REVIEW
LICHEN PLANUS AND LICHEN PLANUS-LIKE ERUPTIONS: PATHOGENESIS AND ASSOCIATED DISEASES AVI SHAI, M.D., AND SIMA HALEVY, M.D.
Lichen planus (LP) is a clearly defined papulosquamous disease characterized by typical cutaneous and mucosal lesions. The term "lichen" was derived from a group of plants to which LP lesions bear some resemblance. The term "lichenoid" describes LP-like eruptions, which may be associated with certain diseases or may be induced by various drugs. The pathogenesis of lichen planus and LP-like eruptions is not well understood. An abnormal immune response is considered to be the basic underlying mechanism. Histologic and immunofluorescence studies, as well as recent data based on monoclonal antibody techniques and human leukocyte antigen (HLA) typing, support this hypothesis. Additional support comes from the association between LP and certain systemic disorders.
The dermal infiltrate of lichen planus is composed of activated DR positive T-helper lymphocytes, which are adjacent to macrophages and Langerhans' cells. Lesions that appear later show T-cytotoxic/suppressor lymphocytes in the epidermis apposed to keratinocytes and Langerhans' cells.'-'' It has been hypothesized that the LP reaction begins with the processing of some unidentified antigens by Langerhans' cells. This is followed by migration and subsequent activation of lymphocytes against basal layer keratinocytes. The damage to basal keratinocytes is thought to be mediated by certain cytokines, lymphotoxins, and cytotoxic T cells.''"'' Saurat et al. suggest that an alteration in epidermal antigenicity, possibly induced by a virus or by drugs, might provoke this reaction.'' A complete disappearance of characteristic pathologic features of LP was ohserved in an experimental study based on transplanted skin grafts from LP lesions onto nude mice.* This may indicate that activation of cellular elements of the immune system play a central role in the pathogenesis of LP. Immunogenetic predisposition of the patient is considered to be a fundmental condition that enables the reaction. Familial appearance of LP and HLA typing results of IP confirm this assumption.''-"' HLA typing in LP. Immune response genes are considered to be linked to the OR locus. Their expression is through la antigens on T-lymphocytes, macrophages, endothelial cells, and Langerhans' cells. A statistically significant increase in the frequency of HLA-DRI was found in LP patients."-'- In a series of 72 patients, Powell et al. found that DRl was present in 80% of patients with generalized LP, in 54% of patients with localized LP, 56% of patients with drug-induced LP, and in 3 1 % of patients with mucosal LP, compared with 25% of normal controls." In another series of 40 patients, Valsecchi et al. showed that DRl was present in 65% of LP patients, compared with 16.3% of normal controls.'-^ The findings presented by Powell and Valsecchi were statistically significant."-'^ In early HLA studies of LP patients, a greater incidence of HLA-A3 was demonstrated.'' Saurat et al. found that HLA-A3, HLA-B5, and HLA-B8 were more frequent in LP patients than in controls;''' however, the differences were not statistically significant. An increased incidence of HLA-A28 was found by Halevy et al. in a group of nondiabetic LP patients.'-' (See: Impaired carbohydrate metabolism in LP.)
PATHOGENESIS
Immunopathogenesis of LP The current available data suggest that LP is a process mediated by immune mechanisms. The basic histologic features of LP and LP-like eruptions are: (1) Liquefaction degeneration of the basal layer of the epidermis. (2) Hyperkeratosis and hypergranulosis with irregular acanthosis of the epidermis. (3) A dense band-like infiltrate in the superficial dermis, composed almost entirely of lymphocytes, with a few macrophages. The damage to basal cells and their incapability of storing melanin results in the appearance of melanophages in that infiltrate. (4) The presence of colloid bodies, also referred to as hyaline, cytoid, or Civatte bodies, which represent necrotic keratinocytes. Colloid bodies have been found in 37% of LP cases in routinely stained sections. On direct immunofluorescence staining, they are demonstrated in about 87% of the cases. They stain mainly with IgM and less frequently with IgG, IgA, and C3.'-From the Department of Dermatology, Soroka Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel. Address for correspondence: Sima Halevy, M.D., Department of Dermatology, Soroka Medical Center, Beer-Sheva 84101, Israel. 379
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The role of human papilloma virus (HPV) in erosive oral LP has not been determined yet. Jantell et al. found that 65% of tissue samples from 20 patients with erosive oral LP were positive for HPV.^^ Pardo et al. present the first reported association of LP and HIV infection.^^ Although the association with HIV could be coincidental, altered T-cell function may be involved in this reaction. LP as a metabolic disorder. Certain abnormalities were found in LP: decreased respiratory enzyme activity, mitochondrial dysfunction, decreased levels of acid phosphatase, and increased levels of lactic dehydrogenase. These enzymatic disorders are regarded now as secondary changes to the basic pathogenetic mechanism of LP, which is still not clear.' Metabolic factors were proposed to play a role in LP, based on the findings of abnormal glucose tolerance and of urolithiasis and hyperuricemia in LP patients. As there is no concrete evidence for the role of metabolic factors in LP, this aspect is discussed along with other associated diseases of LP.
