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European S1 guidelines on the management of lichen planus: a cooperation of the European Dermatology Forum with the European Academy of Dermatology and Venereology – Ioannides – 2020 – Journal of the European Academy of Dermatology and Venereology

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Introduction

Lichen planus (LP) is a common mucocutaneous disease affecting stratified squamous epithelia. The aetiology of the condition is complex and multifactorial, with histopathological features more typical in cutaneous than mucosal lesions, where ulceration is more apparent. LP most commonly affects middle‐aged adults, in particular perimenopausal women and is rare in children. The lesions usually involve the skin (cutaneous lichen planus), the oral cavity (oral lichen planus), the genitalia (penile or vulvar lichen planus), the scalp (lichen planopilaris), nails (lichen unguis), or extracutaneously (e.g. the oesophagus). The diagnosis and management of lichen planus will be reviewed here.

Despite the high prevalence of the disease and the variety of therapeutic options available, no national or international evidence‐based guidelines for treatment exist. That is why the European Dermatology Forum (EDF) initiated a project to develop guidelines for the treatment of lichen planus. Based on expert opinion and literature search, therapeutic recommendations were developed through round mailing (Delphi method). This process was subject to an approval of the guidelines by all the members of the subcommittee.

The purpose of the guideline is to provide all healthcare professionals with a tool for choosing an efficacious and safe therapy for various subgroups of patients, presenting with different subtypes of lichen planus. Healthcare professionals include dermatologists, dentists, gynaecologists, urologists, general practitioner in clinics, as well as in private practice and other specialists who are involved in the treatment of patients with lichen planus.

Methods

These guidelines were conducted as S1 guidelines for the treatment of lichen planus.

Evidence for this guideline was provided by review of the literature of the databases MEDLINE/PubMed, EMBASE and Cochrane Library from 1 January 1986 to October 2018, using the term lichen planus, diagnosis, treatment, therapy and prognosis.

The evaluations of these guidelines are restricted on the efficacy of the particular therapeutic options and based on opinions and personal experiences of the members of the guideline group and the evaluation of the level of evidence of the studies. All recommendations were agreed on in a round mailing consensus. A list of possible treatments for each LP subtype was prepared and sent to all authors. All nominated experts were entitled to report their choice of preferable treatments for each LP subtype in a numerical order. Therefore, the highest possible consensus level of treatment preference was reached.

The resulting therapeutic recommendations aim to optimize the therapeutic process and to support the healthcare practitioner in the individual decision on a suitable therapy.

Definition

Lichen planus is an inflammatory skin disease affecting the skin, mucous membranes, hair and nails. The term lichen planus is derived from the Greek word ‘leichen’, which means to lick or what eats around itself , describing the characteristic way this skin disease appears and evolves and the Latin word ‘planus’, which means ‘flat’, depicting the specific appearance of this disorder. The dermatosis was first described by Erasmus Wilson in 1869.1

Lichen planus is a distinctive entity that affects various areas of the body, either concomitantly or sequentially. It is a chronic inflammatory disease, with the exception of most cutaneous forms that often resolves spontaneously within one to two years. Skin hypertrophic and mucosal lichen planus is considered a potential premalignant condition, as the incidence of squamous cell carcinoma in these LP variants is approximately 1%.2-5

Three systematic reviews were prepared on the treatment of oral and erosive mucosal LP, respectively,6-8 four on the treatment of cutaneous lichen planus9-12 and one on the therapeutic management of lichen planopilaris.13 Data from randomized, controlled trials are limited, and management choices are based mainly on clinical experience.3, 10

Epidemiology

Estimations on the incidence of lichen planus are between 0.14 and 1.27% of the general population.2 At least two‐thirds of the cases occur between the ages of 30 and 60 years. The disease is uncommon in children; however, it can occur at any age. No sexual or racial prevalence is evident in the cutaneous form, whereas 60 to 75% of patients with oral lichen planus are females.3 The prevalence of oral lichen planus is approximately 1.5%.4 Familial cases are rare, but have been described.14

Pathophysiology–Aetiopathogenesis

The pathogenesis of LP remains unclear, but it is likely to be of a multifactorial nature. It is generally considered an immunologically mediated disorder. It affects surfaces covered by stratified squamous epithelium.

