Lichen planus, a relatively common eruption of unknown etiology, displays violaceous, flat-topped papules, which are usually pruritic.35. ^{and 36.} A network of fine white lines (Wickham’s striae) may be seen on the surface of the papules. There is a predilection for the flexor surface of the wrists, the trunk, the thighs, and the genitalia. Palmoplantar lichen planus appears to be more common than once thought.^{37. and 38.} It is one of the most disabling, painful, and therapy-resistant variants of lichen planus. ³⁹ Oral lesions are common; rarely, the esophagus is also involved.^{40. and 41.} Lesions localized to the lip, ⁴² vulva,^{43. and 44.} and to an eyelid⁴⁵ have been reported. Lichen planus localized to a radiation field may represent an isomorphic response.^{46. and 47.} It has also developed in a healed herpes zoster scar. ⁴⁸ Nail changes occur^{49.50.51. and 52.} and, as with oral lesions, these may be the only manifestations of the disease.^{53. and 54.} Clinical variants include atrophic, annular, hypertrophic, linear, zosteriform,^{55.56. and 57.} erosive, oral, actinic, follicular, erythematous, and bullous variants. They are discussed further below. An eruptive variant also occurs. ⁵⁸ Spontaneous resolution of lichen planus is usual within 12 months, although postinflammatory pigmentation may persist for some time afterwards. ⁵⁹

Familial cases are uncommon, and rarely these are associated with HLA-D7.^{60.61.62. and 63.} An association with HLA-DR1 has been found in non-familial cases. ⁶⁴ There is an increased frequency of HLA-DR6 in Italian patients with hepatitis C virus-associated oral lichen planus. ⁶⁵ Lichen planus is rare in children,^{66.67.68.69.70.71.72. and 73.} but some large series have been published.^{74.75. and 76.} Lichen planus has been reported in association with immunodeficiency states, ⁷⁷ internal malignancy,^{78. and 79.} including thymoma, ⁸⁰ primary biliary cirrhosis,^{81. and 82.} peptic ulcer (but not Helicobacter pylori infection), ⁸³ chronic hepatitis C infection,^{84.85.86.87.88.89.90.91.92.93. and 94.} hepatitis B vaccination,^{95.96.97.98.99.100.101.102.103. and 104.} herpesvirus type 7 (HHV-7) replication, ¹⁰⁵ simultaneous measles-mumps-rubella and diphtheria-tetanus-pertussis-polio vaccinations, ¹⁰⁶ stress, ¹⁰⁷ vitiligo, ¹⁰⁸ pemphigus, ¹⁰⁹ porphyria cutanea tarda, ¹¹⁰ radiotherapy, ¹¹¹ ulcerative colitis, ¹¹² chronic giardiasis, ¹¹³ a Becker’s nevus, ¹¹⁴ and lichen sclerosus et atrophicus with coexisting morphea. ¹¹⁵ Despite the association between lichen planus and hepatitis C (HCV) infection, its incidence in patients with lichen planus in some parts of the world is not increased when compared with a control group.^{116. and 117.} The exacerbation or appearance of lichen planus during the treatment of HCV infection and other diseases with alpha-interferon has been reported. ¹¹⁸ Furthermore effective therapy for the HCV does not clear the lichen planus. ¹¹⁹ Reports linking lichen planus to infection with human papillomavirus may be a false-positive result.^{120. and 121.} Squamous cell carcinoma is a rare complication of the oral and vulval cases of lichen planus and of the hypertrophic and ulcerative variants (see below).^{122.123.124.125. and 126.} A contact allergy to metals, flavorings and plastics may be important in the etiology of oral lichen planus. ¹²⁷ The role of mercury in dental amalgams is discussed further below.

Cell-mediated immune reactions appear to be important in the pathogenesis of lichen planus. ¹²⁸ It has been suggested that these reactions are precipitated by an alteration in the antigenicity of epidermal keratinocytes, possibly caused by a virus or a drug or by an allogeneic cell. ¹²⁹ Keratinocytes in lichen planus express HLA-DR on their surface and this may be one of the antigens which has an inductive or perpetuating role in the process.^{130.131. and 132.} Keratinocytes also express fetal cytokeratins (CK13 and CK8/18) but whether they are responsible for triggering the T-cell response is speculative. ¹³³ The cellular response, initially, consists of CD4⁺ lymphocytes; ¹³⁴ they are also increased in the peripheral blood. ¹³⁵ In recent years attention has focused on the role of cytotoxic CD8⁺ lymphocytes in a number of cell-mediated immune reactions in the skin. They appear to play a significant role as the effector cell, whereas the CD4⁺ lymphocyte, usually present in greater numbers, ¹³⁶ plays its traditional ‘helper’ role. In lichen planus, CD8⁺ cells appear to recognize an antigen associated with MHC class I on lesional keratinocytes, resulting in their death by apoptosis. ¹³⁷Bcl-2, a proto-oncogene that protects cells from apoptosis, is increased in lichen planus. ¹³⁸ It may allow some cells to escape apoptosis, prolonging the inflammatory process. ¹³⁸ The recruitment of lymphocytes to the interface region may be the result of the chemokine MIG (monokine induced by interferon-γ). ¹³⁹ Lymphokines produced by these T lymphocytes, including interferon-γ, interleukins-1β, -4 and -6, perforin, ¹⁴⁰ granzyme B, ¹⁴¹ granulysin, ¹⁴² T-cell-restricted intracellular antigen (Tia-1), and tumor necrosis factor, may have an effector role in producing the apoptosis of keratinocytes.143. ^{and 144.} The other pathway involves the binding of Fas ligand to Fas, which triggers a caspase cascade.^{145. and 146.} Gene expression profiling in lichen planus has found that type I IFN inducible genes are significantly expressed. ¹⁴⁷ Plasmacytoid dendritic cells appear to be a major source of these type I interferons in lichen planus. They play a major role in cytotoxic skin inflammation by increasing the expression of IPIO/CXCRIO and recruiting effector cells via CXCR3. ¹⁴⁸ The CXCR3 ligand, CXCL9, is the most significant marker for lichen planus. ¹⁴⁷ A unique subclass of cytotoxic T lymphocyte (γδ) is also found in established lesions. ¹⁴⁹ Langerhans cells are increased and it has been suggested that these cells initially process the foreign antigen. ¹³¹ Factor XIIIa-positive cells and macrophages expressing lysozyme are found in the dermis. ¹³⁴

Increased oxidative stress, increased lipid peroxidation, and an imbalance in the antioxidant defense system are present, but their exact role in the pathogenesis of lichen planus is unknown. ¹⁵⁰

Matrix metalloproteinases may play a concurrent role by destroying the basement membrane. ¹⁵¹ Evidence from an animal model suggests that keratinocytes require cell survival signals, derived from the basement membrane, to prevent the onset of apoptosis. ¹⁵² In oral lichen planus, MMP-1 and MMP-3 may be principally associated with erosion development. ¹⁵³ Altered levels of heat shock proteins are found in the epidermis in lichen planus. ¹⁵⁴

Most studies have found no autoantibodies and no alteration in serum immunoglobulins in lichen planus. ¹⁵⁵ However, a lichen planus-specific antigen has been detected in the epidermis and a circulating antibody to it has been found in the serum of individuals with lichen planus.^{156. and 157.} Its pathogenetic significance remains uncertain. Antibodies to desmoplakins I and II have been found in oral and genital lesions, possibly representing epitope spreading. ¹⁵⁸

Replacement of the damaged basal cells is achieved by an increase in actively dividing keratinocytes in both the epidermis and the skin appendages. This is reflected in the pattern of keratin expression, which resembles that seen in wound healing; cytokeratin 17 (CK17) is found in suprabasal keratinocytes. ¹⁵⁹

A number of clinical variants of lichen planus occur. In some, typical lesions of lichen planus are also present. These variants are discussed in further detail below.

