Tumid Lupus Erythematosus

Etiology

To date, no distinct etiology for TLE has been identified. However, triggering factors such as ultraviolet (UV) radiation have been implicated in worsening lesions of TLE. Its association with autoimmune disease has been controversial; if an autoimmune disease is suspected, an autoimmune workup may be initiated.[5][6] Immunity dysregulation with suppression of T cells is hypothesized. [7] Association with smoking and drugs like tumor necrosis factor antagonists, monoclonal antibodies, angiotensin-converting enzyme inhibitors, thiazide diuretics, and highly active antiretroviral therapy was reported.[8][9]

Epidemiology

CCLE, in general, occurs more frequently in the female population. TLE is rare relative to DLE. Incidence and prevalence of TLE among different races and ethnicities is not known. Men and women have almost equal predilection to TLE.[10] The age of onset is usually around thirty to forty years.[11]

Pathophysiology

Cutaneous lupus has a complex pathogenesis that relies on the interplay between genetic and environmental components. For all types of CCLE, including tumid lupus, UV radiation (specifically UVB) serves as a trigger. Immune alterations have also been implicated in the pathogenesis of TLE, specifically the decrease of T-regulatory cells and epidermal Langerhans cells and increased plasmacytoid dendritic cells. There is upregulation of type-1 interferon, tumor necrosis factor-alpha (TNF-alpha), and Th17 cells.[12] It has been postulated that tobacco smoking is a risk factor for TLE. It has also been suggested that rare drug-induced forms of TLE exist in association with TNF-alpha inhibitors, thiazide diuretics, highly active antiretroviral therapy (HAART), angiotensin-converting enzyme (ACE) inhibitors, bortezomib, and ustekinumab therapy.

Histopathology

TLE is distinguished by abundant dermal mucin deposition and a superficial and deep perivascular and periadnexal lymphocytic infiltrate. Edema in the papillary dermis is noted. There is no involvement of the epidermis or dermo-epidermal junction. Lack of atrophy, scarring, follicular plugging, and dyspigmentation are the salient features of TLE. Direct immunofluorescence studies are usually negative. It is important to note that reticular erythematous mucinosis (REM), and Jessner's lymphocytic infiltrate are indistinguishable histologically from TLE.[13] See images 1, 2, and 4.

History and Physical

History is a valuable tool in evaluating a patient for TLE. Worsening of the eruption with sun exposure supports a diagnosis of TLE, although this finding is not specific to TLE. A full-body skin exam should be performed when a diagnosis of TLE is suspected. TLE favors the face, neck, chest, and back, so special attention should be given to these body regions. Lesions present as edematous, usually annular, plaques with hues ranging from erythematous to violaceous. See images 3, 5, and 6. Epidermal change virtually excludes a diagnosis of TLE (TLE lesions lack atrophy, ulceration, follicular plugging, scarring, or dyspigmentation, and the presence of these features favors a diagnosis of DLE). Although uncommon, TLE may present with a Blaschkoid distribution, periorbital edema, or scalp involvement that appears similar to alopecia areata.

Lesions of TLE persist for days or weeks and chronically recur. Lesions do have the potential to regress spontaneously; however, patients may report recurrence during the summer months.

Evaluation

If the clinical examination is consistent with cutaneous lupus, a lesional biopsy should be taken from an active, erythematous plaque. A punch biopsy (4 mm is recommended on the trunk or 3 mm on cosmetically sensitive areas such as the face) should be performed to include the full thickness of the dermis. As discussed above, the classic histopathologic findings are abundant interstitial mucin and a dermal perivascular and periadnexal lymphocytic infiltrate.[14][15][16]

If the histopathologic findings definitively support a diagnosis of tumid lupus, the patient should be evaluated for systemic disease, despite the weak association with SLE. The evaluation for systemic lupus includes a full history and review of systems, physical examination with special attention to lymphadenopathy or arthritis, and laboratory tests (ANA with anti-dsDNA and anti-Sm profiles), urinalysis, complete blood count (CBC) with differential, chemistries, ESR, CRP, complement levels (C3, C4), and antiphospholipid antibodies. For a more extensive autoimmune workup, autoantibodies such as SS-A/Ro and SS-B/La, anti-U1RNP, and anti-histone antibodies can be drawn.

If the histology is consistent with lupus but not definitive, a lesional biopsy can be sent for direct immunofluorescence (DIF). The most characteristic DIF finding in cutaneous LE is granular IgG and/or IgM deposition at the dermal-epidermal junction and around hair follicles. However, with tumid lupus specifically, DIF is often negative or nonspecific and therefore may not be as valuable as in other forms of cutaneous lupus.

Phototesting can be beneficial for diagnosing TLE; reproduction of lesions after UVA/UVB irradiation may support a diagnosis of tumid lupus.

