Are You Confident of the Diagnosis?
Subacute cutaneous lupus erythematosus (SCLE) is a clinically distinct form of CLE that presents as a highly photosensitive annular-polycyclic or papulosquamous eruption distributed symmetrically on sun-exposed areas (Figure 1). The upper back, chest, shoulders and extensor arms are frequent sites. Lesions below the waist are uncommon. Unlike discoid lupus erythematosus (DLE), SCLE lesions heal without scarring. However, dyspigmentation with hyper- or hypopigmentation can occur and may persist for several months.
Mild systemic disease, such as joint complaints and serologic abnormalities, are common. The majority of patients have a positive anti-nuclear antibody (ANA) and anti-Ro/SSA. Anti-La/SSB may also be present, but is less frequent.
There are two clinical forms of SCLE, psoriasiform and annular-polycyclic. The papulosquamous variant, which is more common, appears as psoriasiform plaques and can be misdiagnosed as photosensitive psoriasis. The annular-polycyclic lesions variant may be confused with figurate erythema or a superficial dermatophyte infection (Figure 2). A KOH scraping can be used to rule out tinea corporis, but typically a biopsy and laboratory tests are needed to help differentiate between the other entities.
Histologically, SCLE shows basal vacuolar changes, which can be intense causing clefts and subdermal vesicles at the dermoepidermal junction, colloid bodies in the lower epidermis and papillary dermis, and dermal edema. There is less hyperkeratosis and inflammation than seen in DLE (Figure 3).
Drug-induced SCLE must always be ruled out by a thorough medication history. Common medications to cause drug-induced SCLE include hydrochlorothiazide, calcium channel blockers, terbinafine, angiotensin converting enzyme inhibitors (ACEi), and tumor necrosis factor-alpha antagonists. Many of these patients have positive anti-Ro/SSA antibodies and occasionally anti-histone antibody. The lesions are indistinguishable from patients with non-drug-induced SCLE.
Who is at Risk for Developing this Disease?
SCLE is more female predominant than discoid lupus. The female to male ratio is 8:1 in SCLE compared with nearly 1:1 in discoid lupus. The age of onset ranges from as early as 18 months to the elderly. However, it most commonly occurs in the 40 to 60 years age range. Unlike DLE, SCLE is uncommon in African Americans.
What is the Cause of the Disease?
Cutaneous lupus erythematosus, including subacute cutaneous lupus, is an autoimmune disease felt to be due to an interplay of genetics, hormones and environment. Given that lupus is more common in women of childbearing age, estrogen is felt to contribute to the disease pathogenesis. In terms of genetics, genes encoding for cytokines, cytokine receptors, adhesion molecules and apoptosis genes are felt to contribute to the development of lupus erythematosus.
SCLE is associated with the extended haplotype HLA DRB1*0301-B08. Inherited deficiencies of complement also play a role in the risk of CLE development. For instance, patients deficient in C1q are seen in photosensitive-LE like eruptions. Deficiencies in C2 and C4 are seen in SCLE.
In terms of environment, the most well-known environmental trigger of SLE and most CLE lesions, including SCLE, is ultraviolet light. UV light induces pro-inflammatory cytokines, chemokines and adhesion molecules, leading to tissue injury. UVB, UVA and visible light can contribute to induction of skin lesions. Trauma or koebnerization may also play a role in CLE development through pro-inflammatory factors.
Autoantibodies are a hallmark of autoimmune diseases. High titer anti-Ro/SSA and anti-La/SSA are a common finding in SCLE. ANA and anti-dsDNA can be seen in some patients with SCLE. However, ANA is not specific for SCLE or SLE, a small percentage of the general population will be positive, and ANA positivity increases with increasing age.
Immunoglobulins and complement can be detected in the skin of patients with CLE and SLE. Their role in local induction of clinical lesions is unknown.
Overall, this complex inflammatory cascade between necrosis, apoptosis, autoantibodies, T and B cells, and vascular changes leads to the development of cutaneous lupus erythematosus. However, a complete understanding of the pathophysiology of cutaneous lupus erythematosus is not known.