Lichen nitidus is a rare, usually asymptomatic chronic eruption characterized by the presence of multiple, small flesh-colored papules, 1–2 mm in diameter.^{396. and 397.} The lesions have a predilection for the upper extremities, chest, abdomen, and genitalia of children and young adult males.^{396. and 398.} The disorder is most often localized but sometimes lesions are more generalized.^{399.400. and 401.} Familial cases are rare. ⁴⁰² It has been reported in association with Down syndrome. ⁴⁰³ Nail changes^{404. and 405.} and involvement of the palms and soles^{406.407. and 408.} have been reported. It has been suggested that cases reported in the past as summertime actinic lichenoid eruption (SALE) should be reclassified as actinic lichen nitidus.^{409.410. and 411.} It has been reported in association with lichen spinulosus. ⁴¹²

Although regarded originally as a variant of lichen planus, lichen nitidus is now considered a distinct entity of unknown etiology. It has followed hepatitis B vaccine. ⁴¹³ The lymphocytes in the dermal infiltrate in lichen nitidus express different markers from those in lichen planus. ⁴¹⁴ Lichen planus has developed subsequent to generalized lichen nitidus in a child. ⁴¹⁵

Although spontaneous remissions of lichen nitidus are common, ³⁹⁹ persistent lesions and those that are refractory to various treatments can pose therapeutic challenges. Sometimes resolution is accompanied by postinflammatory hyperpigmentation. ³⁹⁹ Some of the treatments used include systemic and topical corticosteroids, antihistamines, retinoids, low-dose cyclosporine, itraconazole, isoniazid, and ultraviolet therapy.^{400. and 416.} Generalized lichen nitidus has been successfully treated with narrowband-UVB phototherapy.^{400. and 417.}

Lichen striatus is a linear, papular eruption of unknown etiology which may extend in a continuous or interrupted fashion along one side of the body, usually the length of an extremity.^{427. and 428.} Annular⁴²⁹ and bilateral forms⁴³⁰ have been reported. The lesions often follow Blaschko’s lines;^{431.432.433. and 434.} this is almost invariable for lesions on the trunk and face. ⁴³⁵ Nail changes are not uncommon,^{436. and 437.} resulting in onychodystrophy. ⁴³⁸ Lichen striatus has a predilection for female children and adolescents. ⁴³⁵ Familial cases are rare. ⁴³⁹ An unusual presentation in children is the presence of linear lesions on the nose with some overlap features with lupus erythematosus. ⁴⁴⁰ Spontaneous resolution usually occurs after 6 months, although some cases persist longer. ⁴³⁵ Hypochromic sequelae occur in nearly 30% of cases; hyperchromic sequelae are much less common. ⁴³⁵ Relapses are uncommon. A history of atopy is sometimes present in affected individuals.^{435. and 441.}

Lichen striatus has been reported following BCG vaccination, ⁴³⁴ varicella infection, ⁴⁴² solarium exposure, ⁴⁴³ and following a flu-like illness. ⁴⁴⁴ It has also developed in a pregnant woman, ⁴⁴⁵ and in a patient with plaque psoriasis. ⁴⁴⁶ It has been suggested that lichen striatus represents an autoimmune CD8-mediated response against a mutate keratinocytic clone, which represents a somatic mutation occurring after fertilization. ⁴³⁵

Because lichen striatus usually resolves spontaneously, therapy is not required. ¹⁶⁰ Topical steroids have been used to treat the disease, but they do not appear to influence the duration of the lesions. ⁴³⁵ Tacrolimus (0.1%) is an effective treatment option for lichen striatus of the face and other areas.^{447.448. and 449.} Pimecrolimus cream has also been effective in adult patients.^{450.451. and 452.}

Lichen planus-like keratosis (LPLK) is a commonly encountered entity in routine histopathology.^{460.461.462.463.464.465. and 466.} Synonyms used for this entity include solitary lichen planus, benign lichenoid keratosis, ⁴⁶¹ lichenoid benign keratosis,^{462. and 463.} and involuting lichenoid plaque. ⁴⁶⁴ It should not be confused with lichenoid actinic (solar) keratosis⁴⁶⁷ in which epithelial atypia is a prerequisite for diagnosis. ⁴⁶⁸ Lichen planus-like keratoses are usually solitary, discrete, slightly raised lesions of short duration, measuring 3–10 mm in diameter. Multiple lesions (20–40) have been reported, but the illustration of one such case appears to show a cornoid lamella. ⁴⁶⁹ In a study of 1040 cases, 8% of patients presented with two lesions, and less than 1% with three lesions. ⁴⁷⁰ The sudden appearance of the lesion is often a striking feature. Lesions are violaceous or pink, often with a rusty tinge. ⁴⁶⁰ There may be a thin, overlying scale. The dermoscopic features correlate with the stage of the lesion and the nature of the lesion being regressed.^{471. and 472.} There is a predilection for the arms and presternal area of middle-aged and elderly women. ⁴⁷⁰ Lesions are sometimes mildly pruritic or ‘burning’. ⁴⁶¹ Clinically, LPLK is usually misdiagnosed as a basal cell carcinoma or Bowen’s disease.

Lichen planus-like keratosis is a heterogeneous condition which usually represents the attempted cell-mediated immune rejection of any of several different types of epidermal lesion. In most instances this is a solar lentigo,^{460.473. and 474.} but in some lesions there is a suggestion of an underlying seborrheic keratosis, large cell acanthoma or even a viral wart. ⁴⁷⁵ Constant pressure was incriminated in one case. ⁴⁷⁶ Acetaminophen (paracetamol) was incriminated in another case. ⁴⁷⁷ In one study, a contiguous solar lentigo was present in only 7% of cases and a seborrheic keratosis in 8.4%. ⁴⁶⁵ These findings do not accord with the author’s own experiences.

A lichenoid eruption has been reported following the ingestion of a wide range of chemical substances and drugs.^{487. and 488.} The eruption may closely mimic lichen planus clinically, although at other times there is eczematization and more pronounced, residual hyperpigmentation. Rarely the eruption follows Blaschko’s lines. ⁴⁸⁹ Some of the β-adrenergic blocking agents produce a psoriasiform pattern clinically but lichenoid features histologically.^{490. and 491.} Discontinuation of the drug usually leads to clearing of the rash over a period of several weeks. ⁴⁹² A lichenoid reaction has developed in a temporary henna tattoo, ⁴⁹³ as well as in permanent tattoos.^{494. and 495.}

