Lupus erythematosus tumidus (tumid lupus)

Are You Confident of the Diagnosis?

What you should be alert for in the history

Lupus erythematosus tumidus (LET) is considered a form of chronic cutaneous lupus erythematosus (CLE).

With LET, as with other chronic cutaneous lupus diseases, the prevalence of lupus-related autoantibodies and development of systemic lupus erythematosus (SLE) is low. Overall, LET is characterized by intense photosensitivity, skin lesions, a benign course, the absence of systemic disease, good response to antimalarial treatment, and a tendency to recur.

Characteristic findings on physical examination

Characteristic lesions appear as photodistributed erythematous edematous somewhat urticarial-like smooth plaques that lack epidermal involvement. Most LET lesions are located on the face, V-area of the neck, upper back, and arms. The lesions are intermittent and heal without scarring or atrophy (Figure 1, Figure 2).

Several erythematous, edematous, smooth annular or arcuate plaques with no overlying epidermal change.

Arcuate red dermal plaque of tumid lupus. (Courtesy of Bryan Anderson, MD)
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Expected results of diagnostic studies

Histopathologic findings include a dense lymphocytic perivascular and periadnexal infiltrate, increased interstitial mucin deposition, and absent interface change (Figure 3).

Periadnexal lymphocytic infiltrate with adjacent increased mucin deposition (H&E).

There is some controversy as to whether LET should be classified among the lupus erythematosus (LE) spectrum of skin disease at all. Many feel it is indistinct from lymphocytic infiltrate of Jessner, and more closely resembles polymorphous light eruption, or reticular erythematosus mucinosis. Of particular concern is the lack of characteristic histopathologic findings of vacuolar degeneration at the dermoepidermal junction and the very low association with SLE.

Furthermore, when compared to other CLE subsets, LET lesions are intermittent, and there is less likelihood for systemic disease development. There are rare patients who have “tumid” lesions as part of serious SLE, and in this situation, the lesions have been classified as part of “lupus nonspecific skin lesions.”

Antinuclear antibodies (ANA) occur in only 10%-30% of cases. Unlike other photosensitive dermatoses, anti-Ro/SSA and anti-La/SSB are only rarely found.

Diagnosis confirmation

To confirm a diagnosis, a biopsy is indicated.

Who is at Risk for Developing this Disease?

LET presents only slightly more often in females than males. The mean age of onset is approximately 38 years old. Given the limited attention LET has been given in the literature, further risk factors have not been elucidated.

What is the Cause of the Disease?

Etiology

CLE diseases, including LET, are autoimmune diseases thought to be caused by an interplay of genetics, hormones, and environment. Given that lupus is more common in women of childbearing age, estrogen is thought to be a cause.

Pathophysiology

In terms of genetics, genes encoding cytokines, cytokine receptors, adhesion molecules, and apoptosis genes are thought to contribute to the development of LE. The most well-known environmental trigger of SLE and most CLE lesions is ultraviolet (UV) light, particularly in LET. UV light induces pro-inflammatory cytokines, chemokines, and adhesion molecules that eventually lead to tissue injury. Both UVB and/or UVA can contribute to the induction of skin lesions.

There are no autoantibodies associated with LET, and ANA titers tend to be low or nonexistent in this patient population.

Overall, the complex inflammatory cascade of necrosis, apoptosis, autoantibodies, T and B cells, and vascular changes leads to the development of CLE. However, a complete understanding of the pathophysiology of CLE and LET is not yet available .

Systemic Implications and Complications

LET has the least association with the development of SLE, when compared to other CLE subsets, and thus has the best prognosis. Nonetheless, laboratory studies to evaluate for SLE are warranted, but should be symptom directed in an otherwise healthy patient.

An initial ANA, complete blood count (CBC), and urinalysis are sufficient for those without other symptoms. Symptoms of arthralgias, discoid lesions, malar rash, oral ulcers, serositis, and arthritis, as well as hematologic, neurologic, and renal involvement would warrant concern for SLE .