There is evidence that cell‐mediated immune response plays a major role in the development of the disease. T cells, both CD4+ and CD8+, accumulate in the dermis, while CD8+ T cells infiltrate the epidermis in LP lesions. The majority of lymphocytes in the LP infiltrate consists of CD8+ and CD45RO+ cells and expresses the α‐β T‐cell receptor (TCR), and to a lesser extent the γ‐δ receptor.15 These cells are responsible for the most characteristic change observed in the lichenoid reaction, apoptosis.2

Genetic and environmental factors, such as stress, infections (e.g. HPV16, HSV17), changes in the mucosal microbiome (e.g. Candida sp, various other bacteria18) and dental amalgam, play an important role for disease manifestation. Genetic susceptibility has been documented. Different haplotypes, such as HLA –A3, ‐A5, ‐A28, ‐B8, ‐B16, ‐Bw35, ‐B7, ‐B18, ‐Aw19, ‐Cw8, are associated with different variants of LP.14

Disease associations

A significantly high prevalence of thyroid disease among OLP patients has been observed, 19 whereas contradictory results were found when analysing the relationship between lichen planus and diabetes mellitus.20 Other diseases of altered immunity, particularly alopecia areata, ulcerative colitis, vitiligo, morphea, lichen sclerosus and myasthenia gravis, occur more frequently in patients with LP. Patients with lichen planus present a higher risk for dyslipidaemia, which could be explained by the cytokines involved in the pathogenesis of the disease, such as TNF‐a, IL‐6, IL‐10 and IL‐4. Therefore, lipid‐level screening in LP patients is recommended to detect individuals at risk for the development of cardiovascular diseases.21

Certain disorders and infections, such as hepatitis C,22, 23 hepatitis B (lichen planus pemphigoides),24 hepatitis B25 vaccination and primary biliary cirrhosis, are associated with LP. In contrast, specifically for hepatitis C, there are studies suggesting that there is no association between the two disorders or that such an association is geographically dependent.26-28 Therefore, hepatitis C tests are recommended in LP patients from regions (Africa, Middle East and Asia) with high prevalence of the infection.

There are also specific medications, which are considered responsible for drug‐induced lichen planus (a relevant list is included under the ‘LP and its variants’ part of the guidelines).28-30

Clinical picture

Lichen planus is a unique entity representing skin and mucosal lesions of typical colour, morphology and distribution. Classical cutaneous lichen planus is characterized by pruritic, flat‐topped, polygonal violaceous papules localized to the wrists, forearms, distal lower extremities and the presacral area. The lesions on non‐keratinized epithelium, such as the buccal mucosa, tongue, oesophagus and genitalia, are often non‐pruritic and may present with burning or being entirely non‐symptomatic. Mucosal lesions become often erosive. LP affecting the hair follicles and the nail bed will often lead to permanent scarring resulting in islands of alopecia and pterygium formation with eventual loss of the nail plate.2, 14

LP onset is usually acute with initial lesions almost always appearing on the extremities. A generalized eruption, in approximately one‐third of the cases, may be developed after one week or more with maximal spreading within 2–16 weeks.

Papules are grouped and tend to coalesce and sometimes form a central umbilication. They are usually distributed symmetrically and bilaterally over the extremities and often covered by lacy, reticular, white lines known as Wickham striae. These fine, whitish punctae are considered highly characteristic and observed more easily after applying oil, xylene or water when visualizing the lesions with a magnifying lens or a dermatoscope. The lesions may also appear in a linear configuration, following the lines of trauma (isomorphic response, Koebner phenomenon). The development of the disease usually lasts several weeks. The lesions spread within 1–4 months from onset.

Pruritus of varying severity is the characteristic symptom reported by the patients and depends on the type of lesions and extent of involvement. Some of the affected patients may be completely asymptomatic (approximately 20%), and oral lesions may have a burning sensation or may even be painful.

Classical cutaneous LP is self‐limited and usually resolves within 6 (>50%) to 18 months (85%). Chronic disease is more typical in hypertrophic cutaneous lesions, orogenital lichen planus, and with nail or scalp involvement. Hyperpigmentation as a result of inflammation is often present especially in individuals with darker skin and can become very impacting.2, 14 Lichen planopilaris in the muzzle region is particularly problematical in this respect.

Diagnosis (Histological And Immunofluorescence Features)

The diagnosis of LP relies on the typical morphology of lesions at the affected site with histopathological correlation.

Histopathology

Mucocutaneous biopsies can confirm the diagnosis, especially when taken from the edge of a classical plaque. At this site, the characteristic histology is a dense, band‐like lymphocytic infiltrate, which is seen in the upper dermis underlying a variably acanthotic epidermis with hyperkeratosis, wedge‐shaped hypergranulosis related to the acrosyringia and vacuolization of the basal layer of the epidermis with scattered apoptotic cells (Civatte bodies).

