Lichen planus

Abstract

Lichen planus (LP) is an inflammatory dermatosis of the mucocutaneous surfaces that can present with a variety of clinical manifestations. The prevalence of LP is unknown, but is estimated to be 1% in the USA.1 The frequency of LP varies on the basis of the population studied, with a particularly high rate of disease noted on the Indian subcontinent. LP most commonly affects middle-aged people,2 although childhood-onset LP has also been well described. Women are affected as frequently as men.2 LP is a self-limited condition that, according to one epidemiologic study, may resolve after 1 month to 7 years.2 A range of topical and systemic medications have been shown to improve the symptoms associated with LP and to hasten the resolution of LP. The pathogenesis of LP is not entirely understood. In general, activated T lymphocytes are recruited to the dermal–epidermal junction and induce apoptosis in basal keratinocytes. Both CD4+ and CD8+ T lymphocytes are found in the lichenoid infiltrate of LP, with a predominance of the latter cell type being present in established lesions.3 The interaction between pathogenic T lymphocytes and basal keratinocytes is enhanced by increased expression of intercellular adhesion molecule-1 (ICAM-1) by basal keratinocytes,4 a phenomenon absent in other interface dermatoses, such as subacute cutaneous lupus erythematosus and erythema multiforme.5 The upregulation of the T-helper-1 (Th1) arm of cell-mediated immunity drives basal keratinocyte apoptosis. Implicated cytokines include interferon-γ,6 tumor necrosis factor-α (TNF-α),7 additional nuclear factor-κB (NF-κB)-dependent cytokines, such as interleukin-1α (IL-1α), IL-6, and IL-8,8 and other apoptosis-related molecules, such as Fas/Apo-1 and Bcl-2.9 Another mediator may include CXCL10, a chemokine induced by interferon-γ.10 This chemokine is expressed selectively in the basal keratinocytes that are attacked by cytotoxic T lymphocytes in interface dermatoses, such as LP.10 A localized increase in angiogenesis has been demonstrated in LP,6 although it is unclear whether this contributes to, or occurs as a result of, the development of LP. An association between LP and hepatitis C has been well established.11 It has been opined that hepatitis C-induced aberrations in cytokine and chemokine expression may predispose infected individuals to the development of LP.12, 13 A similar mechanism may underlie the association between LP and the administration of hepatitis B14 and inactivated influenza15 vaccinations. Case reports have documented LP arising in tattoos of various pigments,16 and it has been hypothesized that exogenous tattoo pigments may serve as antigens for activated lymphocytes, thus fueling the development of LP. Moreover, a variety of medications, including β-blockers, nonsteroidal anti-inflammatory agents, methyldopa, penicillamine, and antimalarials, have been implicated in the pathogenesis of LP.17 It is conceivable that these medications function as endogenous antigens in disease promotion. Finally, in a retrospective study of patch test results of patients with oral LP,18 72% of patients with positive patch test reactions showed sensitivity to a relevant allergen. The authors concluded that oral allergens may contribute to the development of oral lichenoid mucositis diagnosed as oral LP. The classic presentation of LP involves the appearance of polygonal, flat-topped, violaceous papules and plaques. Superimposed, reticulated white scale, termed “Wickham's striae” (Fig. 1), may be appreciated on physical examination of oral or cutaneous LP. Visualization of this subtle but specific finding in LP can be enhanced by the application of water or oil to the affected area, or by using dermatoscopy.19 LP most commonly affects the extremities, particularly the flexural wrists and ankles (Fig. 2). Although the lesions tend to be extremely pruritic, secondary excoriations are rarely seen.20 Finally, LP lesions may arise as an isomorphic response to trauma (Fig. 3). Lesion of lichen planus. Note the polygonal, slightly purpuric plaques with overlying white, reticulated scale Lichen planus involving the leg. Note the involvement of the toenails, including the dorsal pterygium Lichen planus arising in and around a surgical scar, demonstrating an isomorphic response to trauma Numerous subtypes of cutaneous LP, which vary by lesion configuration or morphology, have been described (Table 1). Several case reports have described patients with