JOURNAL

of the

AmeRiCaN ACaDemy OF

DerMaTOLOGY

VOLUME 25 NUMBER 4 OCTOBER 1991

Continuing

medical education

Lichen planus Alan S. Boyd, MD, and Kenneth H. Neldner, MD Lubbock} Texas Lichen planus, a papulosquamous disease, in its classical presentation is characterized by pruritic violaceous papules most commonly on the extremities of middle-aged adults. Itmay or may not be accompanied by oral and genital mucous membrane involvement. Its course is generally self-limited for a period of several months to years, but it may last indefinitely. There are many clinical variants described, ranging from lichenoid drug eruptions to association with other diseases such as diabetes mellitus, autoimmune diseases, and the graft-versus-host reaction, The relationship of these, if any, to classical lichen planus is questionable. Multiple therapeutic options exist including corticosteroids, retinoids, griseofulvin, PUVA, and cyclosporine. (J AM ACAD DERMATOL 1991;25:593-619.) Lichen planus (LP) is usually a self-limited eruption that most commonly affects middle-aged adults. It can involve glabrous skin, mucous membranes, hair, and nails. Current concepts of pathogenesis include immunologic and genetic factors. In addition to numerous idiopathic forms, drugs and hepatic disease have also been implicated as causative factors. Treatment is usually efficacious, although well-defined mechanisms of action are lacking. HISTORICAL ASPECTS

Erasmus Wilson initially coined the term lichen planus (LP) in 1869. 1 Wilson l considered this to be the same disease as "leichen ruber" previously described by Hebra. The first variant of LP was reported by Kaposi2 in 1892 and was termed lichen ruber pemphigoides. Wickham3 noted the punctations and striae atop the

The CME articles are made possible through an educational grant from the Dermatological Division, Ortho Pharmaceutical Corporation. From the Department of Dermatology, Texas Tech University Health Sciences Center. Reprint requests: Alan S. Boyd, MD, Department of Dennatology, Texas Tech University Health Sciences Center, Lubbock, TX 79430.

16/2/27781

lesions that currently bear his name. Daner later defined the histopathologic characteristics of this disease. 4 EPIDEMIOLOGY

The prevalence of LP is unknown. Current esti~ mates place the figure at less than 1% of the populace. 5-8 Scandinavian studies have shown a frequency of 0.8%.6 The estimate of LP among Americans as a whole is 0.442%8; it is 0.29% in American blacks. 5 No racial predilection is believed to exist. s Itwas previously believed that LP was an affliction of the educated and largely sedentary classes of society. Subsequent study, however, has refuted this point,9 LP appears to affect women preferentially. Among patients with oral LP 63%10 to 67%11, 12 are women, and between 55% and 65% of patients with cutaneous LP are women. 13 LP usually appears initially during the fifth or sixth decade. In patients withoralLP the average age at onset is 5212 to 53.3 14 years. Men may have cutaneous involvement early in their thirties whereas most women develop LP in their fifties. 7 LP of childhood is unusual, and pediatric patients comprise only 2% to 3% of all patients. 15 Familial LP refers to the occurrence of this 593

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594 Boyd and Neldner

Fig. 1. Typical area of involvement in classical LP. Fig. 2. Flat-topped polygonal papules of LP. Note violaceous hue. disease among members of the same family and is a subset of cutaneous LP. Skin involvement tends to occur at a younger age, with most patients in the 20to 29-year-old age group. Outbreaks occur throughout the year, although in one study it was suggested that an unexplained seasonal influence existed, with an increase between January and JUly.16

CLINICAL FEATURES The cutaneous lesions of LP consist of faintly erythematous to violaceous papules (Fig. 1). They are flat topped and occasionally take on a polygonal form. A thin, somewhat transparent scale may be present atop some lesions. A network of fine white lines or puncta is present in many papules; these are known as Wickham's striae. The papules of LP tend to involve the flexural areas preferentially; the flexural side of the wrist is the classically characteristic site (Fig. 2). The arms and legs are the most common sites of involvement, although the thighs, lower back, trunk, and neck may also bear lesions. The face and scalp are usually spared in classic LP. "Inverse" involvement with LP has been described, with papules in the axillae, groin, and inframammary areas. 17 One study 9 disclosed a 55% prevalence ofleg lesions versus 37% prevalence of arm lesions. Unilateral involvement has been reported. 18, 19 LP tends to be intensely pruritic. Oddly, physical evidence of skin trauma, such as excoriations, secondary infections, and bloody crusts, is seen infrequently. Twenty percent of affected persons are