Small clefts may be present at the dermoepidermal junction, but a clear subepidermal blister is typical only of bullous variant. The epidermis is atrophic, hyperplastic or ulcerated in atrophic, hypertrophic or erosive/ulcerative clinical variants, respectively. A biopsy from a central part on an ulcerated area will often reveal an inflammatory response with plasma cells and lymphocytes and an absence of any typical features. Melanin incontinence with melanophages is usually variable but prominent only in hyperpigmented clinical variants. Eosinophils may be seen in drug‐induced lesions. In follicular variants, the lichenoid reaction involves the basal layer of the follicular epithelium; variable degrees of perifollicular fibrosis may be seen.30

Immunofluorescence features

Direct immunofluorescence (DIF) testing reveals globular deposits of several immunoglobulins, especially IgM and complement or fibrinogen mixed with apoptotic keratinocytes (Civatte bodies). There is a report of 6 cases with linear appearance.31 DIF with a sensitivity of 75%32 is particularly helpful in differentiating erosive LP from immunobullous diseases, such as pemphigus vulgaris.

Dermatoscopic findings

They consist of white crossing lines (Wickham sign), dull red background and peripheral arrangement of vessels.33, 34

Other assays

It has been proposed that future diagnostic adjuncts could include cytokine profiling of involved tissue. However, as other available tests are reasonably accurate for the diagnosis of LP, this is unlikely to become a widely used assay for LP.35

Patch tests in patients with LP usually reveal positive results, which are not associated with specific variants of cutaneous LP or the prognosis of the disease. Patch testing is better to be included in the workup of oral LP, where oral lesions show proximity to dental restorations.36 The material of these restorations can aggravate or induce the lichenoid reaction.36

No imaging studies are necessary for the diagnosis of lichen planus.

Differential diagnosis

There are many disorders to be considered in the differential diagnosis of lichen planus (Table 1):

  • Lichen nitidus, lichen sclerosus, lichen spinulosus, graft‐versus‐host disease, lichen striatus, linear epidermal naevus, naevus unius lateralis
  • Eczema, lichen simplex chronicus, prurigo nodularis
  • Pityriasis rosea, guttate psoriasis, psoriasis vulgaris, eczematid‐like purpura
  • Drug eruption, syphilis, tinea corporis, papular acrodermatitis of childhood
  • Granuloma annulare, lichen amyloidosus, pityriasis lichenoides, Kaposi sarcoma
Table 1.
Differential diagnosis of site‐specific LP
Nail Psoriasis, onychomycosis, alopecia areata, atopic dermatitis
Genital Lichen sclerosus, mucous membrane pemphigoid, vulvar intraepithelial neoplasia, graft‐vs‐host disease, psoriasis, seborrhoeic dermatitis, intertrigo
Palms and soles Secondary syphilis, psoriasis vulgaris, warts, calluses, porokeratosis, hyperkeratotic eczema, pityriasis rubra pilaris, tinea, drug reaction, gloves‐and‐socks disease
Lichen planopilaris Cicatricial alopecia, lupus erythematosus, inflammatory folliculitis, alopecia areata, mucous membrane pemphigoid, frontal fibrosing alopecia
Mucosal Paraneoplastic pemphigus, candidiasis, lupus erythematosus, secondary syphilis, leucokeratosis, traumatic patches, cicatricial pemphigoid

Clinical variants of lichen planus

Several variations have been described, according to (i) the distribution and configuration of lesions, (ii) the morphology of an individual lesion and/or (iii) the site of involvement. The various clinical forms were divided into three general categories, namely cutaneous, appendageal and mucosal lichen planus,37-42 as well as some unclassified other forms of LP29, 43-54 (Table 2). More information about the clinical variants, in the longer version in the EDF homepage.

Table 2.
Clinical variants
Cutaneous LP

Localized cutaneous lesions of LP

Generalized cutaneous LP

Palmoplantar LP with localized erythematous scaly plaques Hypertrophic LP

Atrophic LP

Vesiculobullous LP

Erosive and ulcerative LP

Annular LP

LP pigmentosus

Lichen planus pemphigoides

Appendageal LP

Lichen planopilaris

LP lesions of the nails

Mucosal LP

LP plaque‐like or erosive

Atrophic LP lesions of the oral mucosa Bullous LP of the mucosa

Papular genital LP.

