Subacute Cutaneous Lupus Erythematosus

Etiology

There is no well-defined etiology for systemic lupus erythematosus. The classical precipitating factor is sunlight exposure in a patient with the 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, beta-blockers, and immune modulators, including TNF alpha inhibitors. There have been case reports of the development of SCLE in malignancies.

Epidemiology

Systemic lupus erythematosus primarily occurs in young to middle-aged females, with females 3 to 4 times more likely to develop the lesions compared to males.[1] It usually presents in the third or fourth 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 ACR definition of increased photosensitivity.[2] Drug-induced forms may be seen in either sex and at older ages of onset.

Pathophysiology

The pathogenesis of systemic lupus erythematosus is multifactorial. SCLE is thought to develop due to genetics, environmental triggers, and or immunologic factors. Recent data suggests some potential candidate genes involved with SCLE.[3] HLA1, B8, DR3, HLA1, B8, DR3, DQ2, DRw52, DR3, and C4 null ancestral haplotype have all been associated with SCLE.[4][5] Moreover, deficiencies of C2 and C4 components of complement have been associated with SCLE.[6] Amongst the environmental factors, UV light and drugs have been found to play a role in the development of SCLE. Studies have shown the role of both innate and cell-mediated immunity,  abnormal expression of T helper (Th) cells Th1, Th2, and Th17, several cytokines, and adhesion molecules implicated in the development of SCLE.[7][8] Anti-Ro/SS-A antibodies, apoptotic keratinocytes, including UVB-irradiated keratinocytes, have been implicated in pathogenesis in SCLE, as studies have shown deposition of, autoantibodies, immunoglobulin, and complement at the dermo-epidermal junction. Antibody-dependent cell-mediated cytotoxicity (ADCC), CD8+ cytotoxicity, complement-mediated cytolysis are all involved in the destruction of keratinocytes.[9][10][11]

Histopathology

Histologically, LE specific cutaneous findings share many features, but systemic lupus erythematosus has some distinct findings. Most characteristic findings are moderate hyperkeratosis with focal disorientation, interface dermatitis, and peri-appendageal mononuclear cell infiltrate confined to the superficial dermis. Basement membrane thickening is usually not seen in SCLE,  dermal edema may be noted. The inflammatory infiltrate of the interface dermatitis consists mainly of activated T cells and macrophages.[12] Immunofluorescence studies show the deposition of immunoglobulin G (IgG) and/or complement components in a granular pattern at the dermal-epidermal junction, in about 60% of patients with SCLE. Anti-SS-A/Ro and anti-SS-B/La autoantibodies have been strongly associated with SCLE.[13]

History and Physical

The systemic lupus erythematosus lesions have a characteristic distribution with either papulosquamous lesions or annular lesions with central clearing. These two forms can occur concurrently, and the lesions typically heal without atrophy or scarring. The patient may have hypopigmentation or telangiectasia, but in most patients, the skin returns to normal. Patients with SCLE frequently have a mild illness with musculoskeletal complaints and serologic abnormalities.[12] SCLE has a predilection for sun-exposed areas like neck, shoulders, chest, and extensor surfaces of the arms and usually spares the face.

Evaluation

Systemic lupus erythematosus, along with other forms of CLE, is mainly a clinical diagnosis supported by clinical features. Confirmatory histopathologic examination with skin biopsy is indicated when there is diagnostic uncertainty. Laboratory studies like anti-SSA/Ro and anti-SSB/La are indicated as well. Direct immunofluorescence can be used to help support the diagnosis if histopathology is uncertain. Immunofluorescence shows a granular pattern of deposition of immunoglobulin at the dermal-epidermal junction.

Treatment / Management

Management of systemic lupus erythematosus includes lifestyle management and pharmacological therapy. It is important to address physical protection like broad-brimmed hats and sun-protective clothing, along with the proper use of sunscreen. Educating patients about their disease and avoiding potential triggers like minimizing sun exposure and strict sunscreen adherence with chemical and/or physical blocking agents is essential. The application of broad-spectrum sunscreen with a sun protection factor (SPF) of at least 50 should be applied in sufficient amounts about 20 to 30 minutes before expected exposure.[14]

Tobacco is phototoxic, enhances toll-like receptor 9 responsiveness, and IFN type 1 production in plasmacytoid dendritic cells and up-regulates expression of metalloproteinases 1 through 8.[15] Hence, smoking cessation education is very important.

For the pharmacological approach, the use of topical corticosteroids (CS) and calcineurin inhibitors (tacrolimus 0.1% and pimecrolimus 0.3%) are usually the first-line treatment. Intralesional CS could be used in localized areas. When a patient with SCLE does not respond appropriately to topical therapy and/or the cutaneous disease is widespread, the use of systemic therapy can be considered.

It is recommended that all patients be started on antimalarials (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. 

In patients not responding to the initial treatment, further immunosuppressive agents may be added. Immunosuppressants that have been used methotrexate, dapsone, mycophenolate (MMF), azathioprine, and thalidomide.

Methotrexate was introduced in 1965 and is considered a second line of therapy. A significant reduction in autoantibodies in patients with lupus compared with the control group was found with the use of methotrexate.[16] The dosage ranges from 7.5 mg to 25 mg once per week orally, intravenously, or subcutaneously. MMF is used in lesions refractory to antimalarials and other immunomodulatory agents. MMF acts on both T and B cells by inducing apoptosis of T cells and preventing the B cells from producing antibodies. The dosing for MMF is 1.0 to 3.0 g/day and also needs renal dosage adjustment. Dosing for thalidomide is 400 mg daily, and for lenalidomide 5 to 10 mg/day, with the mechanism of action for this being inhibition of synthesis of tumor necrosis factor-α.(A1)

Third-line treatments include belimumab and dapsone. Belimumab is an IgG1 monoclonal antibody that binds to B lymphocyte stimulator, found to be efficacious in SCLE. Cutaneous symptoms are among the treatment areas in which belimumab, in addition to standard therapy in these patients, is most efficacious.[17] Dapsone is an antibiotic that blocks the myeloperoxidase enzyme and has an anti-inflammatory and immunomodulatory effect. Dapsone is started at 50 mg daily, with a maximum dosage of 200 mg daily.

Furthermore, there have been case reports of using intravenous immunoglobulin (IVIG) and rituximab. Rituximab is a chimeric anti-CD20 monoclonal antibody; it induces B-cell lysis through antibody-dependent cellular toxicity. It is the first choice for patients with severe autoimmune diseases, resistant to conventional treatment, including severe cases of subacute lupus.[14][18] IVIG has shown some promising results in refractory cases of SCLE as well.[19](B3)

Differential Diagnosis

• Psoriasis
• Tinea corporis
• Nummular eczema
• Dermatomyositis
• Pityriasis rubra pilaris
• Sarcoidosis
• Cutaneous T cell lymphoma
• Drug eruptions [20]

Prognosis

Since systemic lupus erythematosus is a photosensitive rash, around 50% of patients with SCLE would meet the criteria for classification as SLE. However, systemic disease is mild, arthralgia, myalgia, oral ulcers, a positive antinuclear antibody (ANA), positive anti-dsDNA, and low complement levels being the most common findings.[21][22] Severe systemic disease is not as common. Central nervous system involvement, vasculitis, or nephritis is seen in around 10% of patients.[23] Renal disease has been associated with papulosquamous variants of SCLE.[24]

Complications

Due to sun protection, patients can develop vitamin D deficiency. Systemic lupus erythematosus rarely can involve large body surface areas to cause excessive discomfort and may affect the quality of life. Systemic manifestations of SCLE may lead to vital organ involvement and result in complications.