplasia, altered vascularity, immune cell infiltration that ultimately leads to the alteration in the structure as well as the function of the healthy skin.¹ The complex interrelationship between the keratinocytes and immune cells contributes to the disease development with a genetic basis. The cytokines like TNF-α, IL-12, IL-23 are immunological mediators in which IL-12 induces Th-1 driven an increase in production of TNF-α and IL-23. These activated cytokines further stimulate Th-17 cells which synthesize pro-inflammatory mediators like IL-17, IL-22. The increased concentrations of TNF-α, IL-12, IL-23, have been found in psoriatic skin when compared with non-lesional skin.² As complex mechanisms develop the disease, experimental animal models that mimic the human disease are very few, concerning the research regarding both pathophysiology and drug discovery.³

Numerous therapeutic options are existing, but the choice of agent depends upon the severity of the disease. Topical therapy (corticosteroids, Vitamin D analogs, topical retinoids, dithranol, calcineurin inhibitors) is the best option for mild disease. The moderate-to-severe disease requires phototherapy (PUVA, excimer laser, narrowband ultraviolet B,) or systemic therapy (methotrexate, cyclosporin).⁴ Current approaches for the treatment aims to target particular molecule involved in the disease like TNF-α, interleukins, T-cells, Janus kinase, phosphodiesterase-4. Although few of them are used clinically, other drugs are still in various stages of drug development. Despite vast research in recent decades with regards to this area, the search for a novel therapy for the total cure remains an essential goal in which the excellent animal model has a significant role.^3,4

Nestle and Nickoloff defined the criteria for an ideal animal model.⁵An animal model should reflect the clinical changes during psoriasis such as epidermal alteration, presence of various inflammatory cells, changes in vascularity. Apart from these clinical features, an ideal model must show the histological changes such as acanthosis, papillomatosis, hyperparakeratosis, and it always should respond to the well-established antipsoriatic drugs. Based upon this information several in vivo and in vitro models are developed. Details of both in vitro and in vivo murine models are described elsewhere.^6,7 Over the years the utilization of IMQ-induced psoriasis mice model has gained much more importance because of its advantages. However, this model also suffers from many limitations which need to be addressed to prevent misinterpretation of the results. In the current review we made an attempt to describe the role of IMQ-induced psoriasis mice model in the psoriasis research.

IMQ-induced psoriasis mice model:

IMQ is a nucleoside analog of aminoquinoline family which has potent immune response modifier activity when used topically. This property of IMQ used in dermatological conditions like cutaneous malignancies. Additionally, it is used in actinic keratosis, basal cell carcinoma, and invasive squamous cell carcinoma.^8,9 The action of IMQ is mediated through agonistic activity towards toll-like receptor (TRL) 7 and 8 and consecutively the activation of nuclear factor kappa B (NF-кB).⁹ TRL is the pattern recognition receptors (PRR) present locally on the cell surface or within the vesicles that are responsible for recognition of pathogen-associated molecular patterns (PAMP) released from dead cells. A group of intracellular TLR referred to an endosomal TLRs contribute in the pathogenesis and development of psoriasis by sensing the endogenous DNA and RNA released by dead cells in damaged tissues.⁹ Apart from activating NF-кB, IMQ also appears to interfere with adenosine receptor signalling pathways. These mechanisms may augment the pro-inflammatory activity.⁸

IMQ was introduced into the market in 1997, but first case of provocation of psoriasis by IMQ was described by Wu JK et al in 2004¹¹ where the 58-years-old women treated with IMQ for multiple superficial basal cell carcinoma had provocation of localized psoriasis at the site of application.⁹ Few incidence of IMQ-induced psoriasis are listed in Table -1.

