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Lichen planus and lichenoid reactions as a systemic disease
Lichen planus and lichenoid reactions as a systemic diseases Judit Luk´acs MD, Sibylle Schliemann MD, Peter Elsner MD PII: DOI: Reference:
S0738-081X(15)00116-9 doi: 10.1016/j.clindermatol.2015.05.001 CID 6950
To appear in:
Clinics in Dermatology
Please cite this article as: Luk´acs Judit, Schliemann Sibylle, Elsner Peter, Lichen planus and lichenoid reactions as a systemic diseases, Clinics in Dermatology (2015), doi: 10.1016/j.clindermatol.2015.05.001
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Lichen planus and lichenoid reactions as a systemic diseases
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Judit Lukács, MD, Sibylle Schliemann, MD, Peter Elsner, MD
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Department of Dermatology, University Hospital Jena, Erfurter Straße 35, D-07743 Jena, Germany
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Correspondence:
Judit Lukács, MD, Department of Dermatology, University Hospital Jena, Erfurter Str. 35, D-
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07743 Jena, Germany, email: [email protected]
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Funding: None
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Conflicts of interest: The authors have declared no conflicts.
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J. LUKÁCS ET AL. Lichen planus and lichenoid reactions as a systemic disease
Abstract Lichen planus (LP) is a chronic disease that involves the skin, scalp, mucous membranes,
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and nails. The etiology of LP is still unknown; however, some external and internal factors
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(e.g. drugs, stress, hepatitis C virus) have been suggested to trigger the disease. Many studies have investigated an immunologic pathogenesis that is probably related to T-cell auto-immunity with the keratinocyte as the target cell. Altered self-antigens on the surface of
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basal keratinocytes modified by viruses or by drugs are believed to be the targets of the Tcell response. Various drugs and contact allergens like amalgam may cause lichenoid
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reactions, which are the main differential diagnosis of LP. Clinically and histologically, LP and lichenoid reactions cannot be distinguished with certainty in many cases. Treatment is mainly symptomatic and can be difficult.
The first-line therapies for LP are topical or
systemic corticosteroids; however, some studies have mentioned acitretin leading to similar improvement. Medical treatment together with patient education and psychosocial support
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can significantly ameliorate the patients’ quality of life.
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Key words: lichen planus, lichenoid reaction, systemic disease
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J. LUKÁCS ET AL. Lichen planus and lichenoid reactions as a systemic disease
Introduction Lichen planus (LP) is a chronic disease that involves the skin, mucous membranes, and nails. The exact prevalence of LP is unknown, but it is estimated to affect 0.9 to 1.2 % of the
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general population (1, 2). It commonly occurs in middle-aged women (3, 4), while men tend
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to develop LP in their thirties (5). LP of childhood is unusual, and it is more common in the
Definition and clinical features
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African-American population (6).
LP by definition is a chronic idiopathic inflammatory papulosquamous disease affecting skin,
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scalp, mucous membranes, and nails. Cutaneous LP and oral LP are the most common
purple
polygonal
pruritic
papules
plaques.
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planar
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presentations(7). LP lesions are described using the six P`s(8) :
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The disease is characterized by shiny, flat-topped, pruritic, and papulosquamous eruptions ,involving the extremities (the flexor surfaces of the wrists, forearms, and legs), genitalia or oral cavity, where it presents differently, as described below (9). The cutaneous lesions are typically bilateral and symmetric. The lesions are often covered by whitish reticular lines, which are visible, especially after application of oil and that are known as Wickham striae. The surrounding skin is normal; however, the morphology of LP may vary widely. Cutaneous LP has different clinical subtypes, based on the morphology of the lesions including classic, hypertrophic, vesiculobullous, actinic, annular, atrophic, linearly oriented, pigmented, and follicular presentation (10)(Figures 1,2). The isomorphic response of Koebner is a common occurrence in LP. The Koebner phenomenon describes the development of new lesions in previously normal skin that has been traumatized either externally or internally (11) (Figure 3). Mucosal LP more commonly affects the oral mucosa but may also involve the genital area. Oral LP has reticular, erosive, atrophic, papular, plaque-like, and bullous subtypes (10), with 3
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J. LUKÁCS ET AL. Lichen planus and lichenoid reactions as a systemic disease
the most common type being the reticular pattern (3) (Figure 4). The buccal mucosa is involved in 80-90% of oral LP lesions. In the oral mucosa, the Wickham striae are typically bilateral, symmetric, and asymptomatic (12). Mechanical trauma of dental procedures, as
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Malignant transformation of oral and genital LP is possible (14).
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well as cigarette smoking, can be Koebnerogenic factors that may exacerbate oral LP (13).
Nail lesions are possible and more commonly seen in children (15). Nail LP can affect only one nail but usually affects several or most nails (16).
Fingernails are more frequently
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involved than toenails (16). Clinically, the involved nails show longitudinal ridging and splitting (onychoschizia), longitudinal striation (onychorrhexis), nail absence (anonychia),
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subungual hyperkeratosis, and thinning nail plate (2)(Figure 5). Most nail changes result from involvement of the nail matrix (2). LP of the nail bed causes onycholysis, and subungual hyperkeratosis and may be very difficult to distinguish from nail psoriasis or onychomycosis (16).