Hypertrophic genital LP

Chronic erosive LP lesions in genitalia lichen planus of the oesophagus

Other forms of LP

Invisible LP

Overlap syndromes: LP erythematosus Lichenoid reaction of graft‐versus‐host disease

Lichenoid keratosis

Drug‐induced lichen planus

Ocular LP

Aural and urethral LP

Complications

Acute complications

Itching is most common in cutaneous LP. In oral LP, eating might be so painful that patients are unable to maintain adequate nutrition. Oral lichen planus and the drugs used for the treatment may predispose to infection from C. albicans. Also, s exual dysfunction may appear, which can also become a long‐term complication in genital erosive lichen planus.

Chronic complications

After the lesions of lichen planus are resolved, the affected area of skin has a postinflammatory hyperpigmentation, which is more noticeable in people with darker skin. Oral lichen planus can be very painful, and ulceration may lead to scarring. Appendageal lichen planus can lead to scarring, while alopecia and nail loss are often permanent.

Cancer

Squamous cell carcinoma may arise from mucosal lesions (mouth, vulva, penile) and hypertrophic LP lesions (distal extremities).

A 1% incidence of SCC has been reported among patients with oral lichen planus.3 Proposed reasons for the increased risk include the following:

  • The oral mucosa affected by oral lichen planus may be more sensitive to C. albicans and to the exogenous mutagens found in tobacco and alcohol.
  • In patients with oral lichen planus, the chronic inflammatory response and simultaneous healing response of epithelial wounds may increase the likelihood of cancer‐forming gene mutations.

Case reports of SCC emerging from hypertrophic cutaneous LP lesions or chronic anogenital or oesophageal lesions have been described.3 Persistent ulcers/lesions should undergo biopsy, particularly when resistant to therapy.

Systemic complications

Infections, osteoporosis, adrenal insufficiency, bone marrow suppression, renal damage and hyperlipidaemia may occur due to medication.

Therapeutic management

Objectives

Lichen planus is a chronic disease, and the primary focus of treatment is to control symptoms and minimize damage. The treatment should be associated with the severity of the disease and the less possible side‐effects and should improve the patients’ quality of life.

In these guidelines, we give recommendations about treatment modalities of the various forms of LP trying to achieve the highest author’s consensus level in the order of preference.

All the drugs, except topical steroid preparations, constitute off‐label treatment modalities.

Management of cutaneous lichen planus

The aim of the management of cutaneous lichen planus is to reduce itching and shorten the duration between onset of the disease and resolution of the lesions.

Topical glucocorticoids are the treatment of choice, although their efficacy has not been proven in well designed, randomized, controlled trials. When topical glucocorticoids are ineffective, oral corticosteroids are administered. Oral corticosteroids are also preferred from the beginning of treatment, when atrophic lesions appear early in the evolution of the disease.

First‐line treatments

The first‐line treatments are summarized in Table 3.

Table 3.
The following interventions are recommended for the treatment of cutaneous lichen planus

Topical steroids (superpotent and potent such as triamcinolone acetonide, fluocinolone acetonide, betamethasone dipropionate and clobetasol propionate) or

Triamcinolone intralesional injection, especially for more hypertrophic or unresponsive lesions (5–20 mg/mL every 2–4 weeks)54

Systemic corticosteroids (oral or intramuscular injections) If lesions are unresponsive to topical treatment, oral prednisone of 30–80 mg/day for 4–6 weeks or intramuscular injections of triamcinolone 40–80 mg every 6–8 weeks are administered.55, 56
Acitretin 20–35 mg/day, or isotretinoin57-59
Oral cyclosporine (3–5 mg/kg/day)60

Symptomatic treatment

Oral Antihistamines

Sedating antihistamines can be more effective in severe pruritus, but the reported adverse reports (safety problems/sleep disturbance/accidents) minimize their use.

Topical antipruritic agents

Menthol, camphor, doxepin, polidocanol, etc., can be prescribed as an adjuvant to the main treatment.

Second‐line treatments

Although numerous treatment modalities exist, the physician should consider the benefits of the prescribed therapy against the possible side‐effects, because cutaneous LP is a self‐limited disease with very few complications.

The second‐line treatments are summarized in the following Table 4.

Table 4.
The following interventions are suggested for the treatment of cutaneous lichen planus
Broadband or narrowband UVB.63, 64
Combination of UV and acitretin
Topical calcineurin inhibitors (tacrolimus, pimecrolimus – twice/day for 1–2 months)61 Topical calcineurin inhibitors (tacrolimus, pimecrolimus – twice/day for 1–2 months)61
Sulphasalazine, initial dose of 1.5 g/day increased by 0.5 g/week to 3 g/day for 4–16 weeks11, 62

The third‐line treatments are summarized in the following Table 5.

