Subacute cutaneous lupus erythematosus (SCLE) is a nonscarring, non–atrophy-producing, photosensitive dermatosis. SCLE commonly develops in sun-exposed areas, including the upper back, shoulders, extensor arms, neck, and upper torso, while the face is often spared. These skin lesions can appear as either papulosquamous (psoriasiform) or annular lesions.
SCLE is a subtype of cutaneous lupus erythematosus (CLE); other subtypes include acute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus. Chronic cutaneous lupus erythematosus includes discoid lupus erythematosus, lupus erythematous panniculitis/profundus, lupus tumidus, and chilblain lupus.
SCLE may occur in patients with systemic lupus erythematosus (SLE), Sjögren syndrome, or deficiency of the second component of complement (C2d), or it may be drug-induced. SCLE is the most common subtype of CLE associated with Sjögren syndrome.[1] Some patients with SCLE may also have acute cutaneous lupus erythematosus (ACLE), if they have concomitant SLE, or the lesions of discoid lupus erythematosus (DLE), and some may develop small-vessel vasculitis. (See the image below.)
View Image | Early lesions of subacute cutaneous lupus erythematosus may simulate polymorphous light eruption. |
See Cutaneous Clues to Accurately Diagnosing Rheumatologic Disease, a Critical Images slideshow, to help recognize cutaneous manifestations of rheumatologic diseases.
Patients with SCLE frequently fulfill 4 or more of the criteria used to classify SLE. Serologic abnormalities are common. Therapy with sunscreens, topical corticosteroids, and antimalarial agents is often effective; however, some patients require additional agents to control their cutaneous disease. (See Workup and Treatment.)
SCLE lesions heal without scarring or atrophy, but they may result in dyspigmentation, which can be prominent. Severe systemic disease is unusual, but when it occurs, the patient may develop life-altering sequelae.
Subacute cutaneous lupus erythematosus (SCLE) occurs in genetically predisposed individuals, most often in patients with human leukocyte antigen B8 (HLA-B8), human leukocyte antigen DR3 (HLA-DR3), human leukocyte antigen DRw52 (HLA-DRw52), and human leukocyte antigen DQ1 (HLA-DQ1). A strong association exists with anti-Ro (SS-A) autoantibodies, as greater than 80% of patients with SCLE have anti-Ro (SS-A) positivity.[2] The reaction is believed to be related to ultraviolet (UV) light modulation of autoantigens, epidermal cytokines, and adhesion molecules, with resultant keratinocyte apoptosis. One study demonstrated that patients with SCLE, as well as those with discoid LE, but not those with lupus tumidus, have elevated levels of type I IFN-regulated genes in their blood. Furthermore, the levels were correlated with the patients' cutaneous disease activity severity levels as measured by the Cutaneous Lupus Area and Severity Index (CLASI).[3]
SCLE usually manifests following UV light exposure, but other triggers or inciting factors may also be involved given that not all patients have disease that follows photoexposure. Exacerbation of disease or induction of lesions is more common following UV-B exposure, but it can also occur in patients exposed to UV-A. Some patients exhibit sensitivity to only UV-A or to UV-A and UV-B.[4]
In perhaps as many as 30% of patients with SCLE, drugs may exacerbate or induce their disease.[5] Traditionally, hydrochlorothiazide has been the most frequently implicated drug; however, other antihypertensive agents, along with a list of over 100 different agents, have been reported in relation to the induction or exacerbation in individual patients.[6]
Additional implicated agents include calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs, antifungal agents (particularly terbinafine), chemotherapy agents, proton pump inhibitors, and tumor necrosis factor (TNF) antagonists.[7, 8, 9, 10, 11] In a recent population-based, matched case-control study of the incidence of SCLE cases in Sweden, the most increased odds ratios (OR) for developing SCLE from drug exposures were found with terbinafine (OR, 52.9), TNF antagonists (OR, 8.0), antiepileptics (OR, 3.4), and proton pump inhibitors (OR, 2.9).[12] Development and worsening of SCLE have also been reported with newer anti-TNF-agents, including golimumab.[13, 14] Therefore, a careful drug history should be part of the initial evaluation of patients with SCLE.[15]
Patients with a deficiency of the second component of complement (C2d) often manifest SCLE lesions as part of their SLE-like disease.