Lichen planopilaris (LPP) is a chronic cicatricial alopecia characterized by follicular
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hyperkeratosis, perifollicular erythema, and loss of follicular orificies(17). LPP is most common in women age 30 to 60 years (18). LPP can be subdivided into three groups: classic LPP, frontal fibrosing alopecia, and Graham-Little syndrome (17). Classic LPP shows scalp
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hair involvement (17). Frontal fibrosing alopecia is characterized by cicatricial alopecia of the frontal and often the temporoparietal hairlines (17). Graham-Little syndrome is a rare variant
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of LPP characterized by multifocal cicatricial alopecia of scalp, non-cicatricial alopecia of
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axillae and pubic region and keratotic follicular papules over a body (19) (Figure 6).
Lichenoid drug reactions (LDR) are the main differential diagnosis of LP.
LDR are
inflammatory lesions with varied etiologies including immune-mediated disorders, reactions to systemic medications and to dental materials (20). The term “lichenoid” refers to papular lesions of skin diseases of which LP is the prototype (21). There are no standardized criteria for the diagnosis of lichenoid reactions.
The condition mimics LP but may have some
eczematous elements (21). Lichenoid lesions are a common finding in the oral cavity, mostly on the buccal mucosa, tongue, and lips (22). In most cases, the lesions are indistinguishable from idiopathic LP, clinically or histologically. LP and LDR have been reported to be associated with different kinds of disorders and triggers, such as stress, liver diseases and viral infections, drugs, and dental materials like amalgam.
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J. LUKÁCS ET AL. Lichen planus and lichenoid reactions as a systemic disease
Pathogenesis The etiopathogenesis of LP remains unclear, but virus antigens, medications, chemical substances, genetic factors, and psychosocial stressors may all participate in the
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development of LP(2). Drugs and contact allergens like amalgam may cause LDR as the
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main differential diagnosis of LP. Many studies have investigated the immunologic pathogenesis of LP. Cell-mediated cytotoxicity is regarded as a major pathogenetic mechanism (23), and epidermal basal cells are considered to be the target cells. LP is
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believed to be a T-cell mediated skin disease expressing altered self-antigens on the surface of basal keratinocytes modified by viruses or by drugs. CD8+ cytotoxic T-cells may trigger
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keratinocyte apoptosis through activation of the cells by an antigen associated with MHC I on basal keratinocytes (3). CD8+ cytotoxic T cells may secrete TNF-alpha, which drives keratinocytes into apoptosis (3, 24).
Natural killer (NK) cells migrate into LP lesions more frequently than into healthy skin (25). They have cytotoxic activity and ability to secrete proinflammatory cytokines (25). NK cells
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and cytotoxic T-cells may also induce apoptosis via the granzyme/perforin pathway (10). The cytoplasm of cytotoxic cells is enriched with granules composed of the potent cytolytic
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molecule perforin together with granzymes (21, 26). Upon contact with the target cell and activation, CTL and NK cells release perforin and granzymes in a contact zone between target and killer cells (21). Perforin induces pores in the target cell membrane and thus
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enables the entry of granzymes, responsible for DNA degradation and apoptosis (21).
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LP and liver disease Several chronic liver diseases have been considered to be associated non-coincidentally with LP (27). The increased risk of chronic liver disorders in LP appears to be independent of age, sex, and alcohol consumption, or a positive hepatitis B surface antigen (HBsAg) reaction (28).
Chronic active hepatitis, primary biliary cirrhosis, and primary sclerosing
cholangitis have the features of an autoimmune process, and this pathogenesis seems to be likely in LP as well (27). Primary biliary cirrhosis used to be treated with D-penicillamine which may provoke a lichenoid reaction (29). Many studies confirm that hepatitis C virus (HCV) is the main correlate of liver disease in LP (30, 31). The coexistence of LP with HCV infection was first reported in 1991 (32). There are no differences in the viral load between HCV positive patients with LP and those without (33). HCV-related oral LP is associated with the HLA-DR6 allele, and most idiopathic LP is associated with HLA-DR1 allele (34, 35). The relationship between HCV and LP has been suggested by studies from different countries. The reported prevalence of HCV infection with 5
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J. LUKÁCS ET AL. Lichen planus and lichenoid reactions as a systemic disease
LP shows variations between different regions. A meta-analysis including 70 studies reported a statistically significant risk for development of LP (36). The OR for this association was 2.5. In another meta-analysis, the summary estimate of OR showed that LP patients have about
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a five-fold higher risk than the controls of being HCV-seropositive (37). In both metaanalyses, the data showed geographical variability. The association between LP and HCV is
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prevalent in the Mediterranean countries, the USA, and Taiwan, suggesting a possible geographic heterogeneity (36, 37). However in studies from countries with the highest HCV
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prevalence, e.g. Nigeria, negative or not significant association was found (38).
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Drugs
LDR are rare, but they have been reported in association with various systemic medications. The most commonly implicated drugs are summarized in Table 1. The list of drugs becomes steadily longer. The time between initial medication intake to lesion appearance is variable, which makes it clinically difficult to establish a connection. This latency period is mostly about
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1 or 2 weeks, but make take up to 1 month (39).
Gold is probably the most common drug that has caused LDR(29). Both cutaneous and oral lichenoid reactions due to gold salts have been described (40, 41). A high incidence of
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lichenoid drug in patients with primary biliary cirrhosis has been reported after treatment with d-penicillamine (29). Resolution of the lesions often occurs within weeks to months after
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discontinuation of the offending drug (39).
