Tumid lupus erythematosus

INTRODUCTION — Tumid lupus erythematosus (TLE), also known as lupus erythematosus tumidus, is a highly photosensitive form of cutaneous lupus erythematosus (cutaneous LE) that classically presents with erythematous, edematous plaques (picture 1A-C). Traditionally, TLE has been classified as a subset of chronic cutaneous LE. However, the classification of TLE is controversial.

TLE is generally a skin-limited disorder that responds well to photoprotection plus topical treatment or oral antimalarial therapy. Unlike other subtypes of cutaneous LE, associated systemic lupus erythematosus (SLE) is very rare.

The clinical features, diagnosis, and management of TLE will be reviewed here (algorithm 1). Other manifestations of cutaneous LE are reviewed separately. (See "Overview of cutaneous lupus erythematosus".)

EPIDEMIOLOGY — TLE is an uncommon disorder. The exact prevalence and incidence are unknown.

Unlike systemic lupus erythematosus, which exhibits a strong female predominance, TLE affects females and males nearly equally [1,2]. Some studies have found a slight male predominance [1]. The age of onset for TLE varies widely but is often around 30 to 40 years [1,3]. TLE in infancy and childhood is rare [4,5].

PATHOGENESIS — The pathogenesis of TLE is unclear. Ultraviolet (UV) light exposure, immune system dysregulation, and other factors may contribute to the development of TLE:

●Ultraviolet light – UV irradiation can trigger clinical manifestations of TLE. The mechanism may involve induction of keratinocyte apoptosis and impaired clearance of apoptotic cells, as well as the induction of externalization of autoantigens [6].

The photosensitive nature of TLE has been verified through phototesting [7,8]. In a review of phototesting results from 32 patients with clinical manifestations of TLE, 81 percent demonstrated photosensitivity, a higher prevalence than seen in patients with discoid lupus erythematosus, subacute cutaneous lupus erythematosus, or systemic lupus erythematosus [7]. In addition, for 22 patients (69 percent), provocative phototesting with ultraviolet A (UVA) or ultraviolet B (UVB) light produced lesions with clinical and histologic findings consistent with lupus erythematosus. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection", section on 'Phototesting'.)

The induction of TLE following exposure to UV light can be delayed, making it difficult for patients to associate exacerbations of TLE with sun exposure. In a study of 60 patients with TLE, phototesting provoked characteristic TLE lesions in 72 percent of patients, with a mean time to induction of TLE of 7.5 days [9]. Some inductions occurred more than 21 days after phototesting. Further, in an analysis of 40 patients with TLE in which provocative phototesting elicited characteristic lesions in 70 percent, 12 of the 20 patients (60 percent) who denied a history of photosensitivity had pathologic test reactions [1].

●Immune system dysregulation – Dysregulation of the immune system, particularly of T cell subsets, is postulated to contribute to TLE. A study of 39 patients with cutaneous lupus erythematosus (including 21 patients with TLE) found a significant decrease in T regulatory cells in patients with TLE [10]. Other immune alterations found in subtypes of cutaneous lupus erythematosus include decreased epidermal Langerhans cells, increased plasmacytoid dendritic cells, upregulated type I interferon and tumor necrosis factor (TNF)-alpha, and the detection of Th17 cells [6].

●Other factors – Increased frequency of smoking compared with the general population has been reported among patients with TLE [11]. In addition, there are rare reports of drug-induced TLE. Examples include TLE secondary to anti-TNF-alpha agents [12-14], a thiazide diuretic [15], highly active antiretroviral therapy [16], an angiotensin converting enzyme (ACE) inhibitor [17], and bortezomib [18,19]. A TLE-like eruption to ustekinumab has also been reported [20]. TLE following sex reassignment surgery has also been described [21].

CLASSIFICATION — The cutaneous manifestations of lupus erythematosus are divided into lupus erythematosus-specific skin disease and lupus erythematosus-nonspecific skin disease. The three major subtypes of lupus erythematosus-specific skin disease are acute, subacute, and chronic cutaneous lupus erythematosus (CCLE). Traditionally, TLE has been classified as a subtype of CCLE (table 1). However, this classification is controversial [3,16,22-25]. Some authors propose classifying TLE as a distinct subtype of cutaneous lupus erythematosus (ie, intermittent cutaneous lupus erythematosus) [16,22], while others question the inclusion of TLE along the lupus erythematosus spectrum [24]. (See "Overview of cutaneous lupus erythematosus".)