Given that an ANA assay has a 99% negative predictive value, it is rare for a patient with SLE to have a negative ANA. This is also a more cost-effective way to use specific autoantibody tests. If the ANA is elevated (> 1:160), or a patient has symptoms suggestive of SLE, further testing is warranted. These may include anti-dsDNA, anti-Smith, CBC with differential, creatinine, albumin, total protein, erythrocyte sedimentation rate, urinalysis, and complements (C3,C4).

Treatment Options

Treatment options are summarized in Table I.

Table I.

MEDICAL
Topical:
Sunscreen, broad spectrum with
UVA and UVB protection
Topical steriods, Class I/II or lower strength topicals for face
Topical calcineurin inhibitors +/-
topical steroids
tacrolimus 0.1% ointment
pimecrolimus 1% cream
Systemic:
Hydroxychloroquine 6.0 – 6.5mg/kg/day ideal body weight (IBW)
Hydroxychloroquine + quinacrine 100mg daily
Chloroquine ≤3.5mg/kg IBW +/- quinacrine 100mg daily
Prednisone 0.5-0.75mg/kg/day
Methotrexate 5-25mg/week
Mycophenolate Mofetil 2-3gm/day
Azathioprine 1-2.5mg/day

Optimal Therapeutic Approach for this Disease

LET is extremely photosensitive, and thus sun avoidance and protection with the use of broad-spectrum sunscreens, to cover UVB and UVA spectrum, is necessary. This ideally includes sunscreens with helioplex, mexoryl, or physical blockers (titanium dioxide, zinc oxide). A sun protection factor of at least 60 should be applied daily to all sun-exposed areas. With appropriate sun protection, some LET lesions may resolve spontaneously.

Cigarette smokers are more likely to develop CLE and SLE, and to suffer from more severe disease. Patients with LET should be counseled on smoking cessation.

Topical therapy with topical steroids can be initiated as first-line therapy, with or without topical calcineurin inhibitors. Topical steroid should be tried for 2-4 weeks in patients with mild skin disease prior to starting systemic therapies. Lower strength topical steroids (Class V or VI) may be used on the face. Topical calcineurin inhibitors have been shown to be effective in some CLE subsets, and offer a decreased risk of telangiectasia development compared to topical steroids. Combining topical steroids and calcineurin inhibitors may provide an added benefit.

Overall, broad-spectrum sunscreen/sun protection and topical steroids are successful in over 50% of LET lesions. For refractory or multiple lesions, antimalarial agents are highly effective.

ANTIMALARIALS

Antimalarials are recommended as first-line systemic therapy for CLE and SLE, given their effectiveness in prevention and treatment of symptoms such as photosensitivity, acute malar rash, discoid lupus erythematosus (DLE), oral ulcers, alopecia, arthritis, pleuritis, and pericarditis. As mentioned earlier, the vast majority of patients with LET respond to antimalarial therapy.

Hydroxychloroquine is the treatment of choice over chloroquine, given its lower ocular toxicity risk. Typically, hydroxychloroquine is started at 200mg-400mg a day. To avoid ocular toxicity, the daily dose should not exceed 6.5mg/kg ideal body weight per day. Antimalarials take 2-3 months for improvement to be noticed and up to 6 months for a complete response.

After 8-12 weeks, if improvement is not satisfactory, quinacrine 100mg daily may be added. Quinacrine can only be obtained at a compounding pharmacy. It may cause yellow discoloration of the skin. If the combination of hydroxychloroquine and quinacrine has not provided complete response after 2-3 months, changing to chloroquine and quinacrine is an option.

Chloroquine is typically started at a dose of 250mg, 5-7 days a week, and should not exceed 3.5mg/kg ideal body weight per day. The lowest possible effective dose should be used for maintenance therapy. Antimalarials may be used safely for long periods of time.

The recommended doses listed in the Table I above are based on the maximal safe dose from an ocular safety perspective. The retinopathy associated with chloroquine may be irreversible. The blurred vision and corneal deposition that may occur is reversible. The use of hydroxychloroquine necessitates eye exams every 6 months, and with chloroquine, every 4 months. The eye exam should include visual acuity, visual fields, and fundoscopic exam.

