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Subacute Cutaneous Lupus Erythematosus
Introduction
Lupus erythematosus is an inflammatory connective tissue disorder characterized by pathogenic autoantibody production and immune complex formation and deposition resulting from a loss of immune tolerance. Dermatological manifestations of lupus constitute one of the diagnostic criteria for systemic lupus erythematosus (SLE). Cutaneous manifestations in lupus cover a broad spectrum and may or may not occur in the context of SLE.[1]
The lesions may be described as lupus erythematosus-specific and lupus erythematosus-nonspecific.[2] Lupus erythematosus-specific manifestations include various subtypes of cutaneous lupus erythematosus (CLE) and are subdivided into 3 different categories described by Gillian et al. These categories are acute, subacute, and chronic CLE.[3] This activity provides updated information on subacute CLE (SCLE), which typically presents as a symmetric, nonscarring, photosensitive erythematous rash over sun-exposed areas such as the face, neck, arms, upper back, and shoulders (see Image. Subacute Cutaneous Lupus Erythematosus Face and Neck Lesions).
Etiology
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Etiology
The etiology of SLE and CLE is not well-defined. The classical precipitating factor is sunlight exposure in a patient with an abnormal milieu of genetic predisposition and immune dysregulation. Drug-induced SCLE has been reported as well. Commonly used drugs that have been associated with SCLE are angiotensin-converting enzyme inhibitors, anticonvulsants, β-blockers, and immune modulators, including biologics, chemotherapeutic agents, and immune checkpoint inhibitors.[4][5][6] SCLE has been reported to develop in association with certain malignancies.
Epidemiology
SCLE primarily occurs in young to middle-aged female individuals, with female cohorts 3 to 4 times more likely to develop the lesions than male individuals. The condition usually presents in the 3rd or 4th decade of life. The mean age of onset of SCLE described by Bizar et al ranged from 50 to 52 years. SCLE is highly photosensitive, with 48% to 90% of patients meeting the American College of Rheumatology's definition of increased photosensitivity. The 2 morphologic variants of SCLE are annular and papulosquamous. Drug-induced forms may be seen in either sex and at older ages of onset.
Pathophysiology
The pathogenesis is multifactorial. SCLE is thought to develop due to genetics, environmental triggers, or immunologic factors. Recent data suggests some potential candidate genes involved in the evolution of SCLE, including HLA1, B8, DR3, HLA1, B8, DR3, DQ2, DRw52, DR3, and C4 null ancestral haplotype.[7][8] Moreover, deficiencies of the C2 and C4 complement components have been associated with SCLE.[9] Environmental factors, such as UV light and certain drugs, contribute to the development of SCLE. Studies have shown that both innate and cell-mediated immunity, along with dysfunction of the T helper (Th) cells, Th1, Th2, and Th17, and abnormal expression of various cytokines and adhesion molecules, are involved in the development of SCLE.[10][11]
Anti-Ro/SS-A antibodies and apoptotic keratinocytes, including UVB-irradiated keratinocytes, have been implicated in SCLE pathogenesis, as studies have shown deposition of autoantibodies, immunoglobulins, and complement at the dermoepidermal junction. Antibody-dependent cell-mediated cytotoxicity, CD8+ cytotoxicity, and complement-mediated cytolysis are all involved in the destruction of keratinocytes.[12][13][14]
Histopathology
Histologically, lupus erythematosus-specific cutaneous findings share many features, but SCLE has some distinct attributes. The most characteristic findings are moderate hyperkeratosis with focal disorientation, interface dermatitis, and periappendageal mononuclear cell infiltrates confined to the superficial dermis. Basement membrane thickening is usually not seen in SCLE, although dermal edema may be noted. The inflammatory infiltrates of interface dermatitis consist mainly of activated T cells and macrophages. Immunofluorescence studies show the deposition of immunoglobulin G (IgG) or complement components in a granular pattern at the dermoepidermal junction in about 60% of patients with SCLE. Anti-SS-A/Ro and anti-SS-B/La autoantibodies have been strongly associated with SCLE.[15]
History and Physical
SCLE lesions typically appear in a characteristic distribution, presenting as either papulosquamous or annular lesions with central clearing. These 2 forms can coexist, and the lesions generally heal without causing atrophy or scarring. Patients may have hypopigmentation or telangiectasia. However, the skin returns to normal in most. Individuals with SCLE frequently have a mild illness with musculoskeletal complaints and serologic abnormalities.[16] SCLE has a predilection for sun-exposed areas like the neck, shoulders, chest, and extensor surfaces of the arms, but it usually spares the face.