asymptomatic.2° Table I lists the different clinical types of LP. Mucous membrane lesions Mucosal lesions in the esophagus, conjunctivae, bladder, nose, larynx, stomach, and anus have been described. 21 In one study esophageal involvement was found in 5 of 19 patients with idiopathic LP (26%).22 Stenosis and dysphagia may result. Oral LP. Next to the cutaneous findings, oral LP is the most commonly reported form ofthis disorder. As the sole manifestation of the disease, it makes up 15% to 35%17, 23 ofthe patient populace. Scandinavian studies suggest that oral involvement is eight times more common than cutaneous involvement, however. 24 Twenty percent l2 to 34% patients with oral LP also have concomitant cutaneous involvement, or, conversely, up to 65% of the patients with classical cutaneous LP have oral involvement.25 Six different types of oral lesions have been described: reticular, plaquelike, atrophic, papular, erosive, and bullous. 26 The reticular variety is usually considered to be the most prevalent form (Fig. 3) although in one large study of 570 patients with oral involvement erosive LP was found to be the most common. 12 Erosive lesions may provoke a painful or "burning" sensation. 13 A metallic taste in the mouth has been described. 27 Older patients tend more often to have erosive lesions at initial presentation. 24 The buccal and glossal mucosa are most commonly involved,l2, 21, 28,29 whereas sublingual and palatal disease is unusual. 21 Gingival involvement

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595

Fig. 3. Reticulated oral LP affecting buccal mucosae. Fig. 4. Genital lesions in annular configuration.

may potentially lead to a picture of desquamative gingivitis. Symmetric involvement is the rule. Oral disease may be precipitated by trauma because lesions have been noted to develop after periodontal surgery30 and after previous irradiation for lymphoma. 31 Genital LP. Involvement of the genitalia with LP has been reported in 25% of men with typical skin findings 8 and in an unknown percentage of women. Lesions of the male genitalia consist of violaceous papules, principally on the glans penis (Fig. 4), but involvement of the penile shaft, scrotum, and perineum also occurs. The female genitalia demonstrate less specific involvement that consists of leukop1akic or erythroplakic lesions with variable atrophy. Desquamative vaginitis is most commonly due to LP and may be the presenting feature of the disease. 32 Genital complaints, such as pruritus, burning, and dyspareunia, are common. 33 ,34 The labia minora agglutinate and vaginal adhesions may prevent sexual intercourse. 32

Nail involvement N ail changes have been reported in from 1% to 16% of patients.17, 35 Usually only a few fingernails or toenails are involved, but occasionally all are affected. Typical cutaneous and oral lesions are usually present as well. Although nail involvement in children is rare,36 isolated LP of the nails may occur. 35 ,37 In fact, twenty-nail dystrophy of childhood is believed by some38 , 39 but not by a1l4o to be a variant oflocalized LP. Nail dystrophy may occur quickly in some patients. 35

Table I. Clinical types of LP Actinic Annular Bullous Classic Erythematosus Exfoliative Familial Guttate Hypertrophic "Invisible" Linear Mucous membrane (e.g., genital, esophageal) Nail Oral Pemphigoides Perforating Pigmentosus Planopilaris Ulcerative Zosteriform

Involved nails show longitudinal ridging and grooving, splitting (onychoschizia), shedding (onychomadesis), longitudinal striation (onychorrhexis), nail absence (anonychia), subungual hyperkeratosis, and thinning ofthe nail plate. Most, if not all, nail changes result from involvement of the nail matrix. 35 Focal atrophy of the proximal matrix results in grooving of the nail, the earliest sign of nail changes, whereas diffuse atrophy at the same site yields thinned nail plates. 36 Total nail matrix destruction produces nail loss (anonychia) that may be temporary or permanent, depending on the chronicity and

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Fig. 5. Actinic LP involving a common location, the sun-exposed forehead. (Courtesy Mouta S. Dilaimy, MD, Glen Burnie, Md.) Fig. 6. Hypertrophic variant of LP. These lesions are usually extremely pruritic and occur on lower extremities.

severity of the involvement.35 A pterygium, one of the classic signs of LP of the nails, is formed when focal destruction of the matrix produces an overhanging proximal nail fold that attaches to the barren nail bed and grows distally. Discrete papules of LP may be present beneath the nail plate,36 and the "pup tent" sign, in which the nail plate splits longitudinally and the lateral edges angle downward, is apparent when viewing the nail on end. Nail findings, however, are neither specific nor pathognomonic. Similar changes can occur with fungal infections, drug reactions, trauma, systemic illness, or other skin diseases. 35

