Pseudo-Behçet's sdisease

Behçet's disease 

The diagnosis of BD is based on clinical criteria [3], [5], [12]. There are no pathognomonic laboratory tests. The pathergic skin test, the development of a pustule 24 hours after cutaneous trauma by a needle prick or the intradermal injection of saline, has been advocated as important diagnostic criteria [5], [14]. The positive pathergic skin test is positive much more often in Mediterranean and Middle-Eastern countries than in Europe and North America.

Several sets of criteria for the diagnosis of BD have been proposed [15], [16], [17], [18]. Some are more useful in defined geographic areas. The various criteria are carefully reviewed by Lee et al [5]. The most recent criteria were promulgated by the International Study Group on Behçet's Disease and published in 1990 (Table 1) [15].

Table 1. International study group on behÇet's disease criteria (1990)

	Recurrent oral ulceration	Minor aphthous, major aphthous, or herpetiform ulceration observed by physician or patient, which occurred at least three times in one 12-mo period.
	Plus 2 of:
	Recurrent genital ulceration	Aphthous ulceration or scarring observed by physician or patient.
	Eye lesions	Anterior uveitis, posterior uveitis, or cells in vitreous on slit lamp examination; or retinal vasculitis observed by ophthalmologist.
	Skin lesions	Erythema nodosum observed by physician or patient, pseudofolliculitis, or papulopustular lesions; or acneiform nodules observed by physician in postadolescent patients not on corticosteroid treatment.
	Positive pathergy test	Read by physician at 24–48 h.

Dermatologists recognize the vagaries of the pustular skin reactions or papulopustular skin lesions, because BD occurs in young persons who may also have folliculitis, acne vulgaris, or corticosteroid-induced acne or folliculitis as secondary or incidental findings [3], [4], [5], [19], [20]. Nevertheless, the papulopustular skin lesions are important cutaneous manifestations of BD.

The mucocutaneous manifestations of BD are the hallmarks of the disease [2], [3], [4], [7], [14], [21], [22]. They are quite common in populations with BD (Table 2). The cutaneous lesions are variable. One classification divides the skin findings into papulopustular lesions, reactive erythema, and vascular-based lesions (Table 3). Obvious overlap between categories is recognized.

Table 2. Mucocutaneous manifestations of Behçet's disease

	Symptom	Frequency of symptoms (%)
		Japan, 1991 [21]	Turkey, 1985 [14]	Germany, 1996 [22]	United States, 1999 [2]
	Oral aphthae	98	100	98	99
	Genital aphthae	73	77	79	83
	Ocular lesions	69	47	47	57
	Cutaneous lesions	87	78	78	100
	Number of patients	3316	496	130	108

Table 3. Cutaneous manifestations of Behçet's disease

	Papulopustular lesions	Reactive erythemas	Vascular-based lesions
	Pathergic skin hyper-reactivity	Erythema nodosum	Superficial thrombophlebitis
	Pseudofolliculitis	Erythema multiforme	Pyoderma gangrenosum-like lesions
	Acneiform nodules	Sweet's syndrome-like lesions	Palpable purpura and lesions of cutaneous small vessel vasculitis
			Pathergic skin hyperactivity

Behçet's disease evolves over time; months to years may elapse before the complete picture is recognized. The patient with complex aphthosis or uveitis may develop other criteria for BD during the evolution of the full-blown disease. The diagnosis should not be made until the patient's disease conforms to the diagnostic criteria. The prognosis of BD, although variable and often benign, is a potentially devastating one. The patient with pseudo-BD should be identified by the disease from which they suffer for both prognostic and therapeutic reasons.

Complex aphthosis 

Virtually all patients with BD suffer from recurrent aphthous stomatitis (RAS) [3], [7], [23], [24], [25]. RAS can be classified as simple versus complex aphthosis [3], [7], [24], [25]. RAS has been reviewed by several authors and is discussed by Zunt elsewhere in this issue. BD is also discussed elsewhere in this issue by MacCarthy, Garton, and Jorizzo.