Evaluation
SCLE, along with other forms of CLE, is mainly a clinical diagnosis. Confirmatory histopathologic examination with skin biopsy is indicated when the diagnosis is uncertain. Laboratory studies like anti-SSA/Ro and anti-SSB/La are warranted as well. Direct immunofluorescence may be used to help support the diagnosis if histopathology is inconclusive. Immunofluorescence shows a granular pattern of deposition of immunoglobulin at the dermopidermal junction.
Treatment / Management
Management of SCLE includes lifestyle modification and pharmacological therapy. Important preventive measures include physical protection, such as wearing broad-brimmed hats and sun-protective clothing, as well as properly applying sunscreen. Educating patients about their disease, avoidance of potential triggers like excessive sun exposure, and strict sunscreen adherence with chemical or physical blocking agents is essential. A broad-spectrum sunscreen with a sun protection factor of at least 50 should be applied in sufficient amounts about 20 to 30 minutes before expected exposure.[17]
Tobacco is phototoxic and enhances the responsiveness of toll-like receptor 9, leading to the increased production of type 1 interferons in plasmacytoid dendritic cells and the upregulation of the expression of metalloproteinases 1 through 8.[18] Hence, smoking cessation education is very important.
For the pharmacological approach, topical corticosteroids, as well as the topical calcineurin inhibitors tacrolimus 0.1% and pimecrolimus 0.3%, are usually the first-line agents. Intralesional corticosteroids may be used in localized areas. Systemic therapy may be considered when a patient with SCLE does not respond appropriately to topical modalities or the cutaneous disease is widespread.
All patients should be started on antimalarials, particularly hydroxychloroquine, chloroquine, or quinacrine, due to their photoprotective and anti-inflammatory properties. Dosage recommendations are as follows:
- Hydroxychloroquine 6.0 to 6.5 mg/kg of ideal body weight
- Chloroquine 3.5 to 4 mg/kg of ideal body weight
- Quinacrine 100 mg/day
Immunosuppressive agents may be considered in patients unresponsive to the standard initial treatment. Immunosuppressants that have been used include methotrexate (MTX), dapsone, mycophenolate (MMF), azathioprine, and thalidomide. MTX was introduced in 1965 and is considered a 2nd line of therapy. Studies have shown that the use of MTX leads to a significant reduction in autoantibodies in patients with lupus compared to the control group.[19] The typical dosage ranges from 7.5 mg to 25 mg, administered once weekly via oral, intravenous, or subcutaneous routes.(A1)
MMF is used in lesions refractory to antimalarials and other immunomodulatory agents. MMF acts on both T and B cells by inducing T cell apoptosis and preventing B cells from producing antibodies. The dosing for MMF ranges from 1.0 to 3.0 g/day, with renal dosage adjustments if required. Thalidomide is administered at a dose of 400 mg daily, while lenalidomide is given at 5 to 10 mg/day. These agents inhibit tumor necrosis factor-α synthesis.