Actinic LP Actinic LP was first described by Niles in 1941. 41 In'the ensuing years it has been given many names, including LP subtropicus, LP tropicus, summertime actinic lichenoid eruption, LP atrophicus annularis, LP actinicus, and lichenoid melanodermatosis. 42, 43 There appears to be a marked geographic variation in actinic LP, with a predilection to Middle Eastern countries. Its incidence is 14% in Lebanon,43 30% in Iraq,44 and 40% in Egypt. 4S It is apparently rare in the United States. The onset of this type of LP is primarily in the spring and summer. Fall and winter often bring a

remission. It is seen more commonly in women,44 younger individuals,42,45 laborers, and outdoor workers. Sunlight appears to be the precipitating influence,45, 46 although heat from a cooking oven has been reported to provoke lesions. 45 Lesions have been reproduced experimentally with UVB.42 Nutritional deficiencies induced by schistosomiasis or intestinal worm infections have also been implicated. 45 Exposed skin of the forehead, face, dorsal surfaces of the arms and hands, and the nape of the neck are principally involved, while the scalp and nails are spared. 43 ,44 Individual papules are hyperpigmented or violaceous to blue-brown, with a thready, rolled edge and well-defined borders (Fig. 5). Scaling is minimal. Typical lesions of LP may also be present elsewhere on the body. Pruritus is minimal44 to absent,43 although annular lesions have been reported to itch. 45 The Koebner reaction is not present.47 This subset of LP is not related to lichenoid actinic solar keratoses. These latter lesions are more often scaling, red to brown in color, and without a known geographic predilection. Histologically nuclear atypia is seen as in any actinic keratosis. A similar eruption may bear close resemblance to

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Lichen planus 597

LP. Benign lichenoid keratosis is the name given to those often solitary lesions that appear in sunexposed areas and that are histologically identical to LP except for the presence of focal parakeratosis. Hypertrophic LP The presence of thickened, hyperkeratotic, intensely pruritic lesions on the anterior aspect of the legs is typical ofhypertrophic LP. Lesions may range in color from purple to gray or black (Fig. 6). The incidence of this variant among LP patients as a whole ranges from 6% to 19%,9,17 although a considerably higher rate of involvement (38%) is found in patients with the familial variant of LP.48 Vesiculobullous LP LP with blister formation is uncommon and was noted in only 3.5% of patients in one studyP Two types are seen, bullous LP and LP pemphigoides. Bullous LP refers to the development of vesicles and bullae on preexisting lesions of LP.49, 50 Bullae typically are tense, with minimal surrounding inflammatory reaction. Nikolsky's and Asboe-Hansen signs have been described. 51 Chemicals such as tolazamide,52 chlorpropamide,52 and mercaptopropionyl glycine53 may precipitate such an outbreak. Histopathologic analysis reveals findings compatible with typical LP and a subepidermal bulla. 51 LP pemphigoides consists of bullae on lesional and nonlesional skin (Fig. 7).49,54,55 This clinical variant is believed to represent an association between LP and bullous pemphigoid (BP).50, 56, 57 Recent investigations, however, have shown that the antigen of LP pemphigoides may be different from that associated with BP.55 Circulating anti-basement membrane zone (BMZ) antibodies have been described. 49, 58, 59 Histopathologic characteristics of LP may be noted, and direct immunofluorescence demonstrates deposition of IgG56 and C3 54 in a manner consistent with that of BP. Captopril6o and cinnarizine49 have reportedly provoked this disorder. The extremities are frequently involved with tense bullae.54 Oral vesicles have also been described. 61 Miscellaneous Lichen planopilaris (Graham Little-Feldman syndrome) is an eruption of hair-bearing areas in which follicular involvement is present. Patients, more frequently women, usually have follicular spinous lesions, classic LP lesions elsewhere on the body or mucous membranes, and noninflammatory

Fig. 7. LP pemphigoides. (Courtesy Charles Carnisa, MD, Cleveland, Ohio.)

alopecia ofthe scalp, pubic region, and axillae27 with or without atrophy.8,20 The end stage of scalp involvement may be clinically and histopathologically identical to that of pseudopelade of Brocq. 17,62 Erythema dyschromicum perstans (ashy dermatosis), a dermatosis that occurs most commonly in Latin Americans, occurs in sun-exposed areas and has been theorized to be a variant of LP pigmentosus63 (also called actinic LP or LP subtropicus). Bhutani et a1. 64 have proposed a role for paraphenylenediamine in the cause of this disorder. LP may present initially in a linear band that most likely represents a koebnerization ofexisting papules and that may resemble a linear epidermal nevus. Annular LP characteristically involves the penis and the scrotum and exhibits a typical papule that enlarges peripheraIIy with central clearing. Grouping of papules may also form this type of disease. Annular lesions are more commonly seen in blacks. 27 Cram and Muller27 described a type of LP they term "invisible." Lesions are not apparent to the naked eye, but may be visualized by illumination with a Wood's lamp. Premonitory pruritus is found, and histopathologic analysis of such lesions reveals changes suggestive of LP. LP erythematosus is a rare form of the disease. Asymptomatic papules appear on the trunk and extremities. They are deep red, soft, and blanch with