Key features used to support a distinction between TLE and CCLE include the following features of TLE:

●Exquisite photosensitivity (greater than in CCLE)

●Absence of common features of CCLE, including atrophy, scarring, and dyspigmentation

●Frequent absence of common histologic features of CCLE, including epidermal involvement, interface dermatitis, and hair follicle alteration

●More prominent mucin deposition than in discoid lupus erythematosus (the most common type of CCLE)

Additional distinctions between TLE and other lupus erythematosus-specific skin diseases include the rarity of associated systemic lupus erythematosus and the less frequent detection of anti-double-stranded DNA (dsDNA) antibodies, anti-Ro/SSA, and anti-La/SSB antibodies in patients with TLE (figure 1) [3]. Moreover, TLE generally has a more favorable prognosis than other types of cutaneous lupus erythematosus. (See 'Laboratory findings' below and 'Prognosis' below.)

CLINICAL MANIFESTATIONS — TLE classically manifests as asymptomatic, erythematous, edematous plaques without scale or ulceration (picture 1A-C) [1]. Unlike discoid lupus erythematosus (DLE), there is a lack of follicular plugging, atrophy, or scarring. TLE tends to involve exposed areas of skin, such as the face, upper back, upper chest (V-neck distribution), extensor arms, and shoulders. However, there are rare reports of TLE involving the lower extremities [26]. In temperate climates, TLE most often occurs during the summer months.

In some patients, papules and plaques of TLE appear less edematous at the center, forming an annular configuration that may mimic annular subacute cutaneous lupus erythematosus (SCLE). A lack of scale and lack of resolution with dyspigmentation distinguishes TLE from SCLE. Less common manifestations of TLE include a Blaschkoid distribution (figure 2) [27,28], scalp involvement mimicking alopecia areata [29], and periorbital edema [30].

TLE tends to persist for days or weeks and typically follows a chronic, recurring pattern. TLE heals without scarring, atrophy, or dyspigmentation; such features should raise suspicion for an alternative diagnosis of DLE or concomitant DLE [1,31,32]. Spontaneous resolution is possible. (See 'Prognosis' below.)

Occasionally, a patient with TLE may first present to a subspecialist other than a dermatologist or rheumatologist. For example, TLE has been reported to initially manifest as eyelid edema, therefore prompting first evaluation by an ophthalmologist [33].

LABORATORY FINDINGS — In the majority of patients with TLE, antinuclear antibodies (ANAs) will be negative. ANA positivity may occur in less than 20 percent of patients [1,34,35]. In rare cases, other serologies (eg, anti-double-stranded DNA, anti-Ro/SSA, or anti-La/SSA antibodies) are positive, or complement levels are decreased [34].

A potential association between higher serum homocysteine levels and cutaneous lupus erythematosus has been reported [36]. Further data are necessary to clarify the relationship between serum homocysteine levels and TLE.

ASSOCIATION WITH SYSTEMIC LUPUS ERYTHEMATOSUS — Coexistence of TLE and systemic lupus erythematosus (SLE) is rare [16]. No occurrences of SLE in patients with TLE were documented in several retrospective studies with 14 to 40 patients with TLE [1,34,37]. Examples of the rare reports of systemic disease include a prospective study that found evidence of SLE in 1 of 15 patients with TLE who were followed for a mean of seven years [31] and a retrospective study that found evidence of SLE in 2 of 15 patients with TLE [38].

HISTOPATHOLOGY — TLE is characterized by a dermal perivascular and periadnexal lymphocytic infiltrate. Interstitial mucin deposition is often abundant in the dermis. Papillary dermal edema is common.

Classically, there is a lack of involvement of the epidermis and the dermal-epidermal junction. However, there are reports of minor involvement of the epidermis in patients with TLE, prompting some authors to question whether an absence of epidermal alterations should be considered a consistent feature [34]. In a retrospective review of 26 patients with TLE, minimal epidermal changes (epidermal atrophy, vacuolar degeneration of basal cells, hyperkeratosis) and minimal follicular plugging were present in skin biopsy specimens of 18 patients, and specimens from 11 patients showed an enhanced and irregular basement membrane at the dermal-epidermal junction [2]. Additionally, in a retrospective review of 25 patients, mild epidermal alterations, most frequently focal basal vacuolization, were observed in 52 percent of tissue biopsies [34].

Direct immunofluorescence (DIF) studies are typically negative but may be positive in up to 50 percent of cases [16,31,38,39]. When DIF studies are positive, generally immunoglobulin G (IgG) and/or immunoglobulin M (IgM) are seen along the dermoepidermal junction [16,31,39].

DIAGNOSIS — The diagnosis of TLE is established based upon the recognition of consistent clinical manifestations and histopathologic findings. TLE should be suspected in patients presenting with erythematous, edematous, smooth plaques, particularly when located in photo-exposed areas on the face, upper trunk, or upper extremities. A skin biopsy is necessary to confirm the diagnosis.