Recurrent aphthous stomatitis has many synonyms: canker sores, aphthosis, aphthous ulcers, or recurrent oral ulcers. The word “aphthae” means ulcers. The author prefers the term recurrent aphthous stomatitis [7], [24], [25]. The lesions of RAS are discrete, round-to-oval erosions or shallow ulcers of the nonmasticatory oral mucosa. They typically have a perilesional erythematous halo and are covered by a grayish fibromembranous slough (Fig. 1). Sites of predilection include the buccal and labial mucosae, the lateral and ventral tongue, the floor of the mouth, and the soft palate and fauces. Lesions of the masticatory mucosa of the hard palate and maxillary and mandibular attached gingivae and dorsal tongue are unusual.

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Fig. 1. Recurrent aphthous stomatitis. Minor aphthous ulcers involve the labial mucosae but spare the lip vermilion and the keratinized gingivae of the masticatory mucosa.

Patients usually develop RAS during childhood or adolescence. Recurrences are less frequent and milder with increasing age. The prevalence of RAS varies with the population studied. Some populations, such as medical and dental students, have a prevalence rate of 50%. It is estimated that 20% of the general population has RAS during their childhood or early adult life.

The presence of the lesions of RAS is critical to the diagnosis of BD [5], [7]. The diagnosis is rarely made in the absence of oral aphthosis (Table 2). Aphthosis can be classified as simple aphthosis or complex aphthosis (Table 4). Patients with BD typically have complex aphthosis. Simple aphthosis is a common, episodic, short-lived type of RAS affecting 20% to 50% of the population in their youth [7], [24], [25]. Complex aphthosis is an uncommon, persistent, chronic type of RAS that may be associated with systemic diseases [7], [25], [26], [27]. Complex aphthosis patients may have anogenital aphthae. The presence of oral plus anogenital aphthae does not constitute a diagnosis of BD. The condition might be considered a forme fruste of BD [26], but the diagnosis of complex aphthosis is preferable to making an inaccurate diagnosis of BD.

Table 4. Classification of recurrent aphthous stomatitis

	Simple aphthosis	Complex aphthosis
	Common	Uncommon
	Episodic	Episodic or continuous
	Short-lived lesions	Persistent
	Few lesions	Few to many lesions
	3–6 episodes/y	Continuous ulcerations
	Heal quickly	Slow healing
	Minimal pain	Marked pain
	Little disability	Disabling
	Limited to oral cavity	May have genital lesions

The recurrent aphthae of both simple and complex aphthosis are classified morphologically as minor aphthous ulcers, major aphthous ulcers, and herpetiform ulcers (Table 5; Fig. 1, Fig. 2, Fig. 3, Fig. 4 [23], [24]. Some authors note an increased prevalence of major aphthous ulcers in patients with BD when compared with all patients with RAS [29], [30].

Table 5. Classification of recurrent aphthous stomatitis

	Type	% F	Age (onset)	Size (mm)	Number	Location	Prevalence (%)
	MiAU	56	10–19	<10	Few	Anterior	85
	MjAU	44	10–19	≥10	Few	Ant>posterior	10
	HU	73	20–29	1–2	Many	Both	5

Abbreviations: HU, herpetiform ulcers; MiAU, minor aphthous ulcers; MjAU, major aphthous ulcers.

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Fig. 2. Recurrent aphthous stomatitis. Minor aphthous ulcers are the most common form. They are less than 1 cm in diameter and heal without scarring.

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Fig. 3. Recurrent aphthous stomatitis. Major aphthous ulcers (periadenitis mucosa necrotica recurrens) are larger than 1 cm in diameter. They are particularly painful and heal with scarring.

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Fig. 4. Recurrent aphthous stomatitis. Herpetiform ulcers are grouped tiny papulovesicles, which become confluent shallow ulcers. Herpetiform ulcers tend to be numerous and painful. This is the least common form of recurrent aphthous stomatitis.

Successful management of patients with complex aphthosis requires an accurate diagnosis, classification of the disease, and recognition of causal or associated conditions, such as the following:

It is incumbent on the clinician to evaluate the patient with complex aphthosis for these conditions. Correction of the underlying condition, such as gluten-sensitive enteropathy by a gluten-free diet, can result in a substantial diminution of disease activity or a remission [31].