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Journal of the American Academy of Dermatology

LIGHT AND ELECTRON MICROSCOPIC FEATURES

Fig. 8. Histologic features of LP. Pronounced "sawtoothing" of epidermis, accentuation of granular cell layer, and bandlike inflammatory cell infiltrate. Pigmentary incontinence is also present. (Hematoxylin-eosin stain; X40.)

pressure. 27 Histopathologic findings are consistent with LP.8 An overlap between LP and lupus erythematosus (LE) has been proposed. 65 Violaceous to erythematous plaques and patches are typically seen on the extremities. The lesions are of long duration, and the clinical differentiation between the two diseases may be impossible. Ulcerative LP may be seen outside the oral cavity, most commonly on the soles. Discomfort, principally a "burning" pain, is often intense, and this disease variant is frequently recalcitrant to therapy. Hanau and Sengel66 have described a perforating variant of LP. Their patient demonstrated lesions on the buttocks and volar surfaces of the wrists that histopathologically showed transepidermal elimination of LP-like material. Lastly, exfoliative, 8 guttate,20 and zosterifonn67 variants of LP have been reported. The development of typical lesions among members of the same family constitutes familial LP. Its incidence has been estimated at 10.7%.68 Sisters seem to be the most commonly affected. 69 Clinically this variant looks identical to classic LP, although a tendency exists to develop linear, ulcerative, erosive, or atypical disease patterns. 48 It may also be more likely to disseminate or become generalized. Familial LP tends to relapse more frequently,68 and in one study48 it was noted that almost 40% of patients developed this disorder before the age of 20.

The stratum corneum in LP usually shows thickening with orthokeratosis. Parakeratosis is unusual. The granular cell layer is increased, with prominent granules that result in a "beaded" appearance (Fig. 8). Irregular acanthosis is usually present, with rete ridges that form a "sawtooth" pattern. Langerhans cells and melanocytes appear normal,70 although there is often an increase in their number. 24 ,71-73 Histiocytes and lymphocytes are occasionally seen within the epidermis. Satellite cell necrosis has been reported in oral LP.74 The reticulated white lines of Wickham's striae appear to be correlated with an increased granular cell layer. 75 Ryan75 proposed that the dermal blood vessels in LP were absorbed, contributing to the atrophy of the striae, but other studies have revealed no discernible differences, qualitatively or quantitatively, in the capillaries. 76 In LP the BMZ figures prominently in the pathogenesis and expression of the disease. Fibrin seems to be deposited early in the disease,77 and most specimens show a duplication of the basal lamina.70, 78 Basilar gaps between the keratinocytes are formed and perhaps account for the pigmentary incontinence. As the BMZ becomes vacuolated, fluid accumulates and leads to the formation of clefts known as Maxlosephspaces. These may be seen in up to 17% of specimens. 79 This separation is believed to precede bullous LP. Civatte bodies (hyaline bodies, colloid bodies, cytoid bodies) represent dyskeratotic basal keratinocytes that have undergone premature keratinization8o and have been extruded into the papillary dermis. 81 They are believed to be formed by a meshwork of 70.A filaments probably derived from intracellular tonofilaments. They are found in 37% to 100% of biopsy specimens from cutaneous LP,72, 79 and were noted in 27% of patients with oral disease. 82 They are considered to be among the earliest pathologic changes. As the disease process continues, there is a steady loss of tonofilaments, desmosomes, and hemidesmosomes.70, 78 The degeneration of hemidesmosomes in the basal layer may explain the blistering. 8o The principal dermal feature is the bandlike interface inflammatory infiltrate that consists of lymphocytes and histiocytes that hug the basal layer.

Volume 25 Number 4 October 1991

Plasma cells79 and dermal melanophages77 are also present. In the early stages of the disease electron microscopic studies show normal mitochondria, but as time progresses a decrease in the number of cristae and changes of vacuolization appear. 70 Clausen et al.78 believed that the mitochondria of basal cells were swollen but that this was indicative of nonspecific cellular injury. The endoplasmic reticulum and Golgi apparatus do not seem to be affected. 7o Swanbeck and Thyresson 83 noted round and oval laminar particles 0.6 JLm in diameter within the nucleus of LP specimens. Their cause and significance remain unclear. Similar findings have been reported by Johnson and Fry.70 Different LP variants may show characteristic histopathologic findings. For example, in lichen planopilaris a perifollicular inflammatory cell infiltrate is seen early, with subsequent destruction ofthe follicles. 84 The involved follicle contains a mass of hyperkeratotic debris and liquefactive degeneration ofthe basement membrane. 17, 84 Eventually the hair follicle is destroyed and the pilosebaceous structures vanish. Lesions of drug-induced LP tend to have more parakeratosis than idiopathic disease. 2o Lesional and plasma eosinophilia frequently occurs. 20 Parakeratosis may be seen more frequently in oral involvement.21 In LP pigmentosus there is melanin deposition in the basal and malpighian layers. 85 Hypertrophic LP usually shows extensive acanthosis. 27 DIFFERENTIAL DIAGNOSIS