Other tests that are not typically necessary, but can support a diagnosis of TLE, are the results of provocative phototesting and the response to antimalarial treatment. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection", section on 'Phototesting'.)

Key findings in TLE are reflected in proposed diagnostic criteria [1]:

●Clinical – Erythematous, succulent, urticarial-like, nonscarring plaques with a smooth surface in sun-exposed areas.

●Histologic – Perivascular and periadnexal lymphocytic infiltration, interstitial mucin deposition, and, in some cases, scattered neutrophils; no epidermal involvement or alteration of the dermoepidermal junction.

●Phototesting – Reproduction of skin lesions after ultraviolet A (UVA) and/or ultraviolet B (UVB) irradiation.

●Treatment – Rapid and effective systemic treatment with antimalarial drugs.

Serologic evaluation is not helpful in establishing the diagnosis of TLE. However, given the rare association of TLE with systemic lupus erythematosus (SLE), a thorough history, review of systems, and physical examination should be performed at the time of diagnosis to evaluate for signs or symptoms of SLE. Serologic evaluation including antinuclear antibodies should be performed in patients with signs or symptoms suggestive of SLE. (See 'Laboratory findings' above and 'Association with systemic lupus erythematosus' above and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults".)

History and physical examination — The clinical evaluation of patients with suspected TLE should include a full skin examination, with particular attention to the head, neck, chest, back, and arms. A photodistributed eruption of smooth, erythematous plaques that lack associated scale, atrophy, scarring, and dyspigmentation is consistent with TLE. Lower extremity involvement is rare. (See 'Clinical manifestations' above.)

When asked, patients with TLE may report an association between exacerbations of skin disease and sun exposure. However, given that exacerbations may occur days to a few weeks after sun exposure, not all patients recognize an association. (See 'Pathogenesis' above.)

Skin biopsy — The skin biopsy should be taken from an active, erythematous plaque. A 4 mm punch biopsy is typically performed and should include the full thickness of the dermis. A 3 mm punch biopsy may be sufficient and is an alternative for cosmetically-sensitive areas, such as the face. The classic histologic findings of TLE are a dermal perivascular and periadnexal lymphocytic infiltrate with abundant interstitial mucin. (See 'Histopathology' above.)

DIFFERENTIAL DIAGNOSIS — TLE can be confused with other disorders that may present with erythematous, smooth plaques on the upper body, such as Jessner's lymphocytic infiltrate (JLI), polymorphic light eruption (PMLE), reticular erythematous mucinosis, and pseudolymphoma. The most challenging distinction is between TLE and JLI:

●Jessner's lymphocytic infiltrate – JLI is a rare disorder often considered to exist along a spectrum with TLE. The clinical appearance of TLE and JLI can be remarkably similar. JLI tends to present with erythematous, dermal papules or nodules without scale, generally involving the face or upper back (picture 2A-B). Similar to TLE, patients with JLI may have positive antinuclear antibodies and direct immunofluorescence studies [40]. (See "Jessner's lymphocytic infiltrate".)

There is significant overlap in the histologic findings of JLI and TLE. Although more abundant mucin in the dermis in TLE has been proposed as a distinguishing factor, a blinded histologic review of 33 biopsy specimens from patients diagnosed with TLE or JLI found only slight epidermal atrophy more common in TLE after a reclassification of specimens during expert histologic review [37].

●Polymorphous light eruption – PMLE most often presents as photodistributed, pruritic, erythematous or skin-colored papules or plaques (picture 3). The skin manifestations typically appear hours after sun exposure, though longer delays can occur. The course of PMLE tends to be shorter than TLE; PMLE usually resolves within several days if sun exposure is avoided [1]. Unlike TLE, exacerbations of PMLE tend to lessen with sequential exposures to ultraviolet light (ie, the "hardening" effect). Therefore, PMLE tends to be most severe in the spring. (See "Polymorphous light eruption".)

●Reticular erythematous mucinosis – Reticular erythematous mucinosis primarily affects young to middle-aged women. It most often occurs on the chest and upper back as reticulated, macular erythema or reticulated, erythematous plaques (picture 4). Histologic features are similar to TLE [41,42]. A study comparing the immunohistochemical and histopathologic features of reticular erythematous mucinosis with TLE found that in reticular erythematous mucinosis, lymphocytes were more scattered and more superficial and mucin deposition was more superficial in the dermis [43]. In addition, in reticular erythematous mucinosis, immunoglobulin and complement deposition along the dermoepidermal junction was seen less frequently, and there were fewer plasmacytoid dendritic cells. Some clinicians consider reticular erythematous mucinosis a variant of TLE or discoid lupus erythematosus.