Ulcus vulvae acutum represents an acute severe episode of oral and vulvar aphthae (Fig. 5) often associated with an infectious gastroenteritis, such as tuberculous enterocolitis, typhoid fever, or Yersinia enterocolitis. On recovery, simple aphthosis may remain as the only remnant of the disease. Patients with rare combinations of signs and symptoms in the context of complex aphthosis have been reported as the MAGIC syndrome (mouth and genital ulcers with inflamed cartilage); the FAPA syndrome (fever, aphthosis, pharyngitis, and adenitis); and cyclic neutropenia. Aphthous-like oral ulcerations have been reported in HIV-positive patients. Lesions tend to be large and disabling. These lesions of complex aphthosis tend to occur in individuals with CD4+ counts less than 100 cells/mL. The differential diagnosis of this profound immunosuppressive state includes infectious or drug-induced oral ulcers. The diagnosis of HIV-associated aphthous-like oral ulcers is one of exclusion.

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Fig. 5. Ulcus vulvae acutum. A large major aphthous ulcer is present on the vulva of this patient who had oral and genital aphthae in association with a severe viral gastroenteritis. All lesions healed when she recovered from the gastroenteritis.

Anemia and hematinic deficiencies have been associated with lesions of RAS for many years. Several studies have confirmed the presence of a subset of patients who may be deficient in iron; folic acid; zinc; vitamins B1, B2, B6, and B12; and whose disease remits or improves dramatically with replacement of their deficiencies [28], [32], [33], [34], [35]. Hematologic screening should be considered for all patients with complex aphthosis, those patients with persistently troublesome signs and symptoms, and any patients with signs or symptoms of malabsorption or nutritional deficiency. Screening includes a complete blood count with red blood cell indices; serum levels of iron, zinc, and vitamin B12; red blood cell or serum folate; and antiendomysial, antigliadin or tissue transglutaminase antibody studies.

Gastrointestinal diseases have been associated with lesions of RAS for many years. Indeed, according to DuBois and van den Berghe [36], the word “sprue,” signifying the gastrointestinal disease, is derived from the Dutch word “spruw,” which means aphthosis. The association of lesions of RAS with gluten-sensitive enteropathy (sprue) has been recognized previously [31]. The malabsorption associated with gluten-sensitive enteropathy can lead to deficiencies of B vitamins and folate. Some authors report that both oral and gut lesions resolve with a gluten-free diet. Furthermore, some patients with lesions of RAS may not have symptoms of gluten-sensitive enteropathy, but yet the oral lesions improve with a gluten-free diet [37]. Patients with RAS may have symptomatic or asymptomatic gluten-sensitive enteropathy with gluten hypersensitivity or nutritional deficiencies, either or both of which may be related to the development of the lesions of RAS. Hunter et al [38] report, however, that in the absence of documented gluten-sensitive enteropathy, a double-blind controlled study of patients with RAS did not confirm that a gluten-free diet or a gluten-supplemented diet consistently yielded benefit or worsening for patients, but did show a large placebo effect.

The lesions of RAS may be associated with IBD, such as ulcerative colitis and Crohn's disease. Simple or complex aphthosis may antedate, coexist, or serve as a marker for increasing intestinal disease activity. Patients with IBD not only have lesions of RAS but may also have erythema nodosum; papulopustular lesions or lesions of pustular vasculitis; and inflammatory ocular disease, such as iritis and uveitis. The distinction between multisystem IBD and BD may be difficult [9], [11], [12], [13].

Clearly, complex aphthosis alone does not constitute BD. Furthermore, the patient with complex aphthosis should be evaluated for associated conditions or diseases, some of which are correctable causes of RAS. The oral lesions of BD are aphthous in nature and are classified best as complex aphthosis. Although some patients with complex aphthosis develop BD, some remain as sufferers of complex aphthosis for years until a cause is identified or the disease enters a spontaneous or therapeutically induced remission. Complex aphthosis is the major pseudo-BD encountered in a referral practice [10].

Erythema multiforme 

Erythema multiforme is a mucocutaneous reaction pattern to a variety of antigenic stimuli. The mucocutaneous nature of EM may lead the clinician to consider BD, particularly when the disease process is recurrent. EM is an immunologically mediated mucocutaneous disease. EM has a wide range of clinical expressions characterized by cutaneous, exanthematic papules and plaques that develop an iris or target pattern of concentric zones of inflammation. These skin lesions may develop severe edema producing a subepithelial blister (Fig. 6). These are the lesions termed erythema in many forms or erythema multiforme. The skin lesions may be limited in distribution or widespread.