Clinically LP must be differentiated from other papulosquamous disorders such as psoriasis and secondary syphilis,86 as well as lichen nitidus (LN) and LE. Annular LP may be confused with granuloma annulare, and linear lesions often look like lichen striatus or linear epidermal nevi. Desquamative vaginitis secondary to LP must be differentiated from lichen sclerosus et atrophicus, atrophic vaginitis, and bullous disorders.32 The actinic variant ofLP may resemble melasma. 47 Candidiasis, leukoplakia, discoid LE, and secondary syphilis may all mimic oral LP. A drug-induced cause must be ruled out as well. The disorder most difficult to differentiate histologically from LP is LE. In LP colloid bodies tend to be more abundant and stain readily with anti-IgG

Lichen planus 599 and anti-IgM. Additionally, a lupus band test may help distinguish the two. 87 Oliver and coworkers88 believe that no microscopic feature exists to differentiateLE from LP conclusively. Benign lichenoid keratosis, lichenoid actinic keratoses, and keratoses lichenoides chronica may also be histologically confusing. THE KOEBNER PHENOMENON (ISOMORPffiC RESPONSE)

An isomorphic response is a common occurrence in LP, and develops in areas previously subjected to some type of trauma. 89 Almost any type of irritant, for example, burns, lacerations, friction, or UV light, may provoke the isomorphic response. Koebnerization is most frequently noted when a patient's disease is unstable or in an acute stage of flaring. NEOPLASTIC CONSIDERATIONS

Although very rare and controversial, the neoplastic transformation of LP has been reported. 90.n Malignant degeneration is usually associated with oral LP, but in a recent literature review it was noted that 10% of LP-associated cancers arose outside the mouth. 92 In contrast, some clinicians have been unable to detect a significant malignant potential for oral LP.29 A study from Denmark1) of 225 patients noted cancer in only one patient; in another study24 of 228 patients followed up for an average of 4.5 years no cancer was found. One morphologic form may be associated with malignant degeneration more than another. Kaplan and Barnes 13 found that in oral squamous cellcarcinoma associated with LP there was a marginally increased incidence of cancerous degeneration, particularly in the chronic, erosive subtype. Others have described a preponderance of atrophic29 ,93 or erythroplakic94 lesions preceding oral malignancies. _ The most common location for malignant degeneration of oral LP appears to be the buccal mucosa, but it may also occur in the tongue and lips. The average duration of the disease ranges from 2 years 92 to 9 to 12 years 13 before malignant degeneration occurs. Some investigators 13 , 92 believe that neoplastic conversion occurs mostly in men, whereas others93 ,94 have noted women to develop oral cancer more frequently. The influences responsible for precipitating malignant degeneration ofLP lesions are not known,but

Journal of the American Academy of Dermatology

600 Boyd and Neldner

Table II. Prevalence of carbohydrate metabolism abnormalities among patients with LP origin

Oinicallicben planus variants

No. of patients

Percent with abnormality

Australia England England Denmark England Australia Sweden United States United States India

Oral Cutaneous/oral Cutaneous/oral Oral Oral Oral Oral Oral Oral Cutaneous/oral

33 21 40 123 47 108 40 99 570 56

85 62 42 14.6 12.8 6 28

Country of

Authors

JOlly120 Powell et al. 121 Lowe et aL!22 Christensen et al. 123 Bussell et al. 124 Lacy et al. 10 Lundstrom125 Lozade-Nur et aI.l26 Silverman et al. 12 Nigam et aL 127

3

5.8

30.3

Experimental methods of detection

OOlT OOlT

oorr FBO/OGTT oorr

History History, FPG, oorr

FPB

History OOlT

FBG, Fasting blood glucose; FPG, fasting plasma glucose; OGTT, oral glucose tolerance test.

may be associated with chronicity, tobacco use,29 quinacrine ingestion,95 and oral yeast contamination. 96 The possibility of clinical confusion between oral LP and leukokeratosis, Candida infection, irritation resulting from tobacco or betel nuts, or simple bite line trauma is great. At the molecular level a neoplastic cellular clone may develop in an epithelium that is undergoing constant renewal. 93 Long-standing inflammation29 ,97 or a reaction to the original underlying provocation25 may also be operative. ASSOCIATED DISEASES