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Impact of stressful life events and psychological disorders Stressful events may induce psychosomatic diseases. Mental disturbance has been debated as one of the causative factors of LP. On the other hand, oral LP and its lesions could be responsible for psychologic problems (42). Depression, anxiety, and stress have been investigated for the etiology. Some patients with LP report development and exacerbation of lesions during periods of greater emotional tension (12, 43). Stressful life events could induce LP by modifying and promoting dysregulation of immune functions with alteration of the proportion of Th1/Th2 cytokines (e.g. IL-18, IL-4, IL-6, TNF-α, IL-10) and increased Th2 response (12); therefore, stressful events should be definitely considered as precipitating factors.
Herpes-zoster virus LP may display a zosteriform distribution pattern. A few cases of LP triggered by herpes zoster infections have been reported (44). Patients with true zosteriform LP-like lesions are 6
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J. LUKÁCS ET AL. Lichen planus and lichenoid reactions as a systemic disease
extremely rare and the pattern may at best be explained by a Koebner phenomenon induced by a preceding herpes zoster infection with secondary trauma or mechanical manipulation of the lesions(45). Negative PCR results in the LP lesions supported the view that there is no
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Amalgam and dental restorative materials
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direct association between varicella-zoster virus infection and the development of LP(46, 47).
Oral lichenoid contact lesions can be induced by delayed immune mediated hypersensitivity
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to dental restorative materials, such as amalgam (48).
The most common site of
involvement is the buccal mucosa (49). In mucosal contact allergy to restorative materials
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lichenoid lesions may develop only at the site of contact, whereas lesions on other body sites are missing (Figure 7) (50). In the case of a causative relationship, replacement of dental restorations will usually lead to clearing of symptoms within several months (51). Some authors also suggest removal of oral amalgam in case of negative patch test results, provided a symptomatic oral lichenoid reaction is anatomically associated with amalgam fillings and abscence of cutaneous LP (52).True cutaneous LP with or without oral lesions in
term use in the mouth.
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association with dental amalgam filling is very rare (53). Dental fillings are intended for longMercury-containing amalgam may induce an immune-mediated
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damage of the basal epithelial keratinocytes only when the amalgam filling is new or damaged resulting in leakage of the heavy metal. Oral lichenoid lesions may also be due to other dental materials, e.g. containing chrome and cobalt (54). Dental materials in direct
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contact with the oral mucosa may directly alter the antigenicity of basal keratinocytes (3).
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Diagnosis and management Before LP and lichenoid reactions can be adequately treated, the correct diagnosis must be made (55). Typical clinical features of LP may be sufficient for diagnosis, but a biopsy is often helpful to confirm it. Skin diseases which mimic LP include lichen sclerosus, prurigo nodularis, pityriasis rosea, psoriasis, eczema, graft-versus-host disease, and lupus erythematosus(55). Autoimmune blistering diseases (e.g. cicatricial pemphigoid, pemphigus vulgaris) may resemble erosive LP (55).The differential diagnosis between LP and other dermatoses may be made clinically and histologically (55). The presence of whitish hyperkeratotic striations (Wickham striae) and skin involvement are important differentiating features. Direct immunofluorescence testing may rule out other immune-mediated vesicobullous diseases (e.g. pemphigus vulgaris, mucous membrane pemphigoid, linear IgA bullous dermatosis) (3). LP and LDR frequently cannot be distinguished on the basis of a dermatopathological examination. The microscopic features of LDR have many similarities to LP, although there 7
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J. LUKÁCS ET AL. Lichen planus and lichenoid reactions as a systemic disease
are some differences (Table 2). Hyperorthokeratosis, acanthosis, hypergranulosis and vacuolar degeneration of the basal cell layer are typical findings (Figure 8) (29). Degenerated basal layer cells and an increased number of Langerhans cells are the earliest signs of
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epidermal changes in both skin diseases (29). Epidermal changes are less common in lichenoid drug eruptions, the stratum granulosum is not always hyperthrophic, and
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hypergranulosis may even be missing completely (10). A higher concentration of necrotic keratinocyte and eosinophils in the infiltrate can be helpful to identify lichenoid drug lesions
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(10).
Patch testing is the only relevant examination method for diagnosing a contact
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hypersensitivity reaction. In case of suspected delayed type hypersensitivity epicutaneous patch testing is recommended (56). When assessing for oral contact allergy to metals, late readings up to 10 days should be considered as some reactions may not occur as early as expected (57). Eventual positive reactions must be thoroughly evaluated for their clinical relevance (58). In the case of lichenoid contact lesions to dental materials, patch testing may assist in determining what alternative materials to use (48). The patch testing is normally
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performed on the back of test subjects. In the case of oral lichenoid reactions, the validity of extrapolating reactions on dorsal skin to mucosal responses is debated (48). Skin patch
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tests should follow clinical and histopathologic examination (22). Many treatment options are availableLP and lichenoid reactions. Resolution of the LDR often
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occurs within weeks to months after discontinuation of the offending drug (39). The treatment of LDR therefore consists of drug withdrawal and/or substitution of the offending drug with
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other medications. Numerous cases of cutaneous LP resolve spontaneously within one to two years (8).The treatment of mucous membrane involvement is more difficult. The lesions can be resistant to treatment, the recurrences are common, and complete resolution is difficult to achieve (8). The first-line therapy for LP is the use of topical corticosteroids (55), although some studies have mentioned acitretin as a first-line therapy (8, 59-61).