Topical application of 5% IMQ induces psoriasis-like dermatitis in laboratory animals was first described by van der fits et al., in 2009.¹⁶ Since then it has become the frequently used murine model for preclinical studies of psoriasis. Over the years, the use of this model has tremendously increased, resulted in rising in the number of publication as depicted in Fig 1. IMQ is a synthetic agent which binds to ligand of TLR-7 and 8.¹⁶As per the criteria for ideal preclinical models defined by Nestle and Nickoloff, most of them are well satisfied by this model including epidermal changes, presence of inflammatory cells like DCs, T cells and neutrophils, functional role of T cells, altered vascularity and response to well established antipsoriatic drugs whereas papillomatosis is sometimes but not always seen.¹⁴Many experimental data has proven that IMQ induced dermatitis in mice closely resembles human psoriasis concerning both phenotype and histopathology.¹⁷ The events occur post-application of IMQ mirror the aspects of human psoriasis, including histological features, activation of pro-inflammatory signalling pathways central to human psoriasis, and recruitment of cellular infiltrate.¹⁸ It has become a popular way to study plaque psoriasis, but it also recapitulates more severe symptoms seen in generalized pustular psoriasis.¹⁹

Fig-1: Graph representing the number of publications against year (The data included case reports, clinical studies, and preclinical research reports. * data represent till July 2019).

Characteristic changes seen in mice post application of IMQ:

As psoriasis is an inflammatory, autoimmune disease, the development of skin inflammation in mice was evidenced after 2 or 3 days of application of IMQ. The back skin of the mice starts displaying signs of erythema, scaling and thickening indicating the development of inflammation. Increased proliferation and altered differentiation of keratinocytes are evident in the form of increased epidermal thickness. Demonstration of disturbed epidermal differentiation is by retention of nuclei in stratum corneum, the absence of granular layer. All match the histological features of plaque psoriasis. One of the disease confirming features of psoriasis is the presence of inflammatory infiltrate, which is effectively satisfied in the model by the presence of abundant infiltrates of mononuclear cells consisting of APCs, T cells and neutrophils. Accumulation of neutrophils just beneath the stratum corneum was comparable to Munro microabscesses in psoriasis.

IHC staining showed increased vascularization in endothelial blood vessels. This change is due to IMQ mediated increase in pro-inflammatory cytokines of the IL-23/17 axis.¹⁶ Further, topical application of IMQ on animal skin causes splenomegaly, the sign of enhanced immunoreactions confirming the systemic effect.²⁰ IMQ also leads to the increased content of MDA, decreased bioactivity of plasma SOD, CAT. IMQ mediated oxidative stress imbalance the cause for these changes.²⁰

Reduced interest in nest building.²¹ Infections and injuries associated with a systemic response such as anorexia, fever, general malaise, and muscle joint pain.²¹ Psoriasis like skin induced by IMQ damages the skin's barrier function. Increased TEWL by IMQ, indicating the disruption of the epidermal barrier by psoriasis.²² Reduce the number of splenic B cells; increase IL-10- producing B cells within the draining LN and blood.²³ Increase in the counts of spontaneous bouts, increase in decarboxylase, tryptophan hydroxylase-1 mRNA expression.²⁴

Advantages:

Easy to use as it demands only topical application of commercially available 5% cream on shaved back and ear of the animal. The model described here develops relatively quickly; within 2-3 days, mice begin to develop the signs of acute skin inflammation like erythema, scaling, and skin thickening with 100% disease occurrence. This short requirement of time between application of IMQ and development of disease allows the generation of huge data within a small duration. The model is effective in both Th-1 and Th-2 prone mouse strains including C57BL/6, BALB/c, 129/Sv and can also be combined with modified mouse strains.^16,18,25 The set-up for this model requires minimum laboratory expertise, does not require pathogen-free conditions like xenotransplantation model and could be easily incorporated into ongoing laboratory protocols.¹⁸

Disadvantages:

Psoriasis is a chronic disease. As the model described here is acute, it does not explain the chronic nature of the disease. The effect of topical IMQ is not confined to the applied area. It also shows systemic effects where sever splenomegaly and worsened the general condition that ultimately leads to death of the animal, therefore in some strains of mice, administration of subcutaneous fluids is required to rescue the animal from dehydration¹⁶, however, if the treatment is prolonged for more than 2 weeks, the animal may die.²⁶ Although most of the clinical and histological features of psoriasis are mirrored by IMQ-induced psoriasis dermatitis, this model does not explain the genetic complexity involved in the genesis of disease. Generally, the psoriasis is associated with co-morbidities like arthritis, cardiovascular disease, but such co-morbid conditions are not generated in this model. The mechanism through with IMQ induces psoriasis is very complex and complete mechanism remain unclear. PASI scoring system used to measure the severity of the disease is susceptible to observer bias. The determination of erythema might be interrupted by the white scaling on the skin surface. Thus the increased erythema value was offset by the scaling.²⁵Histopathologically, the model closely resembles human psoriasis, but the hypogranulosis formed in human psoriasis was absent, reduced filaggrin expression in human psoriasis but not in experimental psoriasis.²⁷ Therefore IMQ-induced psoriasis, not real psoriasis, in spite of its similarity to the psoriatic lesion in many aspects as the experimental results showed. IL-23 is known to have its role pathogenesis of psoriasis since its discovery; however, in one of the study, IL-23 did not show any significant changes in any group, including the IMQ-treated group.¹⁷Although the model provides many similar features with human psoriasis, the causes of psoriasis are still not revealed completely. Therefore research using other models like transgenic mice or a SCID mouse psoriasis skin xenograft model is essential to confirm the antipsoriatic ability of drug molecule.²⁸ In the drug cure experiments, false-positive results may arise due to the decreased inflammation at days 6–8 after the application of IMQ. There are large differences because of the inconsistency in inflammation in various mice.²⁹ IMQ-induced dermatitis exhibited a time-of-day-dependent variation in wild-type mice, possibly in association with circadian IL-23R expression. Mice treated with IMQ at ZT14 exhibited more severe dermatitis than did mice treated with IMQ at ZT2.³⁰ IMQ application has been shown to induce IL-17A-producing gd T cells in the regional lymph nodes and IL-23p19 mRNA in mice¹⁶.However, the source of IL-23 in IMQ-treated areas remained unclear.³¹ The induction of psoriatic lesion in animals is based on local stimulation, and whereas psoriasis in humans results from the modulation of systemic immune response.²⁷ For the measurement of acanthosis in microns, the skin sample should be cut horizontally to avoid artificial acanthosis by tangential sectioning.¹⁸ Despite the fact that IMQ is used to develop an acute model for psoriasis, there is still a query whether the model truly represents psoriasis or other skin inflammatory disorder like systemic or subacute cutaneous lupus. Although 5% IMQ cream develops the disease, different brands of the creams reported having differential effects both macroscopically and histopathologically. Aldara cream showed more characteristic alterations of psoriasis form.³⁰ Generic IMQ cream produced more severe disease than Aldara.²¹ As variations in IMQ-induced psoriasis mice model, a fluctuation of cytokine expression was observed during the IMQ cream treatment period. The cytokine are responsible for the development and maintenance of the psoriatic lesion. However, one of the studies revealed that, though the cytokine expressions are reduced at the end, the symptom about psoriatic lesion may be progressive day by day.²⁷ Van der fits et al.,¹⁶ showed that the IMQ-induced skin inflammation in mice with a complete deletion of the IL-17RA receptor is profoundly suppressed compared with WT control mice. However, one of the studies showed that the PASI score of IL-17RA (del) mice is significantly reduced in comparison with the control group when treated with IMQ, but that there is no reduction of the IMQ-induced skin thickening and from day-4 onward, there is no difference in scaling between the two groups.³³To overcome the systemic side effect of the model, Horváth S et al. modified the model by using finn chambers over the dorsal skin of the mice. This model prevented the undesirable systemic effect of IMQ on mice and also permitted prolonged IMQ treatment studies to reflect the chronic nature of the psoriasis.³⁴

Different strain of animals used to develop model:

Although, IMQ induces psoriasis dermatitis, the severity of the disease in the different mice strain was found to be different. The skin inflammation developed more severely in BALB/c mice than C57BL/6, while systemic side effects are found more severe in C57BL/6 mice.¹⁶Balb/c mice is Th1 sensitive therefore expression level of a Th2 cytokine IL-13 was significantly decreased in response to repeated IMQ application. These results confirm that IMQ activated DCs through TLR-7 and TLR-8 to produce an environment dominated by Th1 and Th17 in the skin, as seen in other autoimmune disease models.²⁸ The constitutive expression of IL-13 observed in one of the studies is considered to be attributable to the proneness to Th2 of BALB/c strain used in the study.³⁵ C57BL/6 mice reported to suffer from dehydration, probably due to their response to IMQ is more Th-1 driven whereby more IL-1 and IL-6 are produced, leading to a fever response and dehydration.³⁶129/Sv mice showed more marked hyperkeratosis and hyperplasia than C57BL/6 mice.¹⁶Substrain variation observed between C57BL/6J and C57BL/6N mice where the course of skin inflammation was significantly found sever in C57BL/6J mice.³⁷ C57BL/6J mice provide a better background than other strains for modelling psoriasis disease mechanism.³⁸ This model is sensitive to different types of contact hypersensitivity (CHS) as Th2-type CHS being exacerbated in the Th17 inflammatory microenvironment presented by IMQ-induced psoriasis-like inflammation. Different types of CHS differentially influence psoriasis-like inflammation. DNFB-induced Th1-type CHS had no obvious impact on IMQ-treated psoriasis-like inflammation. However, FITC-induced Th2-type CHS exacerbated IMQ-treated psoriasis-like inflammation. Therefore, solely relying on the Th1/Th2 paradigm to explain the relationship between psoriasis and atopic disease is an oversimplification of the disease. Various sensitizers may affect different inflammatory pathways to develop psoriasis.³⁹In an experiment, Okasha et al. applied IMQ on the back skin of adult male albino rats. Further, skin section examination revealed hyperkeratosis with retention of nuclei in the stratum corneum, epidermal hypergranulosis, hyperproliferation of keratinocytes with increased epidermal thickening and epidermal rete ridges as well as abundant inflammatory cellular infiltrates indicating the hallmarks of psoriasis.⁴⁰ IMQ induced K14-VEGF mouse is more appropriate for long-term studies compared with the IMQ-wild type (WT), which is a type of acute chemical-stimulated model. Differences exist between them, and the long-term model (IMQ-K14) can better mimic the progression of psoriasis.²⁹

The outcome of studies on the model:

Various synthetic and natural products with antipsoriatic potential were investigated via this model. For better understanding, some of the plant products used in this model are described in Table-2. Many conditions that are known to exacerbate this model included, obesity,⁴¹osteopontin deficiency,⁴² liver fibrosis,⁴³ deficiency of L-selectin and ICAM-1,⁴⁴ prolactin,⁴⁵ overexpression of glucocorticoid-induced leucine zipper,⁴⁶microbiota infections,⁴⁷ decreased expression of caveolin-1,⁴⁸lipocalin-2.⁴⁹Further, IMQ-induced psoriasis is also found to associated with hepatitis ^49,51and depression.⁵²

The detailed study of IMQ-induced psoriasis model provided vast knowledge regarding the key pathways and involvement of cytokines in the development of the disease. These include IL-23/17 axis¹⁶, the importance of which is now well established in human psoriasis.²⁵ IL-23 induces CCR6+ϒδT cells found to have a pivotal role in psoriasis-like skin inflammation.⁵³ IL-35 (pIL-35) administered as a prophylactic treatment, weakened the inflammatory process.⁵⁴ IL-33 appears to be a major risk factor for severity of psoriasis-like skin inflammation.⁵⁵ IL-18 found to exacerbate psoriatic skin inflammation.⁵⁶

Further study using this model provided information about targeting certain pathways to improve the disease. Targeting both JAK1 and TYK2- mediated cytokines,⁵⁷ CX3 chemokine receptor 1 (CX3C1),⁵⁸ duel inhibition of TNFR1 & IFNAR1⁵⁹ may represent the potential novel strategic treatment.

Table-2: Different molecules screened for the antipsoriatic activity employing IMQ-induced psoriasis mice model:

S.No	Plant products	Mechanism	Conclusion	Reference
1.	Resveratrol	Decrease in mRNA levels of IL17-A and IL-19.	Significantly diminishes the severity of psoriasis like skin inflammation.	Kjaer TN et al⁶⁰
2.	Glycyrrhizin	Inhibit ICAM-1 expression via interference with the ERK/p38 MAPK and NF-кB signaling pathways in keratinocytes.	Ameliorates skin inflammation	Xiong et al⁶¹
3.	Paeoniflorin	Decrease the population of dermal macrophages, neutrophils and Th1/Th17 – associated cytokine production.	Ameliorates inflammation and skin lesions	Y.Sun et al⁶²
4.	Curcumin Aromatic-turmerone	Decrease the cytokine production like IL-17A, IL-17F, IL-22, IL-6 IL-1β and TNF-α.	Can relive imiquimod induced psoriasis- like inflammation similar to that of clobetasol	Sun J et al,⁶³ Li YL et al⁶⁴
5.	β,β dimethylacryloylalkanin (Lithospermumerythrorhizon)	Suppress the expression of IL-23 in skin lesions secreted by mature DCs	Suppress the function of activated DC in imiquimod –induced psoriasis mouse model	Wang Y et al⁶⁵
6.	Mustard seed (Sinapis Alba Linn)	Alter the expression of NF-кB, IFN-α, IL-17, IL-22 and composition of immunocytes	Attenuates imiquimod induced psoriasiform inflammation but did not clear it completely	R. Yung et al⁶⁶
7.	Andrographolide	Inhibits IMQ transduction via inducing the autophagic proteolysis of MyD88 and inhibit the production of inflammatory cytokines in DC.	Alleviates imiquimod induced psoriasis	F. Shao et al⁶⁷
8.	Astilbin (Smilax glabra)	Reduce the inflammatory cell differentiation (Th17) and cytokine secretion (IL-17A)	Alleviates imiquimod induced psoriasis like inflammation	T-T Di et al⁶⁸
9.	Cucurbitacin	Inhibit the expression of Il-8, CCL20 via downregulation of NF-кB and STAT signaling pathway in human keratinocytes	Has a potential for inhibiting imiquimod induced inflammatory reaction in keratinocytes	Z.J. Li et al⁶⁹
10.	Antrodiacinnamomea	Inhibit the development of Th17 cells by blocking STAT3 activity and RORϒt function.	Reduce the skin inflammation in imiquimod mediated epidermal damage	M-H Li et al⁷⁰
11.	Tripterygiumwilfordii	Downregulate the function of Th17 through inhibiting STAT3 phosphorylation	Inhibits the formation of imiquimod- induced skin lesions	ZHAO et al⁷¹
12.	Isoliquiritigenin (licorice)	Downregulate IL-6, IL-8 via suppression of NF-кB activity	Ameliorates inflammatory process in psoriasis models	Wu Y et al⁷²
13.	Quercetin	Improve the antioxidant and anti-inflammatory status by inhibiting the activation of non-canonical NF-кB signaling	Has a antiopsoriatic effect on imiquimod induced mice model	Chen H et al⁷³
14.	Black seed oil (Nigella sativa seeds)	Suppress the hyperproliferation and abnormal differentiation of keratinocytes	Inhibits imiquimod induced psoriasis and improve all epidermal and dermal changes observed post treatment of imiquimod	Okasha et al⁷⁴
15.	Isograninol (Garciniamangostana L.)	Reduces the differentiation of CD4+T cells into TH17 cells and decreases IL-17, IL-22 expression	Reduces imiquimod induced psoriasis like skin lesions in mice	Chen S et al⁷⁵
16.	Solanumxanthocarpum	Inhibits the expression of cytokine such as TNF-α, IL-β1, IL-6,IL-17.	Possesses significant antipsoriatic activity	Parmar KM et al⁷⁶
17.	Rhodhodendrin (Rhodhodendronbrachycarpum)	Inhibits NF-кB , MAPK and P13K/AKT signaling	Strongly inhibits imiquiimod induced psoriasis- like skin inflammation in mice	Jeon YJ et al⁷⁷
18.	Berberis arista extract	--	Extract loaded transferosomal gel shown improved anti-inflammatory activity and also has efficacy against imiquimod induced psoriasis.	Nimisha et al⁷⁸
19.	Epigallocatechin -3-gallate (tea polyphenols)	Reduce the expression of epidermal PCNA, promote the expression of caspase-14, reduce the level of IL-17A, IL-17F,IL-22,IL-23, MDA, increase the bioactivity of SOD and Catalase.	Alleviates psoriasiform dermatitis, improve skin pathology structure, attenuates skin inflammation	Zhang et al²⁰
20.	Luteolin-7-glycoside	Impairs the nuclear translocation of phosphorylated STAT3, blocking the IL-22 signaling cascadre.	Promising compound for the treatment of hyperproliferative and skin inflammatory skin disease like psoriasis.	R Palombo et al⁷⁹
21.	Plant antimicrobial solution	Inactivation and translocation of P65 protein into cellular nucleus, inhibition of the inflammatory NF-кB signaling pathway.	Promising drug candidate for the treatment of inflammatory skin disorder such as psoriasis	Dou R et al⁸⁰
22	DaturaMetel L	inhibition of the TLR7/8-MyD88-NF-κb-NLRP3 inflammasome pathway	Provided insight into the therapeutic effect of DaturaMetel L for psoriasis, and exploring the mechanism of the inflammation-signaling pathway	Yang BY et al⁸¹
23	Ferulic acid	Alters IL-17A/IL-17RA interaction	FA protected against IMQ-induced psoriatic skin injury in mice	Lo HY et al⁸²
24	Berberine	inhibit CDK4/6-RB-CDC6 signaling in keratinocytes, leading to reduced proliferation of keratinocytes, repression of JAK1, JAK2, and TYK2, which in turn inhibits activation of STAT3	It may serve as a potential therapeutic option for patients with psoriasis.	Sun S et al⁸³
25	Hesperidin	inhibits the activation of the IRS-1/ERK1/2 signaling pathway and regulated HaCaT cells metabolism	Hesperidin could have significant therapeutic value for the prevention and clinical treatment of psoriasis	Li X et al⁸⁴
26	Actinidiaarguta	Antipsoriatic activities are mediated via inhibition of NF-κB and signal transducer of activation (STAT) signaling	Actinidiaarguta has potential as a safe and effective reagent for the treatment of psoriasis	Kim HK et al⁸⁵
27	Esculetin (Fraxinusrhynchophylla)	Induces CD4+Foxp3+ Regulatory T Cells.	Esculetinmay be a potential therapeutic candidate for the treatment of psoriasis in clinic	Chen Y et al⁸⁶