Worldwide, subacute cutaneous lupus erythematosus (SCLE) prevalence ranges from 17-48 cases per 100,000 persons, while the incidence of cutaneous lupus erythematosus (CLE) is 4.3 cases per 100,000 persons and that of SCLE specifically is 0.63 case per 100,000 persons.[16] The highest prevalence of systemic lupus erythematosus (SLE) occurs in patients aged 40-60 years. The male-to-female ratio of SLE is approximately 1:10. The male, to-female ratio of CLE is approximately 1:2-3.[17] Of patients with CLE, 10-50% have SCLE.
SCLE is more common in whites (>85%). The male-to-female ratio of SCLE is 1:4. The condition typically occurs in patients aged 15-70 years, with the mean age being approximately 43 years. It is estimated that 50% of patients with SCLE meet criteria for having SLE, and approximately 10% of SLE patients have SCLE lesions.
Subacute cutaneous lupus erythematosus (SCLE) uncomplicated by severe systemic lupus erythematosus (SLE) has a good prognosis. Some patients may manifest spontaneous remission; however, most have chronically active disease or a course punctuated by intermittent exacerbations. Exacerbation in the spring or summer is common. By definition, skin lesions heal without scarring or atrophy but may leave residual dyspigmentation.
Approximately half the patients with SCLE meet four or more of the criteria for classification as SLE[18] ; In these patients, the systemic disease is generally mild, with arthralgia and myalgia being the most common symptoms. However, in up to 10% of patients, severe systemic disease, including central nervous system involvement, vasculitis, or nephritis, is possible.[19] Individuals with the papulosquamous type of SCLE may be more likely to develop renal disease.[20]
Patients with SCLE usually have relatively minimal systemic disease. In a 2016 retrospective study assessing 85 patients with SCLE who fulfilled both the 1997 American College of Rheumatology (ACR) and the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria for SLE, patients with SLCE who formally met criteria for SLE did not have more significant systemic disease when compared with SCLE-only patients. Patients with SCLE who met SLE criteria were more frequently found to have oral ulcers, a positive antinuclear antibody (ANA), positive anti-dsDNA, and low complement levels.[21]
Instruct patients about sun-avoidance techniques, the use of sun-protective clothing, and the appropriate use of broad-spectrum sunscreens.
Because subacute cutaneous lupus erythematosus (SCLE) is exacerbated by sunlight or other UV light exposure, advise patients to take precautions. One precaution is to discourage exposure to sunlight between the hours of 10 am and 4 pm. While this is beneficial to some patients, many are so exquisitely photosensitive that this alteration does not help. In addition, advise patients to avoid artificial light sources, such as tanning beds.
Discuss the expectations for prognosis. Patients should be educated on the systemic manifestations of systemic lupus erythematosus (SLE) and be followed regularly for these.
For patient education information, see the Arthritis Center, as well as Lupus (Systemic Lupus Erythematosus).
Subacute cutaneous lupus erythematosus (SCLE) typically manifests in 1 of 2 forms: annular/polycyclic or psoriasiform/papulosquamous. SCLE lesions can begin as erythematous macules or papules that evolve into either annular polycyclic or psoriasiform plaques. Lesions typically occur in a photosensitive distribution. Many patients notice that sun exposure results in an exacerbation of their disease, and some report worsening each spring and summer. Photosensitivity is more frequently observed in patients with SCLE compared with discoid lupus erythematosus (DLE) lesions. Patients may report mild pruritus, but most persons with SCLE are asymptomatic.
Approximately 50% of patients with SCLE have accompanying joint involvement. Arthralgias are common, often symmetrical, and usually affect small joints, such as the wrists or those of the hands. Arthritis may occur but is unusual (< 2%).
Patients commonly complain of fatigue. Some patients have Sjögren syndrome, while others note dryness of their eyes and mouth. Patients may manifest symptoms of SLE; therefore, the history should include an assessment for symptoms of pleuritis, pericarditis, neurologic involvement, and renal impairment.
The primary lesion of subacute cutaneous lupus erythematosus (SCLE) is an erythematous papule or a small plaque with a slight scaling. Primary lesions expand and may merge and eventually form either plaques with scaling, in the papulosquamous variant, or annular and/or polycyclic lesions, in the annular variant. (See the images below.)