Lichenoid eruptions have been produced by gold, ⁴⁹⁶ gold-containing liquor,^{497. and 498.} methyldopa, ⁴⁹⁹β-adrenergic blocking agents, ⁵⁰⁰ penicillamine, ⁵⁰¹ quinine, ⁵⁰² quinidine, ⁵⁰³ synthetic antimalarials, ⁵⁰⁴ and ethambutol. ⁵⁰⁵ Less common causes of a lichenoid reaction are captopril, ⁵⁰⁶ enalapril,^{507. and 508.} amlodipine, ⁵⁰⁹ naproxen,^{510.511. and 512.} dapsone, simvastatin, ⁵¹³ pravastatin, ⁵¹⁴ indapamide, arsenicals, mercury, ⁵¹⁵ iodides, imatinib,^{516. and 517.} etanercept, ⁵¹⁸ adalimumab, ⁵¹⁹ infliximab, ⁵²⁰ acetylsalicylic acid, ⁵²¹ orlistat, ⁵²² ticlopidine, ⁵²³ sodium valproate, ⁵²⁴ nicorandil, ⁵²⁵ terazosin, ⁵²⁶ carbamazepine, ⁵²⁷ phenothiazine derivatives, salsalate, ⁵²⁸ chlorpropamide, ⁵²⁹ suramin, ⁵³⁰ tiopronin, ⁵³¹ docetaxel, ⁵³² dactinomycin, ⁵³³ doxorubicin,^{534.535.536. and 537.} cyanamide, ⁵³⁸ omeprazole, lansoprazole, pantoprazole, ⁵³⁹ spironolactone, ⁵⁴⁰ metformin, ⁵⁴¹ glimepiride, ⁵⁴² indoramin, ⁵⁴³ interferon alfa-2b, intravenous immunoglobulin, ⁵⁴⁴ and streptomycin. ⁵⁴⁵Photodistributed lesions may occur with thiazides, ⁵⁴⁶ some tetracyclines, ⁵⁴⁷ sparfloxacin, ⁵⁴⁸ nimesulide, ⁵⁴⁹ torsemide (a loop diuretic), ⁵⁵⁰ clopidogrel, ⁵⁵¹ solifenacin, ⁵⁵² capecitabine, ⁵⁵³ diltiazem,^{554.555. and 556.} ethambutol, ¹⁶⁰ quinine, ¹⁶⁰ pyritinol, ¹⁶⁰ carbamazepine, ¹⁶⁰ and pyrazinamide. ⁵⁵⁷ Hyperpigmentation may follow. ⁵⁵⁶ A lichenoid stomatitis, which may take time to clear after cessation of the drug, can be produced by methyldopa and rarely by lithium carbonate⁵⁵⁸ or propranolol. Contact with color film developer may produce a lichenoid photodermatitis. ⁴⁹² A topical mixture of the local anesthetic agents lidocaine and prilocaine produced basal clefting similar to epidermolysis bullosa simplex with basophilic granules in the cleft.^{559. and 560.} A lichen planus-like eruption has been reported at sites repeatedly exposed to methacrylic acid esters used in the car industry⁵⁶¹ and also at injection sites of granulocyte colony-stimulating factor (GCSF). ⁵⁶² A severe lichenoid eruption and stomatitis developed in a patient receiving GCSF, interferon-α-2A, and ribavirin. ⁵⁶³ Voriconazole has induced a blistering eruption with histological lichenoid features. The eruption occurred in the setting of graft-versus-host disease. ⁵⁶⁴ A list of the drugs that produce lichenoid eruptions is included in Table 3.5.

A fixed drug eruption is a round or oval erythematous lesion which develops within hours of taking the offending drug and which recurs at the same site with subsequent exposure to the drug. ⁵⁷³ Lesions may be solitary or multiple. A bullous variant with widespread lesions also occurs.^{574.575. and 576.} Fixed eruptions subside on withdrawal of the drug, leav­ing a hyperpigmented macule. ⁵⁷⁷ Non-pigmenting lesions have been described^{578.579. and 580.} and depigmented areas may be the result in patients whose skin is naturally heavily pigmented. Sometimes there is a burning sensation in the erythematous lesions, but systemic manifestations such as malaise and fever are uncommon. ⁵⁷³ Rare clinical variants include eczematous, necrotizing, ⁵⁸¹ cellulitis-like, ⁵⁸²‘Dalmatian dog’-like, ⁵⁸³ urticarial, linear,^{584. and 585.} ‘wandering’, ⁵⁸⁶ butterfly rash-like, ⁵⁸⁷ and erythema dyschromicum perstans-like⁵⁸⁸ types. A unilateral eruption of the breast has been reported. ⁵⁸⁹ In two cases the eruption occurred at the sites of ear piercing. ⁵⁹⁰ An interesting presentation concerns the fixed drug eruption that developed in a male after coitus, which was thought to have resulted from the trimethoprim-sulfamethoxazole that his wife was taking. ⁵⁹¹ Other ‘sexually transmitted’ cases have since been reported. ⁵⁹² Common sites of involvement include the face, lips, ⁵⁹³ buttocks, and genitals.^{594. and 595.} Paronychia is a rare presentation. ⁵⁹⁶

In one series of 446 cases of drug eruption, 92 (21%) were instances of fixed drug eruptions and, of these, 16 were bullous and gen­eralized. ⁵⁹⁷ Over 100 drugs have been incriminated, but the major offenders are sulfonamides, ⁵⁹⁸ particularly the combination of trimethoprim-sulfamethoxazole,^{591.599. and 600.} tetracyclines,^{600.601. and 602.} tranquilizers, quinine, phenolphthalein (in laxatives), and some analgesics.^{603. and 604.} In some countries, antituberculous drugs and antimalarials are a major cause of a fixed drug eruption. ⁶⁰⁵ Specific drugs incriminated in the literature include minocycline, ⁶⁰² nystatin, ⁶⁰⁶ colchicine, ⁶⁰⁷ clioquinol, ⁶⁰⁸ penicillin, ⁶⁰⁹ amoxicillin, ⁶¹⁰ erythromycin, ⁶¹¹ clarithromycin, ⁶¹² ciprofloxacin, ⁶¹³ vancomycin, ⁶¹⁴ rifampicin, ⁶⁰⁴ tranexamic acid, ⁶¹⁵ griseofulvin, ⁶¹⁶ terbinafine, ⁶¹⁷ dimen­hydrinate (Gravol),^{618.619. and 620.} diphenhydramine, ⁶²¹ levocetirizine, ⁶²² paclitaxel, ⁶²³ topotecan, ⁵⁸² temazepam, ⁶²⁴ mefenamic acid,^{575.583. and 625.} carbamazepine,^{626. and 627.} acetylsalicylic acid, ⁶²⁸ acetaminophen (paracetamol),^{628.629.630.631.632.633.634.635. and 636.} fluconazole,^{637. and 638.} ketoconazole, ⁶³⁹ itraconazole, ⁶³⁹ feprazone, ⁶⁴⁰ tartrazine, ⁶⁴¹ ticlopidine, ⁶⁴² phenytoin, ⁶²⁷ lamotrigine, ⁶⁴³ pseudoephedrine,^{644. and 645.} dextromethorphan, ⁶⁴⁶ iomeprol, ⁶⁴⁷ phenylpropanolamine hydrochloride, ⁶⁴⁸ tropisetron, ⁶⁴⁹ metramizole, ⁶⁰⁰ phenylbutazone, ⁶⁰⁰ etodolac, ⁶⁵⁰ metamizole, ⁶⁵¹ naproxen,^{589.652. and 653.} piroxicam,^{590. and 654.} tenoxicam, ⁵⁹⁰ interferon-β-1b, ⁶⁵⁵ ibuprofen, ⁶⁵⁶ acetaminophen/indomethacin/granisetron/IL-2 in combination, ⁶⁵⁷ celecoxib, ⁶⁰⁴ chlormezanone, ⁶⁰⁴ omeprazole, ⁶²⁸ diltiazem, ⁶²⁸ enalapril, ⁶²⁸ lansoprazole, ⁶²⁸ fluoxetine, ⁶²⁸ amplodipine, ⁶²⁸ S-carboxymethyl-L-cysteine, ⁶⁵⁸ eperisone hydrochloride, ⁶⁵⁹ lactose,^{660. and 661.} metronidazole,^{662.663. and 664.} tinidazole, ⁶⁶² nimesulide, ⁶⁶⁵ cetirizine,^{666. and 667.} and theophylline. ⁵⁸⁸ More complete lists are included in several reviews of the subject.^{573.603. and 604.} The drugs responsible are listed in Table 3.5. Two different drugs have been involved in the same patient.^{668. and 669.} In yet another report, three different drugs each produced a fixed drug eruption at a different site. ⁶⁷⁰ It has been suggested that the distribution of lesions is influenced by the drug in question; tetracyclines and cotrimoxazole tend to involve the glans penis, while pyrazolones and naproxen affect mainly the lips and mucosae.^{599. and 671.} Antimalarials mainly involve the face and lips. ⁶⁰⁵ There are rare reports of fixed food eruptions. Lentils⁶⁷² and strawberries⁶⁷³ have been implicated. Foods may sometimes produce a flare in a fixed drug eruption. ⁶⁷⁴ The Japanese herbal drug ‘kakkon-to’ has produced an extensive fixed drug eruption. ⁶⁷⁵ A solitary lesion has been produced by the Chinese herbal medicine, ma huang (Ephedra Hebra), mainly containing pseudoephedrine and ephedrine. ⁶⁷⁶ Influenza vaccination has resulted in a generalized bullous eruption. ⁵⁷⁶ In some instances no agent can be incriminated. Such cases have been called ‘fixed drug-like eruption’. ⁶⁷⁷