Systemic Implications and Complications
Nearly one-half of patients with SCLE have sufficient criteria for a diagnosis of systemic lupus erythematosus (SLE), yet only 10% go on to develop severe SLE disease. Serious central nervous system and progressive renal disease are uncommon, and SCLE is felt to have a good prognosis. However, follow-up visits should be used to evaluate for new signs or symptoms that suggest progression to SLE.
Screening for underlying SLE with clinical history, physical examination and laboratory evaluation to assess for involvement of the central nervous system, renal, hematologic, pulmonary, and cardiovascular system is warranted in all patients newly presenting with CLE.
An initial ANA, complete blood count (CBC) and urinalysis is sufficient for those without other symptoms. 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 systemic lupus, further testing is warranted. These may include anti-dsDNA, anti-Smith, CBC with differential, creatinine, albumin, total protein, erythrocyte sedimentation rate, urinalysis, and complement (C3,C4). If significant systemic symptoms of SLE are suspected, a rheumatologist should be involved in the case.
Treatment options are summarized in the Table 1.
|Sun protection and avoidance Broad spectrum ,UVA and UVB, sunscreen protectionSmoking cessation TopicalTopical steroids, Class I or II; lower strength for the faceTopical calcineurin inhibitors with or without topical steroid Tacrolimus 0.1% ointment Pimecrolimus 1% cream SystemicAntimalarials: Hydroxychloroquine 6.0 to 6.5mg/kg/day IBW Hydroxychloroquine + quinacrine 100mg daily Chloroquine <3.5mg/kg/day IBW +/- quinacrine 100mg dailyThalidomide 50 to 200mg/dayDapsone 50 to 150mg/dayPrednisone 0.5 to 0.75mg/kg/dayMethotrexate 5 to 25mg/weekMycophenolate Mofetil 2 to 3g/dayAzathioprine 1 to 2.5 mg/kg/day|
IBW, ideal body weight
Optimal Therapeutic Approach for this Disease
The treatment goal for SCLE is to decrease the inflammation in active lesions and hopefully avoid severe dyspigmentation. Assessment of treatment response should be focused on improvement in erythema and scale. Established dyspigmentation will not resolve with the above treatments, but may slowly improve over time. Cosmetics such as Covermark and Dermablend may be used for dyspigmentation in cosmetically sensitive areas, such as the face.
SCLE is highly photosensitive, to sun avoidance and sun protection is the first step to therapy and must be discussed with all patients. The use of broad spectrum sunscreens to cover the UVB and UVA spectrum is necessary. Products with helioplex, mexoryl and physical blockers (titanium dioxide, zinc oxide) offer the broadest protection. An SPF of at least 30 should be applied daily to all sun-exposed areas.
Cigarette smokers are more likely to develop CLE and SLE and suffer from more severe disease. Antimalarials may be less effective in smokers, and smokers are more likely to have skin disease that is refractory to all therapies. As a result, all patients with CLE and SLE should be counseled on smoking cessation.
Topical therapy with steroids can be initiated as first-line therapy, with or without calcineurin inhibitors. Class I or II topical steroids should be tried in patients with mild skin disease prior to starting systemic therapies. Lower steroid strengths can be used on the face. Topical calcineurin inhibitors are effective in SCLE and offer a decreased risk of telangiectasia development compared with topical steroids. Combining topical steroids and calcineurin inhibitors may provide an added benefit.
In addition to sunscreen and topical therapies, antimalarials are the next step in the therapeutic ladder and are highly effective in SCLE.
Antimalarials are recommended as first-line systemic therapy for CLE and SLE given its effectiveness in prevention and treatment of symptoms, such as photosensitivity, acute malar rash, DLE, oral ulcers, alopecia, arthritis, pleuritis, and pericarditis. Up to two thirds of patients with SCLE respond to single-agent or combination antimalarial therapy.