Other treatment options include systemic steroids, belimumab, dapsone, and anifrolumab. Belimumab is an IgG1 monoclonal antibody that targets the protein B lymphocyte stimulator and has shown efficacy in treating SCLE. This agent is particularly effective for managing cutaneous symptoms when used in conjunction with standard therapies.[20] Dapsone is an antibiotic that blocks the myeloperoxidase enzyme and has anti-inflammatory and immunomodulatory effects. Dapsone is started at 50 mg daily, with a maximum dosage of 200 mg daily. Anifrolumab, a human monoclonal antibody against type I interferon receptor subunit 1, is now used in the treatment of cutaneous and systemic lupus.[21][22][23](B2)
The use of intravenous immunoglobulin and rituximab has also been documented in case reports. Rituximab is a chimeric anti-CD20 monoclonal antibody. This agent induces B-cell lysis through antibody-dependent cellular toxicity. Rituximab is the first choice for severe autoimmune diseases resistant to conventional treatment, including severe subacute lupus cases.[24] Intravenous immunoglobulin has also shown some promising results in refractory cases of SCLE.[25](B3)
Differential Diagnosis
The differential diagnosis of SCLE includes the following:
- Psoriasis
- Tinea corporis
- Nummular eczema
- Dermatomyositis
- Pityriasis rubra pilaris
- Sarcoidosis
- Cutaneous T-cell lymphoma
- Drug eruptions [26]
Careful clinical investigation and diagnostic test selection can differentiate SCLE from other conditions, guiding management appropriately.
Prognosis
Since SCLE is a photosensitive rash, around 50% of patients with SCLE meet the criteria for classification as SLE. However, systemic disease is usually mild, with arthralgia, myalgia, oral ulcers, positivity for antinuclear antibody and anti-dsDNA, and low complement levels being the most common findings.[27][28] Severe systemic disease is uncommon. Central nervous system involvement, vasculitis, and nephritis are seen in around 10% of patients.[29] Renal disease has been associated with papulosquamous variants of SCLE.[30]
Complications
Patients may develop vitamin D deficiency due to sun protection. SCLE rarely may involve large body surface areas, causing excessive discomfort and impairing a patient's quality of life. Systemic manifestations of SCLE may lead to vital organ involvement and result in complications.
Consultations
Consultations with dermatology and rheumatology are recommended. Other specialties may also need to get involved, such as nephrology, pulmonary, and neurology, depending on what other organs are affected and the severity of tissue damage and symptoms.
Deterrence and Patient Education
Patients need to be counseled and educated about sun protection, smoking cessation, and vitamin D replacement. Affected individuals should also be advised to avoid any drugs that can lead to SCLE exacerbation or worsening of lesions.
Pearls and Other Issues
The diagnosis of SCLE involves recognizing characteristic skin lesions and confirming the presence of the relevant autoantibodies. Treatment typically includes topical corticosteroids, immunomodulators, and strict sun protection measures. Smoking cessation and correction of vitamin D deficiency are other aspects of management. Regular follow-up is essential to monitor disease progression and adjust treatment as needed.
Enhancing Healthcare Team Outcomes
Early recognition of SLE and SCLE can lead to prompt initiation of treatment to avoid complications. Communication between primary care providers and specialists is key to limiting morbidity in patients with diseases like SCLE or SLE.
Primary care providers can help reinforce lifestyle changes, including sun protection and smoking cessation, which can improve long-term outcomes. Dermatology nurses assist with patient education and arrange for follow-up appointments and laboratory tests. Pharmacists review prescriptions, check for drug interactions, and inform patients about the importance of compliance and potential side effects. These professionals may also consult with the clinician regarding optimal agent selection and dosing. Both nurses and pharmacists need to alert the clinician if they encounter any issues of concern. These examples of interprofessional coordination can help drive better patient outcomes for SLE.
Media
(Click Image to Enlarge)
Subacute Cutaneous Lupus Erythematosus Face and Neck Lesions. Multiple papulosquamous and annular polycyclic lesions of subacute cutaneous lupus erythematosus.
Contributed by Scott Jones, MD
References
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