Numerous studies have attempted to elucidate the pathogenesis of fixed eruptions. It appears that the offending drug acts as a hapten and binds to a protein in basal keratinocytes and sometimes melanocytes. ⁵⁷³ As a consequence, an immunological reaction is stimulated, which probably takes the form of an antibody-dependent, cellular cytotoxic response. ⁶⁷⁸ CD8⁺ T lymphocytes attack the drug-altered epidermal cells producing apoptosis; it appears to be mediated by Fas ligand (FasL), in the presence of interferon-γ, triggering a caspase cascade. ¹⁴⁵ Drug-specific CD8⁺ memory T cells also play a role in preserving the cutaneous memory function which characterizes a fixed eruption.^{590. and 679.} It appears that these memory T cells transiently acquire a natural killer-like phenotype and express cytotoxic granules upon activation. ⁶⁸⁰ Keratinocytes at the site of a fixed drug eruption express one of the cell adhesion molecules (ICAM-1) that is involved in the adherence reaction between lymphocytes and epidermal keratinocytes. ⁶⁸¹ It has been suggested that localized expression of this adhesion antigen may be one factor that explains the site specificity of fixed drug eruptions. ⁶⁸¹ The occurrence of some fixed drug eruptions at sites of trauma or previous inflammation may be a manifestation of an isotopic response. ⁵⁹⁰ It is also possible that preformed cytokines may exist at such sites. These findings have been incorporated into the following hypothesis: that the causative drug activates mast cells or keratinocytes to release cytokines or induces keratinocytes to express adhesion molecules on their surfaces, leading to the activation of epidermal CD8⁺ T cells, ⁶⁸² and resulting in death of keratinocytes by a FasL-mediated pathway. ¹⁴⁵ This theory has been put forward in an attempt to explain the early onset of symptoms, which occur much earlier than traditional cell-mediated responses could produce.

Although CD8⁺ cells are more numerous than CD4⁺ cells in the epidermis and dermis, cells which are CD25⁺ CD4⁺ appear to migrate into the epidermis of active lesions and exert a regulatory function by releasing interleukin-10, resulting in the resolution of the lesion(s). ¹⁴⁵ These same cells have also been shown to be involved in the induction of desensitization to a fixed drug eruption. ¹⁴⁵

There appears to be a genetic susceptibility to fixed drug eruptions, with an increased incidence of HLA-B22⁶⁸³ and HLA-A30 B13 Cw6. ⁶⁸⁴

Erythema multiforme is a self-limited, sometimes episodic disease of the skin, which may also involve the mucous membranes. It is characterized by a pleomorphic eruption consisting of erythematous macules, papules, urticarial plaques, vesicles, and bullae.^{687. and 688.} Individual lesions may evolve through a papular, vesicular and target (iris) stage in which bullae surmount an erythematous maculopapule. ⁶⁸⁹ Lesions tend to be distributed symmetrically with a predilection for the extremities, particularly the hands.

Graft-versus-host disease (GVHD) is a systemic syndrome with important cutaneous manifestations. It is usually seen in patients receiving allogeneic immunocompetent lymphocytes in the course of bone marrow transplants used in the treatment of aplastic anemia, ⁹⁷⁵ leukemia, or in immunodeficiency states.^{739.976.977.978.979. and 980.} Acute GVHD develops in approximately one-third of HLA-matched recipients of allogeneic bone marrow.^{981. and 982.} It also follows stem cell transplantation. ⁹⁸³ Risk factors for the development of acute cutaneous GVHD after allogeneic stem cell transplantation include a diagnosis of chronic myeloid leukemia, HLA disparity, and conditioning regimens such as total body irradiation. ⁹⁸³ It may also occur following maternofetal blood transfusions in utero, ⁹⁸⁴ intrauterine exchange transfusions and the administration of non-irradiated blood products to patients with disseminated malignancy and a depressed immune system.^{985.986.987.988.989.990. and 991.} It is seen only rarely after solid organ transplantation.^{992. and 993.} It is also less common with cord-blood than with bone marrow transplants in children receiving either product from HLA-identical siblings. ⁹⁹⁴ Rarely, immunocompetent patients are at risk, particularly those subject to cardiac surgery.^{995.996. and 997.} The acute stage can be precipitated in some individuals by autologous and syngeneic bone marrow transplantation;^{998.999. and 1000.} chronic lesions (see below), particularly lichenoid ones, are rare. ¹⁰⁰¹ Acute GVHD superimposed on pre-existing lichenoid chronic GVHD has been reported; it followed reinduction chemotherapy. ¹⁰⁰² GVHD has been reported in patients with a thymoma or lymphoma.^{1003.1004.1005. and 1006.} Sclerodermoid GVHD-like lesions have also developed long after the clinical resolution of drug-induced hypersensitivity syndrome. ¹⁰⁰⁷

There is an early acute phase with vomiting, diarrhea, hepatic manifestations, and an erythematous macular rash.^{978.1008. and 1009.} Rarely, it is confined to the flexures. ¹⁰¹⁰ Uncommonly, there are follicular papules¹⁰¹¹ or blisters; ¹⁰¹² rarely, toxic epidermal necrolysis ensues.^{978. and 1013.} Just two erythematous nodules were the presenting features in one case. ¹⁰¹⁴ A pustular acral erythema with associated eccrine squamous syringometaplasia has also been reported. ¹⁰¹⁵ Ichthyosiform features may occur in both the acute and chronic forms.^{1016. and 1017.} Localization to an area of skin affected by piebaldism, and in another case herpes zoster, has been reported.^{1018. and 1019.} Lichenoid nail changes also occur. ¹⁰²⁰ They usually persist in chronic disease. ¹⁰²¹ The chronic stage develops some months or more after the transplant. A preceding acute stage is present in 80% of these patients.^{978. and 1022.} Chronic GVHD has an early lichenoid phase which resembles lichen planus and includes oral lesions.^{1023. and 1024.} Linear lichenoid lesions have been reported both in a dermatomal distribution and following Blaschko’s lines.^{1025.1026.1027.1028. and 1029.} Rarely, dermatomal lesions occur at sites of varicella-zoster infection.^{1029. and 1030.} A poikilodermatous phase may precede the eventual sclerodermoid phase. The lesions of the latter may be localized¹⁰³¹ or generalized.^{978. and 1032.} Sclerodermatous GVHD (see p. 312) has a prevalence of approximately 3% in patients receiving allogeneic bone marrow transplants. ¹⁰³³ Other late manifestations include alopecia, a lupus erythematosus-like eruption, cicatrizing conjunctivitis, ¹⁰³⁴ pyogenic granuloma and angiomatous lesions, ¹⁰³⁵ wasting, diffuse melanoderma, ¹⁰³⁶ leukoderma and leukotrichia, ¹⁰³⁷ esophagitis, liver disease, and the sicca syndrome. Acute GVHD may be a late manifestation (>100 days after transplantation), following the suspension or tapering of immunosuppressive drugs. It can be seen after traditional transplants and the newer non-myeloablative technique. ¹⁰³⁸ Late-onset acute GVHD is a predictor of chronic GVHD. ¹⁰³⁸