Patients with a history of retinopathy should not get hydroxychloroquine or chloroquine. Patients who get a drug exanthem with hydroxychloroquine may be able to tolerate chloroquine, while an urticarial reaction from hydroxychloroquine would preclude use of chloroquine. Other side effects include nausea, headaches, myopathy, and bluish-gray hyperpigmentation of the skin.

In addition to a baseline eye exam, a CBC and liver function, at baseline and after 1 month of use, should be performed.

In the few cases that do not respond to antimalarials, short courses of prednisone or other immunosuppressive agents have been used, but limited data are available to indicate which agent is superior. For widespread disease and nonresponders to topical therapy, it is reasonable to use a short course of prednisone while waiting for the onset of action of antimalarials.

PREDNISONE

Given the chronic and recurrent nature of most CLE subsets, use of steriods should be avoided. However, while awaiting antimalarials to take effect in widespread LET, prednisone at dosages of 0.5mg/kg/day-0.75mg/kg/day can be used. Prednisone should not be used alone, as lesions recur once prednisone is stopped. Tapering prednisone once the LET lesions are stable is recommended.

The well-known side effects of prednisone include weight gain, fluid retention, psychiatric disturbances, hypertension, and hyperglycemia. Osteoporosis, myopathy, and cushingoid changes are additional adverse reactions that can be avoided with short therapeutic courses. Of note, osteonecrosis can occur with even short courses of prednisone.

The degree and extent of bone loss is most closely related to cumulative corticosteroid dose. The most rapid rate of bone loss is during the first 3 to 6 months of therapy. All patients starting gluocorticoids at any dose with an anticipated duration of at least 3 months or longer should start calcium 1200-1500mg/day and vitamin D 800-1000 international units/day supplementation. These patients should also be counseled on smoking cessation and weight-bearing activities. Additionally, they should be assessed for fall risk, baseline height, and history of fragility fractures.

A baseline bone mineral density scan, radiographic imaging of the spine, or vertebral fracture assessment may be done; particuarly in postmenopausal woman.

In women of childbearing age, the use of bisphosphonates is only considered for those women with a history of fragility fractures, given the unknown risk of long-term bisphosphonate use and risk to the fetus. However, postmenopausal woman should begin a bisophosphonate, such as alendronate or risedronate, if the corticosteroid dose is greater than 5mg and the anticipated length of treatment is at least 3 months.

Although unlikely, if after 3 months of therapy with antimalarials and oral prednisone, the results are unsatisfactory, a steroid-sparing agent should be initiated. Methotrexate, mycophenolate mofetil, or azathioprine are reasonable choices; however, minimal data exist as to their use in LET .

METHOTREXATE

Methotrexate can be used in doses of 5-25mg weekly. MTX typically takes 3-4 weeks for clinical improvement. A typical test dose is 5mg, and then increase 5mg weekly to the dose needed to control symptoms. The lowest possible maintenance dose needed to control disease should be used. Doses as low as 5mg a week have been successfully used to maintain clinical remission in CLE.

The potential for hepatotoxicity (with long-term use) and pulmonary toxicity is an important consideration. Patients who drink alcohol should not receive methotrexate; underlying viral hepatitis, obesity, and diabetes are associated with an increased risk of hepatotoxicity, including liver fibrosis.

Bone marrow suppression is a severe adverse reaction. Risk factors for this side effect include drug interactions (trimethoprim/sulfamethoxazole and nonsteroidal anti-inflammatory drugs), renal insufficiency, older age (>65), and no folate supplementation. Frequent CBCs are important to monitor for this adverse reaction and all patients should be on folate supplementation.

Baseline laboratory tests should include CBC, comprehensive metabolic panel (liver and renal function), hepatitis B and C serologies, and human immunodeficiency virus testing. After the first dose of methotrexate, CBC and liver function labs should be done in one week. If labs are normal, repeat testing of CBC and liver function, every week as the dose is increased and then monthly thereafter for 3 months, is warranted.

After a year of a stable dose with no serious toxicity, blood monitoring can decrease to every 3 months. Renal function can be evaluated once a year, or sooner if renal dysfunction is suspected. Weekly intramuscular injections may improve gastrointestinal (GI) intolerance due to oral methotrexate.