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Fig. 6. Cutaneous target lesions of erythema multiforme. These vesiculobullous lesions are typical for the target or iris lesions of erythema multiforme. The center is the site of greatest damage with concentric rings of lesser damage noted by color and morphologic changes. These lesions are believed by some authors to represent the sine qua non lesion of erythema multiforme.

In addition to skin lesions, the mucosae may be involved. The oral lesions of EM are discussed by Ayangco and Rogers elsewhere in this issue. Oral, ocular, and genital mucosae may be affected. Oral lesions are erythematous plaques (Fig. 7), which may develop a subepithelial blistering process producing erosion covered by a hemorrhagic or fibromembranous crust. The vermilion of the lips is characteristically affected by oral EM (Fig. 8). This is a site not typically involved by aphthous lesions.

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Fig. 7. Oral lesions of erythema multiforme major. Oral lesions may be diffuse, causing a generalized stomatitis. The gingivae and buccal mucosae are involved by a confluent inflammatory reaction with erosions and a covering fibromembranous slough.

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Fig. 8. Oral lesions of erythema multiforme major. Lesions of the vermilion of the lip are characteristic of erythema multiforme. Vesiculobullous lesions erode; are covered by a fibromembranous slough; and may become hemorrhagic with deeper, more necrotic involvement.

The spectrum of disease diagnosed as EM is broad and includes (1) EM minor, (2) EM major, (3) Stevens-Johnson syndrome (SJS), (4) toxic epidermal necrolysis (TEN), and (5) oral EM Table 6, Table 7.

Table 6. The spectrum of erythema multiforme

	Disorder	Original Author
	Erythema multiforme minor	Hebra [39]
	Erythema multiforme major	Thomas [41]
	Stevens-Johnson syndrome	Stevens and Johnson [40]
	Toxic epidermal necrolysis	Lyell [42]
	Oral erythema multiforme	Kennett [43]

Table 7. Spectrum of erythema multiforme

		Course	Cutaneous involvement	Mucous membrane involvement	Duration	Prognosis
	Erythema multiforme minor	Acute, self limited, occasionally recurrent	Typical symmetric target lesions/raised atypical targets acrally distributed. Blisters, when present, involve <10% of BSA.	Absent or limited to one mucosal site, usually oral	1–3 wk	Recovery; may be episodic
			(−) Nikolsky's sign
	Erythema multiforme major	Acute, self limited	Typical symmetric target lesions/raised atypical targets acrally distributed. Blisters, when present, involve <10% of BSA.	Involvement almost exclusively limited to the oral cavity; may be the most prominent element of the disease	1–6 wk	Mortality may occur; may be episodic
			(−) Nikolsky's sign
	Stevens-Johnson syndrome	Acute, progressive systemic illness	Widespread small blisters, purple macules or flat atypical target lesions predominantly occurring on the torso.	Involvement of one or more mucous membrane with possibility of scarring; extensive mucosal involvement is characteristic	2–6 wk	10% mortality
			(+) Nikolsky's sign.
			Epidermal detachment <10% of BSA
	Toxic epidermal necrolysis	Prodromal mucosal inflammation followed by acute systemic illness	Widespread small blisters, purple macules or flat atypical target lesions predominantly occurring on the torso.	Involvement of one or more mucous membrane with possibility of scarring; extensive mucosal involvement.	2–6 wk	30% mortality
			(+) Nikolsky's sign.
			Epidermal detachment 30% or more of BSA.
			Nails may be shed.
	Oral erythema multiforme	Acute, self-limited, occasionally recurrent or chronic	Typical symmetric target lesions acrally distributed in 25% of patients	Limited to the oral cavity and the lips	Cyclic episodes last from 10 days to 6 wk. Frequency of episodes occur from every 3 wk to annually.	Chronic with recurrent episodes over protracted period of time.

Abbreviations: BSA, body surface area.