A mid-potency corticosteroid
preparation (e.g. betamethasone valerate or triamcinolone) should be used for topical therapy in LP (55). Erosive LP may require a potent or ultra-potent corticosteroid cream (55).For severe widespread lesions and exudation, systemic therapy should be considered after failure of topical treatment (55). The initial medication to improve erosive LP are systemic corticosteroids (40-60mg each morning for 2-4 weeks) (55).Topical and oral retinoids have shown a benefit for cutaneous and erosive oral LP as well (55, 62, 63), and they are recommended for more severe cases of LP that do not respond to topical treatment (8, 60). Because of the teratogenic risk and other side effects (e.g. xerosis, cheilitis), this 8
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J. LUKÁCS ET AL. Lichen planus and lichenoid reactions as a systemic disease
medication should be well discussed with patient.Topical calcineurin inhibitors (e.g. tacrolimus, pimecrolimus) are second-line off-label therapies (8). A comparative study showed that topical tacrolimus is as effective as the high-potency corticosteroid clobetasol in
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the treatment of oral LP (8, 61, 64). Several studies have mentioned the use of phototherapy (narrowband UVB, PUVA) the treatment (59, 65, 66).However, it is important to know that
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some cases of exacerbation of LP with phototherapy have been published (67, 68). Topical lidocaine can be used for pain relief in mucosal LP, and oral histamines can be used to
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control pruritus (8). Carbon-dioxide laser evaporation has been reported to lead to remission in patients with oral LP (69).
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A number of different treatments of lichen planopilaris have been tried with varying success. There are no definitive treatment options for LPP. If symptoms persist after corticosteroids and hydroxychloroquine treatment, other immuno-modulating agents should be considered. Mycophenolate mofetil (MMF) has been successfully used for the treatment of LPP (18, 70). MMF has a safer and more tolerable adverse-effect profile than cyclosporine or azathioprine
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(18, 70).
The prognosis of LP is variable and not predictable.
The lesions may be resistant to
treatment, recurrences are common, and complete resolution is difficult to achieve. The
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management of LP can sometimes be challenging especially by lichen planopilaris. Treatments are less effective for LPP than for LP. Patients especially women are distressed
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by the permanent hair destruction.
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Conclusions
Lichen planus is a relatively common chronic inflammatory disease with defined clinical and histopathological characteristics. The etiology of LP is still unknown; however, some external and internal factors (e.g. drugs, stress, hepatitis C virus) have been suggested to trigger the disease. Cutaneous lichen planus may resolve spontaneously, although lichen planus affecting mucosal surfaces may be more resistant to treatment. Medical treatment only together with patient education and psychosocial support can provide a significant improvement in quality of patient’s life.
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Table 1: Inducers of lichenoid reactions (see separate file)
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Table 2: Differential diagnosis between lichen planus and lichenoid reactions (see separate file)
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Figure 1:Typical cutaneous lesions of lichen planus (see separate file)
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Figure 2:Bullous lichen planus (see separate file)
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Figure 3:Polygonal lichenoid papules in lichen planus with Koebner´s phenomenon after scratching (see separate file)
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Figure 4:Erosive lichen planus mucosae (see separate file)
Figure 5:Nail plate defects in lichen planus (see separate file)
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Figure 6:Scarring alopecia in lichen follicularis capillitii (Graham Little Syndrome) (see separate file)
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Figure 7:Lichenoid plaque of the buccal mucosa in a patient with amalgam fillings. In this patient, positive patch test reactions (+) to both mercury (II)-amide-chloride and amalgam were observed at the d3 readings, and the dermatopathologic investigation of a biopsy was consistent with lichen planus. (see separate file)
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Figure 8:Typical dermatopathologic features of lichen planus (conventional Hematoxylin &Eosin staining). 1: Wedge-shaped hypergranulosis in acanthotic epidermis. 2: Single necrotic keratinocytes in basal layers of the epidermis as a result of lymphocytic interface dermatitis. 3: Brownish cells in the upper dermis, so-called melanophages, which represent melanin-loaded histiocytes (see separate file)
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Anticonvulsants
Carbamazepine (72) Valproate sodium (73)
Antidiabetics
Chlorpropamide (74) Tolazamide (74)
Antifungal drugs
Ketoconazole (75)
Antihypertensive agents
Captopril (76) Diazoxide (77) Enalapril (78) Methyldopa (79)
Antimalarials
Chloroquine (80) Quinidine (81) Quinine (82)
Antitubercural drugs
Ethambutol (83) Isoniazid (84) Streptomycin (85)
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Antiretrovirals
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Zidovudine (86)
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Chemotherapeutic agents
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Diuretics
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Tetracycline (71)
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Antibiotics
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Table 1: Drugs reported to induce lichenoid reactions
Dactinomycin (87) Hydroxyurea (88) Imatinib (89) Furosemide (90) Spironolactone (91)
Immunomodulatory drugs Gold salts (92) Penicillamine (93) Heavy metals
Mercurials (94)
NSAIDs
Aspirin (95) Indomethacin (96) Naproxen (97)
Psychiatric drugs
Benzodiazepines (98) SSRI (99) Lithium (100)
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Table 2: Differential diagnosis between LP and lichenoid reactions
Lichenoid reactions
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LP Etiology
Unknown
Clinical presentation
shiny, flat-topped, pruritic and papulosquamous eruptions bilateral and symmetric; reticular>erosive
white or atrophic striations
Localization
Skin: flexor surfaces; Oral: buccal mucosa, tongue, gingival Genital: vulvovaginal, penile
Oral: buccal mucosa, lateral and ventral tongue, contact with dental materials
Diagnosis
clinics, histology, DIF
clinics, histology, patch test
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related to contact, inhalation, or ingestion of various drugs, chemicals, dental materials
less dense and less bandlike dermal infiltrate; focal parakeratosis; eosinophils, plasma cells and melanin incontinence
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Histopathological features band-like inflammatory infiltrate; civatte bodies; wedge-shaped hypergranulosis; hyperorthokeratosis; pigment incontinence
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S0738-081X(15)00116-9 doi: 10.1016/j.clindermatol.2015.05.001 CID 6950
To appear in:
Clinics in Dermatology
Please cite this article as: Luk´acs Judit, Schliemann Sibylle, Elsner Peter, Lichen planus and lichenoid reactions as a systemic diseases, Clinics in Dermatology (2015), doi: 10.1016/j.clindermatol.2015.05.001
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Lichen planus and lichenoid reactions as a systemic diseases
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Judit Lukács, MD, Sibylle Schliemann, MD, Peter Elsner, MD
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Department of Dermatology, University Hospital Jena, Erfurter Straße 35, D-07743 Jena, Germany
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Correspondence:
Judit Lukács, MD, Department of Dermatology, University Hospital Jena, Erfurter Str. 35, D-
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07743 Jena, Germany, email: [email protected]
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Funding: None
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Conflicts of interest: The authors have declared no conflicts.