The pathogenesis appears to be complex, ¹⁰³⁹ but the essential factor is the interaction of donor cytotoxic T lymphocytes with recipient minor histocompatibility antigens.^{1040.1041. and 1042.} Several effector cell populations appear to be involved.^{1043. and 1044.} Recent work suggests that this is an over-simplistic explanation of the pathogenesis. ¹⁰⁴⁵ Not only is direct cellular cytotoxicity involved, but also soluble mediators such as IFN-γ, CXCR3, TNF-α, FasL, and TNF-related apoptosis-inducing ligand (TRAIL) play a significant role in the pathogenesis of acute GVHD.^{1045. and 1046.} Young rete ridge keratinocytes¹⁰⁴⁷ and Langerhans cells^{1042. and 1048.} are preferred targets. The acute stage is associated with HLA-DR expression of keratinocytes.^{1049.1050. and 1051.} Factor XIIIa-positive dermal dendrocytes appear to play some role,^{1052. and 1053.} possibly in the regulation of the connective tissue remodeling that follows epidermal destruction. Recent work suggests that HHV-6 reactivation may play a role in the pathogenesis of rash/GVHD after allogeneic stem cell transplantation. ¹⁰⁵⁴

The treatment of acute GVHD is beyond the scope of this book, involving as it does a disease in which the cutaneous manifestations may be a small component of a systemic disease. Chronic cutaneous GVHD has been treated with corticosteroids and immunosuppressants such as cyclosporine. They have had a limited effect on the disease, not to mention the long-term effects of corticosteroids. Chronic disease may also be treated by extracorporeal photopheresis (ECP). ¹⁰⁵⁵ It also induces, as a side effect, immediate and progressive apoptosis. ¹⁰⁵⁶ A consensus statement on its use was published in 2008. ¹⁰⁵⁵ UVA1 phototherapy, ¹⁰⁵⁷ tacrolimus ointment, ¹⁰⁵⁸ and pimecrolimus¹⁰⁵⁹ have also been used in chronic cutaneous GVHD.

The original description of this ‘entity’ involved patients who developed a maculopapular eruption after receiving cytoreductive therapy (without bone marrow transplant) for acute myelogenous leukemia. ¹⁰⁹⁰ The lesions usually developed 14–21 days later, coincident with the return of lymphocytes to the circulation. ¹⁰⁷⁸ The histological similarities between this eruption and those seen with mild GVHD and with the administration of cyclosporin A (cyclosporine) led to the suggestion that all three conditions represent variations on the theme of lymphocyte recovery. ¹⁰⁷⁸

A lichenoid reaction pattern with interface changes resembling those seen in erythema multiforme or fixed drug eruptions has been reported in some patients with the acquired immunodeficiency syndrome and in whom the clinical presentation suggested a drug reaction. ¹⁰⁹⁴ The patients had numerous opportunistic infections and all had received at least one medication prior to the onset of the rash. It has been suggested that systemic and cutaneous immune abnormalities may be relevant in the pathogenesis. ¹⁰⁹⁴

There is little justification for the continuation of this diagnosis as a discrete entity.

Lupus erythematosus is a chronic inflammatory disease of unknown etiology which principally affects middle-aged women. It has traditionally been regarded as an immune disorder of connective tissue, along with scleroderma and dermatomyositis. However, a striking feature of cutaneous biopsies is the presence in most cases of the lichenoid reaction pattern (interface dermatitis). It may not be present in tumid forms, in lupus profundus (panniculitis) and in lymphocytic infiltration of the skin, if indeed this is truly a variant of lupus erythematosus.

Three major clinical variants are recognized – chronic discoid lupus erythematosus which involves only the skin, systemic lupus erythematosus which is a multisystem disease, and subacute lupus erythematosus in which distinct cutaneous lesions are sometimes associated with mild systemic illness.^{1095. and 1096.} Some overlap exists between the histological changes seen in these various clinical subsets. ¹⁰⁹⁷ There are several less common clinical variants which will be considered after a discussion of the major types.

A recent addition to these subsets is undifferentiated connective tissue disease, also called latent or incomplete lupus, in which signs and symptoms do not fulfill any of the accepted classification criteria for the various named connective tissue diseases.^{1098. and 1099.}

The traditional variants of lupus erythematosus (discoid, subacute, and systemic) have already been discussed. This section covers uncommon, but distinct, clinicopathological variants.

Dermatomyositis is characterized by the coexistence of a non-suppurative myositis (polymyositis) and inflammatory changes in the skin.^{1550.1551.1552.1553. and 1554.} Cutaneous lesions may precede the development of muscle involvement by up to 2 years or more.^{1555.1556. and 1557.} Cases without muscle involvement (amyopathic dermatomyositis, dermatomyositis sine myositis) exist.^{1558.1559.1560.1561.1562.1563. and 1564.} Amyopathic dermatomyositis is defined as the finding of dermatomyositis in the absence of any clinical or laboratory signs of muscle disease for at least 6 months (formerly 2 years) after the onset of skin pathology.1565. ^{and 1566.} It accounts for 10–20% of the total population of dermatomyositis patients seen in referral clinics in the United States. ¹⁵⁶⁶ There is a strong association between amyopathic dermatomyositis and nasopharyngeal carcinoma in China. ¹⁵⁶⁷ Its association with familial polyposis coli was probably fortuitous. ¹⁵⁶⁸ An ‘adermatopathic’ variant of dermatomyositis has also been postulated. ¹⁵⁶⁶

Dermatomyositis may occur in either sex and at any age. Those cases commencing in childhood are sometimes considered as a separate clinical group (juvenile dermatomyositis), because of the greater incidence in them of multiorgan disease.^{1569.1570.1571.1572. and 1573.} Rarely this includes a necrotizing vasculitis that may involve the gut and other organs with a fatal outcome. ¹⁵⁶⁹ The initial physical and laboratory findings in patients with juvenile dermatomyositis may be non-specific. Instead of the heliotrope rash and Gottron’s papules classically associated with dermatomyositis (see below), there may be a non-specific extremity rash, periungual erythema, and sometimes pruritus. ¹⁵⁷⁴ An amyopathic variant also occurs. ¹⁵⁷⁵ Vasculopathy does not seem to occur in this amyopathic form of juvenile dermatomyositis. ¹⁵⁷⁵ Other manifestations of juvenile dermatomyositis include lipoatrophy, generalized hyper­trichosis, and infrapatellar hypertrichosis¹⁵⁷⁶ Associations include the 22q11.2 deletion syndrome. ¹⁵⁷⁷

The skin lesions in adult dermatomyositis are violaceous or erythematous, slightly scaly lesions with a predisposition for the face, shoulders, the extensor surfaces of the forearms and the thighs. ¹⁵⁷⁸ Poikilodermatous features (telangiectasia, hyperpigmentation, and hypopigmentation) may be seen. ¹⁵⁷⁹ Photosensitivity is sometimes present. ¹⁵⁸⁰ Pruritus is not uncommon, but it has not been highlighted in the literature. ¹⁵⁸¹ Other characteristic findings are nail fold changes, gingival telangiectases, ¹⁵⁸² purplish discoloration and edema of the periorbital tissues (heliotrope rash), and atrophic papules or plaques over the knuckles (Gottron’s papules). ¹⁵⁷⁹ Plaques of calcification sometimes develop.^{1583. and 1584.} Unusual presentations include severe periorbital edema, ¹⁵⁸⁵ an isolated flagellate eruption on the back,^{1586.1587. and 1588.} a plaque-like mucinosis,^{1589. and 1590.} the presence of follicular keratotic papules with some features of pityriasis rubra pilaris,^{1591.1592.1593. and 1594.} lesions resembling malignant atrophic papulosis, ¹⁵⁹⁵ a panniculitis,^{1596. and 1597.} stasis dermatitis, ¹⁵⁹⁸ erythroderma,^{1599. and 1600.} or vesiculobullous eruption. ¹⁶⁰¹ A patient with vesiculobullous disease and a panniculitis but without muscle disease has been reported. ¹⁶⁰² In another patient with acute onset vesiculobullous dermatomyositis, massive mucosal necrosis of the intestines occurred. ¹⁶⁰³ A Dermatomyositis Skin Severity Index has recently been developed and validated. ¹⁶⁰⁴ This will allow a comparison of various treatment modalities in future clinical trials.