●Pseudolymphoma – Cutaneous pseudolymphoma has a variable clinical presentation but may present with a single or multiple erythematous dermal nodules, typically occurring on the face, chest, or upper extremities (picture 5). The condition is not photosensitive, and nodules or plaques tend to persist without treatment. Histopathology readily distinguishes cutaneous pseudolymphoma from TLE. (See "Cutaneous B cell pseudolymphoma" and "Cutaneous T cell pseudolymphomas".)

●Granuloma faciale – Granuloma faciale is a rare, chronic inflammatory skin disorder that most often presents as a red-brown or violaceous, asymptomatic plaque or nodule on the face. Multiple sites of facial involvement and extrafacial involvement may also occur. The histopathologic findings distinguish granuloma faciale from TLE. Characteristic histopathologic findings include a diffuse inflammatory infiltrate in the upper half of the dermis that contains neutrophils, eosinophils, lymphocytes, histiocytes, and plasma cells. A "Grenz zone," a thin zone of uninvolved papillary dermis that separates the epidermis from the inflammatory infiltrate, is often present. (See "Granuloma faciale".)

Other disorders may resemble TLE. In a case report, pseudovasculitis due to microthrombi in a patient with catastrophic antiphospholipid antibody syndrome mimicked the erythematous papules and plaques of TLE [44].

TREATMENT — TLE is a benign, typically asymptomatic condition that may spontaneously resolve over time. However, TLE can be disfiguring, and spontaneous resolution is unpredictable. Therefore, most patients desire treatment. (See 'Prognosis' below.)

Most patients can be treated effectively with photoprotection and pharmacologic therapy with topical corticosteroids, intralesional corticosteroid injections, topical calcineurin inhibitors, and/or oral antimalarial drugs (algorithm 1). The extent of skin involvement determines the initial approach to treatment. (See 'Limited disease' below and 'Extensive disease' below.)

General measures — Due to the photosensitive nature of TLE, diligent photoprotection is paramount to treatment. Other interventions that may be beneficial include periodic assessment for vitamin D deficiency and smoking cessation:

●Photoprotection – Patients should engage in:

•Daily application of a water-resistant, broad-spectrum sunscreen with a sun protection factor (SPF) of 30 or higher as well as frequent reapplication during sun exposure, including exposure through window glass

•Avoidance of peak sun hours (ie, 10 AM to 4 PM) when possible

•Use of sun-protective clothing

Proper use of sunscreen and sun-protective measures are reviewed in detail separately. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection", section on 'Photoprotection' and "Selection of sunscreen and sun-protective measures".)

The benefit of photoprotection is illustrated in an intraindividual study in which 25 patients with cutaneous lupus erythematosus (cutaneous LE), including 17 patients with TLE, received ultraviolet A (UVA) irradiation on one side of the upper back in SPF 60 sunscreen-treated, vehicle-treated, and untreated sites [45]. The same procedure was performed with ultraviolet B (UVB) light on the contralateral back. Although none of the 17 patients with TLE developed TLE in the sunscreen-treated areas after UVA or UVB irradiation, 14 patients (82 percent) developed lesions in the vehicle or untreated areas.

●Periodic assessment for vitamin D deficiency – Strict photoprotection is a risk factor for vitamin D deficiency. Assessment for vitamin D deficiency and supplementation are reviewed separately. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

●Smoking cessation – Cigarette smoking may play a role in the development of cutaneous LE and may negatively impact antimalarial therapy [46,47]. In a retrospective analysis of 405 patients with cutaneous LE and/or systemic lupus erythematosus, the frequency of cigarette smoking was higher amongst patients with cutaneous LE and particularly amongst those with discoid lupus erythematosus or TLE [11]. We encourage smokers with TLE to discontinue smoking. (See "Overview of smoking cessation management in adults" and "Initial management of discoid lupus erythematosus and subacute cutaneous lupus erythematosus", section on 'Smoking cessation'.)

Limited disease — Local therapy is usually sufficient for patients with limited body surface area involvement (eg, one to several small plaques).

Preferred initial therapy — Topical corticosteroids are the typical initial therapies for limited TLE (algorithm 1). However, efficacy data are limited.

Topical corticosteroids

●Administration – A typical initial treatment course is twice-daily application of a topical corticosteroid for two to four weeks. Marked improvement (ie, a significant reduction in erythema and plaque thickness) from topical corticosteroid therapy is usually evident within two weeks.

TLE on the trunk or extremities can be treated with a moderate- or high-potency (group 1 to 4) topical corticosteroid (table 2). Although lower-potency agents (group 5 or 6) are generally preferred for facial involvement to minimize risk for corticosteroid-induced cutaneous atrophy, moderate- or high-potency topical corticosteroids may be used for short periods to accelerate improvement (table 2). For example, a high-potency agent (group 1 to 3 (table 2)) can be used twice daily for the first four days, followed by use of the lower-potency agent.