Erythema multiforme was first described by Hebra [39] in 1886 as a relatively benign condition characterized by skin lesions with concentric color changes, which were symmetrically distributed. Lesions of EM are located primarily on the extremities and have a tendency to recur. The disease tends to have an episodic course with duration of 1 to 4 weeks. It usually occurs in young, healthy individuals. The entity described by Hebra [39] did not mention mucosal involvement, but most authors have accepted occasional erythematous or erosive oral lesions as part of EM.

Stevens and Johnson [40] reported two children who had fever, conjunctivitis, stomatitis, and a generalized exanthem with skin lesions of purplish cutaneous maculae and necrotic centers, which were distinct from EM. In 1950, Thomas [41] suggested that EM and SJS were variants of the same pathologic process. He proposed that the mild cutaneous form of Hebra [39] be called EM minor, and the more severe mucocutaneous varieties, as described by Stevens and Johnson [40] and others, be called EM major.

In 1956, Lyell [42] reported a series of patients with a life-threatening, rapidly evolving mucocutaneous reaction characterized by widespread erythema, necrosis, and bullous detachment of the epidermis resembling scalding, a condition currently known as toxic epidermal necrolysis.

In 1968, Kennett [43] described an inflammatory stomatitis with lesions typical of the oral lesions of EM as “EM affecting the oral cavity.” In 1978, Lozada and Silverman [44] reported 50 patients with oral EM lesions dominating the clinical picture. Similar patients were reported by Bean and Quezada [45] in 1983. Some authors including Huff et al [46] aver that “…diagnosis of EM of illnesses characterized by only acute mucosal inflammation without skin lesions is unjustified: the typical skin lesion is sine qua non for the diagnosis of EM.”

Significant differences exist among EM minor, EM major, SJS, and TEN with regard to severity and clinical expression. All variants, however, share two common features: typical or less typical cutaneous target lesions and satellite cell or more widespread necrosis of the epithelium. These features are considered to be sequelae of a cytotoxic immunologic attack on keratinocytes expressing non–self-antigens. These antigens are primarily microbial (viruses) or drugs and in rare instances histocompatibility antigens [47]. Although the precise pathogenesis is unknown, there is currently a tendency to consider EM, both minor and major, as part of one spectrum that is most often triggered by viral infections, and SJS and TEN as a separate one most often elicited by drugs with EM major and SJS representing a bridge in the continuum of EM [48], [49].

The oral lesions of EM begin as erythematous maculae, which evolve by a vesiculobullous process to superficial erosions covered by a yellow fibropurulent membrane or a hemorrhagic crust (see Fig. 7, Fig. 8). Lesions affect both nonkeratinized and keratinized mucosal surfaces and the vermilion of the lips, whereas aphthae affect only the nonkeratinized mucosa. The lesions are less discrete than aphthae and become confluent as the reactive process evolves. The genital lesions have a similar morphology and progression. The oral lesions are painful. Patients suffer eating, drinking, and swallowing difficulties.

In severe episodes, mucosal lesions of EM may extend from the anterior oral cavity to involve the oropharynx, hypopharynx, larynx, esophagus, and upper respiratory tree. Lesions may also involve the nasopharynx and nose. Ocular lesions involve the bulbar and palpebral conjunctivae with severe external eye involvement (Fig. 9). Scarring in the form of cicatrizing conjunctivitis and symblephara may occur. Approximately 40% of patients with the SJS-TEN forms of EM develop ocular or anogenital lesions [47]. Oral and lip lesions usually heal without scarring, but scarring sequelae can occur with throat, esophageal, bronchial, or anogenital involvement.

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Fig. 9. Ocular lesions of Stevens_Johnson syndrome. The bulbar and palpebral conjunctivae are involved. Symblephara or scar bands between the conjunctival surfaces may follow such severe involvement.

The rapid onset of the clinical picture, the characteristic nature of the cutaneous lesions of EM, and the diffuse nature and distribution of the mucosal lesions permit a diagnosis of the EM spectrum of disease in most circumstances. Few clinicians include BD in this exanthematic mucocutaneous presentation. Some patients, however, have recurrent episodes of EM with oral, ocular, anogenital, and skin involvement. When recurrent disease is present with mucocutaneous manifestations, BD is included in the differential diagnosis. Other EM patients have a recurrent or chronic mucosal disease, which is centered on oral lesions (oral EM) [43], [44], [45], [50].