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J. LUKÁCS ET AL. Lichen planus and lichenoid reactions as a systemic disease
Abstract Lichen planus (LP) is a chronic disease that involves the skin, scalp, mucous membranes,
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and nails. The etiology of LP is still unknown; however, some external and internal factors
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(e.g. drugs, stress, hepatitis C virus) have been suggested to trigger the disease. Many studies have investigated an immunologic pathogenesis that is probably related to T-cell auto-immunity with the keratinocyte as the target cell. Altered self-antigens on the surface of
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basal keratinocytes modified by viruses or by drugs are believed to be the targets of the Tcell response. Various drugs and contact allergens like amalgam may cause lichenoid
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reactions, which are the main differential diagnosis of LP. Clinically and histologically, LP and lichenoid reactions cannot be distinguished with certainty in many cases. Treatment is mainly symptomatic and can be difficult.
The first-line therapies for LP are topical or
systemic corticosteroids; however, some studies have mentioned acitretin leading to similar improvement. Medical treatment together with patient education and psychosocial support
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can significantly ameliorate the patients’ quality of life.
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Key words: lichen planus, lichenoid reaction, systemic disease
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J. LUKÁCS ET AL. Lichen planus and lichenoid reactions as a systemic disease
Introduction Lichen planus (LP) is a chronic disease that involves the skin, mucous membranes, and nails. The exact prevalence of LP is unknown, but it is estimated to affect 0.9 to 1.2 % of the
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general population (1, 2). It commonly occurs in middle-aged women (3, 4), while men tend
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to develop LP in their thirties (5). LP of childhood is unusual, and it is more common in the
Definition and clinical features
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African-American population (6).
LP by definition is a chronic idiopathic inflammatory papulosquamous disease affecting skin,
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scalp, mucous membranes, and nails. Cutaneous LP and oral LP are the most common
purple
polygonal
pruritic
papules
plaques.
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planar
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presentations(7). LP lesions are described using the six P`s(8) :
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The disease is characterized by shiny, flat-topped, pruritic, and papulosquamous eruptions ,involving the extremities (the flexor surfaces of the wrists, forearms, and legs), genitalia or oral cavity, where it presents differently, as described below (9). The cutaneous lesions are typically bilateral and symmetric. The lesions are often covered by whitish reticular lines, which are visible, especially after application of oil and that are known as Wickham striae. The surrounding skin is normal; however, the morphology of LP may vary widely. Cutaneous LP has different clinical subtypes, based on the morphology of the lesions including classic, hypertrophic, vesiculobullous, actinic, annular, atrophic, linearly oriented, pigmented, and follicular presentation (10)(Figures 1,2). The isomorphic response of Koebner is a common occurrence in LP. The Koebner phenomenon describes the development of new lesions in previously normal skin that has been traumatized either externally or internally (11) (Figure 3). Mucosal LP more commonly affects the oral mucosa but may also involve the genital area. Oral LP has reticular, erosive, atrophic, papular, plaque-like, and bullous subtypes (10), with 3
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the most common type being the reticular pattern (3) (Figure 4). The buccal mucosa is involved in 80-90% of oral LP lesions. In the oral mucosa, the Wickham striae are typically bilateral, symmetric, and asymptomatic (12). Mechanical trauma of dental procedures, as
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Malignant transformation of oral and genital LP is possible (14).
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well as cigarette smoking, can be Koebnerogenic factors that may exacerbate oral LP (13).
Nail lesions are possible and more commonly seen in children (15). Nail LP can affect only one nail but usually affects several or most nails (16).
Fingernails are more frequently
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involved than toenails (16). Clinically, the involved nails show longitudinal ridging and splitting (onychoschizia), longitudinal striation (onychorrhexis), nail absence (anonychia),
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subungual hyperkeratosis, and thinning nail plate (2)(Figure 5). Most nail changes result from involvement of the nail matrix (2). LP of the nail bed causes onycholysis, and subungual hyperkeratosis and may be very difficult to distinguish from nail psoriasis or onychomycosis (16).