Table 5.
The following interventions can be considered for the treatment of cutaneous lichen planus
Topical calcipotriol ointment65
Metronidazole66 (250 mg every 8 h for 12 weeks)
Trimethoprim–sulphomethoxazole
Hydroxychloroquine sulphate11 (200–400 mg/day)
Itraconazole67, terbinafine68, griseofulvin (why antifungal therapy is sometimes effective in LP remains to be elucidated)
Tetracycline69, doxycycline
Mycophenolate mofetil (0.5 g twice daily for four weeks, and then 1 g twice daily for at least 20 weeks)70
Azathioprine (50 mg twice daily orally or 1–2 mg/kg/day, for a period varying from 3 to 7 months)71
Methotrexate (15–20 mg/week for 4–15 weeks)72
Cyclophosphamide73 (50–100 mg/day for 3–6 months)
Thalidomide74
Adalimumab75
Interferon a2b. Interesting approach especially if lichen planus is associated with hepatitis C.76
Alitretinoin77
Low molecular weight heparin (enoxaparin 3 mg/week)78
Photodynamic therapy79
Extracorporeal photochemotherapy80
Nd‐YAG laser, low‐dose 308 nm excimer laser81
Apremilast82
Ustekinumab83

Management of mucosal–oral LP

Mucosal LP is often difficult to treat, particularly when ulcerations and erosions are present. For many years, treatment modalities for mucosal LP had been aimed at palliation rather than cure of oral symptoms.84-86 However, current treatments should intend to the elimination of symptoms and potentially reduce the risk of malignant transformation.

General measures

Based on studies and expert opinions, measures of general care can be discussed before the onset and during the treatment. Patients should be advised of the need to maintain good oral hygiene and to avoid mucosal trauma. Depending on the severity of the disease, regular personal and professional dental care, replacement of amalgam or gold dental restorations,87 avoidance of smoking, spicy food and alcohol may be indicated for some patients with oral lichen planus.6, 7

If the cause of oral lichenoid lesions is suspected to be a systemic drug (Table 6), the physician should change the implicated drug to another medication.

Table 6.
Drug‐induced lichen planus
Antihypertensive ACE inhibitors, beta‐blockers, nifedipine, methyldopa, diuretics (hydrochlorothiazide, furosemide, spironolactone, chlorothiazide)
Non‐steroidal anti‐inflammatory drugs (NSAIDs) Aspirin, diflunisal, ibuprofen, indomethacin, leflunomide, mesalamine, naproxen, rofecoxib, sulindac, sulphasalazine, tolbutamide
Metals Gold salts, arsenic
Anticonvulsants Carbamazepine, phenytoin, oxcarbazepine, valproate sodium
Drugs to treat tuberculosis Ethambutol, isoniazid, rifampicin
Antifungal drug Ketoconazole, amphotericin B, griseofulvin
Chemotherapeutic agents Hydroxyurea, 5‐fluorouracil, imatinib, olmutinib
Antimalarial agents Hydroxychloroquine, chloroquine, pyrimethamine, quinidine, quinine
Sulpha drugs Sulphonylurea, hypoglycaemic agents, dapsone, mesalazine, sulphasalazine
Tumour necrosis factor antagonists Infliximab, etanercept and adalimumab
Other drugs Allopurinol, iodides and radiocontrast media, interferon‐α, omeprazole, penicillamine, tetracycline, levamisole, clopidogrel, palifermin, mercaptopropionyl glycine, misoprostol, nandrolone, furyl propionate, norflex, omeprazole, pyrithioxin, sildenafil, tiopronin, isotretinoin, zidovudine, vaccines, solifenacin
Antidiabetics Chlorpropamide, glyburide, glipizide, insulin, tolazamide, tolbutamide
Antidiarrheals Bismuth
Lipid‐lowering drugs Gemfibrozil, orlistat, pravastatin, simvastatin
Psychiatric drugs Antipsychotics (chlorpromazine, levomepromazine, methopromazine, thioridazine), benzodiazepines (lorazepam), lithium, selective serotonin reuptake inhibitor (escitalopram), tricyclic antidepressants (amitriptyline, imipramine)

There is some evidence to suggest that stress and anxiety are possible risk factors for the development of oral lichen planus (OLP). However, this association remains controversial.88 It is assumed that psychological support may be beneficial to some patients with recurrent oral lichen planus. In case mucosal lesions persist despite treatment, frequent biopsies are necessary to exclude malignant transformation.