LP and graft-versus-host reactions. The immune response theory is also supported by the similarities between LP and the graft-versus-host reaction, and its associations to certain systemic disorders. Lichen planus-like reactions are common among bone marrow transplant patients with graft-versus-host disease.^-"' LP and lichenoid eruptions that appear in graft-versus-host disease have common histologic features, both are thought to result from activated lymphocytes attacking basal cells. Skin biopsies of patients with lichenoid eruption of chronic graft-versus-host disease revealed injury of basal cells, numerous colloid bodies, and lymphocytes in proximity to injured keratinocytes.'^ Similar patterns of histologic and immunologic features exist in certain disorders associated with LP and graftversus-host disease, like chronic active hepatitis, primary biliary cirrhosis, and sicca syndrome.'* Other Pathogenetic Hypotheses There is little solid evidence to support emotional stress and viral infections as other possible pathogenetic factors of LP. Emotional stress. The possible influence of severe emotional stress on LP was documented during the Second World War. Recurrent attacks of LP were attributed to psychologic stress.'' Currently, psychologic stress is not considered to be a sole causative factor for LP, but it may participate in activating an underlying organic mechanism. Viral etiology. An infectious cause for LP has never been demonstrated. An indirect relationship may exist between LP and a specific virus or several viruses, perhaps by immunologic mechanisms. Positive results of tests for hepatitis B virus surface antigen are associated with LP.-^"-^' The presence of hepatitis B surface antigen was found in 26 of 561 LP patients compared with 27 of 1008 controls. This finding was statistically significant.^" Ayala et al. found that the prevalence of hepatitis B surface antigen in oral erosive LP patients was 4.7%.^' In the population of comparahle age in the south of Italy it was 4.3%. Powell proposed that differences in the prevalence of liver disorders, which were reported in LP patients in various geographic areas, might be attributed to variability in genetic susceptibility of each population to hepatitis B virus infection.^^--^^ Yet, LP is not thought to be a clinical manifestation of hepatitis B virus infection. Non-A non-B hepatitis virus was proposed as an etiologic factor for liver damage and LP.^' Since its identification as hepatitis C,^'' further investigation may include search for hepatitis C antibodies in LP. Recently, one case has been reported (personal communication). DRl antigen, which has an increased frequency in LP patients, has been linked to reduced serologic response to Epstein Barr viral capsid antigen, but there is no further evidence for the involvement of Epstein Barr virus
ASSOCIATED DISEASES
LP and Liver Diseases A significantly higher occurrence of liver abnormalities is found in LP patients compared with the normal population, including serologic liver function tests and liver histopathologic changes. In recent years, there have been an increasing number of reports of LP occurring in association with chronic active hepatitis and primary biliary cirrhosis.^°-^'-^'*'-'^ Korkij et al. in a case control study found an excess of liver abnormalities in LP patients.^** Abnormal liver function tests were found in 38 (52%) of 73 LP patients, compared with 69 (36%) of 193 controls. Hepatitis B antigens and/or antibodies were found in three LP patients, two of whom had chronic active hepatitis, and one had post-necrotic cirrhosis. In a retrospective survey of 44 patients with nonerosive LP, Rebora and Rongioletti report the high prevalence (11.3%) of chronic active hepatitis;^' the global prevalence of chronic active hepatitis in the same geographic area is about 0.25 to 0.5%. In a prospective study of oral LP patients, chronic liver disease was found in 22 (33.8%) of 65 oral LP patients^" (including seven patients with liver cirrhosis, and two patients with chronic active hepatitis). The high incidence of chronic active hepatitis was not found among LP patients in other surveys made in the United States, Sweden, and England.^^-^^ Of 55 LP patients examined by Monk, liver abnormalities were discovered in three patients (5.4%).^^ In the control group consisting of 10,000 patients, 5.85% had a significantly elevated level of gamma-glutamyl transaminase, 4.38% a raised alkaline phos-
in LP. 25
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phatase, and 2.18% a raised glutamate oxaloacetate transaminase. No further data are given in this report concerning the exact type of liver abnormalities found in the LP patients. The differences in the prevalence of liver disorders among LP patients in different geographic areas might be attributed to the genetic susceptibility of each population to hepatitis B virus infection.--' Monk'pointed out that the prevalence of hepatitis B virus markers is vastly higher in the Italian population surveyed by Rebora and Rongioletti-' than that seen in London. Powell et al. document the coexistence of LP and primary biliary cirrhosis in 24 of 268 patients with primary biliary cirrhosis.'^ In 17 patients, appearance of the cutaneous eruption was attributed to D-penicillamine, whereas in seven patients LP developed unrelated to therapy with the drug. There are histologic and immunologic similarities between LP and chronic active hepatitis that resemble graft-versus-host reactions (i.e., the typical lymphocyte infiltrate and the fibrosclerotic healing process that may take place). A similar pattern exists for primary biliary cirrhosis.^'-'^ It is possible that the immunologic attack against kerotinocytes can also damage hepatocytes. Liver pathology is found to be much more severe in mucosal erosive LP.^'-'" Perhaps the morbid process in that type of LP is directed at higher levels of aggressiveness against both epidermal cells of the skin and parenchymal cells of the liver.