Lichen planopilaris (LPP) is a chronic cicatricial alopecia characterized by follicular
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hyperkeratosis, perifollicular erythema, and loss of follicular orificies(17). LPP is most common in women age 30 to 60 years (18). LPP can be subdivided into three groups: classic LPP, frontal fibrosing alopecia, and Graham-Little syndrome (17). Classic LPP shows scalp
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hair involvement (17). Frontal fibrosing alopecia is characterized by cicatricial alopecia of the frontal and often the temporoparietal hairlines (17). Graham-Little syndrome is a rare variant
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of LPP characterized by multifocal cicatricial alopecia of scalp, non-cicatricial alopecia of
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axillae and pubic region and keratotic follicular papules over a body (19) (Figure 6).
Lichenoid drug reactions (LDR) are the main differential diagnosis of LP.
LDR are
inflammatory lesions with varied etiologies including immune-mediated disorders, reactions to systemic medications and to dental materials (20). The term “lichenoid” refers to papular lesions of skin diseases of which LP is the prototype (21). There are no standardized criteria for the diagnosis of lichenoid reactions.
The condition mimics LP but may have some
eczematous elements (21). Lichenoid lesions are a common finding in the oral cavity, mostly on the buccal mucosa, tongue, and lips (22). In most cases, the lesions are indistinguishable from idiopathic LP, clinically or histologically. LP and LDR have been reported to be associated with different kinds of disorders and triggers, such as stress, liver diseases and viral infections, drugs, and dental materials like amalgam.
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Pathogenesis The etiopathogenesis of LP remains unclear, but virus antigens, medications, chemical substances, genetic factors, and psychosocial stressors may all participate in the
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development of LP(2). Drugs and contact allergens like amalgam may cause LDR as the
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main differential diagnosis of LP. Many studies have investigated the immunologic pathogenesis of LP. Cell-mediated cytotoxicity is regarded as a major pathogenetic mechanism (23), and epidermal basal cells are considered to be the target cells. LP is
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believed to be a T-cell mediated skin disease expressing altered self-antigens on the surface of basal keratinocytes modified by viruses or by drugs. CD8+ cytotoxic T-cells may trigger
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keratinocyte apoptosis through activation of the cells by an antigen associated with MHC I on basal keratinocytes (3). CD8+ cytotoxic T cells may secrete TNF-alpha, which drives keratinocytes into apoptosis (3, 24).
Natural killer (NK) cells migrate into LP lesions more frequently than into healthy skin (25). They have cytotoxic activity and ability to secrete proinflammatory cytokines (25). NK cells
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and cytotoxic T-cells may also induce apoptosis via the granzyme/perforin pathway (10). The cytoplasm of cytotoxic cells is enriched with granules composed of the potent cytolytic
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molecule perforin together with granzymes (21, 26). Upon contact with the target cell and activation, CTL and NK cells release perforin and granzymes in a contact zone between target and killer cells (21). Perforin induces pores in the target cell membrane and thus
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enables the entry of granzymes, responsible for DNA degradation and apoptosis (21).
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LP and liver disease Several chronic liver diseases have been considered to be associated non-coincidentally with LP (27). The increased risk of chronic liver disorders in LP appears to be independent of age, sex, and alcohol consumption, or a positive hepatitis B surface antigen (HBsAg) reaction (28).
Chronic active hepatitis, primary biliary cirrhosis, and primary sclerosing
cholangitis have the features of an autoimmune process, and this pathogenesis seems to be likely in LP as well (27). Primary biliary cirrhosis used to be treated with D-penicillamine which may provoke a lichenoid reaction (29). Many studies confirm that hepatitis C virus (HCV) is the main correlate of liver disease in LP (30, 31). The coexistence of LP with HCV infection was first reported in 1991 (32). There are no differences in the viral load between HCV positive patients with LP and those without (33). HCV-related oral LP is associated with the HLA-DR6 allele, and most idiopathic LP is associated with HLA-DR1 allele (34, 35). The relationship between HCV and LP has been suggested by studies from different countries. The reported prevalence of HCV infection with 5
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LP shows variations between different regions. A meta-analysis including 70 studies reported a statistically significant risk for development of LP (36). The OR for this association was 2.5. In another meta-analysis, the summary estimate of OR showed that LP patients have about
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a five-fold higher risk than the controls of being HCV-seropositive (37). In both metaanalyses, the data showed geographical variability. The association between LP and HCV is
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prevalent in the Mediterranean countries, the USA, and Taiwan, suggesting a possible geographic heterogeneity (36, 37). However in studies from countries with the highest HCV
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prevalence, e.g. Nigeria, negative or not significant association was found (38).
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Drugs
LDR are rare, but they have been reported in association with various systemic medications. The most commonly implicated drugs are summarized in Table 1. The list of drugs becomes steadily longer. The time between initial medication intake to lesion appearance is variable, which makes it clinically difficult to establish a connection. This latency period is mostly about
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1 or 2 weeks, but make take up to 1 month (39).
Gold is probably the most common drug that has caused LDR(29). Both cutaneous and oral lichenoid reactions due to gold salts have been described (40, 41). A high incidence of
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lichenoid drug in patients with primary biliary cirrhosis has been reported after treatment with d-penicillamine (29). Resolution of the lesions often occurs within weeks to months after
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discontinuation of the offending drug (39).
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Impact of stressful life events and psychological disorders Stressful events may induce psychosomatic diseases. Mental disturbance has been debated as one of the causative factors of LP. On the other hand, oral LP and its lesions could be responsible for psychologic problems (42). Depression, anxiety, and stress have been investigated for the etiology. Some patients with LP report development and exacerbation of lesions during periods of greater emotional tension (12, 43). Stressful life events could induce LP by modifying and promoting dysregulation of immune functions with alteration of the proportion of Th1/Th2 cytokines (e.g. IL-18, IL-4, IL-6, TNF-α, IL-10) and increased Th2 response (12); therefore, stressful events should be definitely considered as precipitating factors.