Management of oral LP

First‐line treatments

Topical application of potent or ultrapotent steroids is the mainstay of treatment in the case of localized OLP. Clobetasol propionate 0.05%, triamcinolone, betamethasone, fluocinonide, fluticasone, dexamethasone and prednisolone in different forms have been proved to be effective and safe.89 They can be applied topically either in Orabase® or as lozenges. They have been also used as an ointment, as an oral suspension or aqueous solution, pellets, aerosol or spray, mouthwashes and usually in an adhesive paste. The frequency of application and the duration of maintenance treatment is a topic of discussion. Usually, twice‐daily application of topical steroids for 1‐2 months, and then administered as needed, is a common practice.

Intralesional injection of corticosteroids (triamcinolone acetonide hydrocortisone, dexamethasone and methylprednisolone) in ulcerative OLP is also an effective treatment approach.89, 90 Injections can be painful; to avoid mucosal atrophy, we usually administer a corticosteroid dilution of 10 mg/mL.

Systemic corticosteroids, methylprednisolone or prednisone (30–80 mg/day) are the most effective treatment modality for patients with diffuse recalcitrant erosive OLP or multisite lesions of severe erosive OLP. This should be used in short burst to induce remission rather than as a long‐term maintenance therapy.

Systemic retinoids, such as acitretin (25–50 mg/day) initially, followed by isotretinoin (0.5–1 mg/kg/day), have been used in the treatment of OLP. Topical retinoids (isotretinoin 0.05–0.1%) or other forms of vitamin A derivatives can eliminate white lesions, but in all cases reported the lesions relapsed 2–5 weeks after discontinuation of treatment.91

Systematic use of cyclosporine (3–10 mg/kg/day) has been found to be effective in different studies and for some authors is considered to be the drug of choice. Topical cyclosporine was used in the form of mouthwashes or adhesive base, 2–3 times daily for 1 month. However, the application of cyclosporine solution proved to be less effective than the application of clobetasol or triamcinolone acetonide, with no significant differences between the two treatments. Furthermore, a large patient‐to‐patient variability regarding the efficacy of topical cyclosporine was observed in both studies.92, 93

The first‐line treatments are summarized in the following Table 7.

Table 7.
The following interventions are recommended for the treatment of mucosal lichen planus
Topical steroids (clobetasol propionate 0.05%, triamcinolone, betamethasone, fluocinonide, fluticasone, dexamethasone and prednisolone in different forms). Intralesional injection of corticosteroids (triamcinolone acetonide hydrocortisone, dexamethasone and methylprednisolone) in ulcerative OLP.
Systemic corticosteroids (oral) Systemic corticosteroids, methylprednisolone or prednisone (30–80 mg/day)
Systemic retinoids , such as acitretin (25–50 mg/day) initially, followed by isotretinoin (0.5–1 mg/kg/day),
Topical retinoids (isotretinoin 0.05–0.1%) or other forms of vitamin A derivatives can eliminate white lesions
Oral cyclosporine (3–10 mg/kg/day)

Second‐line treatments

In OLP recalcitrant to topical corticosteroids, the use of topical calcineurin inhibitors, tacrolimus and pimecrolimus, is suggested.61, 94 Twice‐daily application for 4–6 weeks has been proven safe and efficacious.61, 94, 95

In few patients treated with topical calcineurin inhibitors, transformation in squamous cell carcinoma has been described, but it is not clear whether it can be attributed to the medications applied or to the disease or to any other reason.2, 96, 97

The second‐line treatments are summarized in the following Table 8.

Table 8.
The following interventions are suggested for the treatment of mucosal lichen planus
Topical calcineurin inhibitors, tacrolimus and pimecrolimus
Sulphasalasine98 (2.5 g/day for 6 weeks)
Azathioprine71, 99 (50 mg twice daily orally or 1–2 mg/kg/day, for a period varying from 3 to 7 months)
Hydroxychloroquine sulphate100 (200–400 mg/day for 2 months)
Methotrexate101 (15 mg/week for 3 months)
Mycophenolate mofetil102 (1 to 3 g/daily twice daily for 4 weeks)
TNF‐a inhibitors (alefacept, adalimumab, etanercept)103-105 can be used with uncertain efficacy, because studies of large series of patients are lacking

Third‐line treatments

The third‐line treatments are summarized in the following Table 9.