MYCOPHENOLATE MOFETIL

Mycophenolate mofetil (MMF) is well tolerated and has been shown to be effective in CLE and SLE . The most common adverse reaction is GI side effects, including nausea, vomiting, diarrhea, and abdominal cramps.

These symptoms are typically dose dependent and may be avoided by starting at a lower dose. In patients with GI side effects, one can start with 500mg once or twice a day, and then titrate dose up, per tolerability, every 2-4 weeks to the goal dose of 2-3gm/day. As with any immunosuppressant, MMF can increase the risk of infections. Less common side effects include myelosuppression and transaminitis. MMF typically takes approximately 4 weeks to take effect.

Baseline laboratory tests include CBC with differential and liver function tests. Labs should be checked 2 weeks after starting therapy, and 2 weeks after increases in dose. Monthly CBC and liver function tests for the first year, then every 3 months, is recommended. Maintenance doses of 1.5-3gm a day can be used safely.

AZATHIOPRINE

Azathioprine is an immunosuppressant that has been extensively studied in LE as a steroid-sparing agent. An initial dose of 50mg a day is suggested to determine acute toxicity/sensitivity. The dose can be increased by 25mg every 2 weeks, with a goal of achieving a range between 2-3mg/kg/day.

In CLE, azathioprine doses of 100-150mg are commonly needed to achieve desired effects. Clinical effects are typically seen in 4-8 weeks. The maintenance dose can range from 50-150mg daily and may be continued for years.

Side effects include GI symptoms of nausea, vomiting, and abdominal cramping. Pancreatitis and hepatotoxicity have also been reported. Hypersensitivity reaction, aseptic meningitis, and increased cancer risk are also known adverse reactions. Flu-like symptoms may occur within the first 2 weeks of use.

Prior to the use of azathioprine, a thiopurine methyltransferase (TPMT) enzyme level can be done, particularly if doses above 50mg a day are used initially. Low levels increase the risk of myelosuppression and potentially fatal neutropenia. CBC and liver function tests should be performed every 2 weeks while the dose is being adjusted, every month for the first year, and then every 3 months thereafter.

Patient Management

The majority of patients have mild recurrences, usually during spring or summer, related to the first sun exposure. Educating patients on this phenomenon will help them avoid seasonal exacerbations. The majority of patients with recurrences clear with reinitiating their prior treatment regimen.

The vast majority of patients with LET have disease that primarily affects the skin. These patients should be reassured that their risk of disease progression to SLE is very low.

The next step is to provide patients with therapeutic modalities that minimize disease progression and improve treatment response. The role of smoking in disease severity and medication effectiveness must be stressed at the initial visit. All patients who smoke should be encouraged to stop smoking and should begin a smoking cessation program.

Mainstay therapies for the majority of CLE subsets, including LET, are sun protection, topical therapies, and antimalarials. These therapies have limited severe adverse reactions; however, patients with refractory or widespread disease may need therapies that carry higher side effect risks.

It is important to discuss all side effects and monitoring guidelines prior to initiating therapy. After antimalarials, there is no one agent that is superior in the treatment of LET lesions. Thus, when ascending the therapeutic ladder, individualizing therapy for each patient based on their comorbidities is necessary. Furthermore, after clearance of LET lesions, therapies should be reduced to the lowest effective dose, or discontinued.

For LET, therapies may only be needed during the spring and summer months to prevent or control disease, limiting long-term use during inactive periods of disease.

Unusual Clinical Scenarios to Consider in Patient Management

Reticular erythematosus mucinosis (REM), or plaque-like cutaneous mucinosis, is a photoaggravated dermatosis that is associated with many autoimmune diseases, including LE . Clinically, the central part of the chest and back has pink reticulate erythema.

Histopathology typically shows perivascular, and sometimes perifollicular, lymphocytic infiltrate, dilated vessels, and increased dermal mucin deposition. Direct immunofluorescence may be normal or can show IgG and C3 granular deposition.

REM and lupus share many similar features, such as photosensitivity, mucin deposition, and perivascular and perifollicular lymphocytic infiltrate. Occasionally, these diseases produce a positive direct immunofluorescence. In patients with a positive ANA and other signs of LE, REM can be considered a presentation of LE. Some consider it a variant of LET.