Herpes-zoster virus LP may display a zosteriform distribution pattern. A few cases of LP triggered by herpes zoster infections have been reported (44). Patients with true zosteriform LP-like lesions are 6
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extremely rare and the pattern may at best be explained by a Koebner phenomenon induced by a preceding herpes zoster infection with secondary trauma or mechanical manipulation of the lesions(45). Negative PCR results in the LP lesions supported the view that there is no
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Amalgam and dental restorative materials
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direct association between varicella-zoster virus infection and the development of LP(46, 47).
Oral lichenoid contact lesions can be induced by delayed immune mediated hypersensitivity
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to dental restorative materials, such as amalgam (48).
The most common site of
involvement is the buccal mucosa (49). In mucosal contact allergy to restorative materials
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lichenoid lesions may develop only at the site of contact, whereas lesions on other body sites are missing (Figure 7) (50). In the case of a causative relationship, replacement of dental restorations will usually lead to clearing of symptoms within several months (51). Some authors also suggest removal of oral amalgam in case of negative patch test results, provided a symptomatic oral lichenoid reaction is anatomically associated with amalgam fillings and abscence of cutaneous LP (52).True cutaneous LP with or without oral lesions in
term use in the mouth.
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association with dental amalgam filling is very rare (53). Dental fillings are intended for longMercury-containing amalgam may induce an immune-mediated
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damage of the basal epithelial keratinocytes only when the amalgam filling is new or damaged resulting in leakage of the heavy metal. Oral lichenoid lesions may also be due to other dental materials, e.g. containing chrome and cobalt (54). Dental materials in direct
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contact with the oral mucosa may directly alter the antigenicity of basal keratinocytes (3).
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Diagnosis and management Before LP and lichenoid reactions can be adequately treated, the correct diagnosis must be made (55). Typical clinical features of LP may be sufficient for diagnosis, but a biopsy is often helpful to confirm it. Skin diseases which mimic LP include lichen sclerosus, prurigo nodularis, pityriasis rosea, psoriasis, eczema, graft-versus-host disease, and lupus erythematosus(55). Autoimmune blistering diseases (e.g. cicatricial pemphigoid, pemphigus vulgaris) may resemble erosive LP (55).The differential diagnosis between LP and other dermatoses may be made clinically and histologically (55). The presence of whitish hyperkeratotic striations (Wickham striae) and skin involvement are important differentiating features. Direct immunofluorescence testing may rule out other immune-mediated vesicobullous diseases (e.g. pemphigus vulgaris, mucous membrane pemphigoid, linear IgA bullous dermatosis) (3). LP and LDR frequently cannot be distinguished on the basis of a dermatopathological examination. The microscopic features of LDR have many similarities to LP, although there 7
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J. LUKÁCS ET AL. Lichen planus and lichenoid reactions as a systemic disease
are some differences (Table 2). Hyperorthokeratosis, acanthosis, hypergranulosis and vacuolar degeneration of the basal cell layer are typical findings (Figure 8) (29). Degenerated basal layer cells and an increased number of Langerhans cells are the earliest signs of
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epidermal changes in both skin diseases (29). Epidermal changes are less common in lichenoid drug eruptions, the stratum granulosum is not always hyperthrophic, and
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hypergranulosis may even be missing completely (10). A higher concentration of necrotic keratinocyte and eosinophils in the infiltrate can be helpful to identify lichenoid drug lesions
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(10).
Patch testing is the only relevant examination method for diagnosing a contact
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hypersensitivity reaction. In case of suspected delayed type hypersensitivity epicutaneous patch testing is recommended (56). When assessing for oral contact allergy to metals, late readings up to 10 days should be considered as some reactions may not occur as early as expected (57). Eventual positive reactions must be thoroughly evaluated for their clinical relevance (58). In the case of lichenoid contact lesions to dental materials, patch testing may assist in determining what alternative materials to use (48). The patch testing is normally
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performed on the back of test subjects. In the case of oral lichenoid reactions, the validity of extrapolating reactions on dorsal skin to mucosal responses is debated (48). Skin patch
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tests should follow clinical and histopathologic examination (22). Many treatment options are availableLP and lichenoid reactions. Resolution of the LDR often
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occurs within weeks to months after discontinuation of the offending drug (39). The treatment of LDR therefore consists of drug withdrawal and/or substitution of the offending drug with
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other medications. Numerous cases of cutaneous LP resolve spontaneously within one to two years (8).The treatment of mucous membrane involvement is more difficult. The lesions can be resistant to treatment, the recurrences are common, and complete resolution is difficult to achieve (8). The first-line therapy for LP is the use of topical corticosteroids (55), although some studies have mentioned acitretin as a first-line therapy (8, 59-61).