ing raised the possibility that there may be two forms of LP, one associated with A28, and the other not associated with A28 and probably etiologically related to diabetes. Considering the immunopathogenetic aspects of diabetes, one may think that parallel mechanisms may play a role in diabetes associated with LP. Histopathologic examination of the islets of Langerhans of some diabetics reveal an inflammatory infiltrate, predominantly lymphocytic. Studies using monoclonal antibodies have revealed elevation in the number of circulating la positive T cells in patients with early type I diabetes;^'* however, the pattern of insulin response in LP patients with abnormal glucose tolerance was similar to that seen in type II diabetics.-'-'^-'''' Furthermore, none of the LP patients with glucose intolerance examined by Lowe et al. had demonstrable islet cell antibodies,^'' as compared with the 20.2% prevalence of islet cell antibodies in insulin-dependent diabetes, and 6 to 8% in noninsulindependent diabetes. Urolithiasis and Hyperuricemia A recent survey of 130 Israeli LP patients conducted by Halevy and Feuerman'"' revealed an increased incidence (14.6%) of urolithiasis as compared with that in the normal Israeli population. In most of those patients, the appearance of urolithiasis preceded LP by an average period of 13 years and could not be regarded as secondary to the skin disease. It has been proposed that basic metabolic disorders responsible for the development of urolithiasis may exist in LP and may play some part in the etiogenesis of LP." In another study of 42 LP patients, the prevalence of hyperuricemia has been found to be higher (12%)) than the recorded prevalence of hyperuricemia in the Israeli general population (5-7%), and in 40 matched controls (0%).'" Lichen planus is not considered to include overproduction of uric acid from accelerated epidermal cell proliferation, as in psoriasis, because the kinetic features of the epidermal cells differ in these two diseases.'"' Yet, tritiated thymidine studies in LP suggest that there is an increase in basal cell layer DNA synthesis, and that there is a continuous state of disintegration and repair of basal cells.''- Currently, there is not sufficient data to identify the cause of urolithiasis and hyperuricemia in LP patients or their possible role in LP.
Impaired Carbohydrate Metabolism in LP Impaired carbohydrate metabolism as manifested by abnormal glucose tolerance has been observed in LP patients.^''^''"-''' These findings have been documented in patients with oral LP''*-'-' and also in patients with only cutaneous lesions or combined cutaneous and oral lesions.^'-^''-'^ The largest series of oral LP patients is presented by Hornstein et al.''' In 177 patients with oral LP and in 177 sex- and age-matched healthy control subjects, abnormal glucose tolerance was observed in 30.1% of the patients and in 11.9% of the control group. In another study documented by Halevy and Feuerman,'^ consisting of 52 LP patients, abnormal glucose tolerance was found in 19 patients (36%) including five cases of overt diabetes. The possible role of this finding in the pathogenesis of LP is not well understood. Although an underlying metabolic defect was proposed as a pathogenetic factor, no correlation between glucose tolerance abnormalities and duration and distribution of lesions was observed.'-'' The incidence of HLA-A28 was found by Halevy et al. to be significantly increased in a group of nondiabetic LP patients.'-'-^* Among 52 LP patients, HLA-A28 was found in 8 (36.4%) of 22 nondiabetic LP patients, compared with 52 (8.2%) of 631 healthy, ethnically matched controls, and 1 (7.7%) of 13 diabetic LP patients. This find-
Autoimmune Disorders There have been a few case reports of patients with LP and LP-like reactions in association with other autoimmune disorders among which are bullous pemphigoid,''^ pemphigus vulgaris,'''' dermatomyositis,''-' ulcerative colitis,'"^-'*^ sicca syndrome,*'* and myasthenia gravis;*" however, evaluation of disease association should be supported by valid epidemiologic data and not be based solely on presentation of case reports. 381
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The association of LP with sicca syndrome''* and myasthenia gravis'" may be coincidental but is of special interest in view of the presence of these disorders in graft-versus-host reactions."*-'"" The association of LP and vitiligo is based on a statistical study of 100 patients with vitiligo, nine of whom also had LP.^' The coexistence of discoid lupus erythematosus and systemic lupus erythematosus with LP has already been reported.-"~'''' In most of the reported cases, the clinical, histoiogic, and immunofluorescence features showed an overlap pattern between lupus erythematosus and LP. Long-term follow-up did not allow an unequivocal diagnosis of either lupus erythematosus or LP in eleven patients examined by Romero et al.^'' In another study,''' diagnosis of one disease or the other could be accepted, based on: (1) the American Rheumatism Association criteria for the diagnosis of systemic lupus erythematosus, and (2) histologic and immunofluorescence studies that were strongly suggestive of LP. Razzaque Ahmed et al. presented clinical, laboratory, and immunopathologic evidence for the simultaneous occurrence of systemic lupus erythematosus and LP.^^ The authors proposed that a common agent (or agents) may cause either disease or overlap syndrome, depending on the immunogenetic predisposition of the patient.