There is little evidence regarding therapy for LET during pregnancy. Although the risk of SLE is small in patients with LET, the recommendations in this scenario are the same as those for patients with other lupus variants.

Patients with active SLE and mild disease are managed during pregnancy with oral corticosteroids. If the disease is more severe, treatment with corticosteroids, azathioprine, cyclosporine, and intravenous gammaglobulin may be used. At this time, there is not enough safety information on the use of MMF in pregnancy. Hydroxychloroquine has evidence for its safety and efficacy during pregnancy; however, it is still considered a class C drug by the Food and Drug Administration.

What is the Evidence?

Kuhn, A, Bein, D, Bonsmann, G. “The 100th anniversary of lupus erythematosus tumidus”. Autoimmun Rev. vol. 8. 2009. pp. 441-8. (An overview on the different aspects of LET, including a historic perspective on why LET has been neglected in the literature. The authors also discuss the new classification system for LET as the intermittent subtype of CLE [ICLE].)

Hugel, R, Schwartz, T, Glaser, R. “Resistance to hydroxychloroquine due to smoking in a patient with lupus erythematosus tumidus”. Br J Dermatol. vol. 157. 2007. pp. 1081-3. (A case is discussed of a patient with LET that initially did not respond to hydroxychloroquine therapy. After the patient reduced her smoking to three cigarettes a day, her LET lesions resolved completely in 3 months.)

Vieira, V, Del Pozo, J, Yebra-Pimentel, MT, Martinez, W, Fonseca, E. “Lupus erythematosus tumidus: a series of 26 cases”. Int J Dermatol. vol. 45. 2006. pp. 512-7. (A retrospective study of twenty-six patients diagnosed with LET over 6 years at one hospital in Spain. Analysis of the clinical characteristics, histopathologic and laboratory findings, response to treatment, association with other subsets of lupus, course, and diagnostic criteria are discussed in detail.)

Kuhn, A, Richter-Hintz, D, Oslislo, C, Ruzicka, T, Megahed, M, Lehmann, P. “Lupus erythematosus tumidus—a neglected subset of cutaneous lupus erythematosus: report of 40 cases”. Arch Dermatol. vol. 136. 2000. pp. 1033-41. (One of the largest groups of patients with LET is analzed in this article. Based on the characteristic findings in all these cases, the authors feel that LET should be considered a separate entity and differentiated from other variants of cutaneous LE.)

Dekle, CL, Mannes, KD, Davis, LS, Sangueza, OP. “Lupus tumidus”. J Am Acad Dermatol. vol. 4. 1999. pp. 250-3. (Four cases of LET are discussed as a distinct form of CLE )

Kreuter, A, Gaifullina, R, Tigges, C, Kirschke, J, Altmeyer, P, Gambichler, T. “Lupus erythematosus tumidus: response to antimalarial treatment in 36 patients with emphasis on smoking”. Arch Dermatol. vol. 145. 2009. pp. 244-8. (A retrospective study designed to determine the efficacy of antimalarial drugs in the treatment of LET. The authors found that both hydroxychloroquine and chloroquine were highly effective in treating LET; however, hydroxychloroquine offered lower incidences of adverse effects. They also found that patients who smoked seemed to have worse disease and demonstrate less response to antimalarial treatment than nonsmokers.)

Schmitt, V, Meuth, AM, Amler, S, Kuehn, E, Haust, M. “Lupus erythematosus tumidus is a separate subtype of cutaneous lupus erythematosus”. Br J Dermatol. vol. 162. 2010. pp. 233-4. (Two centers in Germany compared a total of forty-four patients with LET, DLE, or SCLE to identify characteristic features of the different subtypes of CLE. The purpose of the study was to demonstrate that LET significantly differs from the other subtypes of CLE, and thus should be defined as a separate entity in the classification of CLE.)

Ruiz, H, Sanchez, J. “Tumid lupus erythematosus”. American Journal of Dermatopathology. vol. 21. 1999. pp. 356-60. (The authors describe the clinical presentation and histopathologic description of four patients with LET. The patients in this study had concurrent lesions of LET and classic DLE.)

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