Long-term, continuous treatment with topical corticosteroids is not desirable because of the potential for adverse cutaneous effects, including skin atrophy. Alternative therapies should be implemented if there is an insufficient response after four weeks. (See "Topical corticosteroids: Use and adverse effects" and 'Failure of initial therapy' below.)

●Efficacy – Data to support topical corticosteroid therapy include a Spanish retrospective study in which 21 of 26 patients treated with moderate-potency topical corticosteroids in conjunction with photoprotective measures had clearance of skin manifestations of TLE [2]. In addition, a German retrospective study found that 18 of 40 patients treated only with topical corticosteroids (potency not specified) or sunscreen with an SPF of 15 or higher experienced complete resolution of TLE plaques [1]. In contrast, in a retrospective study conducted in Thailand, only 1 of 14 patients experienced complete remission with topical corticosteroids (potency not specified) and sunscreen [38].

●Adverse effects – Potential adverse effects of topical corticosteroids include skin atrophy, telangiectasias, striae, and hypopigmentation. Adverse effects of topical corticosteroids are reviewed in detail separately. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)

Failure of initial therapy — Patients with insufficient responses to topical corticosteroid therapy may benefit from other treatments (algorithm 1). Intralesional corticosteroid therapy is our preferred next treatment for limited disease, particularly for thick lesions, as insufficient penetration of the topical corticosteroid may contribute to a poor response to topical corticosteroids. Patients who respond poorly to intralesional corticosteroid injections or are poor candidates for injections because of thin lesions, lesion location, difficulty tolerating the procedure, lack of availability, or other reasons may be treated with oral antimalarial drugs. (See 'Intralesional corticosteroid injections' below and 'Antimalarial drugs' below.)

Intralesional corticosteroid injections — Intralesional injection allows for direct delivery of corticosteroids to the site of inflammation in the dermis. The efficacy of intralesional corticosteroid injections for TLE has not been studied. Use is based upon clinical experience.

Typically, 0.1 mL of a 2.5 to 5 mg/mL concentration of triamcinolone acetonide is delivered at each injection site, with individual injections into involved skin placed approximately 1 cm apart. Injections may be repeated every four weeks. Clinical improvement is expected within one to two treatments. If significant improvement is not noted after two or three injection sessions, we discontinue this treatment.

As with topical corticosteroids, intralesional corticosteroid therapy is associated with risk for cutaneous atrophy, telangiectasias, striae, and hypopigmentation. The 2.5 mg/mL concentration is preferred for locations at greatest risk for cutaneous atrophy, such as the face. Caution must be taken to avoid injection directly into a vessel, particularly in the periocular region due to the potential for central retinal artery occlusion. Side effects and precautions of intralesional corticosteroid injection are reviewed separately. (See "Intralesional corticosteroid injection", section on 'Adverse effects and pitfalls'.)

Antimalarial drugs — Antimalarial drugs, such as hydroxychloroquine and chloroquine, can be effective therapies for local corticosteroid-resistant TLE. Hydroxychloroquine is the preferred initial agent because of a more favorable side effect profile compared with chloroquine. The treatment regimens and precautions for antimalarial therapy for limited TLE and extensive TLE are similar. (See 'Antimalarial drugs' below.)

Recurrent disease — Recurrence after the cessation of local corticosteroid therapy is common. The timing and frequency of recurrence(s) influence the approach to treatment (algorithm 1) (see 'Prognosis' below):

●Delayed and infrequent recurrences – For patients in whom recurrences are separated by several weeks or more, we repeat the effective local corticosteroid regimen, as needed.

●Rapid or frequent recurrences – Patients in whom disease recurs rapidly after treatment cessation or who experience frequent flares may benefit from maintenance therapy. Examples of topical maintenance regimens include intermittent use of topical corticosteroids during remission and the use of topical calcineurin inhibitors. Oral antimalarial therapy may be utilized when topical interventions are insufficient:

•Intermittent topical corticosteroid use – Patients may benefit from application of a topical corticosteroid to the affected area twice daily on two days per week during periods of remission. When necessary, a more aggressive maintenance regimen can be implemented for patients in whom frequent recurrences occur during a defined period (eg, summer months). For such patients, the topical corticosteroid can be applied twice daily for five to seven days on an every-other-week basis. Moderate- to high-potency (group 1 to 4) topical corticosteroids may be used for the trunk or extremities, and low-potency topical corticosteroids (group 5 to 6) are typically used for the face.