linear lesions of LP following a “blaschkoid” distribution (Fig. 4).21 Unilateral “blaschkoid LP” involving one half of a 30-year-old man's entire body22 and involving the chest and abdomen of another patient has been documented.23 Linear LP arising in a child has been described.24 Blaschko reported “lichen planus in a streaky arrangement.”21 Less common is LP configured in a zosteriform distribution. “Zosteriform LP” is felt to represent an isotopic response to herpes zoster in many cases.25 In a patient with zosteriform LP, but no history of preceding lesions of herpes zoster, immunoglobulin A (IgA) antibodies directed against varicella zoster virus were found to be elevated.26“LP inversus” involves the intertriginous areas (Fig. 5). Lesions are associated with minimal scaling because of tissue occlusion in this anatomic distribution. Lichen planus in a blaschkoid distribution Lichen planus inversus “Hypertrophic LP” is marked by the development of hyperkeratotic, flat-topped plaques, typically affecting the anterior lower legs (Fig. 6). Findings of “bullous LP” include vesicles and bullae, thus necessitating that other immunobullous disorders be excluded before making this diagnosis. In this condition, dermal–epidermal separation probably results from the presence of a particularly brisk interface dermatitis. “Actinic LP,” arising in sun-exposed areas, is felt to be triggered by ultraviolet (UV) light and tends to affect patients with deeply pigmented skin in India, the Middle East, and eastern Africa.27, 28“Annular atrophic LP” is a rare subtype of LP characterized by the development of violaceous plaques with central clearing and atrophy.29 Central atrophy may arise as a result of elastase produced by lichenoid-activated lymphocytes.29“Erosive LP” is a painful variant of LP which causes mucocutaneous erosion and ulceration. Unlike most other forms of LP, erosive LP can lead to scarring and tissue mutilation. Hyperpigmented, lichenoid plaques distributed in sun-exposed or flexural areas are seen in “LP pigmentosus.”28, 30 This variant is much more common in patients with higher phototypes, and may arise from melanin incontinence from interface dermatitis. Hypertrophic lichen planus “LP pemphigoides” refers to a cross-over syndrome of LP and bullous pemphigoid. LP pemphigoides has been associated with psoralen plus UVA (PUVA),31 simvastatin,32 angiotensin-converting enzyme (ACE) inhibitors,33 UVB phototherapy, acetaminophen, and ibuprofen.34 Circulating antibodies may be directed against BP180 or other targets, such as 130-kDa34 and 200-kDa35 epidermal antigens. A cross-over syndrome between LP and lupus erythematosus has also been described.36, 37 Other reported manifestations of LP include “perforating LP” and “invisible LP.”20 Oral LP is the most common autoimmune condition of the oral mucosa,38 and oral involvement is present in 30–70% of patients with LP.39 Lesions of oral LP most commonly appear as asymptomatic or tender, white, reticulated patches or plaques (reticulated form), or as painful erosions and ulcers (erosive form) (Fig. 7). Oral LP is more common in white women, tends to arise in the fourth and fifth decades of life, and presents most commonly on the buccal mucosa, followed by the alveolar mucosa and tongue.38 Oral lichen planus Bullous oral LP, a subtype of LP distinct from LP pemphigoides and mucosal blistering conditions, has been reported to involve the lower mucosal lip.40 LP of the genitalia most commonly presents with pruritus or hyperalgesia and may lead to vaginal discharge or hemorrhage. The most common LP subtype in this anatomic location is erosive LP, with hypertrophic or papulosquamous LP being less common variants.41, 42 In women with LP of the genitalia, the vulva or vagina may be affected (Fig. 8). Without adequate treatment, substantial erosion and anatomic disfigurement may occur.42 Differentiation from lichen sclerosus (LS) may be challenging in some cases, although LS tends not to involve the vagina. In men with LP of the genitalia, the glans penis is most commonly involved (Fig. 9). Bacterial or fungal superinfection should be investigated and, where present, should be treated. Lichen planus of the vulva Lichen planus of the glans penis Vulvovaginal gingival syndrome is a subtype of LP characterized by oral and genital involvement, and tends to heal with scarring. This entity has been found to be associated with class II human leukocyte antigen (HLA) allele DQB1*0201.43 Since the appearance of