Hydroxychloroquine is the treatment of choice over chloroquine given its lower ocular toxicity risk. Typically, hydroxychloroquine is started at 200mg to 400mg a day. To avoid ocular toxicity, the daily dose should not exceed 6.5mg/kg ideal body weight (IBW)/day.
Ideal body weight is calculated as follows: 45.5kg (use 50kg for males) + 2.3 kg for each inch over 5 feet; or 45.5kg + 2.3kg * (height [inches]-60).
Antimalarials take 2 to 3 months for improvement to be noticed and up to 6 months for a complete response. After 8 to 12 weeks, if improvement is not satisfactory, addition of quinacrine 100mg daily may be added. Quinacrine can only be obtained at compounding pharmacies. It may cause yellow discoloration of the skin.
If the combination of hydroxychloroquine and quinacrine have not provided complete response after 6 months, changing to chloroquine plus quinacrine is an option. Chloroquine is typically started at a dose of 250mg 5 to 7 days a week and should not exceed 3.5mg/kg IBW/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 are based on the maximal safe dose from an ocular safety perspective. The retinopathy associated with antimalarials (chloroquine) may be irreversible. The blurred vision and corneal deposition that may occur is reversible. The use of hydroxychloroquine necessitates eye examinations every 6 months and with chloroquine every 4 months. The eye examination should include visual acuity, visual fields, and fundoscopic examination. 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 examination, a CBC and liver function test are recommended at baseline and after one month of use.
If antimalarials are not effective, second-line systemic therapies including thalidomide, dapsone, and immunosuppressives may be required. Specifically, if refractory and widespread SCLE lesions persist, or patients have concomitant SLE symptoms, they may benefit from these steroid-sparing immunosuppressants. In some instances, these immunosuppressants are initially used in combination with prednisone. Once the medication takes effect, the goal is to taper off the prednisone.
If antimalarials are ineffective, thalidomide can be used as a second-line agent together with antimalarials. Thalidomide is also an option for patients who are unable to tolerate antimalarials. Thalidomide produces relatively rapid improvement, as soon as 2 to 3 weeks, and clinical remission is typically achieved within 8 weeks. Up to 90% of patients are responsive to thalidomide therapy. A starting dose of 50mg nightly of thalidomide is recommended and may be increased to normally 100mg at night over 6 to 8 weeks for peak effect, assuming tolerable side effects.
Thalidomide dose can often be decreased once SCLE lesions are improved. The dose of thalidomide can be decreased to 50mg per day and then 50mg every 2 or 3 days as maintenance if continued therapy is needed. Thalidomide can also be used in short courses for disease flare in patients on maintenance antimalarials. Of note, thalidomide is effective for SCLE and associated arthralgias, but has little effect on the visceral symptoms associated with SLE.
Thalidomide is known to be efficacious in SCLE, but its utility in clinical practice is limited by its toxicities. The most common side effects of thalidomide is dose-related sedation, headaches, and amenorrhea. Severe side effects include teratogenicity, reversible sensory neuropathy and venous thromboembolic events. Sensory neuropathy can present with tingling or numbness in the distal extremities. If symptoms are severe, the dose can be decreased or discontinued. Of note, abnormal sensory nerve action potentials have been found in clinically asymptomatic patients.
To prevent birth defects, physicians are required to enroll in the System for Thalidomide Education and Prescribing Safety (STEPS) program. To decrease the risk of deep vein thrombosis, the use of an antimalarial or aspirin is recommended.
In cases refractory to antimalarials, dapsone may be an adjunctive treatment in SCLE at dosages of 25 to 150 mg daily. Bullous SLE, SCLE and oral ulcerations have been shown to benefit the most from dapsone therapy. A starting dose of 50mg can be increased by 25mg weekly to 150mg a day if laboratory tests permit. Maintenance doses as low as 50mg may be used once disease is stable. Dapsone has been used successfully in the setting of SCLE, and hypocomplementemia with urticarial vasculitis.