LP has been reported to be associated with a variety of totally unrelated disorders. It is difficult to detennine if there is a causal or a purely fortuitous association. Itis entirely possible that the associated LP may be little more than a lichenoid drug reaction. In those patients with an immunodeficiency it seems more likely that an underlying cause may trigger both conditions. Malignancies LP, usually the vesiculobullous variants, has been reported in association with underlying malignancies. LP pemphigoides has been described in association with stomach cancer, 55 lymphosarcoma, 3I reticulum cell sarcoma,31 neuroblastoma,98 craniopharyngioma,99 and a "pararenal malignancy."loo A pituitary adenoma was found in a 50-year-old man with bullous LP.99 Goihman-Yahr et al. lOI reported a patient whose LP coincided temporally with a malignant fibrohistiocytoma. The association of LP with thymomal02.105 and with IgA kappa monoclonal paraproteinemia has also been described,lo5

Gastrointestinal diseases A potential but unproved link exists between LP and gastrointestinal disease. Abnormal hepatic enzyme elevations have been noted in 7% to 52% of patients with LP.106, 107 In 12% biopsy has revealed liver disease,106 and in one study108 52% of patients with erosive oral LP developed cirrhosis. Patrone et al. 109 reported a higher incidence of hepatic disease among patients with nonerosive LP of greater than 1 year's duration compared with those patients whose disease was present less than a year. Once again, this suggests that a lichenoid dermatitis may be a nonspecific cutaneous marker of an underlying disease. Primary biliary cirrhosis (pBq. Graham-Brown et al. l1O were among the first to describe the association of LP and PBC. A larger studylll reported that 7 of 268 patients with PBC (2.6%) had LP. D-Penicillamine, used to treat PBC can also provoke an LP-like drug eruption. 112 Powell et al. lll described 17 patients. with PBC who developed LP during treatment with D-penicillamine, thus raising the question of a lichenoid drug eruption. Nine of these 17 seemed to have had the severity of their LP exacerbated by penicillamine. Powell and coworkers concluded that there did seem to be an association between LP and PBC separate from D-penici11amine administration. Chronic active hepatitis (CAR). An association between LP and CAH has also been proposed. The incidence of this disease in LP varies between 9.5% and 13.5%.105, IQ8, 113 Rebora and Rongioletti 114 evaluated 44 patients with LP and noted CAH in 5 (11.3%). The prevalence of CAB in their locale (Genoa, Italy) was 0.25% to 0.5%, which prompted

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these authors to propose that LP may be a significant risk factor for hepatic cirrhosis. Itmay be that the association between CAH and LP is more prevalent in southern EurOpe.114 LP has also been described in· a patient who received hepatitis B vaccine. 115 Ulcerative colitis. Several reports have described patients with ulcerative colitis and LP.105,116-118 Cusano and Errico 1l9 reported a patient whose cutaneous and gastrointestinal symptoms paralleled one another, and Wyatt 118 noted two patients whose LP onset coincided with that of their bowel disease. Diabetes mellitus. Investigations have shown a wide range of plasma glucose values (Table II) in patients with LP. In those studies that utilized oral glucose tolerance testing, the prevalence of an abnormal result or overt diabetes mellitus ranged from 12.8%124 to 85%.120 Christensen et al. 123 and Lozadu-Nur and coworkers 126 utilized fasting blood and plasma glucose findings, respectively, to categorize their patients. They found no evidence of an increased prevalence of glucose intolerance in 222 patients with LP. Differences in the interpretation of oral glucose tolerance tests may account from some of the wide discrepancy. The two American investigations 12, 126 revealed a low prevalence of diabetes, whereas a high120 and low10 prevalence was found in two Australian studies. English 121 , 122, 124 and Scandinavian123, 125 investigators have found the prevalence of abnormal glucose tolerance in patients with LP to fall between the two extremes. In the Bedford diabetic survey128 it was found that 12% to 14% of the general populace, ifstudied, will demonstrate glucose intolerance. Multiple investigations have shown a substantially higher percentage of such patients in the LP populace.120-122, 125, 127 The reason for such an increase remains obscure. JOlly120 has suggested that defective carbohydrate handling may cause LP. Others122 have noted that, like necrobiosis lipoidica diabeticorum, LP may antedate diabetes. Halevy et al. 129 found a significant elevation of HLA-A28 in nondiabetic patients with LP. They postulated that two populations of LP patients may exist, one of which may be genetically prone to diabetes mellitus. Other investigators, however, have noticed no differences between the diabetic and nondiabetic LP population. Those LP patients with erosive oral disease showed no major differences in fasting plasma glucose values compared with patients with nonerosive lesions. 126 Additionally, among LP patients as a whole there is no association between age, sex, distribution, duration, or mucosal