oral and genitalia disease may be separated temporally, a high index of suspicion may be required to diagnosis this entity accurately. Esophageal LP, a rare but serious variant, may be heralded by dysphagia or odynophagia, or may be asymptomatic.44 Long-term complications of esophageal LP include dysphagia and esophageal stricture.44, 45 When LP involves hair follicles in a condition known as lichen planopilaris (LPP), cicatrizing alopecia may result. Women are affected much more commonly than men.46, 47 Clinically, patients most frequently develop irregularly shaped patches of scarring alopecia on the parietal, frontal, or occipital scalp (Fig. 10). Lesions tend to be painful or pruritic. Follicular hyperkeratosis may be present. Rare LPP variants include frontal fibrosing alopecia (scarring alopecia of the frontal scalp) and Graham–Little syndrome (triad of cicatricial alopecia of the scalp, nonscarring alopecia of the axillae and pubis, and perifollicular keratotic papules).47, 48 Of patients with LPP, 28–50% have LP involvement elsewhere.46, 47 Although the etiology of LPP is not entirely understood, one group found that 31% of patients with LPP had associated nutritional abnormalities.47 It is unknown whether correction of the nutritional deficiencies leads to improvement of LPP. The differential diagnosis of LPP includes discoid lupus erythematosus, cicatricial pemphigoid, and alopecia areata. Lichen planopilaris Several nail changes are observed in LP (Fig. 11). The most specific nail abnormality in LP is the formation of dorsal pterygium, a raised, wedge-shaped deformity of the nail bed.49 Changes of onychorrhexis, with longitudinal ridging, distal splitting, and thinning of the nail plate, are nonspecific.50 Trachyonychia may also develop. The differential diagnosis of nail changes may include idiopathic onychorrhexis, psoriasis, alopecia areata, nail–patella syndrome, or onychomycosis. Dorsal pterygium, a nail finding specific to lichen planus LP can affect children. Most reports of childhood LP have come from the Indian subcontinent. A British study found that childhood LP was overrepresented in children of Indian origin compared with Caucasian children.51 In this series, LP was twice as common in boys as in girls, and the most common LP subtypes among children were typical LP (22/26), linear LP (4/26), and hypertrophic LP (2/26). LP has been associated with the development of cutaneous malignancy. Although cases of cutaneous squamous cell carcinoma associated with LP have been reported, a large epidemiologic study of LP and malignancy did not demonstrate an increased risk for malignant transformation of cutaneous LP or internal malignancy with LP of the glabrous skin.52 The malignant potential of oral LP is controversial.53, 54 LP of the genitalia has been linked to a low incidence of squamous cell carcinoma.42 Vulvovaginal LP is felt to increase the risk of vulvovaginal malignancy.55, 56 A recent report has documented penile carcinoma arising from LP of the glans penis.57 Most authorities recommend routine follow-up to screen for secondary cutaneous malignancy. Other cutaneous diseases observed in association with LP in one epidemiologic study included alopecia areata, LS, vitiligo, and discoid lupus erythematosus.2 Diagnostic methods were not outlined in this article, however, so it is conceivable that patients diagnosed with discoid lupus erythematosus or alopecia areata, for example, may have actually had concomitant involvement of the scalp by LP. The link between mucocutaneous LP and hepatitis C has long been recognized.13, 58 The strength of association between hepatitis C and LP appears to be correlated directly with the background rates of hepatitis C positivity in a given population. Some experts recommend routine hepatitis screening, particularly in patients with persistent or oral disease or located in areas with high rates of hepatitis C infection. Thymoma has been reported in association with LP.59, 60 In a study of 172 patients with LP, two had thymoma.60 Resection of thymoma tends not to improve LP.59, 60 Good syndrome, an adult immunodeficiency state requiring long-term immunoglobulin replacement, has been reported in oral LP61, 62 and vulvovaginal gingival LP.63 LP has also been linked with Laugier–Hunziker syndrome,64 primary biliary cirrhosis,65 primary sclerosing cholangitis,66 ulcerative colitis,20 and diabetes mellitus.20 A bidirectional relationship appears to exist between LP and psychosocial stress.67 