The most commonly recognized cause for recurrent EM is recurrent herpes simplex virus infections. The eruption of the lesions of recurrent herpes simplex virus labialis (or other sites) is followed by the reactive efflorescence of EM. Despite important clinical differences, these patients may be considered to have BD.

Oral EM patients often have lesions of the vermilion of the lip [44], [45], [50]. Such lesions are quite unusual for BD. In addition, the oral lesions are not discrete aphthae but are more diffuse vesiculoulcerative lesions (see Fig. 8). About 25% of oral EM patients have typical EM target lesions of the skin or anogenital lesions of EM (see Fig. 6). This clinical pattern may be confused with BD. Ocular involvement with oral EM is rare.

The clinician must be aware of the diagnostic dilemma of recurrent EM or recurrent oral EM in the differential diagnosis of BD. Recognition of morphologic and other clinical differences permits the careful clinician to recognize EM and recurrent oral EM as pseudo-BD.

Mucous membrane pemphigoid 

Mucous membrane pemphigoid is an immunologically mediated subepithelial blistering disease with a predilection for oral, ocular, and, occasionally, anogenital and cutaneous lesions [51], [52], [53]. MMP is part of the spectrum of pemphigoid diseases, which include bullous pemphigoid; pemphigoid gestationis; oral pemphigoid; ocular pemphigoid; Brunsting-Perry pemphigoid; and several other variants of bullous pemphigoid, such as pruritic pemphigoid and pemphigoid nodularis [51], [54]. Scarring can occur resulting in permanent sequelae (cicatricial pemphigoid). Lesions of pemphigoid result from an immunologic attack on components of the basement membrane zone resulting in a subepithelial blister.

The mucosal lesions are characterized by erythema, edema, blisters, and erosions. Lesions tend to be diffuse affecting the nonkeratinized and the keratinized oral mucosa, similar to the mucosal lesions of EM (Fig. 10). Gingival involvement is typical of MMP [55], [56]. It presents as a desquamative gingivitis (Fig. 11). Individual lesions are vesiculoerosive patches, which do not resemble the discrete aphthae of complex aphthosis or BD. Genital lesions also tend to be diffuse and vesiculoerosive rather than discrete.

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Fig. 10. Oral lesions of mucous membrane pemphigoid. Erosive, ulcerative lesions develop from erythematous plaques by the subepithelial vesiculobullous pathogenic mechanism. Note the large lesion of the hard palate.

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Fig. 11. Desquamative gingivitis lesions of mucous membrane pemphigoid. Desquamative gingivitis begins as erythema and edema of the attached gingivae. It progresses to desquamation of the epithelium as the subepithelial vesiculobullous process continues. Blisters are noted on the left lower alveolar gingivae.

Ocular lesions of MMP begin as conjunctivitis, as can the ocular lesions of BD. The inflammatory process of MMP, however, leads to symblepharon formation with scar bands developing between the palpebral and bulbar conjunctivae (Fig. 12). The ocular manifestations of MMP are chronic and usually slowly progressive, whereas the ocular manifestations of EM, SJS, and TEN tend to be acute and progressive. The ocular findings of BD include iritis and uveitis, which are uncommon in EM, SJS, TEN, or MMP.

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Fig. 12. Ocular lesions of mucous membrane pemphigoid. Ocular lesions begin as conjunctivitis and progress to symblephara and entropion in advanced disease. Scarring forms in the conjunctival tissues.

The cutaneous lesions of MMP are vesiculobullous with large, diffuse, inflammatory patches and plaques, which may develop a subepidermal blister. Again, the lesions differ from the cutaneous lesions of BD by being bullous and diffuse.

The diffuse blistering and erosive nature of MMP separates it from BD. Nevertheless, some clinicians, when faced with a patient suffering oral, ocular, and anogenital lesions, implicate BD in the differential diagnosis. Recognition of morphologic and clinical manifestations of MMP permits the careful clinician to recognize MMP as pseudo-BD.

VVG variant of erosive oral LP 

The VVG variant of erosive oral LP is an immunologically mediated mucocutaneous disease with oral, genital, and cutaneous manifestations [57], [58], [59], [60]. Lesions result from inflammatory destruction of epithelial basal cell keratinocytes resulting in an interface inflammatory reaction pattern (lichenoid tissue reaction).