Lichen planus 601 Table III. Autoimmune diseases observed in patients with LP Alopecia areata102, 117, 130-132 Dermatomyositis102 Dermatitis herpetiformis133 Hashimoto's thyroiditis32,55 Keratoconjunctivitis sicca and xerostomia134 Morphea 130 Myasthenia gravis 103,116, 117 Pemphigus foliaceus135 Pemphigus vulgaris135, 136 Pernicious anemia132 Systemic sclerosis110 1Lhymomal02-105 Vitiligo 105, 117, 130, 131

involvement and with glucose intolerance.122, 127 Within the diabetic population the incidence of LP has been recorded as 1.6%.126 Miscellaneous As Table III shows, LP has been associated with a number of autoimmune disorders. Itis not known whether patients with LP are more inclined to develop these diseases or if the diseases are somehow etiologically related. Shuttleworth et al. 132 studied 54 patients with LP and an equal number of matched control subjects. They noted no increased association with autoimmune disease. An early investigation by Lynch 137 included 67 patients with LP and showed a positive correlation between LP and increased blood pressure. The triad of hypertension, diabetes mellitus, and LP was reported as Grinspan's disease. 25 Subsequent studies of oral138, 139 and cutaneous138 disease, however, have demonstrated no such association, and currently none is believed to exist. In 1983 Halevy and Feurerman140 reported 130 patients with LP, 19 of whom (14.6%) had concomitant urolithiasis. This prevalence of renal stones was 6 to 12 times greater than in the general population. They postulated that perhaps a similar metabolic derangement led to both disorders. Additional studies in patients with LP have noted iron or folate deficiencies,141 normal bone marrow,142 decreased erythrocyte glucose-6-phosphate dehydrogenase,143 compensatory hyperhidrosis of the head and neck,97 and an increased prevalence of type 0 blood. l44 Not all investigators agree that LP is associated with other systemic diseases in more than a fortuitous manner. Altman and Perry,17 in an analysis of

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307 LPpatients, found no consistent link with other disorders.

sites showed LP and LE consistently.147 Ahmed et al. 87 postulated overlapping etiologic factors.

LE OVERLAP SYNDROME

LICHENOID DRUG ERUPTIONS

Copeman et a1. 6S described four patients with features characteristic of LE and LP in what is now known as the overlap syndrome. They reported violaceous round to oval plaques that were centrally ulcerated and slow to heal. One patient had bullae and later developed fatal systemic LE. Similar occurrences have subsequently been reported.145-147 Clinically these lesions are acrally located, with a clinical appearance that combines features of both LE and LP. Patches and plaques are livid red to violaceous, with mild scaling, fine telangiectases, and a thinned epidermis. The typical flat-topped papules of LP are not usually present. These patients frequently have systemic complaints consistent with those found in LE.65, 87,147 The presence of systemic immunologic markers is controversial. A report by Ahmed et al. 87 documented three patients with significant ANA titers. Romero and coworkers,l46 however, found that of their 11 patients with the overlap syndrome only 3 were positive for ANA, and then only in low titers. A report by Jamison et al. 145 described a patient with cryoglobulinemia, positive rheumatoid factor, and C4 deficiency. Differentiating between the two disorders usually requires histopathologic analysis. Again, these two disorders may display similar features microscopically. Points of differentiation include colloid (Civatte) bodies, basement membrane changes, and immunologic findings. Civatte bodies may be found in both conditions, but in LP they tend to be more numerous ahd situated deeper, even into the upper area of the reticular dermis. 146 Binkley et aI,148 analyzed the disulfide bonds found in colloid bodies and noted differences between those of the two diseases. A different pathophysiologic mechanism may' account for such discrepancies. In LP basement membrane clefts may be due to lysis of keratinocytes, whereas in LE vacuolization forms on either side of this membrane. 146 Additionally, areas of thickened BMZsare more common in LE. Lastly, direct immunofluorescence shows immunoglobulin and complement deposition in a granular, linear band along the dermoepidermal junction in LE, whereas in LP these immunoreactants tend to be limited to colloid bodies. 146 Itshould be noted, however, that a patient has been described in whom biopsies from separate