Table 9.
The following interventions can be considered for the treatment of mucosal lichen planus
Cyclophosphamide (100 mg/day),73
Thalidomide106 (initial dose of 50 to 100 mg/day and then progressively decreased to the minimal effective dose),
Antibiotic treatment for 1–3 month (metronidazole – 250 mg every eight hours daily‐66, trimethoprim–sulphomethoxazole, tetracycline 500 mg twice daily, doxycycline 100 mg twice daily),69
Itraconazole67, griseofulvin,107
Dapsone (initial dose of 50 mg/day is given for the first 15 days, and then, the dose is increased to 100 mg/day),108
Low molecular weight heparin (enoxaparin 3 mg/week),109
Interferon has been used as a treatment modality in cases of LP associated with hepatitis C110
Levamisole (50 mg thrice daily or 150 mg once daily, for three consecutive days per week for at least 3 months),111
Lycopene (8 mg/day for 8 weeks),112
Purslane (235 mg/day),113
Curcuminoids (6000 mg/day 3 divided doses),114
Aloe vera115
Topical tocopherol116
Colchicine117
0.5 mL of intralesional BCG (bacillus Calmette‐Guerin) injection118 was used every other day for two weeks and proved to be as effective as 10 mg triamcinolone acetonide injections every week for 2 weeks.
Extracorporeal photochemotherapy119
Psoralen plus UVA (PUVA), UVA1, broadband or narrowband UVB120
Er: YAG laser (2940 nm),121 diode laser (630 nm),122 carbon dioxide laser (CO2)123

In the most recent Cochrane review (2012), authors suggested that there is only weak evidence for the effectiveness of any of the treatments for oral erosive LP.7

Management of genital LP

The general principles of the management of genital LP are similar with those of the LP confined to the oral mucosa.124 We will discuss briefly some additional therapeutic measures. Also, most cases of papulosquamous genital LP are self‐limited, and treatment with emollient and mid‐potency steroids for a few weeks is only required (Table 10).

Table 10.
The following interventions are recommended for the treatment of genital lichen planus
Topical steroids (hydrocortisone acetate 25 mg rectal suppositories can be inserted in the vagina nightly, or 1 g clobetasol or another potent topical corticosteroid ointment)
The following interventions are suggested for the treatment of genital lichen planus
Calcineurin inhibitor, tacrolimus – pimecrolimus
Local anaesthetic gel, sedating antihistamines, low‐dose tricyclic antidepressants or anticonvulsants

Prevention or limitation of scarring is the major therapeutic aim for erosive genital lesions of LP. In women, synechia formation with vaginal stenosis may be prevented by the use of vaginal dilators and vaginal steroids to treat mucosal inflammation; in uncircumcised men, foreskin retraction is usually recommended to avoid phimosis. In rare cases, surgery may be needed to breakdown vaginal adhesions and phimosis to restore sexual functions.

Local anaesthetic gel, sedating antihistamines, low‐dose tricyclic antidepressants or anticonvulsants may prevent scratching and ease discomfort. Hydrocortisone acetate 25 mg rectal suppositories can be inserted in the vagina nightly, or 1 g clobetasol or another potent topical corticosteroid ointment can be inserted with an applicator to minimize scar formation.125

Our suggestion is to start with clobetasol or a calcineurin inhibitor and maintain the treatment with a less potent topical steroid, applied less frequently.

Long‐term follow‐up is necessary to monitor disease activity and to exclude malignant transformation of the erosive lesions.

Management of appendageal LP

Lichen planopilaris

The aim of the treatment is the reduction of itching, burning and cessation of scarring. If the disease can be controlled in early stages, hair follicular units may be preserved and hairs can regrow.

First‐line treatments

Topical steroids (superpotent, potent, mild) are the medication most frequently used in the management of LPP.13, 126-128 They are sometimes effective and easy to apply to widespread lesions. However, most of the authors believe that their use is of doubtful value. Intralesional injection of corticosteroids (e.g. triamcinolone 5–20 mg/mL every 2–4 weeks) into localized lesions could be more efficacious in most cases (Table 11).129

Table 11.
The following interventions are recommended for the treatment of appendageal lichen planus
Topical steroids (superpotent, potent, mild)
Intralesional injection of corticosteroids (e.g. triamcinolone 5‐20 mg/mL every 2–4 weeks)
Systemic steroids (30–80 mg/day of prednisone)
Cyclosporine in systemic administration (3–10 mg/kg/day)
Hydroxychloroquine sulphate (200–400 mg/day or 6.5 mg/kg per day for 6 to 12 months)128, 133, 135
Methotrexate (15 mg/weekly for 6 months)136
Topical calcineurin inhibitors , primarily tacrolimus134

Systemic steroids (30–80 mg/day of prednisone equivalent) are administered especially if the disease is rapidly progressive leading to severe scarring.130

It has been suggested by a systematic review of the literature and supported by experts’ opinion that cyclosporine in systemic administration (3–10 mg/kg/day) may be an effective drug in appendageal LP.131, 132

Several studies investigated the efficacy of hydroxychloroquine in lichen planopilaris have been published.