Neurologic Disorders The association of LP with neurologic diseases, such as syringomyelia, bulbar paralysis, and peripheral neuritis, and its occasional localization along neural pathways, was thought to imply a neurologic etiology." Currently, there is no additional evidence for that hypothesis. In the last 20 years documentation of such an association is extremely rare. CONCLUSIONS
In this review we have focused mainly on the pathogenesis of LP and LP-associated diseases. Immune mechanisms are thought to play a central role in the pathogenesis of LP. An alteration in epidermal antigenicity, possibly induced by a virus or by drugs, might provoke this reaction. Various drugs may be associated with lichenoid eruptions; however, an infectious factor has never been demonstrated in LP. The therapeutic implication of the data presented here is an issue for future investigation. REEERENCES
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The coexistence of psoriasis and LP has rarely been reported.^^ The sparse documentation of this issue consists mainly of case reports. The paucity of reports in the literature is attributed to under-reporting. Epidemiologic data presented by Naldi et al.,'* which compare the prevalence of psoriasis among LP patients and controls, did not reach statistical significance. Shiohara et al. raise the possibility that the coexistence of the two diseases is indeed rare.'' A genetic predisposition to psoriasis may provide an unfavorable predisposition to the development of LP and vice versa. The observation that spontaneous improvement of psoriasis occurred during development of LP, and that the disappearance of LP was followed by an exacerbation of the psoriatic eruption, supports this hypothesis. Interferon gamma, a substance released by T-!ymphocytes, may explain the possible dissociation of these two diseases.'^ This compound participates in the damage process to basal cells in LP.''-^ On the other hand, interferon gamma has been reported to have some therapeutic activity in certain patients with psoriasis.'^" Further investigation may confirm the possible relation between LP and psoriasis and the role of certain cytokines and lymphokines concerning this relationship.
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Eosinophilia-Myalgia Syndrome In October 1989, the State Health Department of New Mexico was notified of three patients with an unexplained acute illness characterized by intense myalgia and eosinophilia. Each patient had been ingesting L-tryptophan-containing preparations for the treatment of insomnia. Within weeks, a nationwide outbreak of the disease, termed the eosinophilia-myalgia syndrome, was recognized. Case-control studies confirmed an unequivocal epidemiologic association between tbe eosinophilia-myalgia syndrome and the use of L-tryptophan-containing products. By August 1990, 1536 cases of the eosinophilia-myalgia syndrome had been reported to the Centers for Disease control (CDC), and it was suggested that the actual number may be considerably bigher. Eigbty-five percent of the affected patients developed symptoms between July 1989 and February 1990. One tbird of the patients required hospitalization, and twenty-seven deaths directly attributable to the eosinophilia-myalgia syndrome have been reported. ...The early phase was characterized by intense myalgia, various skin rashes, edema, dyspnea, and constitutional symptoms. Despite the discontinuation of Ltryptophan use, substantial proportion of patients developed a protracted course that was dominated by manifestations of cutaneous and neuromuscular involvement. Approximately one balf of tbe patients developed diffuse scleroderma-like cutaneous induration. Histopathologic examination of full-thickness skin biopsy specimens in these cases showed marked thickening of the fascia and dermis caused by accumulation of collagen and mucopolysaccharides, accompanied by an inflammatory infiltrate of variable severity. Diffuse peripberal neuropathy, which became progressively more prevalent during the first year of the illness, was the most common form of neurologic dysfunction. Histologic findings included epineurial and perineurial infiltration with mononuclear cells and occasional eosinophils, increased connective tissue deposition, loss of myelinated nerve fibers, and axonal degeneration. Myopathy manifested by muscle cramps and weakness occurred frequently. Muscle biopsies showed inflammation and fibrosis in the connective tissue surrounding the muscle, but only minimal muscle fiber damage. Occlusive microangiopathy with thickening of vessel walls by inflammatory cell infiltration and endothelial swelling has been observed in muscle and nerve biopsies. From Varga J, Uitto ], Jimenez SA. The cause and pathogenesis of the eosinophilia-myalgia syndrome. Ann Intern Med 1992; 116:140-147. 384
LICHEN PLANUS AND LICHEN PLANUS-LIKE ERUPTIONS: PATHOGENESIS AND ASSOCIATED DISEASES AVI SHAI, M.D., AND SIMA HALEVY, M.D.