Treatment / Management

Photoprotection and topical or intralesional corticosteroids are first-line therapy for localized TLE. Application of water-resistant sunscreen with a sun protection factor of 30 or higher, using protective clothing, avoiding peak sun exposure, and smoking cessation are recommended. Corticosteroids are applied topically twice a day for 2-4 weeks. Clinical improvement is usually observed in about 2 weeks. Moderate to high potency corticosteroids are used for treating lesions on the trunk or extremities and low potency corticosteroids are used for the treatment of facial lesions. Cutaneous atrophy, striae, hypopigmentation, and telangiectasias are adverse effects of topical or intralesional corticosteroids. If there is no improvement in 4 weeks, other therapies should be tried. For solitary and thick TLE lesions, intralesional triamcinolone (2.5 to 5 mg/mL) is often effective. 0.1 ml of triamcinolone acetonide can be injected into the lesion at multiple sites 1 cm apart. Intralesional injection can be repeated in 4 weeks. If there is no improvement in 8-12 weeks, intralesional corticosteroids are discontinued. Topical calcineurin inhibitors (e.g., tacrolimus, pimecrolimus) improve the lesions clinically, while decreasing the topical corticosteroid use.[17] Atrophy of the skin is not caused by topical calcineurin inhibitors, making them ideal for maintenance therapy.(B3)

Patients with limited TLE refractory to topical therapy and patients with extensive TLE should be treated with first line antimalarial therapy. Hydroxychloroquine or chloroquine can be used initially. Hydroxychloroquine is usually well tolerated than chloroquine. Between 200 and 400 mg per day of hydroxychloroquine is a reasonable dose. For chloroquine, a dose of 125 to 250 mg per day (for 5 to 7 days per week) is commonly used. Hydroxychloroquine and chloroquine may not be used in combination due to the risk of retinal toxicity. Their risk of retinal toxicity limits the maximal dose of these antimalarials. It is important to note that it may take 8 to 12 weeks to appreciate the effects of antimalarials.[18] Patients should have an eye exam at baseline and then periodically while on the antimalarials. Patients need to be aware of the skin depigmentation that can occur with both hydroxychloroquine and chloroquine. This presents as a blue-gray discoloration on the shins, palate, nails, or face, and this discoloration may be permanent. Gastrointestinal side effects are the most common reason for discontinuation of antimalarial treatment. Neuromuscular and hematological side effects are also noted.(B3)

TLE refractory to antimalarial therapy is rare. However, second-line therapy includes methotrexate (7.5 to 25 mg once weekly) or mycophenolate mofetil (1 to 3 gm per day). Folic acid 1 mg per day typically lessens the severity of the side effects associated with methotrexate. Side effects of methotrexate include gastrointestinal upset, pulmonary fibrosis, bone marrow suppression, alopecia, apart from being teratogenic. Mycophenolate mofetil’s side effects include gastrointestinal upset, reversible cytopenias, immunosuppression, gastrointestinal perforation or ulcer, hypercholesterolemia, and hypertension. Clinical improvement is usually observed with 2-3 months of therapy.

Third-line treatment options, although uncommonly used, include thalidomide and lenalidomide. Thalidomide (50 to 100 mg daily), lenalidomide (5 to 10 mg daily) are used at least for a month for clinical response. Teratogenicity, neuropathy, thromboembolism, sedation are some of the adverse effects associated with the use. Treatment regimens are usually tapered to the lowest potent dose to maintain remission.

Differential Diagnosis

The differential diagnoses of TLE include lymphocytic infiltrate of Jessner, polymorphic light eruption, pseudolymphoma of the skin, reticular erythematous mucinosis, and granuloma faciale. Jessner's lymphocytic infiltrate presents very similarly to tumid lupus with erythematous papular or nodular lesions without scale, on the upper back or the face. Histopathology also shows dermal mucin deposition.[19] Direct immunofluorescence and antinuclear antibodies may be positive.[20] 

Polymorphic light eruption (PMLE) presents as skin-colored or erythematous plaques or papules that are pruritic in the sun-exposed areas of the body. Lesions typically occur within hours of photo exposure and resolve soon than tumid lupus lesions. With progressive exposure to UV light, PMLE lesions do not get worse(hardening effect), which differentiates them from TLE.[21]

Reticular erythematous mucinosis presents as erythematous, reticular macules, or plaques, usually on the upper back and chest. Dermal mucin deposition is more superficial. Lymphocytes are more dispersed and superficial.[22] Complement and immunoglobulin deposition along the dermo-epidermal junction is not commonly seen.

Pseudolymphoma of the skin presents as erythematous nodules in the dermis, usually on the chest, arms, and face. Lesions are not photosensitive. Histopathology differentiates it from TLE, due to the presence of histiocytes and plasma cells along with lymphocytes.[23]

Granuloma faciale presents as a violaceous nodule or plaque on the face. Lesions are usually asymptomatic. Grenz zone is the characteristic histologic finding that distinguishes it from TLE. A thin zone of the uninvolved papillary dermis that divides the dermal inflammatory infiltrate (lymphocytes, histiocytes, plasma cells, neutrophils, and eosinophils) from the epidermis is called the Grenz zone.[24]

Prognosis

Tumid Lupus Erythematosus has a benign course.[25] Solitary lesions are mostly self-limiting, often without any need for topical or systemic therapy. However, recurrence is noted to be high with the disease-free period in between. Long-term remission is observed in some patients.[11] TLE lesions have a favorable prognosis than lesions of discoid lupus erythematosus or subacute cutaneous lupus erythematosus.[11] Spontaneous resolution of the lesions without residual dyspigmentation or scarring may be noted within days or weeks, despite the relapses.[26][27] Photoprotection alone was effective for lesion resolution in more than 50% of patients without any symptoms.[10]

Complications

Association with Systemic Lupus Erythematosus or discoid lupus erythematosus is rare.[25][28][29] Patients might be prone to vitamin D deficiency by avoiding sun exposure. Hence evaluation of the vitamin D deficiency with 25-hydroxyvitamin D level and adequate supplementation with at least 400 IU of cholecalciferol is suggested.[30][31]