Clinically, the cutaneous lesions of LP are papulosquamous. These scaly papules are purple, polygonal, and pruritic. They are not reminiscent of any skin lesions of BD but are discrete.

The mucosal lesions may be discrete or diffuse (Fig. 13). Oral lesions of LP are discussed by Eisen and oral and genital manifestations of LP are discussed by Rogers and Eisen elsewhere in this issue. Oral lesions of LP may be reticular, white, lacy or lattice-like, hyperkeratotic, raised lesions (Fig. 14). Some may be erythematous, diffuse patches and plaques. A third type of lesion is erosive patches. The gingivae are typically involved in the VVG variant (Fig. 15). The lesions are similar to the desquamative gingivitis of MMP but tend to be less erosive and more firm and infiltrated with a white hyperkeratotic element at times. Genital lesions are also discrete or desquamative and erosive (Fig. 16).

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Fig. 13. Erosive oral lesions of lichen planus. A large erosive lesion present in the deep left buccal mucosa. It is surrounded by reticular white hyperkeratosis.

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Fig. 14. Hyperkeratotic lesions of oral lichen planus. The hyperkeratotic reticular lesions may be asymptomatic until they become erosive. These are the best lesions for biopsy material.

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Fig. 15. Gingival lesions of the vulvovaginal_gingival variant of erosive oral lichen planus. The gingivae are involved by a desquamative gingivitis form of erosive oral lichen planus. This patient has unilateral involvement.

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Fig. 16. Vulvar lesions of the vulvovaginal_gingival variant of erosive oral lichen planus. The introitus is erythematous, eroded, and very tender. The erosive disease can extend into the vagina. Vaginal stenosis may develop.

Ocular lesions are rare. The papulosquamous cutaneous and reticular, erythematous, or erosive mucosal lesions are distinct. They may affect the nonkeratinized or keratinized oral mucosa. Neither the oral lesions nor the cutaneous lesions resemble the mucocutaneous manifestations of BD. Nevertheless, some clinicians, when faced with a mucocutaneous disorder, particularly with active genital lesions, may implicate BD in the differential diagnosis. Recognition of the clinical and morphologic manifestations of the VVG variant of erosive oral LP permits the careful clinician to recognize this condition as pseudo-BD.

Summary 

The conditions of complex aphthosis, EM, MMP, and the VVG variant of erosive oral LP may be confused by clinicians who refer patients for diagnosis and management of BD (Table 8). The mucocutaneous presentations or the presence of complex aphthosis, the hallmark of BD, can be confusing and lead to the referral of the patient for a diagnosis of BD. The astute clinician evaluating patients for BD considers pseudo-BD in the differential diagnosis of the mucocutaneous manifestations of BD.

Table 8. Differential diagnosis of pseudo-Behçet's disease

		Behçet's disease	Complex aphthosis	Erythema multiforme	Mucous membrane pemphigoid	VVG variant of erosive oral LP
	Age	15–30 y	15–30 y	20–35 y	50–75 y	40–70 y
	Oral lesions	Typical discrete aphthae	Typical discrete aphthae	Red patches, erosions, crusts	Desquamative gingivitis, erosions	Desquamative gingivitis, hyperkeratotic plaques, erosions
	Genital lesions	Aphthae	Occasional aphthae	Red patches, erosions, crusts	Erosions	Hyperkeratotic papules, erosions
	Ocular lesions	Conjunctivitis, iritis, uveitis	Nil	Conjunctivitis	Conjunctivitis, symblephara	Rare
	Cutaneous lesions	Variable, papulopustular, erythema nodosum	Nil	Red patches, target lesions, bullous lesions	Bullous lesions	Purple polygonal pruritic papules
	Histopathology	Vascular-based inflammation, lymphocytic inflammation	Lymphocytic inflammation	Perivascular round cell inflammation with epithelial damage	Subepithelial blister	Lichenoid tissue reaction
	Immunopathology	Nonspecific	Nonspecific	Nonspecific	Linear deposition of IgG, C3 along the basement membrane zone	Shaggy deposition of fibrinogen +/− cytoid bodies IgM, IgA

Abbreviations: LP, lichen planus; VVG, vulvovaginal-gingival.