View Image | Early lesions of subacute cutaneous lupus erythematosus may simulate polymorphous light eruption. |
View Image | Papulosquamous lesions of subacute cutaneous lupus erythematosus may simulate psoriasis. |
View Image | Annular lesions of subacute cutaneous lupus erythematosus. |
Papulosquamous lesions may mimic psoriasis or lichen planus, while annular lesions may mimic erythema annulare centrifugum or tinea corporis. Most patients exhibit one predominant type of lesion, and some also manifest isolated lesions of discoid lupus erythematosus (DLE) during the course of their disease.
SCLE lesions primarily are photodistributed. When they occur on the lower extremities, they often are purpuric. Early lesions of SCLE may be difficult to distinguish from polymorphous light eruption (PMLE). Despite this, and the fact that both disorders have prominent photosensitivity, SCLE and PMLE are considered distinct disorders with differing histopathologic features.
Neonatal lupus erythematosus (NLE) most often manifests as a nonscarring form of lupus erythematosus (see the image below). Skin lesions are worsened by UV light and usually resolve by age 4-6 months. The cutaneous findings resemble those of SCLE. NLE lesions are typically annular erythematous plaques with a slight scale, which appear predominately on the scalp, neck, or face, but similar plaques may appear on the trunk or extremities. Infants with NLE should be evaluated for cardiac, hematologic, hepatic, and neurologic involvement. NLE is thought to be caused by the transplacental passage of maternal autoantibodies, most often anti-SSA/Ro, but also anti-SSB/La or anti-RNP antibodies.
View Image | Neonatal lupus erythematosus. |
Annular erythema of Sjögren syndrome has been reported in Japanese and Polynesian patients. The authors believe that this is not a distinct entity, but rather SCLE with Sjögren syndrome in a particular ethnic population.
An infrequent variant including erythema multiforme–like lesions in association with lupus erythematosus (known as Rowell syndrome) and chilblains may exist, but it is not clear whether this is a distinct entity.
Patients with SCLE may have arthritis and pleuritis or pericarditis that manifest physical findings on joint or cardiopulmonary examination, respectively. Patients may also have nonspecific cutaneous manifestations of lupus erythematosus, such as livedo reticularis, palpable purpura, urticaria, ischemic changes of the distal fingertips (resulting from Raynaud phenomenon), or mucosal leukoplakic or ulcerative lesions.
In order to ensure proper diagnosis, relevant clinical history, detailed skin and physical examinations, laboratory tests, serologic tests, and skin biopsy should be used. It is important to classify cutaneous lupus skin lesions correctly when possible and evaluate for any evidence of systemic involvement.
The extent of laboratory workup should be individualized and based on the level of suspicion for systemic involvement, as follows:
As mentioned, most patients with subacute cutaneous lupus erythematosus (SCLE) manifest a positive antinuclear antibody (ANA) when tested with human substrates. HEp-2 cells are the substrate used most commonly in commercial laboratories. In a multicenter study, 70% of patients with SCLE were found to have positive ANA and only 5% had positive dsDNA.[22]
Anti-Ro (SS-A) autoantibodies are present in a high proportion of patients, as follows:
Anti-La (SS-B) autoantibodies are often present, but in a lower percentage of patients (typically < 50%). Antinative DNA (double-stranded or nDNA) antibodies usually reflect systemic lupus erythematosus (SLE), but may occur in up to 12% of patients with SCLE. It is also possible to have negative ANA but positive anti-Ro antibody in SCLE patients.[21]
Characteristic histopathologic alterations observed in subacute cutaneous lupus erythematosus (SCLE) include (1) vacuolar alteration of the basal cell layer and (2) an inflammatory cell infiltrate (usually lymphocytic) around vessels (perivascular), around appendiceal structures (periappendiceal), and in a subepidermal location. Epidermal changes, such as atrophy, are common, but follicular plugging is less frequent than in patients with discoid lupus erythematosus (DLE). An abundance of mucin often is seen within the dermis.
Histopathologic features differ depending on the type and age of the lesion. For example, papulosquamous lesions of SCLE are much more likely to manifest diagnostic findings than are annular lesions of SCLE.
Occasionally, direct immunofluorescence (DIF) testing may aid in diagnosis. A positive lupus band test (LBT) is defined as findings of immunoglobulin and/or complement at the dermoepidermal junction. These deposits appear granular and contain IgG, IgM, and occasionally IgA.[23] Examination of tissue may be performed on skin lesions (lesional) or healthy skin (nonlesional). However, nonlesional positive LBTs can be seen in SLE, rheumatoid arthritis, Sjögren syndrome, and other autoimmune diseases.[24] In the majority of cases, clinical and histologic findings are sufficient to make the diagnosis of cutaneous lupus without the need for DIF testing.