The efficacy of methotrexate has been studied in a randomized clinical trial comparing hydroxychloroquine (400 mg daily) versus methotrexate (15 mg weekly) administered for 6 months. Methotrexate showed significant improvement in all the assessed variables.136

The use of topical calcineurin inhibitors, primarily tacrolimus (twice daily for at least one month), either as monotherapy or as an adjuvant to systemic therapy, has been suggested in the management of LPP. 134

Second‐line treatments

The following medications have been proposed as second‐line therapies in the management of LPP, according to the highest author’s consensus level in the order of preference (Table 12):

Table 12.
The following interventions are suggested for the treatment of appendageal lichen planus
Systemic retinoids such as acitretin (25–30 mg/day) and isotretinoin (0.5–1 mg/kg/day) for 3–6 months, especially in cases with pronounced perifollicular hyperkeratosis.128, 129
Tetracycline/doxycycline (100 mg/d for one month)125, 129
Mycophenolate mofetil (0.5 g twice daily for four weeks, and then 1 g twice daily for at least 20 weeks)125, 132, 135, 137
Adalimumab, at the same dose and schedule as in psoriasis138
Pioglitazone, an oral PPAR‐γ agonist (15 mg orally once a day for 8 months)139, 140
Minoxidil solution 5%129
Thalidomide (initial dose 100–300 mg per day)141, 142
Rituximab (IV 375 mg/m2 once weekly for 4 or 8 doses)143
308 nm excimer laser144

Frontal Fibrosing Alopecia

Treatment modalities for FFA include all medications described for the treatment of LPP. However, several authors believe that oral cyclosporine (3–6 mg/kg/day)131 and oral finasteride (2, 5 mg daily) or dutasteride (0.5 mg daily) for 12 months could be of considerable value.145, 146 However, since the coexistence of FFA and androgenetic alopecia is very common, the effect of finasteride/dutasteride in FFA is doubtful.

Topical minoxidil or intralesional corticosteroids have been prescribed more often as an adjuvant to the previous treatments, depending on the stage of the disease and association with androgenetic alopecia.147-149

Nail lichen planus

Ungual LP is generally difficult to treat. Prognosis of this disease subtype is poor, with a high rate of recurrences. Treatment should be implemented immediately to prevent irreversible changes, like pterygium, or total nail loss. About 50% of the patients will not be cured, despite any treatment.150

As first‐line treatment, triamcinolone acetonide injections 0.5 mg/kg IM every 30 days can be used and then tapered off for isolated nail involvement. Also, intralesional injections of triamcinolone acetonide 0.5–0.1 mg/nail every 2 months seem to be effective but painful. Oral prednisone 0.5 mg/kg for 3 weeks demonstrated a marked improvement and is useful when multiple nails are affected.150, 151

Topical steroids applied to the involved sites, especially in occlusive dressing, appear to have good results in some patients.

The following treatment modalities (Table 13) can be considered as an alternative therapy to steroids.151, 152

Table 13.
Treatments that can be considered as an alternative therapy to steroids in nail lichen planus
Alitretinoin (30 mg once a day for 3–6 months)152, 153
Chloroquine phosphate (250 mg twice daily for 10–30 weeks)150
Cyclosporine (3 mg/kg for several months)154
Acitretin155
Tacrolimus ointment 0.1% twice daily for 6 months156
5% Fluorouracil applied topically150
Biotin 2.5 mg (children) and 7.5–10 mg (adults) daily for 6 months150
Etanercept (25 mg sc. twice weekly for the first 6 months and 50 mg sc. once weekly thereafter)157

Other forms of LP

The treatment of other forms of LP is symptomatic and depends on the location of that lichenoid reaction on skin or mucosal according to the above suggestions.

In these guidelines, the authors express their expert opinion based on their clinical knowledge and review of the literature, and authors and publishers cannot take responsibility for dosages and therapeutic choices, as therapy of lichen planus may change between cycles of the guideline. Therefore, the use of this guideline is at the physician’s responsibility and users are requested to keep informed about new knowledge published in parallel to the guidelines. The authors and publishers of the guideline would be grateful if readers could inform them of any inaccuracies.

Acknowledgements

The guidelines are produced on behalf of the following organizations: the European Academy of Dermatology and Venereology (EADV); the European Dermatology Forum (EDF).

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