Lichen planus (LP) is a clearly defined papulosquamous disease characterized by typical cutaneous and mucosal lesions. The term "lichen" was derived from a group of plants to which LP lesions bear some resemblance. The term "lichenoid" describes LP-like eruptions, which may be associated with certain diseases or may be induced by various drugs. The pathogenesis of lichen planus and LP-like eruptions is not well understood. An abnormal immune response is considered to be the basic underlying mechanism. Histologic and immunofluorescence studies, as well as recent data based on monoclonal antibody techniques and human leukocyte antigen (HLA) typing, support this hypothesis. Additional support comes from the association between LP and certain systemic disorders.
The dermal infiltrate of lichen planus is composed of activated DR positive T-helper lymphocytes, which are adjacent to macrophages and Langerhans' cells. Lesions that appear later show T-cytotoxic/suppressor lymphocytes in the epidermis apposed to keratinocytes and Langerhans' cells.'-'' It has been hypothesized that the LP reaction begins with the processing of some unidentified antigens by Langerhans' cells. This is followed by migration and subsequent activation of lymphocytes against basal layer keratinocytes. The damage to basal keratinocytes is thought to be mediated by certain cytokines, lymphotoxins, and cytotoxic T cells.''"'' Saurat et al. suggest that an alteration in epidermal antigenicity, possibly induced by a virus or by drugs, might provoke this reaction.'' A complete disappearance of characteristic pathologic features of LP was ohserved in an experimental study based on transplanted skin grafts from LP lesions onto nude mice.* This may indicate that activation of cellular elements of the immune system play a central role in the pathogenesis of LP. Immunogenetic predisposition of the patient is considered to be a fundmental condition that enables the reaction. Familial appearance of LP and HLA typing results of IP confirm this assumption.''-"' HLA typing in LP. Immune response genes are considered to be linked to the OR locus. Their expression is through la antigens on T-lymphocytes, macrophages, endothelial cells, and Langerhans' cells. A statistically significant increase in the frequency of HLA-DRI was found in LP patients."-'- In a series of 72 patients, Powell et al. found that DRl was present in 80% of patients with generalized LP, in 54% of patients with localized LP, 56% of patients with drug-induced LP, and in 3 1 % of patients with mucosal LP, compared with 25% of normal controls." In another series of 40 patients, Valsecchi et al. showed that DRl was present in 65% of LP patients, compared with 16.3% of normal controls.'-^ The findings presented by Powell and Valsecchi were statistically significant."-'^ In early HLA studies of LP patients, a greater incidence of HLA-A3 was demonstrated.'' Saurat et al. found that HLA-A3, HLA-B5, and HLA-B8 were more frequent in LP patients than in controls;''' however, the differences were not statistically significant. An increased incidence of HLA-A28 was found by Halevy et al. in a group of nondiabetic LP patients.'-' (See: Impaired carbohydrate metabolism in LP.)
PATHOGENESIS
Immunopathogenesis of LP The current available data suggest that LP is a process mediated by immune mechanisms. The basic histologic features of LP and LP-like eruptions are: (1) Liquefaction degeneration of the basal layer of the epidermis. (2) Hyperkeratosis and hypergranulosis with irregular acanthosis of the epidermis. (3) A dense band-like infiltrate in the superficial dermis, composed almost entirely of lymphocytes, with a few macrophages. The damage to basal cells and their incapability of storing melanin results in the appearance of melanophages in that infiltrate. (4) The presence of colloid bodies, also referred to as hyaline, cytoid, or Civatte bodies, which represent necrotic keratinocytes. Colloid bodies have been found in 37% of LP cases in routinely stained sections. On direct immunofluorescence staining, they are demonstrated in about 87% of the cases. They stain mainly with IgM and less frequently with IgG, IgA, and C3.'-From the Department of Dermatology, Soroka Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel. Address for correspondence: Sima Halevy, M.D., Department of Dermatology, Soroka Medical Center, Beer-Sheva 84101, Israel. 379
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The role of human papilloma virus (HPV) in erosive oral LP has not been determined yet. Jantell et al. found that 65% of tissue samples from 20 patients with erosive oral LP were positive for HPV.^^ Pardo et al. present the first reported association of LP and HIV infection.^^ Although the association with HIV could be coincidental, altered T-cell function may be involved in this reaction. LP as a metabolic disorder. Certain abnormalities were found in LP: decreased respiratory enzyme activity, mitochondrial dysfunction, decreased levels of acid phosphatase, and increased levels of lactic dehydrogenase. These enzymatic disorders are regarded now as secondary changes to the basic pathogenetic mechanism of LP, which is still not clear.' Metabolic factors were proposed to play a role in LP, based on the findings of abnormal glucose tolerance and of urolithiasis and hyperuricemia in LP patients. As there is no concrete evidence for the role of metabolic factors in LP, this aspect is discussed along with other associated diseases of LP.