•Topical calcineurin inhibitors – Use of topical calcineurin inhibitors (tacrolimus, pimecrolimus) for TLE is primarily based upon clinical experience and observed benefit for other forms of cutaneous LE. Topical calcineurin inhibitors may help maintain improvement and decrease dependence on topical corticosteroid therapy in cutaneous LE. The major advantage of topical calcineurin inhibitors over topical corticosteroids is that topical calcineurin inhibitors do not induce cutaneous atrophy.

Our typical maintenance regimen for topical calcineurin inhibitors involves application of a topical corticosteroid to the affected area two days per week and twice-daily application of the topical calcineurin inhibitor on the remaining days. Use under occlusion may increase efficacy. Provided relapse does not occur, patients may be transitioned to topical calcineurin inhibitor monotherapy.

Efficacy data for TLE are limited, and additional study is necessary to clarify the effects of topical calcineurin inhibitors on TLE. Although a 12-week, randomized trial in which 30 patients with various subtypes of cutaneous LE found evidence of benefit of tacrolimus 0.1% ointment for improving cutaneous LE during the first several weeks of treatment, the difference in effect between tacrolimus and vehicle dissipated by the end of the study [48]. Early improvement in TLE appeared largely due to improvement in edema. In a separate uncontrolled study of 11 patients with cutaneous LE (including 2 patients with TLE), all patients experienced significant regression of cutaneous LE after twice-daily application of pimecrolimus 1% cream for three weeks [49]. An occlusive dressing was applied after the evening application.

Topical calcineurin inhibitors may induce a burning sensation at sites of application. This occurs more frequently with topical tacrolimus than with pimecrolimus. Risk for carcinogenesis appears negligible. (See "Treatment of atopic dermatitis (eczema)", section on 'Topical calcineurin inhibitors'.)

Refractory disease — Limited TLE is usually adequately controlled with local therapy and/or oral antimalarial therapy. Other systemic therapies typically reserved for antimalarial-resistant, extensive disease are options for the rare patients with refractory, limited TLE; however, the risks of such therapies should be carefully considered prior to therapy. (See 'Extensive disease' below.)

Extensive disease — Systemic therapy is appropriate for patients with widespread TLE or for limited TLE that cannot be managed with local therapy (algorithm 1). While data on systemic treatment of TLE are limited, the general algorithm is similar to other forms of cutaneous LE. When necessary, topical corticosteroids may be incorporated as adjunctive therapy to assist with achieving satisfactory control of TLE. (See 'Topical corticosteroids' above.)

Preferred initial therapy — Antimalarial therapy is the preferred initial systemic therapy for TLE (algorithm 1). Most patients who are adhering to photoprotection respond well to antimalarial drugs.

Antimalarial drugs — Antimalarial therapies used in the treatment of cutaneous LE include hydroxychloroquine and chloroquine:

●Administration – Either hydroxychloroquine or chloroquine can be used for initial therapy. Hydroxychloroquine is generally preferred because of a more favorable side effect profile.

Adult patients are generally treated with 200 to 400 mg per day of hydroxychloroquine. A typical dose of chloroquine for adults is 125 to 250 mg per day for five to seven days per week. Risk for retinal toxicity limits the maximum dose for hydroxychloroquine and chloroquine and precludes simultaneous use of these therapies.

Use of doses of hydroxychloroquine that do not exceed 5 mg/kg of real body weight per day has been recommended to minimize the risk for retinal toxicity [50]. However, in patients with extensive skin involvement, we often prescribe 400 mg of hydroxychloroquine per day even if this exceeds 5 mg/kg of real body weight. We then reduce the dose of hydroxychloroquine to weight-appropriate dosing once adequate disease control has been achieved.

Doses of chloroquine exceeding 2.3 mg/kg of real body weight per day may increase the risk of retinal toxicity; therefore, dosing that does not exceed this level is suggested [50].

Response to antimalarial drugs in cutaneous LE may not be evident for 8 to 12 weeks, and most studies designed to prospectively assess response have excluded patients treated for less than eight weeks for this reason [51-53]. In regards to TLE in particular, there is limited literature suggesting that response to antimalarial drugs may be sooner, with efficacy noted within the first month of treatment and complete resolution within one to three months [1,35,54]. Three months is a reasonable trial period to assess drug efficacy.

●Efficacy – Benefit of hydroxychloroquine and chloroquine for TLE is supported by retrospective studies [1,34,35,38]. In one of the largest retrospective studies, treatment of 36 patients with TLE with chloroquine (500 mg per day for 14 days, then 250 mg per day) or hydroxychloroquine (400 mg per day) was associated with a significant reduction in the Cutaneous Lupus Erythematosus Disease Area and Severity Index score. Moreover, 22 patients (61 percent) had complete or almost complete clearance of skin lesions.