Other clinical features include the presence of proximal muscle weakness and elevation of certain serum enzymes such as creatine phosphokinase.^{1578. and 1605.} Muscle ultrasound is sometimes abnormal in patients with dermatomyositis and normal muscle enzyme levels. ¹⁶⁰⁶ Raynaud’s phenomenon, dysphagia, Sjögren’s syndrome, morphea profunda, ¹⁶⁰⁷ retinopathy, and overlap features with scleroderma^{1608. and 1609.} and with lupus erythematosus sometimes occur.^{1579. and 1610.} Interstitial lung disease is an uncommon but debilitating complication which is usually associated with the presence of the anti-Jo-1 antibody.^{1611.1612.1613.1614. and 1615.} Digital infarcts showing microangiopathy may occur in patients with severe pulmonary disease. ¹⁶¹⁶ Other autoantibodies, such as to histone and Ro/SS-A, are sometimes present.^{1617. and 1618.}

An underlying malignancy is present in 10% or more of cases.^{1619.1620.1621.1622.1623.1624.1625.1626.1627.1628. and 1629.} In one series the prevalence of malignancy was high (23%). ¹⁵⁸⁸ Predictive factors for malignancy include male gender and older age of onset.^{1630. and 1631.} Although the malignancies have spanned nearly every organ in the body, specific variants published in recent years have included nasopharyngeal carcinoma,^{1632. and 1633.} ovarian cancers,^{1624.1625. and 1634.} melanoma, ¹⁶³⁵ breast cancer, ¹⁶³³ squamous cell carcinoma of the penis, ¹⁶³⁶ transitional cell carcinoma of the bladder,^{1627. and 1637.} lymphoma, ¹⁶³⁸ myeloma, ¹⁶²⁹ and cancers of the esophagus, ¹⁶³⁹ lung, stomach, and colon. ¹⁶⁴⁰ The cutaneous manifestations may precede the diagnosis of the malignancy by up to a year or more. Amyopathic cases of para­neoplastic dermatomyositis have been reported. ¹⁶⁴¹ Dermatomyositis occurring in patients with stage IV melanoma has a poor prognosis.^{1642. and 1643.} Subepidermal vesiculation is an uncommon finding in dermatomyositis; its presence may be related to the occurrence of an internal malignancy.^{1601. and 1644.} Bullous pemphigoid has also been recorded as a coexisting disease. ¹⁶⁴⁵

A dermatomyositis-like syndrome has been associated with certain viral illnesses, including parvovirus B19, ¹⁶⁴⁶ toxoplasmosis, ¹⁶⁴⁷ and leishmaniasis. ¹⁶⁴⁸ It has followed administration of hydroxyurea,^{1649.1650.1651.1652.1653.1654.1655.1656.1657.1658. and 1659.} omeprazole, ¹⁶⁶⁰ carbimazole, ¹⁶⁶¹ terbinafine, ¹⁶⁶² tegafur, interferon-α, BCG vaccination, the various statins, ¹⁶⁶² cyclophosphamide, ¹⁶⁶³ etoposide, ¹⁶⁶³ a herbal medicine, ¹⁶⁶⁴ and penicillamine. ¹⁵⁷⁸ A heliotrope-like eruption mimicking dermatomyositis occurred in a patient receiving imatinib mesylate. ¹⁶⁶⁵ Dermatomyositis, including the amyopathic form, has developed in pregnancy with rapid improvement following delivery^{1666. and 1667.} and in the postpartum period. ¹⁶⁶⁸ It has been reported in a patient with hereditary complement (C9) deficiency, ¹⁶⁶⁹ and in a patient with chronic graft-versus-host disease. ¹⁶⁷⁰ Cytoplasmic inclusions resembling the paramyxovirus-like structures seen in lupus erythematosus (see p. 62) have also been found in blood vessels in cases of dermatomyositis. ¹⁶⁷¹

The etiology and pathogenesis are unknown but immunological mechanisms are certainly involved. In addition to the various auto­antibodies that are often present, activated T cells and natural killer cells have been demonstrated in biopsied muscle. ¹⁵⁷⁸ In the skin, the infiltrate consists predominantly of macrophages expressing HLA-DR and of T cells, especially of the CD4 subset. ¹⁶⁷² Plasmacytoid dendritic cells (bone-marrow derived dendritic cells with an ability to secrete large amounts of IFN-α in vivo after appropriate stimulation, including viral infection) are present in the skin. ¹⁶⁷³ These cells, which stain with CD123, play a central role in the pathogenesis of lupus erythematosus, ¹⁶⁷³ but in contrast to lupus erythematosus where they are found in the dermis, in dermatomyositis there is a preferential epidermal localization. ¹⁶⁷³ The deposition of membrane attack complex of complement (MAC) has been demonstrated along the dermoepidermal junction and in some dermal blood vessels. ¹⁶⁷⁴ Endothelial cell injury may play an important role in producing some of its clinical manifestations, including lung disease. ¹⁶⁷⁵ There are elevated levels of soluble vascular cell adhesion molecule-1 (sVCAM-1). ¹⁶⁷⁶ There is increasing evidence that a type I interferon-driven immune response, and the recruitment of potentially autoreactive T cells via IP10/CXCR3 interaction are involved in the pathogenesis of dermatomyositis skin lesions.^{1677.1678. and 1679.} Plasmacytoid dendritic cells appear to be an important source of these type I interferons. ¹⁶⁷⁹

Over 250 cases of poikiloderma congenitale (Rothmund–Thomson syndrome; OMIM 268400) have now been reported in the English literature.^{1706. and 1707.} It is an autosomal recessive, genomic instability syndrome. It is a multisystem disorder which affects principally the skin, eyes, and skeletal system.^{1708.1709.1710.1711.1712.1713. and 1714.} There is a predisposition to malignancy. ¹⁷¹⁵ A reticular erythematous eruption commences in the first year of life and this is followed by the development of areas of hypo/hyperpigmentation. Warty keratoses may appear on the hands, elbows, knees, and feet. Other clinical features include a short stature, cataracts, hypogonadism, mental retardation, photosensitivity to ultraviolet A radiation,^{1706. and 1716.} and, rarely, the development of skin cancers,^{1717. and 1718.} including melanoma, ¹⁷¹⁹ hematological malignancies, ¹⁷²⁰ including mye­lodysplasia,^{1721.1722. and 1723.} and osteogenic sarcoma.^{1724. and 1725.} Sometimes only a few of these features are present in an individual case, illustrating the variable presentation of this syndrome. ¹⁷²⁶ Late onset has also been recorded. ¹⁷²⁷ Reduced DNA repair capacity might be related to the photosensitivity in early childhood. ¹⁷²⁸ There appears to be instability in chromosome 8, sometimes leading to trisomy 8 or other abnormalities. ¹⁷²⁶ The condition appears to be genetically heterogeneous. Mutations in the RECQL4 helicase gene which maps to chromosome 8q24.3¹⁷²⁹ are present in about 60% of cases. ¹⁷¹⁹ This gene encodes a RecQ DNA helicase. ¹⁷¹⁵ It appears to have a role in the initiation of DNA replication and in sister chromatid adhesion. ¹⁷¹⁵ The RECQL4 gene has also been associated with two other diseases, the Baller–Gerold syndrome (OMIM 218600) and RAPADILINO syndrome (RAdial hypoplasia/aplasia, PAtellar hypoplasia/aplasia, cleft or highly arched PAlate, DIarrhea, DIslocated joints, LIttle size, LImb malformations, and slender NOse and NOrmal intelligence; OMIM 266280). They appear to be allelic with different phenotypic expressions. Poikilodermatous features are usually absent in this latter variant, ¹⁷³⁰ but they have been recorded in the Baller–Gerold syndrome, in which craniosynostosis, radial ray defects, and growth retardation are present.