Severe adverse effects are related to hematotoxicity and can be seen as hemolytic anemia and/or methemoglobinemia. Both are dose dependent and occur, to some degree, in all patients who take dapsone. A glucose-6-phosphate dehydrogenase (G6PD) level should be tested in all patients being considered for dapsone, as the risk of hemolytic anemia is significantly increased if there is a deficiency.
Peripheral motor neuropathy can be observed and typically resolves completely after dose reduction or drug discontinuation. Agranulocytosis is a serious, idiosyncratic adverse effect of dapsone. Patients normally will experience a 2g/dL drop in hemoglobin, but greater drops below 10g/dL necessitate an adjustment of dose. Patients may experience a clinically unimportant drop in their 02 saturation, which is not routinely monitored.
Baseline laboratory tests include CBC with differential, complete metabolic panel (liver function tests and renal function), urinalysis and G6PD level. During each visit assess peripheral motor neuropathy, CBC with differential every 1 week while the dose is being increased, then monthly for 3 months, then every 3 months, and a complete metabolic panel every 3 months.
Given the chronic and recurrent nature of CLE, including SCLE, use of steroids should be avoided. Use in cases of severe widespread disease, while awaiting antimalarials or other less toxic therapies to take effect is reasonable.
Typically, prednisone has been used in severe SCLE at dosages of 0.5 mg/kg/day to 0.75 mg/kg/day in combination with antimalarials, or other anti-inflammatory or immunosuppressive agents discussed above. Prednisone should not be used alone, as lesions recur once prednisone is stopped. Tapering prednisone as tolerated once the SCLE 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 short courses of therapy.
Methotrexate (MTX) in lupus erythematosus can be used in doses of 5 to 25mg weekly. MTX typically takes 3 to 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.
A potential for hepatotoxicity, with long-term use, and pulmonary toxicity are important considerations. Patients who drink alcohol should not receive MTX, and 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 [TMP/SMX] and NSAIDS), 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, complete metabolic panel (liver and renal function), hepatitis B and C serologies, and HIV testing. After the first dose of MTX, a CBC and liver function laboratory tests should be done in 1 week. If laboratory tests 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 MTX.
Mycophenolate mofetil (MMF) is well tolerated and has been shown to be effective in CLE, including SCLE, and SLE. The most common adverse reaction from this therapeutic agent 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 to 4 weeks to goal dose of 2 to 3g/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, as well as hepatitis B and C serologies and HIV testing. Laboratory tests 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, are recommended. Maintenance doses of 1.5 to 3g a day can be used safely.
Azathioprine is an immunosuppressant that has been extensively studied in lupus erythematosus as a steroid-sparing agent. However, experience in SCLE is limited. 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 to 3mg/kg/day. In SCLE, azathioprine doses of 100 to 150mg are commonly needed to achieve desired effects. Clinical effects are typically seen in 4 to 8 weeks. The maintenance dose can range from 50 to 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 performed, particularly if doses above 50mg a day are used initially. Low levels increase the risk of myelosuppression and potentially fatal neutropenia. A CBC and liver function tests should be performed every 2 weeks while the dose is being adjusted, then every month for the first year, and then every 3 months.
In drug-induced SCLE, the lesions can resolve with minimal therapy once the causative medication is withdrawn. In addition to sun avoidance and sunscreen, topical steroids may be used to expedite the resolution of active lesions.
All patients newly diagnosed with CLE should be counseled on the specific disease course, including any potential risk for scarring and disfigurement. The vast majority of patients with CLE, particularly CCLE and SCLE, have disease that primarly affects the skin. These patients should be reassured that their disease progression is relatively benign. Patients with SCLE should be aware that there is a risk of progression to SLE, but that the diease is typically mild.
The next step is to provide patients with therapeutic modalities that minimize disease progression and improve treatment response. All patients must be counseled on sun avoidance and protection, including avoidance of artificial tanning beds and photosensitizing medications. On a similar note, the role of smoking in disease severity must be stressed at the initial visit. All patients should be encouraged to stop smoking and should begin a smoking cessation program.