●Adverse effects – Both hydroxychloroquine and chloroquine can cause retinal toxicity. Risk for retinal toxicity is greater with chloroquine than with hydroxychloroquine. Patients treated with either agent should have a baseline ophthalmologic examination and periodic examinations thereafter. Recommendations for monitoring for ocular toxicity are reviewed in detail separately. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Administration, dosing, and monitoring'.)

Due to the risk of retinal toxicity, hydroxychloroquine and chloroquine may not be used in combination.

Other potential adverse effects of antimalarial medications include gastrointestinal upset, hematologic abnormalities, and neuromuscular abnormalities. Gastrointestinal side effects are less common with hydroxychloroquine than chloroquine and may be improved by starting with a 200 mg daily dose of hydroxychloroquine and titrating upward if needed.

Skin dyspigmentation may occur with hydroxychloroquine or chloroquine, including blue-gray discoloration that often occurs on the palate, nails, face, or shins. Such dyspigmentation may be permanent. Bleaching of hair may also occur.

Failure of antimalarial drugs — Typical therapeutic options for patients who fail to respond to an antimalarial drug include a switch to chloroquine for patients initially given hydroxychloroquine and the initiation of methotrexate or mycophenolate mofetil (MMF) (algorithm 1).

Data are insufficient to confirm the optimal approach to these patients. Transitioning to chloroquine is based upon clinical experience that suggests occasional patients with cutaneous LE respond better to chloroquine [53,55]. Use of methotrexate or MMF is based upon benefit for cutaneous LE observed in retrospective studies that have included few patients with TLE as well as relatively favorable side effect profiles compared with other therapies for refractory cutaneous LE [38,56-58]. (See "Management of discoid lupus erythematosus and subacute cutaneous lupus erythematosus refractory to antimalarial therapy", section on 'Methotrexate' and "Management of discoid lupus erythematosus and subacute cutaneous lupus erythematosus refractory to antimalarial therapy", section on 'Mycophenolate mofetil'.)

Our approach — Our approach most often begins with a switch from hydroxychloroquine to chloroquine, given that most of our patients receive hydroxychloroquine as the initial systemic treatment. If the response remains inadequate following three months of chloroquine therapy, we add methotrexate or MMF while continuing chloroquine therapy. Occasionally, we proceed directly from hydroxychloroquine to methotrexate or MMF. This option is typically reserved for patients with severe disease that has responded minimally to hydroxychloroquine or patients exhibiting poor tolerance to antimalarial therapy. (See 'Antimalarial drugs' above.)

Methotrexate — In general, methotrexate is given to adults in doses of 7.5 to 25 mg once weekly for cutaneous LE, with doses on the higher end of this spectrum often necessary. Methotrexate is typically taken by mouth; however, subcutaneous administration is often used, particularly with doses of 20 mg per week or higher, in order to improve absorption. Subcutaneous administration may also be used to reduce gastrointestinal side effects. Two to three months may be needed to note maximum efficacy.

Methotrexate is teratogenic and may cause gastrointestinal distress, mucosal ulcerations, bone marrow suppression, pulmonary fibrosis, and alopecia. Folic acid 1 mg per day may lessen the severity of some side effects. Dose adjustments are necessary for patients with renal insufficiency, and use of methotrexate in patients with pre-existing liver disease is relatively contraindicated. The use and adverse effects of methotrexate for cutaneous lupus are reviewed separately. (See "Management of discoid lupus erythematosus and subacute cutaneous lupus erythematosus refractory to antimalarial therapy", section on 'Methotrexate' and "Major side effects of low-dose methotrexate".)

Mycophenolate mofetil — Mycophenolate mofetil (MMF) is administered orally and typically dosed twice daily. Adult patients are treated with a total of 1 to 3 grams per day. Treatment for two to three months is generally necessary prior to reaching full therapeutic benefit.

Gastrointestinal upset is a potential side effect. Mycophenolic acid, an enteric formulation of mycophenolate sodium, may be substituted if gastrointestinal upset is severe, although dosing regimens differ. MMF is teratogenic. Other side effects include reversible cytopenias, immunosuppression, potential increased risk for malignancy, gastrointestinal perforation or ulcer, hypercholesterolemia, and hypertension. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)

Refractory disease — Thalidomide and lenalidomide are occasionally used for the treatment of refractory forms of cutaneous LE. Benefit for refractory TLE has been documented in individual patients [59-61]. Thalidomide is generally administered to adults at doses of 50 to 100 mg/day, with doses titrated down to the lowest effective dose. Responses are often noted within one month of treatment. However, tolerability of thalidomide limits treatment in many patients. Major side effects include neuropathy, sedation, teratogenicity, and thromboembolism. Due to the teratogenic effects, in the United States, patients and prescribers must register with a Risk Evaluation and Mitigation Strategy (REMS) program.