Kindler’s syndrome (OMIM 173650) is a rare autosomal recessive genodermatosis characterized by acral trauma-induced blistering that improves with age and by progressive poikiloderma in later life. ¹⁷³³ There are variable degrees of photosensitivity beginning in childhood. ¹⁷³⁴ Other clinical features include webbing of the fingers and toes, nail dystrophy, pitted palmoplantar keratoderma, ¹⁷³⁵ periodontal disease, phimosis, ¹⁷³⁶ esophageal and anal strictures, and gastrointestinal erosions.^{1733.1737.1738.1739. and 1740.} Clinical heterogeneity is well recognized.^{1741. and 1742.} Kindler’s syndrome is included as a category of epidermolysis bullosa in the new classification of this disease (see Ch. 6, p. 141).

Kindler’s syndrome is due to a loss of function mutation in the KIND1 gene, also known as C20orf42. ¹⁷⁴⁰ The gene encodes a protein called kindlin-1 which is involved in linking the actin cytoskeleton to integrin-associated platforms in the extracellular matrix.^{1743. and 1744.} It is mainly found in keratinocytes. Loss of kindlin-1 leads to decreased cell adhesion, reduced proliferation of keratinocytes, and increased apoptosis. ¹⁷⁴¹ Kindler’s syndrome is the first inherited disorder that has been found to result from primary defects in the actin cytoskeleton/focal contacts. ¹⁷⁴¹ More than 25 different mutations have so far been described in KIND1, but they do not provide an explanation for the clinical heterogeneity of this disease.^{1741.1743.1745. and 1746.} Furthermore, KIND1 gene expression and kindlin-1 protein labeling are not always reduced in this syndrome. ¹⁷⁴⁷

Some cases are initially misdiagnosed as dystrophic epidermolysis bullosa, but there is no mutation in COL7A1.^{1748. and 1749.} Kindler’s syndrome was initially thought to represent the association of poikiloderma congenitale with dystrophic epidermolysis bullosa.^{1750.1751.1752. and 1753.} Similar cases have been reported under the title hereditary acrokeratotic poikiloderma.^{1754. and 1755.}

Congenital telangiectatic erythema (OMIM 210900) is a rare auto­somal recessive disorder usually known by the eponymous designation Bloom’s syndrome. In addition to the telangiectatic, sun-sensitive facial rash, there is stunted growth, proneness to respiratory and gastrointestinal infections, chromosomal abnormalities, and a variety of congenital malformations.^{1761.1762. and 1763.} The facial rash has lupus-like qualities. ¹⁷⁶⁴ Various chromosomal breakages are found in cultured lymphocytes, the most characteristic being a high rate of sister chromatid exchanges during metaphase. ¹⁷⁶⁵ As a consequence, there is a significant tendency to develop various malignancies, ¹⁷⁶⁶ particularly acute leukemia and lymphoma.^{1761. and 1767.} The gene responsible, RECQ3, has been mapped to chromosome 15q26.1. ¹⁷⁶³ Other RECQ helicase defects are found in Werner’s syndrome (a defect in RECQ2), and Rothmund–Thomson syndrome (RECQL4).

Dyskeratosis congenita is a rare, sometimes fatal genodermatosis characterized primarily by the triad of reticulate hyperpigmentation, nail dystrophy, and leukokeratosis of mucous membranes.^{1768.1769. and 1770.} Other less constant features include a Fanconi-type pancytopenia,^{1771.1772. and 1773.} eye and dental changes, mental deficiency, deafness, ¹⁷⁷⁴ intracranial calcification, ¹⁷⁷⁵ palmoplantar hyperkeratosis, scarring alopecia, ¹⁷⁷⁶ esophageal and anal strictures, ¹⁷⁷⁷ choanal atresia, ¹⁷⁷⁸ Chiari 1 malformation, ¹⁷⁷⁹ and an increased incidence of malignancy, particularly related to the mucous membranes,^{1774.1780. and 1781.} and, less commonly, the skin. ¹⁷⁸² Bone marrow failure is the major cause of premature death.

Although found predominantly in Caucasian males, it has been reported in several races and occasionally in females. ¹⁷⁸³ Most cases are inherited as a sex-linked recessive trait, ¹⁷⁷⁴ but kindreds with both autosomal dominant and autosomal recessive inheritance have been reported.^{1784. and 1785.} The various types of dyskeratosis congenita are listed in Table 3.6. In all characterized cases of dyskeratosis congenita, the causative mutations are present in components of the telomerase complex. Chromosomes shorten during DNA replication and it is the function of telomerase to add telomere repeats (a repeat comprises six nucleotides) to the ends of chromosomes. ¹⁷⁸⁵ The gene for X-linked recessive dyskeratosis congenita, DKC1, which encodes a 514 amino acid protein, dyskerin, is located at Xp28. ¹⁷⁸⁶ The disease is predominantly caused by missense mutations in this gene. ¹⁷⁸⁷ It is thought that dyskerin is a nucleolar protein that is responsible for some early steps in ribosomal-RNA processing. ¹⁷⁸⁶ This defect appears to be associated with a more severe phenotype than the autosomal dominant form, which has heterozygous mutations in either TERC or TERT, the RNA and enzymatic components of telomerase, respectively. ¹⁷⁸⁵ The majority of documented cases of this form involve TERC mutations. The TINF2 gene appears to be another candidate gene. Autosomal recessive dyskeratosis congenita is more enigmatic. Recently, a homozygous mutation in NOP10 (NOLA3) was found in a consanguineous family. This mutation results in short telomeres and low TERC levels. ¹⁷⁸⁵

The skin changes, which may resemble poikiloderma, usually develop on the face, neck, and upper trunk in childhood. It has been suggested that there may be pathogenetic features in common with graft-versus-host disease. ¹⁷⁶⁸

Treatment with an anabolic steroid and hematopoietic growth factors can produce an improvement in hematopoietic function for some time, ¹⁷⁸⁸ but eventually allogeneic stem cell transplantation is needed. Because of the pulmonary vascular complication, this procedure has not been particularly successful. ¹⁷⁸⁵ In the future, gene therapy with the introduction of the wild-type form of the defective gene into stem cells should correct downstream defects in this disease. ¹⁷⁸⁵

Poikiloderma of Civatte is a common dermatosis, particularly in Greece and other parts of Europe; it can produce cosmetic disfigurement. ¹⁷⁸⁹ It is a neglected and controversial entity that has received little attention in other parts of the world. It most often affects fair-skinned individuals in their fourth to seventh decades. It is characterized by red to brownish, reticular patches with irregular borders and symmetrical distribution. It may involve the V and sides of the neck, the upper chest, and parts of the face. ¹⁷⁹⁰ Erythemato-telangiectatic and pigmented types occur. The etiology is unknown but it is considered to be the cumulative effect of sun exposure exacerbated by the application of fragrances to the neck in combination with genetic predisposition and lighter skin phenotypes.^{1789. and 1791.}

Sun protection and the avoidance of documented allergens should be practiced. ¹⁷⁸⁹ Several patients who have been treated with pulsed dye laser have developed severe depigmentation. ¹⁷⁹¹ Depigmenting agents can be used as adjuvants in the pigmented variant of the disease. ¹⁷⁹⁰

In early lesions, the inflammatory infiltrate is quite heavy with band-like qualities mimicking lichen planus. Both vacuolar change and apoptotic basal keratinocytes are present. The infiltrate is eventually pushed downwards by an expanding zone of edema and sclerosis (see p. 313).

In the acute form of pityriasis lichenoides, pityriasis lichenoides et varioliformis acuta (PLEVA), there is a heavy lymphocytic infiltrate which obscures the dermoepidermal interface in much the same way as it does in erythema multiforme and fixed drug eruption (Fig. 3.34). This may be associated with focal epidermal cell death and overlying parakeratosis or confluent epidermal necrosis. ¹⁷⁹² The dermal infiltrate varies from a mild lymphocytic vasculitis to a heavy infiltrate which also extends between the vessels and is accompanied by variable hemorrhage. The dermal infiltrate is often wedge-shaped in distribution with the apex towards the deep dermis. PLEVA is considered further with the lymphocytic vasculitides in Chapter 8 (p. 230).