LP and graft-versus-host reactions. The immune response theory is also supported by the similarities between LP and the graft-versus-host reaction, and its associations to certain systemic disorders. Lichen planus-like reactions are common among bone marrow transplant patients with graft-versus-host disease.^-"' LP and lichenoid eruptions that appear in graft-versus-host disease have common histologic features, both are thought to result from activated lymphocytes attacking basal cells. Skin biopsies of patients with lichenoid eruption of chronic graft-versus-host disease revealed injury of basal cells, numerous colloid bodies, and lymphocytes in proximity to injured keratinocytes.'^ Similar patterns of histologic and immunologic features exist in certain disorders associated with LP and graftversus-host disease, like chronic active hepatitis, primary biliary cirrhosis, and sicca syndrome.'* Other Pathogenetic Hypotheses There is little solid evidence to support emotional stress and viral infections as other possible pathogenetic factors of LP. Emotional stress. The possible influence of severe emotional stress on LP was documented during the Second World War. Recurrent attacks of LP were attributed to psychologic stress.'' Currently, psychologic stress is not considered to be a sole causative factor for LP, but it may participate in activating an underlying organic mechanism. Viral etiology. An infectious cause for LP has never been demonstrated. An indirect relationship may exist between LP and a specific virus or several viruses, perhaps by immunologic mechanisms. Positive results of tests for hepatitis B virus surface antigen are associated with LP.-^"-^' The presence of hepatitis B surface antigen was found in 26 of 561 LP patients compared with 27 of 1008 controls. This finding was statistically significant.^" Ayala et al. found that the prevalence of hepatitis B surface antigen in oral erosive LP patients was 4.7%.^' In the population of comparahle age in the south of Italy it was 4.3%. Powell proposed that differences in the prevalence of liver disorders, which were reported in LP patients in various geographic areas, might be attributed to variability in genetic susceptibility of each population to hepatitis B virus infection.^^--^^ Yet, LP is not thought to be a clinical manifestation of hepatitis B virus infection. Non-A non-B hepatitis virus was proposed as an etiologic factor for liver damage and LP.^' Since its identification as hepatitis C,^'' further investigation may include search for hepatitis C antibodies in LP. Recently, one case has been reported (personal communication). DRl antigen, which has an increased frequency in LP patients, has been linked to reduced serologic response to Epstein Barr viral capsid antigen, but there is no further evidence for the involvement of Epstein Barr virus
ASSOCIATED DISEASES
LP and Liver Diseases A significantly higher occurrence of liver abnormalities is found in LP patients compared with the normal population, including serologic liver function tests and liver histopathologic changes. In recent years, there have been an increasing number of reports of LP occurring in association with chronic active hepatitis and primary biliary cirrhosis.^°-^'-^'*'-'^ Korkij et al. in a case control study found an excess of liver abnormalities in LP patients.^** Abnormal liver function tests were found in 38 (52%) of 73 LP patients, compared with 69 (36%) of 193 controls. Hepatitis B antigens and/or antibodies were found in three LP patients, two of whom had chronic active hepatitis, and one had post-necrotic cirrhosis. In a retrospective survey of 44 patients with nonerosive LP, Rebora and Rongioletti report the high prevalence (11.3%) of chronic active hepatitis;^' the global prevalence of chronic active hepatitis in the same geographic area is about 0.25 to 0.5%. In a prospective study of oral LP patients, chronic liver disease was found in 22 (33.8%) of 65 oral LP patients^" (including seven patients with liver cirrhosis, and two patients with chronic active hepatitis). The high incidence of chronic active hepatitis was not found among LP patients in other surveys made in the United States, Sweden, and England.^^-^^ Of 55 LP patients examined by Monk, liver abnormalities were discovered in three patients (5.4%).^^ In the control group consisting of 10,000 patients, 5.85% had a significantly elevated level of gamma-glutamyl transaminase, 4.38% a raised alkaline phos-
in LP. 25
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phatase, and 2.18% a raised glutamate oxaloacetate transaminase. No further data are given in this report concerning the exact type of liver abnormalities found in the LP patients. The differences in the prevalence of liver disorders among LP patients in different geographic areas might be attributed to the genetic susceptibility of each population to hepatitis B virus infection.--' Monk'pointed out that the prevalence of hepatitis B virus markers is vastly higher in the Italian population surveyed by Rebora and Rongioletti-' than that seen in London. Powell et al. document the coexistence of LP and primary biliary cirrhosis in 24 of 268 patients with primary biliary cirrhosis.'^ In 17 patients, appearance of the cutaneous eruption was attributed to D-penicillamine, whereas in seven patients LP developed unrelated to therapy with the drug. There are histologic and immunologic similarities between LP and chronic active hepatitis that resemble graft-versus-host reactions (i.e., the typical lymphocyte infiltrate and the fibrosclerotic healing process that may take place). A similar pattern exists for primary biliary cirrhosis.^'-'^ It is possible that the immunologic attack against kerotinocytes can also damage hepatocytes. Liver pathology is found to be much more severe in mucosal erosive LP.^'-'" Perhaps the morbid process in that type of LP is directed at higher levels of aggressiveness against both epidermal cells of the skin and parenchymal cells of the liver.