The clinical findings of typical mucocutaneous LP are reasonably specific. No specific serum-based laboratory tests for LP have been developed, although screening for hepatitis C infection, particularly in patients with chronic, persistent oral LP or in endemic areas, is recommended.1, 11 Screening for nutritional deficiency may have a role in patients with LPP.47 Mucocutaneous biopsy can confirm the diagnosis. On standard histopathology, LP is characterized by the presence of a band-like lymphohistiocytic infiltrate at the dermal–epidermal junction with hydropic degeneration of the epidermis (Fig. 12). Resultant dyskeratosis is represented by the presence of necrotic keratinocytes (Civatte bodies or cytoid bodies) which are extruded into the papillary dermis. Subepidermal clefts (Max-Joseph clefts) may form as a consequence of interface inflammation. Irregular acanthosis may assume a saw-toothed appearance. Hyperorthokeratosis is also seen, and the presence of hyperparakeratosis is suspicious for lichenoid drug eruption. It is believed that Wickham's striae result from hypergranulosis.20 Histopathologic features of lichen planus (hematoxylin and eosin, ×100). Note the lichenoid lymphocytic infiltrate with associated scattered necrotic keratinocytes and melanin incontinence. Also present is a saw-toothed appearance to the rete pegs, hypergranulosis, and hyperorthokeratosis Histopathology of oral LP reveals a lymphocytic band under the epithelium, with associated hydropic degeneration of the basal cell layer. Hyperparakeratosis, acanthosis, hypergranulosis, satellite cell necrosis, and a saw-toothed pattern of rete ridges may also be visualized.38 Features of active lichen planopilaris include lichenoid lymphocytic inflammation surrounding the upper portion of the outer sheath and lower infundibular epithelium of the hair follicle.46, 47 Areas between hair follicles may appear unchanged on histopathologic examination. In late lesions, inflammation may be minimal and hair follicles may be replaced by fibrosis and scarring.46 Direct immunofluorescence (DIF) testing demonstrates the deposition of several immunoglobulins at cytoid bodies with IgM and shaggy fibrinogen deposition at the basement membrane (13, 14).46, 68 DIF has a sensitivity approaching 75%68 and can be helpful in excluding mimicking immunobullous disorders, particularly in patients with bullous or erosive LP. Necrotic keratinocytes, also termed cytoid bodies, Civatte bodies, or colloid bodies, present at and below the dermal–epidermal junction with direct immunofluorescence (×100). Courtesy of Michael J. Camilleri, MD Shaggy deposition of fibrinogen at the basement membrane zone with direct immunofluorescence (×100). Courtesy of Michael J. Camilleri, MD It has been proposed that future diagnostic adjuncts could include cytokine profiling of involved tissue.8 As other available tests are reasonably accurate for the diagnosis of LP, this is unlikely to become a widely used assay for LP. Patients should be questioned about the use of medications known to induce a lichenoid drug eruption. Lesions of lichenoid drug eruption may be identical to those of LP and are distributed on the trunk and extremities, with or without a predilection for photo-exposed areas. Histologically, lesions of lichenoid drug eruption can be similar to or even indistinguishable from LP. Commonly implicated agents include β-blockers, nonsteroidal anti-inflammatory drugs, ACE inhibitors, antimalarial medications, and penicillamine.10, 69 Patch testing to metals, flavorings, and plastics may be indicated in patients with oral LP.18 Various medical therapies are used for the treatment of LP; however, there is a paucity of data on which to make evidence-based recommendations, as there have been few well-performed randomized, controlled trials regarding treatment. A step-wise approach to therapy is generally favored. Here, we review the different methodologies used for each major type of LP. The first-line therapy generally used for cutaneous LP is medium- to high-potency topical corticosteroids, although there are no specific clinical trials addressing their use in LP. Topical corticosteroids that are commonly used include triamcinolone acetonide, fluocinolone acetonide, betamethasone dipropionate, and clobetasol propionate, depending on the severity of the disease and experience of the practitioner.70-73 Intralesional corticosteroid injections are also commonly used for more discrete or more hypertrophic