An LP-like skin eruption has been associated with the contact, inhalation, or ingestion of various chemicals (Table IV). Clinically these lesions may display findings typical or atypical of classical LP. Eczematization, hypertrophy, unusual pigmentation, scaling, and intense postinflammatory hyperpigmentation commonly occur l51 , 174; however, mucous membrane lesions are unusual. 151,191,197 Alopecia may be profound and unrelenting. lSI Atrophy of dermal sweat glands has been reported.15l, 174 Watanabe et al. l90 evaluated drug-induced LP with lesional immunofluorescence and noted no significant differences from idiopathic LP. Most substances that provoke LP-like lesions are ingested or given parenterally. Many Allied servicemen developed LP after receiving quinacrine for malaria prophylaxis while serving in the South Pacific during World War II (New Guinea LP).198 Follicular involvement frequently ensued and led to alopecia. Fellner20 has proposed that gold is the drug that most commonly leads to lichenoid eruptions. A lichenoid contact dermatitis has been described after exposure to nickel,199 aminoglycoside antibiotics,2°0 color developers,l83 and dental amalgams. 24 A photocontact lichenoid eruption occurred after musk ambrette application. 193 De Graciansky and Boulle201 investigated patients with lichenoid dermatitis resulting from color film developer contact and divided them into two general categories. First are those who experience a slight but continuous exposure to the offending agent and who develop classic LP. The second category includes patients who have a single but much larger acute exposure. They display the typical findings of contact dermatitis that ultimately result in lichenoid lesions. Patch testing has shown some correlation with color film developers 183 but not with dental amalgams. 24 Inhalation of substances may be partially responsible. 201 The cause oflichenoid drug eruptions remains unclear. The adulteration of cellular molecules by the offending agents may be operative. Penicillamine changes cell surface antigens, l I I and the sulfhydryl groups of captopril are known to alter enzyme systems. 149 These aberrations may precipitate an immune response to epidermal neoantigens with production of LP-like lesions. I 11 Stereochemical

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Table IV. Drugs associated with an LP-like reaction Antihypertensives Captopri}60, 149, \ 50 Chlorothiazide 151 Enaiapril l50 Hydrochlorothiazide 151 Labetolol l52 Methyldopal53-155 Practolol 136 PropranoloJl57, 158 Spironolactone 159

Antibiotics Demeclocyclinel60, 161 Ethambutol 162 Griseofulvin163 Ketoconazole 164 Levamisole\ 65 Para-amino salicylic acid 166 Streptomycin I67 Tetracycline l68 Nonsteroidal antiinflammatory drugs Naproxen l69 Indomethacin 170

Feclofenac l70

Diflunisal170

Fluribiprofen 170 Ibuprofen 170

Benoxaprofen170

Acetylsalicylic acid J71 Antimalarials Chloroquine 172 Quinacrine l ?3,174

similarities between drugs may also represent a po~ tential etiologic link. I80 It is also possible that the compounds in question merely unmask latent LP.25, 110, 164,202 HLA phenotypes may determine which patients are susceptible. 164 MISCELLANEOUS LICHENOID DERMATOSES Lichen nitidus (LN)

LN was described by Pinkus in 1907. 203 It had previously been considered a variant of LP, perhaps a "miliary" form. 204 This is a comparatively rare eruption with no sexual predilection. Itmay occur in any age or race. 20S In the limited form of the disease patients develop shiny, 1to 2 mm flesh-colored papules on the arms, abdomen, and penis. They may be round, flat topped, or polygonal and tend to be oflong duration. A central punctum can be faintly visible on isolated lesions. Compared with LP, pruritus is rare, The

Antimalarials (cont'd)

Quinidine /7 5-177 Quinine 178

Psychotropic/neurologic

Carbamazepine 179

Laevomepromazine180

Lorazepam 181

Metopromazine 180 Film developing agents 4.Amino-N-diethyI-analine sulfate (TIS) 182 CD_2 182,183 and CD-3 183 p-Isopropylamino-diphenylamine (IPPD) 184 Sulfonylureas

ChiorpropamideS2, 185

Tolazamide52 Tolbutamide l82 years) had normal immunoglobulin values. LP has also been reported in patients with hypogammaglobulinemia. 102,104,132 In one study cryoglobulins were found in 31 % of patients with oral and cutaneous LP.!05 The role these immunoglobulins may be playing in LP is speculative. LP seems to be less strongly associated with the humoral arm of the immune system than with the cellular arm. T cells. Dermal T lymphocytes have been postulated to initiate or stimulate the pathogenic mechanisms responsible for LP. Grafting of lesional skin onto nude (immunoincompetent) mice results in a disappearance of histologic abnormalities. 255 De Panfilis et al.236 proposed that activated T cells may view keratinocytes as "target" cells and interact with them. Some investigators 101 believe that tumor antigens, to which patients with LP have become sensitized, may crOSHeact with epidermal antigens and lead to clinical lesions. Recent evidence has shown that interferon-'Y, produced by T cells, may induce monocyte expression of lymphocyte function-asso-

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Lichen planus.

Lichen planus, a papulosquamous disease, in its classical presentation is characterized by pruritic violaceous papules most commonly on the extremitie...
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