ing raised the possibility that there may be two forms of LP, one associated with A28, and the other not associated with A28 and probably etiologically related to diabetes. Considering the immunopathogenetic aspects of diabetes, one may think that parallel mechanisms may play a role in diabetes associated with LP. Histopathologic examination of the islets of Langerhans of some diabetics reveal an inflammatory infiltrate, predominantly lymphocytic. Studies using monoclonal antibodies have revealed elevation in the number of circulating la positive T cells in patients with early type I diabetes;^'* however, the pattern of insulin response in LP patients with abnormal glucose tolerance was similar to that seen in type II diabetics.-'-'^-'''' Furthermore, none of the LP patients with glucose intolerance examined by Lowe et al. had demonstrable islet cell antibodies,^'' as compared with the 20.2% prevalence of islet cell antibodies in insulin-dependent diabetes, and 6 to 8% in noninsulindependent diabetes. Urolithiasis and Hyperuricemia A recent survey of 130 Israeli LP patients conducted by Halevy and Feuerman'"' revealed an increased incidence (14.6%) of urolithiasis as compared with that in the normal Israeli population. In most of those patients, the appearance of urolithiasis preceded LP by an average period of 13 years and could not be regarded as secondary to the skin disease. It has been proposed that basic metabolic disorders responsible for the development of urolithiasis may exist in LP and may play some part in the etiogenesis of LP." In another study of 42 LP patients, the prevalence of hyperuricemia has been found to be higher (12%)) than the recorded prevalence of hyperuricemia in the Israeli general population (5-7%), and in 40 matched controls (0%).'" Lichen planus is not considered to include overproduction of uric acid from accelerated epidermal cell proliferation, as in psoriasis, because the kinetic features of the epidermal cells differ in these two diseases.'"' Yet, tritiated thymidine studies in LP suggest that there is an increase in basal cell layer DNA synthesis, and that there is a continuous state of disintegration and repair of basal cells.''- Currently, there is not sufficient data to identify the cause of urolithiasis and hyperuricemia in LP patients or their possible role in LP.
Impaired Carbohydrate Metabolism in LP Impaired carbohydrate metabolism as manifested by abnormal glucose tolerance has been observed in LP patients.^''^''"-''' These findings have been documented in patients with oral LP''*-'-' and also in patients with only cutaneous lesions or combined cutaneous and oral lesions.^'-^''-'^ The largest series of oral LP patients is presented by Hornstein et al.''' In 177 patients with oral LP and in 177 sex- and age-matched healthy control subjects, abnormal glucose tolerance was observed in 30.1% of the patients and in 11.9% of the control group. In another study documented by Halevy and Feuerman,'^ consisting of 52 LP patients, abnormal glucose tolerance was found in 19 patients (36%) including five cases of overt diabetes. The possible role of this finding in the pathogenesis of LP is not well understood. Although an underlying metabolic defect was proposed as a pathogenetic factor, no correlation between glucose tolerance abnormalities and duration and distribution of lesions was observed.'-'' The incidence of HLA-A28 was found by Halevy et al. to be significantly increased in a group of nondiabetic LP patients.'-'-^* Among 52 LP patients, HLA-A28 was found in 8 (36.4%) of 22 nondiabetic LP patients, compared with 52 (8.2%) of 631 healthy, ethnically matched controls, and 1 (7.7%) of 13 diabetic LP patients. This find-
Autoimmune Disorders There have been a few case reports of patients with LP and LP-like reactions in association with other autoimmune disorders among which are bullous pemphigoid,''^ pemphigus vulgaris,'''' dermatomyositis,''-' ulcerative colitis,'"^-'*^ sicca syndrome,*'* and myasthenia gravis;*" however, evaluation of disease association should be supported by valid epidemiologic data and not be based solely on presentation of case reports. 381
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The association of LP with sicca syndrome''* and myasthenia gravis'" may be coincidental but is of special interest in view of the presence of these disorders in graft-versus-host reactions."*-'"" The association of LP and vitiligo is based on a statistical study of 100 patients with vitiligo, nine of whom also had LP.^' The coexistence of discoid lupus erythematosus and systemic lupus erythematosus with LP has already been reported.-"~'''' In most of the reported cases, the clinical, histoiogic, and immunofluorescence features showed an overlap pattern between lupus erythematosus and LP. Long-term follow-up did not allow an unequivocal diagnosis of either lupus erythematosus or LP in eleven patients examined by Romero et al.^'' In another study,''' diagnosis of one disease or the other could be accepted, based on: (1) the American Rheumatism Association criteria for the diagnosis of systemic lupus erythematosus, and (2) histologic and immunofluorescence studies that were strongly suggestive of LP. Razzaque Ahmed et al. presented clinical, laboratory, and immunopathologic evidence for the simultaneous occurrence of systemic lupus erythematosus and LP.^^ The authors proposed that a common agent (or agents) may cause either disease or overlap syndrome, depending on the immunogenetic predisposition of the patient.