SUMMARY AND CONCLUSION:

An animal model should be robust, easy to develop, and mimic clinically in all the aspects. Therefore, the selection of an animal model for drug screening is very crucial. Considering the complexity of psoriasis and its multifactorial nature, always there is some difference between the animal model and clinical scenario. Therefore, the goal achievement is questionable. Although mouse models do not represent all the aspects of psoriasis, they serve as the tools to understand some mechanisms or events underlying the pathophysiology of the disease. Knowledge about mouse model best represents the pathways of interest for a given study, that could offer more specific research into a particular area of psoriasis pathogenesis. IMQ-induced psoriasis mice model provides a powerful tool to understand early events during psoriasiform plaque formation, the role of various cytokines, cell types, and cellular pathways involved in the disease formation. It also serves as a model to investigate the potential antipsoriatic effect of a drug molecule. Apart from offering many benefits for researchers; this model still suffers from some significant limitations. Selection of this model needs scientific justification, and one should thoroughly study all its merits and demerits, its mechanisms, and possible errors while interpretation of the results. Therefore there is a need to take a step toward overcoming those limitations so that the model could serve as a promising tool for psoriasis research.

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Received on 21.09.2019 Modified on 17.11.2019

Research J. Pharm. and Tech. 2020; 13(7): 3508-3515.

DOI: 10.5958/0974-360X.2020.00621.6

S. No.	Patient (Age in year/sex)	IMQ indication	Clinical event	Treatment & Outcome	Reference
1	58/F	Multiple superficial basal cell carcinoma	Provocation of localized psoriasis	Psoriasis resolved slowly with conventional treatment (Calcipotriol, Mometasonefuroate)	Wu JK et al¹¹
2	77/M	Actinic keratosis	Generalized psoriasis	Interrupted the treatment of the IMQ and the Psoriatic lesions were improved	Fanti PA et al¹²
3	35/M	Penile warts	Exacerbation of eczema	Lesions resolved after a repeat course of antibiotics and steroids	Taylor CL et al¹³
4	64/F	Superficial basal cell carcinomas	Generalized exacerbation of psoriasis	Treatment with IMQ was stopped, topical steroid and topical calcipotriol creams were given for psoriasis which slowly improved over 10 weeks	Rajan N et al¹⁴
5	i)37/M ii)21/M	i) Viral wart ii)Keratinized warts in the preputial area	i) Florid lichen sclerosus ii) Lichen planus	Unresponsive to steroid treatment plastic surgery and a circumcision was done. --- do ---	O'Mahony C et al¹⁵