The goal of any therapy for SCLE is to improve the patient’s appearance and to minimize new lesions to prevent more areas of potential dyspigmentation. Mainstay therapies for the majority of SCLE subsets include topical therapies and antimalarials. Both of these therapies have limited severe adverse reactions. However, patients with refractory or widespread disease may need treatment with 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 SCLE lesions. Thus, when ascending the therapeutic ladder, individualizing therapy for patients based on their co-morbidities is necessary. Furthermore, after clearance of SCLE lesions, therapies should be reduced to the lowest effective dose, or discontinued.
Unusual Clinical Scenarios to Consider in Patient Management
There have been rare cases of “paraneoplastic” SCLE associated with malignancies, including those of the lung, breast, stomach, liver, larynx, uterus, and lymphoma. Consideration of an age-appropriate malignancy workup may be warranted in those cases that are either not responding to standard therapy or in the presence of systemic symptoms or signs that might suggest that the patient has a malignancy.
What is the Evidence?
Callen, JP. “Drug-induced subacute cutaneous lupus erythematosus”. Lupus. vol. 19. 2010. pp. 1107-11. (A comprehensive discussion of medications that may cause SCLE. Useful tables of the most frequent medications are included.)
Vera-Recabarren, MA, Garcia-Carrasco, M, Ramos-Casals, M, Herrero, C. ” Comparative analysis of subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus: clinical and immunological study of 270 patients”. Br J Dermatol. vol. 162. 2010. pp. 91-101. (The distribution and type of lesions, systemic features and immunologic findings between CCLE and SCLE are discussed. SCLE patients have a higher frequency of laboratory and serologic abnormalities than patients with CCLE.)
Herrero, C, Bielsa, I, Font, J, Lozano, F, Ercilla, G, Lecha, M. “Subacute cutaneous lupus erythematosus: clinicopathologic findings in thirteen cases”. J Am Acad Dermatol. vol. 19. 1988. pp. 1057-62. (A review of thirteen cases of SCLE reveal that histopathologic findings of many epidermal colloid bodies and severe epidermal necrosis are seen clinically in patients with annular lesions, anti-Ro antibodies and human leukocyte antigen-DR3.)
David-Bajar, KM, Bennion, SD, DeSpain, JD, Golitz, LE, Lee, LA. “Clinical, histologic, and immunofluorescent distinctions between subacute cutaneous lupus erythematosus and discoid lupus erythematosus”. J Invest Dermatol. vol. 99. 1992. pp. 251-7. (A comprehensive description of SCLE features and a comparison of these findings to the presentation of discoid lupus and SLE.)
Sontheimer, RD. “Subacute cutaneous lupus erythematosus: 25-year evolution of a prototypic subset (subphenotype) of lupus erythematosus defined by characteristic cutaneous, pathological, immunological, and genetic findings”. Autoimmunity Reviews. vol. 4. 2005. pp. 253-63. (The author discusses the pathogenesis of SCLE from susceptibility genes to loss of tolerance.)
Black, DR, Hornung, CA, Schneider, PD, Callen, JP. “Frequency and severity of systemic disease in patients with subacute cutaneous lupus erythematosus”. Arch Dermatol. vol. 138. 2002. pp. 1175-8. (This article compares systemic and serologic findings in patients with SLCE to those with SLE. Those patients with SCLE show less internal organ involvement.)
Callen, JP, Spencer, LV, Burruss, JB, Holtman, J. “Azathioprine: an effective, corticosteriod-sparing therapy for patients with recalcitrant cutaneous lupus erythematosus or with recalcitrant cutaneous leukocytoclastic vasculitis”. Arch Dermatol. vol. 127. 1991. pp. 515-22. (An open-label clinical trial of azathioprine use in 12 patients with SCLE, CCLE and vasculitis. The response to therapy and management of azathioprine dose is discussed.)
Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.