lesions, although the data regarding this method are also largely anecdotal. Systemic corticosteroids (oral or intramuscular injection) are often used as second-line treatment. Intramuscular injections of triamcinolone may be used at doses of 40–80 mg every 6–8 weeks, although oral prednisone is used more commonly and usually at a dose of 30–60 mg/day for 4–6 weeks.72, 74 A recent study comparing a short 1-day course of oral prednisolone with placebo in patients with LP showed a significant decrease in time to clear in the medication group;75 however, it is unknown whether the short course or the conventional longer course is superior in effect. Oral retinoids are another treatment modality that may be considered. One of the only double-blind, placebo-controlled trials regarding any treatment of LP involved acitretin.76 In that study, 30 mg of acitretin daily for 8 weeks showed increased efficacy over placebo. With cross-over of the medication to the placebo group, 83% of patients were determined to have an overall favorable response; however, because of the potential adverse effects with acitretin, most practitioners reserve its use as second-line therapy for patients with severe cutaneous LP. Etretinate, isotretinoin, and tretinoin have been reported to be beneficial for cutaneous LP in small case series.74, 77-79 Phototherapy has been used in the treatment of LP for many years. Most patients who are treated with phototherapy receive narrow-band UVB therapy. Although no controlled trials have been performed with UVB therapy, several case series have suggested improvement and even remission of disease in up to 85% of patients in a recent series with therapy three to four times per week, with a total of approximately 30–40 treatments.80-82 PUVA has been studied in one small controlled trial in a bilateral comparison study, with eight or ten patients partially improving, and five being completely cured on the side treated with PUVA.83 There was no change in disease on the side that was not treated in these patients. Bath PUVA has also been studied, with similar reports of efficacy in uncontrolled case series.84-86 Comparison of PUVA with narrow-band UVB showed no significant difference in the long-term outcome with either treatment.87 Thus, when potential side-effects are taken into account, narrow-band UVB appears to be a more viable treatment option. Many other medications and treatment modalities, including griseofulvin, oral metronidazole, efalizumab, thalidomide, sulfasalazine, mycophenolate mofetil, and azathioprine,88-95 have been used on a much smaller basis, and are generally accepted as third-line therapies, as most have been reported only anecdotally in case reports or small series without evidence of significant impact on disease. Ciclosporin has been reported to be beneficial in severe resistant cutaneous LP in very small case series.96-98 Although numerous potential modalities exist for the treatment of cutaneous LP, the benefits of therapy must be carefully weighed against the possible risks, as cutaneous LP is largely a self-limited disease with low potential for severe complications. Mucosal LP is often difficult to treat and can be quite refractory to treatment, particularly when ulceration and erosion are present. Thus, treatment modalities for mucosal LP are often aimed at palliation rather than cure. Below, we discuss the treatment options in a tiered approach. Topical corticosteroids are the mainstay of treatment of oral LP. Several randomized, placebo-controlled trials have investigated the use of topical corticosteroids, such as betamethasone valerate, fluocinonide, and clobetasol, two to four times daily in the treatment of oral LP, all favoring the use of these preparations over placebo.99-103 Higher potency preparations are generally more effective than mid-potency topical corticosteroids. Thus, recommendations often propose starting with higher potency medications and tapering as quickly as possible. Although treatment with high-potency topical corticosteroids applied to the oral mucosa has not been reported to cause significant adrenal suppression, the potential for this and other complications, such as oropharyngeal candidiasis, should be considered when prescribing. Intralesional injection of triamcinolone (10–20 mg/mL) can also be used as an effective treatment modality.104 Systemic corticosteroids are commonly used in the short-term treatment of oral LP; however, one study comparing the use of oral prednisone