Neurologic Disorders The association of LP with neurologic diseases, such as syringomyelia, bulbar paralysis, and peripheral neuritis, and its occasional localization along neural pathways, was thought to imply a neurologic etiology." Currently, there is no additional evidence for that hypothesis. In the last 20 years documentation of such an association is extremely rare. CONCLUSIONS
In this review we have focused mainly on the pathogenesis of LP and LP-associated diseases. Immune mechanisms are thought to play a central role in the pathogenesis of LP. An alteration in epidermal antigenicity, possibly induced by a virus or by drugs, might provoke this reaction. Various drugs may be associated with lichenoid eruptions; however, an infectious factor has never been demonstrated in LP. The therapeutic implication of the data presented here is an issue for future investigation. REEERENCES
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The coexistence of psoriasis and LP has rarely been reported.^^ The sparse documentation of this issue consists mainly of case reports. The paucity of reports in the literature is attributed to under-reporting. Epidemiologic data presented by Naldi et al.,'* which compare the prevalence of psoriasis among LP patients and controls, did not reach statistical significance. Shiohara et al. raise the possibility that the coexistence of the two diseases is indeed rare.'' A genetic predisposition to psoriasis may provide an unfavorable predisposition to the development of LP and vice versa. The observation that spontaneous improvement of psoriasis occurred during development of LP, and that the disappearance of LP was followed by an exacerbation of the psoriatic eruption, supports this hypothesis. Interferon gamma, a substance released by T-!ymphocytes, may explain the possible dissociation of these two diseases.'^ This compound participates in the damage process to basal cells in LP.''-^ On the other hand, interferon gamma has been reported to have some therapeutic activity in certain patients with psoriasis.'^" Further investigation may confirm the possible relation between LP and psoriasis and the role of certain cytokines and lymphokines concerning this relationship.
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Eosinophilia-Myalgia Syndrome In October 1989, the State Health Department of New Mexico was notified of three patients with an unexplained acute illness characterized by intense myalgia and eosinophilia. Each patient had been ingesting L-tryptophan-containing preparations for the treatment of insomnia. Within weeks, a nationwide outbreak of the disease, termed the eosinophilia-myalgia syndrome, was recognized. Case-control studies confirmed an unequivocal epidemiologic association between tbe eosinophilia-myalgia syndrome and the use of L-tryptophan-containing products. By August 1990, 1536 cases of the eosinophilia-myalgia syndrome had been reported to the Centers for Disease control (CDC), and it was suggested that the actual number may be considerably bigher. Eigbty-five percent of the affected patients developed symptoms between July 1989 and February 1990. One tbird of the patients required hospitalization, and twenty-seven deaths directly attributable to the eosinophilia-myalgia syndrome have been reported. ...The early phase was characterized by intense myalgia, various skin rashes, edema, dyspnea, and constitutional symptoms. Despite the discontinuation of Ltryptophan use, substantial proportion of patients developed a protracted course that was dominated by manifestations of cutaneous and neuromuscular involvement. Approximately one balf of tbe patients developed diffuse scleroderma-like cutaneous induration. Histopathologic examination of full-thickness skin biopsy specimens in these cases showed marked thickening of the fascia and dermis caused by accumulation of collagen and mucopolysaccharides, accompanied by an inflammatory infiltrate of variable severity. Diffuse peripberal neuropathy, which became progressively more prevalent during the first year of the illness, was the most common form of neurologic dysfunction. Histologic findings included epineurial and perineurial infiltration with mononuclear cells and occasional eosinophils, increased connective tissue deposition, loss of myelinated nerve fibers, and axonal degeneration. Myopathy manifested by muscle cramps and weakness occurred frequently. Muscle biopsies showed inflammation and fibrosis in the connective tissue surrounding the muscle, but only minimal muscle fiber damage. Occlusive microangiopathy with thickening of vessel walls by inflammatory cell infiltration and endothelial swelling has been observed in muscle and nerve biopsies. From Varga J, Uitto ], Jimenez SA. The cause and pathogenesis of the eosinophilia-myalgia syndrome. Ann Intern Med 1992; 116:140-147. 384