A mid-potency corticosteroid
preparation (e.g. betamethasone valerate or triamcinolone) should be used for topical therapy in LP (55). Erosive LP may require a potent or ultra-potent corticosteroid cream (55).For severe widespread lesions and exudation, systemic therapy should be considered after failure of topical treatment (55). The initial medication to improve erosive LP are systemic corticosteroids (40-60mg each morning for 2-4 weeks) (55).Topical and oral retinoids have shown a benefit for cutaneous and erosive oral LP as well (55, 62, 63), and they are recommended for more severe cases of LP that do not respond to topical treatment (8, 60). Because of the teratogenic risk and other side effects (e.g. xerosis, cheilitis), this 8
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J. LUKÁCS ET AL. Lichen planus and lichenoid reactions as a systemic disease
medication should be well discussed with patient.Topical calcineurin inhibitors (e.g. tacrolimus, pimecrolimus) are second-line off-label therapies (8). A comparative study showed that topical tacrolimus is as effective as the high-potency corticosteroid clobetasol in
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the treatment of oral LP (8, 61, 64). Several studies have mentioned the use of phototherapy (narrowband UVB, PUVA) the treatment (59, 65, 66).However, it is important to know that
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some cases of exacerbation of LP with phototherapy have been published (67, 68). Topical lidocaine can be used for pain relief in mucosal LP, and oral histamines can be used to
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control pruritus (8). Carbon-dioxide laser evaporation has been reported to lead to remission in patients with oral LP (69).
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A number of different treatments of lichen planopilaris have been tried with varying success. There are no definitive treatment options for LPP. If symptoms persist after corticosteroids and hydroxychloroquine treatment, other immuno-modulating agents should be considered. Mycophenolate mofetil (MMF) has been successfully used for the treatment of LPP (18, 70). MMF has a safer and more tolerable adverse-effect profile than cyclosporine or azathioprine
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(18, 70).
The prognosis of LP is variable and not predictable.
The lesions may be resistant to
treatment, recurrences are common, and complete resolution is difficult to achieve. The
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management of LP can sometimes be challenging especially by lichen planopilaris. Treatments are less effective for LPP than for LP. Patients especially women are distressed
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by the permanent hair destruction.
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Conclusions
Lichen planus is a relatively common chronic inflammatory disease with defined clinical and histopathological characteristics. The etiology of LP is still unknown; however, some external and internal factors (e.g. drugs, stress, hepatitis C virus) have been suggested to trigger the disease. Cutaneous lichen planus may resolve spontaneously, although lichen planus affecting mucosal surfaces may be more resistant to treatment. Medical treatment only together with patient education and psychosocial support can provide a significant improvement in quality of patient’s life.
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Table 1: Inducers of lichenoid reactions (see separate file)
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Table 2: Differential diagnosis between lichen planus and lichenoid reactions (see separate file)
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Figure 1:Typical cutaneous lesions of lichen planus (see separate file)
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Figure 2:Bullous lichen planus (see separate file)
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Figure 3:Polygonal lichenoid papules in lichen planus with Koebner´s phenomenon after scratching (see separate file)
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Figure 4:Erosive lichen planus mucosae (see separate file)
Figure 5:Nail plate defects in lichen planus (see separate file)
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Figure 6:Scarring alopecia in lichen follicularis capillitii (Graham Little Syndrome) (see separate file)
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Figure 7:Lichenoid plaque of the buccal mucosa in a patient with amalgam fillings. In this patient, positive patch test reactions (+) to both mercury (II)-amide-chloride and amalgam were observed at the d3 readings, and the dermatopathologic investigation of a biopsy was consistent with lichen planus. (see separate file)
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Figure 8:Typical dermatopathologic features of lichen planus (conventional Hematoxylin &Eosin staining). 1: Wedge-shaped hypergranulosis in acanthotic epidermis. 2: Single necrotic keratinocytes in basal layers of the epidermis as a result of lymphocytic interface dermatitis. 3: Brownish cells in the upper dermis, so-called melanophages, which represent melanin-loaded histiocytes (see separate file)
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Anticonvulsants
Carbamazepine (72) Valproate sodium (73)
Antidiabetics
Chlorpropamide (74) Tolazamide (74)
Antifungal drugs
Ketoconazole (75)
Antihypertensive agents
Captopril (76) Diazoxide (77) Enalapril (78) Methyldopa (79)
Antimalarials
Chloroquine (80) Quinidine (81) Quinine (82)
Antitubercural drugs
Ethambutol (83) Isoniazid (84) Streptomycin (85)
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Zidovudine (86)
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Chemotherapeutic agents
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Diuretics
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Tetracycline (71)
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Antibiotics
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Table 1: Drugs reported to induce lichenoid reactions
Dactinomycin (87) Hydroxyurea (88) Imatinib (89) Furosemide (90) Spironolactone (91)
Immunomodulatory drugs Gold salts (92) Penicillamine (93) Heavy metals
Mercurials (94)
NSAIDs
Aspirin (95) Indomethacin (96) Naproxen (97)
Psychiatric drugs
Benzodiazepines (98) SSRI (99) Lithium (100)
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Table 2: Differential diagnosis between LP and lichenoid reactions
Lichenoid reactions
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LP Etiology
Unknown
Clinical presentation
shiny, flat-topped, pruritic and papulosquamous eruptions bilateral and symmetric; reticular>erosive
white or atrophic striations
Localization
Skin: flexor surfaces; Oral: buccal mucosa, tongue, gingival Genital: vulvovaginal, penile
Oral: buccal mucosa, lateral and ventral tongue, contact with dental materials
Diagnosis
clinics, histology, DIF
clinics, histology, patch test
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related to contact, inhalation, or ingestion of various drugs, chemicals, dental materials
less dense and less bandlike dermal infiltrate; focal parakeratosis; eosinophils, plasma cells and melanin incontinence
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Histopathological features band-like inflammatory infiltrate; civatte bodies; wedge-shaped hypergranulosis; hyperorthokeratosis; pigment incontinence
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