The use and interpretation of these tests vary according to the site of biopsy. Only 60% of patients with SCLE test positive on lesional skin. Some, usually those with systemic lupus erythematosus (SLE), have a positive LBT.
Older lesions may be more likely to be negative on immunofluorescence microscopy. The frequency of positive tests also is affected by tissue handling techniques. Snap frozen tissue is less likely to be falsely positive than tissue sent to the laboratory in Michel transport media.
The goals of management in subacute cutaneous lupus erythematosus (SCLE) are to improve the patient's appearance, mitigate any associated symptoms, prevent the development of additional lesions, and assess for potential associated systemic disease.[25] Counsel patients regarding the risk of serious systemic disease. Although many patients fulfill the criteria for systemic lupus erythematosus (SLE), the severity of systemic manifestations tends to be more mild, and renal and central nervous system (CNS) disease occur less frequently than in patients with SLE without associated SCLE.
Surgical approaches rarely are needed in patients with SCLE. Cosmetic measures are often less important in patients with this condition than in patients with discoid lupus erythematosus (DLE), given the lack of associated scarring; however, active disease and postinflammatory dyspigmentation may still cause notable cosmetic concerns in patients with SCLE. No special diet is required with SCLE.
Inpatient care is rarely needed for patients with skin disease; however, since these patients may have SLE, they may occasionally manifest internal complications that require hospitalization. In these instances, consultation with other physicians may be helpful.
Therapy begins with sun-protective measures, including sunscreens, protective clothing, and behavior alteration. A sunscreen containing Mexoryl SX and Mexoryl XL, tested in a randomized, placebo-controlled trial, was demonstrated to prevent the development of UV-induced cutaneous lesions.[26, 27]
Another study demonstrated that in an experimental setting, cutaneous lupus erythematosus (CLE) can be prevented by the use of a particular broad-spectrum sunscreen. The use of sunscreens in a clinical setting is not as effective as would be predicted from studies such as this one, perhaps because patients do not perform sunscreen application on a daily basis in a manner that might be effective.[28]
Broad-spectrum sunscreen with a sun protection factor (SPF) of 30 or greater should be applied at least 20 minutes prior to sun exposure and be reapplied every 2-3 hours. Often, sun avoidance and protective clothing are necessary in patients with subcutaneous lupus erythematosus (SCLE). Of note, skin disease in SCLE is often very challenging to control without adequate photoprotection.
Standard therapy includes topical and/or intralesional corticosteroids and antimalarials such as hydroxychloroquine or chloroquine. In patients with skin lesions refractory to hydroxychloroquine monotherapy, adding quinacrine can improve response.[29] A French multicenter study found that the measurement of hydroxychloroquine blood levels may correlate with the incidence of remission in patients with cutaneous lupus erythematosus. The most practical portion of this study is the potential use of blood levels to demonstrate a lack of compliance with therapy as those patients with very low levels had little clinical response.[30]
Additional therapies that may be considered in selected patients include thalidomide, methotrexate, mycophenolate mofetil, azathioprine, retinoids, dapsone, intravenous immunoglobulin, cyclosporine, auranofin, clofazimine, interferon, immunosuppressive agents such as cyclophosphamide and rituximab, and the monoclonal antibody belimumab.[31, 32, 33, 34, 35]
Lenalidomide, a thalidomide analogue, can be helpful in treating patients with refractory cutaneous lupus erythematosus (CLE) as well. Studies have shown skin improvement measured by CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) scores as early as 2 weeks after treatment initiation, although clinical relapse was common following medication withdrawal.[36]
Avoid systemic corticosteroids except for acute short-term usage or when the presence of systemic disease warrants use. Patients who smoke appear to respond less well to antimalarial therapy. Note that clofazimine is primarily beneficial for cutaneous, not systemic, disease.
Some patients with CLE have been found to be vitamin D deficient, particularly those who use careful photoprotection; therefore, the use of vitamin D and calcium should be considered following an assessment of vitamin D levels.[37]
Several upcoming therapeutic targets focus on type I interferons and receptors, anti-B-cell strategies, the toll-like receptor signaling pathway, and the JAK-STAT signaling pathway and may lead to additional treatment options for patients with cutaneous lupus in the future.[38]
Consultations with the following specialists may be helpful:
Follow patients with subacute cutaneous lupus erythematosus (SCLE) at regular intervals. Response to therapy varies, depending on the therapeutic agent prescribed. Avoid changes in therapy until a sufficient period elapses to note a response.