There is increasing recognition that viral and putative viral infections may be followed by a spectrum of cutaneous reactions that often includes the lichenoid tissue reaction. Examples include lichenoid lymphocytic vasculitis (see p. 226) which occurs with persistent herpes simplex infection, the Gianotti–Crosti syndrome (see p. 116) ¹⁷⁹³ and reactions resembling mild pityriasis lichenoides. A chronic lichenoid dermatosis has been reported in several patients as an unusual manifestation of both herpes simplex and varicella-zoster infection. There was a lichenoid reaction but no cytolytic host response. ¹⁷⁹⁴ Late stages of pityriasis rosea (included here as a putative viral infection) often show prominent epidermal cell death. Basal vacuolar change is usually present in these various reactions.

Asymmetric periflexural exanthem of childhood, also known as unilateral laterothoracic exanthem, is a putative viral disease with pruritic, unilateral macules and papules. It has a distinctive perisudoral CD8⁺ infiltrate at the interface. Lymphocytes have also been found around the eccrine coils. Apoptotic basal keratinocytes are also present.^{1795. and 1796.}

In some cases of perniosis, a mild lichenoid reaction is present. It is mostly focal. The changes are more prominent in cases of chilblain lupus (lupus pernio). There is usually no parakeratosis, unlike pityriasis lichenoides which also combines a lichenoid and vasculitic tissue reaction. In perniosis there is usually a thick layer of orthokeratin reflecting the acral site.

Paraneoplastic pemphigus (see p. 151) resembles erythema multiforme, with a lichenoid tissue reaction and dyskeratotic cells at different levels of the epidermis. Usually, foci of suprabasal acantholysis and clefting are also present. Subepidermal clefting has also been reported. A lichenoid variant of paraneoplastic pemphigus has been described without detectable autoantibodies. ¹⁷⁹⁷

Some lesions of pigmented purpuric dermatosis may show lichenoid as well as purpuric and chronic vasculitic features (see p. 233). The presence of purpura and hemosiderin are important clues to the diagnosis.

A lichenoid contact dermatitis has been seen after contact with rubber and certain clothing dyes, and following contact with chemicals used in the wine industry. In two personally studied cases, there was a patchy, band-like dermal infiltrate of lymphocytes with a few eosinophils and very mild basal spongiosis.

A unique pattern of dyskeratosis has been reported in cases of adult-onset Still’s disease (fever, polyarthralgia, lymphadenopathy, evanescent rash).^{1798. and 1799.} There are multiple dyskeratotic cells, singly or in aggregates, mainly located in the upper epidermis, including the stratum corneum. ¹⁷⁹⁸ There are no associated lymphocytes. The presence of neutrophils in the dermal infiltrate is another characteristic feature. ¹⁷⁹⁸

Some lesions of late secondary syphilis show a lichenoid reaction pattern (see p. 575). There is usually extension of the inflammatory infiltrate into the mid and deep dermis. Plasma cells are usually present in the infiltrate.

In lesions of porokeratosis, particularly the disseminated superficial actinic form, a lichenoid tissue reaction associated with a heavy superficial lymphocytic infiltrate can occur. A careful search will reveal the diagnostic cornoid lamella at the periphery of the infiltrate. The lichenoid infiltrate may be directed against the abnormal epidermal clones which emerge in this condition. Porokeratosis is considered in detail in Chapter 9 (p. 262).

The lichenoid reaction pattern is a prominent feature in lichenoid and fixed drug eruptions. In many other drug-induced cutaneous reactions, a very occasional Civatte body (apoptotic keratinocyte) may be seen in the basal layer or at a higher level within the epidermis. There may be an associated exocytosis of a few lymphocytes. Apoptotic cells are a valuable clue to the drug etiology of an otherwise non-specific spongiotic tissue reaction (see p. 116). These cells are usually easier to find in morbilliform drug eruptions.

In a phototoxic dermatitis there are scattered apoptotic keratinocytes (dyskeratotic cells, sunburn cells) at all levels of the epidermis. In severe cases confluent necrosis may be present. There is some telangiectasia of superficial dermal vessels, but very little dermal inflammation.

A patchy lichenoid reaction with associated melanin incontinence is seen in this uncommon condition (see p. 296).

A lichenoid reaction is present in some patients with erythroderma (see p. 507). Many of these cases may be drug induced.

A subset of patients with mycosis fungoides has lichenoid changes on biopsy. One study has found that lichenoid changes tend to be associated with intense pruritus and may connote a poor prognosis. ¹⁸⁰⁰ The presence of basal epidermotropism, nuclear atypia in the lymphocytes, and the presence of eosinophils and sometimes plasma cells in the dermal infiltrate are helpful in identifying the underlying mycosis fungoides. ¹⁸⁰⁰

The regression of viral warts, particularly plane warts, is associated with a lichenoid reaction pattern and exocytosis of cells into the epidermis. Keratinocytes in the stratum malpighii, presumably expressing viral antigen, are attacked by lymphocytes, resulting in death of the keratinocytes by apoptosis. Sometimes two or more lymphocytes ‘surround’ a keratinocyte, similar to the ‘satellite cell necrosis’ (lymphocyte-associated apoptosis) of graft-versus-host disease.

A lichenoid reaction pattern can be associated with a variety of epidermal tumors, where it appears to represent the attempted immunological regression of those lesions. This may be seen in seborrheic keratoses (the so-called ‘irritated’ seborrheic keratosis), solar keratoses (lichenoid solar keratoses) and intraepidermal carcinomas. The lichen planus-like keratosis represents a similar reaction in a solar lentigo and probably some other epithelial lesions.

A similar mechanism is involved in the partial regression of basal and squamous cell carcinomas and other cutaneous tumors. However, these circumstances do not conform to the definition of the lichenoid reaction pattern, namely basal epidermal cell damage. Accordingly they will not be considered further in this section.

In lichen amyloidosus there is an accumulation of filamentous material in basal cells, with their eventual death. The filamentous material is extruded into the dermis in a manner similar to the formation of colloid bodies. The basal cells possibly die by apoptosis but the accumulation of the filamentous material obscures this basic process (see p. 380).

In active lesions of vitiligo, careful search will often reveal an occasional lymphocyte in contact with a melanocyte. The destruction of melanocytes by lymphocyte-mediated apoptosis would explain the features of vitiligo (see p. 283).

A lichenoid reaction, localized to the red areas, is a rare complication in a tattoo.

A lichenoid reaction may be seen in several other circumstances in which it is not usually a feature. Examples include candidiasis of the lip and pityriasis rubra pilaris. A pin-point lichenoid reaction may also be seen in polymorphic light eruption. A mild lichenoid reaction with pigment incontinence was seen in one case of immunosseous dysplasia (OMIM 242900), which is caused by mutations in the SMARCAL1 gene. ¹⁸⁰¹

Magro and Crowson have reported 40 cases of lichenoid inflammation with a granulomatous component. ³⁴ A drug was implicated in 14 cases. Over one-third of these patients with drug-related eruptions had other medical illnesses associated with cutaneous granulomatous inflammation, such as rheumatoid arthritis, Crohn’s disease, and hepatitis C. ³⁴ A microbial trigger was implicated in 12 patients in the context of infective ‘id’ reactions to viral, fungal, or bacterial diseases. Hepatobiliary disease, rheumatoid arthritis, and cutaneous T-cell lymphoma were other associations. ³⁴ The drugs included antibiotics, lipid-lowering agents, ACE inhibitors, and anti-inflammatory drugs. ³⁴

A lichenoid and granulomatous reaction has since been reported in a patient presenting with erythroderma resulting from erythro­poietin. ¹⁸⁰² The author has seen a similar pattern produced by allopurinol.

Breza and Magro have also reported three cases of this combined pattern in three patients with atypical (non-tuberculous) mycobacterial infection. ¹⁸⁰³