Lenalidomide is a structural derivative of thalidomide that may improve refractory cutaneous LE at doses of 5 to 10 mg per day [59,60]. Sedation, constipation, and neuropathy are seen less commonly with this derivative. Other side effects, including teratogenicity, are similar to thalidomide. The risk of agranulocytosis may be higher with lenalidomide. Use and adverse effects of thalidomide and lenalidomide for cutaneous LE are described separately. (See "Management of discoid lupus erythematosus and subacute cutaneous lupus erythematosus refractory to antimalarial therapy", section on 'Thalidomide'.)

Other systemic therapies with demonstrated efficacy for cutaneous LE include dapsone, azathioprine, systemic retinoids, and intravenous immune globulin; however data specific to TLE are lacking. Use of these medications is generally limited to patients who are refractory to or intolerant of other medications. Given the favorable prognosis of TLE and the tendency of TLE to respond to photoprotection, local therapy, and/or antimalarial drugs, use of these systemic agents is often unnecessary.

Maintenance therapy — The optimal regimens for maintenance therapy following successful remission of TLE are unclear. In general, the dose of an effective therapy is progressively tapered to the lowest dose required to maintain remission. The aggressiveness of the tapering regimen may be influenced by certain factors, such as disease severity and season of the year. For example, a more cautious approach to tapering is reasonable for patients with greater disease severity, and a delay in tapering may be prudent during summer months in temperate climates, when sun exposure is likely to be more significant.

PROGNOSIS — The prognosis of TLE generally is favorable, given its rare association with systemic disease; resolution without scarring; and its tendency to respond to photoprotection, topical therapy, and antimalarial therapy.

TLE has the potential to spontaneously regress, and in one cohort, spontaneous regression occurred in 10 of 24 patients with TLE (42 percent) [3]. However, recurrence, especially during summer months, is common. In the same study, 12 of 18 patients (67 percent) experienced recurrence [3]. Thus, long-term treatment is often warranted.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cutaneous lupus erythematosus".)

SUMMARY AND RECOMMENDATIONS

●Tumid lupus erythematosus (TLE) is an uncommon manifestation of cutaneous lupus erythematosus (cutaneous LE). TLE traditionally has been classified as a subtype of chronic cutaneous lupus erythematosus; however, the classification of TLE within the spectrum of cutaneous LE is controversial. (See 'Classification' above.)

●TLE most often occurs in adults. Pediatric TLE is rare. (See 'Epidemiology' above.)

●The pathogenesis of TLE is unclear. Ultraviolet light can trigger exacerbations of TLE, suggesting an important role for ultraviolet light exposure. Immune dysregulation may be another important contributor to the development of TLE. (See 'Pathogenesis' above.)

●The classic clinical manifestations of TLE are erythematous, edematous, smooth plaques (picture 1A-C). TLE usually occurs on the face, upper chest, upper back, shoulders, and/or extensor surfaces of the arms. Lower extremity involvement is rare. Scale, atrophy, scarring, and dyspigmentation are not features of TLE and should raise suspicion for an alternative diagnosis of discoid lupus erythematosus (DLE) or concomitant DLE. (See 'Clinical manifestations' above.)

●Antinuclear antibodies are negative in the majority of patients with TLE, and the occurrence of systemic lupus erythematosus in patients with TLE is rare. (See 'Laboratory findings' above and 'Association with systemic lupus erythematosus' above.)

●The diagnosis of TLE can be made based upon the recognition of consistent clinical and histologic findings. Disorders often in the differential diagnosis include Jessner's lymphocytic infiltrate, polymorphous light eruption, reticular erythematous mucinosis, pseudolymphoma, and granuloma faciale. (See 'Diagnosis' above and 'Differential diagnosis' above.)

●The extent of TLE influences the approach to the treatment (algorithm 1). We suggest topical corticosteroid therapy rather than systemic therapy as initial treatment for patients with limited TLE (eg, one to several small plaques) (Grade 2C). For thick plaques that fail to improve with topical corticosteroid therapy, we suggest intralesional corticosteroid injections (Grade 2C). (See 'Limited disease' above.)

●For patients with widespread TLE or with limited disease that is refractory to local therapy, we suggest treatment with systemic antimalarial drugs (Grade 2C). Patients may be treated with hydroxychloroquine or chloroquine. Hydroxychloroquine is generally preferred because of a more favorable side effect profile. (See 'Extensive disease' above.)

●TLE refractory to antimalarial therapy is uncommon. For patients with insufficient responses to antimalarial drugs, we suggest treatment with methotrexate or mycophenolate mofetil (Grade 2C). Options for refractory disease include thalidomide, lenalidomide, and other agents. (See 'Failure of antimalarial drugs' above and 'Refractory disease' above.)