At least once each year, and perhaps twice, assess stable patients using routine laboratory tests, including complete blood count (CBC), renal function tests, and urinalysis. Repeat autoantibody testing is of little use in patients with SCLE, unless they have systemic lupus erythematosus (SLE). Regularly assess historical information concerning additional systemic manifestations.
The basic therapy of skin disease uses sun-protection methods, such as sunscreens, sun-protective clothing, and alteration of exposure by decreasing activities during times of high intensity UV light. Topical corticosteroids are used and selected by the appropriate strength for the area of the body. Intralesional injection of triamcinolone acetonide is useful for individual recalcitrant lesions. Antimalarials are the mainstay of systemic therapy and are associated with lower rates of disease progression and lower risk of thrombovascular disease in patients with systemic lupus erythematosus (SLE).[39, 40]
Anecdotal reports or small, open-label trials, as reported by Callen, suggest that the following agents may be of use in some patients[29, 41, 42, 43, 44, 45, 46, 47] :
Clinical Context: Hydroxychloroquine inhibits chemotaxis of eosinophils and locomotion of neutrophils, and it impairs complement-dependent antigen-antibody reactions. Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate.
Clinical Context: Chloroquine inhibits the effects of immune cells, impairing complement-dependent antigen-antibody reactions.
Antimalarials have immunomodulatory effects that may improve symptoms of the disease. Hydroxychloroquine is the drug of choice for systemic therapy of subacute cutaneous lupus erythematosus (SCLE). Chloroquine is second line. The lowest possible dose needed to control the patient’s disease should be used.
Clinical Context: Dapsone's mechanism of action is similar to that of sulfonamides, with competitive antagonists of para-aminobenzoic acid (PABA) preventing the formation of folic acid, inhibiting bacterial growth.
Clinical Context: Azathioprine antagonizes purine metabolism and inhibits the synthesis of DNA, RNA, and proteins. It may decrease the proliferation of immune cells, which results in lower autoimmune activity.
Clinical Context: Thalidomide may suppress the excessive production of tumor necrosis factor alpha (TNF-alpha), and it may down-regulate selected cell-surface adhesion molecules involved in leukocyte migration.
If the patient weighs less than 50 kg (110 lb), start at the low end of the dose regimen. Thalidomide can cause severe, life-threatening birth defects and is contraindicated in pregnant women. It is also contraindicated in women of childbearing potential unless they are using 2 forms of reliable contraception and are complying with serial pregnancy testing while on therapy. In addition, thalidomide is contraindicated in sexually active men who are not using latex condoms as barrier contraception.
The drug is available only under a special, restricted distribution program called the STEPS (System for Thalidomide Education and Prescribing Safety) Program. Only prescribers and pharmacists registered with this program may prescribe and dispense thalidomide. For more information, contact the Celgene Corporation at 1-888-423-5436.
Clinical Context: Mycophenolate inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their proliferation. The drug inhibits antibody production.
Clinical Context: Methotrexate reversibly inhibits dihydrofolate reductase; it limits the availability of 1-carbon fragments necessary for the synthesis of purines and the conversion of deoxyuridylate to thymidylate in the synthesis of DNA and cell reproduction. The drug is extensively used for cancer treatment, rheumatoid arthritis, and psoriasis and as a steroid-sparing agent in various autoimmune conditions.
Immunomodulators are effective in the treatment of diseases with autoimmune etiology.
Clinical Context: Gold is taken up by macrophages, which in turn inhibit phagocytosis and lysosomal membrane stabilization. It alters immunoglobulins, decreasing prostaglandin synthesis and lysosomal enzyme activity.
Clinical Context: Acitretin is a retinoic acid analogue similar to etretinate and isotretinoin. Etretinate is the main metabolite, and acitretin has demonstrated clinical effects close to those seen with etretinate. The mechanism of action is unknown.
Clinical Context: Isotretinoin decreases sebaceous gland size and sebum production. It may inhibit sebaceous gland differentiation and abnormal keratinization.
A US Food and Drug Administration (FDA)–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to decrease the risk of pregnancy and unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.