and topical corticosteroids vs. topical corticosteroids alone showed no significant difference between the two groups, thus indicating limited efficacy of parenteral over local corticosteroids in the treatment of oral LP.105 Topical calcineurin inhibitors have received a great deal of attention recently regarding their use in the treatment of oral LP, and seem to be an effective treatment modality. Controlled trials evaluating topical ciclosporin at doses ranging from 500 mg daily to 500 mg three times daily found the ciclosporin group to be superior to placebo in both clinical signs and symptoms;106-109 however, one study compared topical ciclosporin with triamcinolone 0.1% paste and found no difference between the two.109 Tacrolimus has been documented recently as an effective treatment for oral LP in several open studies and patient series.110-115 Unfortunately, no randomized controlled trials exist regarding its use, but a 0.1% formulation appears to be most effective and is widely used both as first-line therapy and in steroid-resistant disease. Comparisons of tacrolimus 0.1% ointment vs. clobetasol 0.05% ointment have shown tacrolimus to be as effective or even more effective than the topical steroid.116, 117 A recent double-blind, placebo-controlled, randomized trial using pimecrolimus 1% cream in the treatment of oral erosive LP showed it to be effective and well tolerated.118 Although the new topical calcineurin inhibitors seem to be promising treatment modalities, the Food and Drug Administration's “black box” warning regarding their use and theoretical increased risk of malignancy should be considered before initiating treatment. Topical and oral retinoids have been used in the management of oral LP and appear to have some benefit, although less than with topical corticosteroids, and should be considered as second-line therapy.119-125 The antimalarial hydroxychloroquine has been shown in a small open trial to be effective for oral LP, and may be used as second-line therapy.126 There is limited published evidence of the efficacy of the systemic immunosuppressives azathioprine and mycophenolate mofetil in recalcitrant oral LP, but they can be considered in severe oral LP recalcitrant to first-line therapies.127, 128 In addition, PUVA, aloe vera gel, thalidomide, etanercept, efalizumab, and low-dose excimer laser, amongst others, have been used on a very limited basis with varied success.129-135 First-line therapy for genital LP is with ultrapotent topical corticosteroids, such as clobetasol propionate, with weaning to a maintenance regimen of decreased frequency of application and/or decreased potency corticosteroid whenever possible. Again, there have been no randomized, double-blind, placebo-controlled trials. Nevertheless, one prospective cohort study with a mean follow-up of 7.2 years showed relief of symptoms in patients with vulvar erosive LP with ultrapotent topical corticosteroids, most commonly 0.05% clobetasol propionate ointment.136 Topical tacrolimus (0.1% ointment) and pimecrolimus (1% cream) have also been studied on a limited basis, one in a small retrospective series and one in a small prospective series, and both appear to be of benefit.137, 138 Most practitioners recommend the use of high-dose parenteral steroids for severe or recalcitrant disease. The management of lichen planopilaris can be quite difficult because of its recalcitrant nature. First-line therapy is with ultrapotent topical corticosteroids or intralesional corticosteroids. Oral corticosteroids and oral retinoids can be used as second-line therapy.139 Other steroid-sparing medications, such as ciclosporin, mycophenolate mofetil, and thalidomide, have been used successfully in case reports.140-142 LP involving the nail can also be difficult to manage. Many practitioners advocate intralesional corticosteroid administration; however, patients seem to be quite susceptible to relapse.143 Oral and parenteral corticosteroids are also commonly used.50 LP is a relatively common, chronic condition affecting the skin, hair, nails, and mucous membranes. LP is diagnosed by historical and physical findings, biopsy results, and, in some cases, features on DIF. LP tends to have a chronic course. Depending on disease severity, however, LP may respond to a combination of topical or systemic therapies. The authors wish to acknowledge Michael J. Camilleri, md, Department of Dermatology, Mayo Clinic, Rochester, Minnesota for kindly supplying the DIF photomicrographs.