Continuing Education Activity

Lupus erythematosus is a multisystem disorder that predominately affects the skin. There are several types of cutaneous lupus. The most common types are acute cutaneous lupus (ACLE), subacute cutaneous lupus (SCLE), and discoid lupus (DLE). Dr. James Gilliam described the most commonly used classification of cutaneous lesions in lupus erythematosus. Gilliam segregated skin lesions into those that are specific and those that are not specifically based upon whether an interface dermatitis was seen on histopathologic examination. This activity reviews the pathophysiology of discoid lupus, its presentation, and management by an interprofessional team.

Objectives:

• Describe how genetic and environmental factors play an important role in the pathogenesis of DLE.

• Review the categorization of the lesions associated with DLE.

• Summarize how topical and intralesional corticosteroids, oral corticosteroids, oral antimalarials, and corticosteroid-sparing immunomodulatory agents are used for treating DLE lesions.

• Explain how monitoring adverse effects of the medications by all interprofessional team members is crucial for a patient's comprehensive recovery.

Introduction

Lupus erythematosus is a multisystem disorder that predominantly affects the skin. There are several types of cutaneous lupus. The most common types are acute cutaneous lupus (ACLE), subacute cutaneous lupus (SCLE), and discoid lupus (DLE). Dr. James Gilliam described the most commonly used classification of cutaneous lesions in lupus erythematosus. Gilliam segregated skin lesions into those that are specific and those that are not specifically based upon whether an interface dermatitis was seen on histopathologic examination. Within the category of specific cutaneous lesions, he subdivided these into acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, and chronic cutaneous erythematosus.[1][2]

The most common subset of chronic cutaneous lupus erythematosus is DLE. These patients may or may not report photosensitivity, but lesions are frequently photo distributed and tend to have secondary atrophy or scarring. Most patients with DLE do not have significant systemic disease. DLE can also occur as a manifestation of SLE in approximately 20% of patients. Other less common forms of chronic cutaneous lupus erythematosus include hypertrophic lupus erythematosus, tumid lupus erythematosus, lupus erythematosus panniculitis (LEP or lupus profundus), chilblain LE, oral DLE, as well as DLE lesions on the palms and/or soles.[3][4]

Etiology

Lupus erythematosus is an inflammatory, connective-tissue disease of generalized autoimmunity characterized by pathogenic autoantibodies and immune complexes, attributed to a loss of immune tolerance. For discoid lupus erythematosus without associated SLE (CDLE), the evidence does not show whether circulating inflammatory cells and autoantibodies are involved in the pathogenesis, but it is evident that the cutaneous inflammatory infiltrates are dominated by Th1, but not Th17, cells in contrast to systemic lupus erythematosus.[5][6]

Epidemiology

Lupus can occur in all age groups, but DLE occurs more frequently in women in their fourth and fifth decades of life. Twenty-five percent of patients with SLE may develop typical discoid lesions at some point during their illness, and 1% to 5% of patients with discoid lupus may develop SLE.

Ethnicity is also a major risk factor for developing LE, and its effect in some populations is almost as strong as that of gender. SLE prevalence is four-fold higher in African-American women than White-race American women (4 in 1000 versus 1 in 1000). In addition, African-Americans tend to develop the disease at an earlier age and have a higher mortality rate.[7][8]

Pathophysiology

The pathogenesis of cutaneous lupus erythematosus is multifactorial, with an interplay between genetic and environmental factors. Some contributing environmental factors include ultraviolet radiation (UVR), medications, cigarette smoking, and possibly, viruses. The interaction between these multiple factors triggers an inflammatory cascade of cytokine, chemokine, and inflammatory cell responses. Genes previously associated with SLE are TYK2, IRF5, and CTLA4 and confer an increased risk of developing DLE.

An analysis of 405 patients by Bockle et al. found that smoking is highly associated with discoid lupus erythematosus. Bockle et al. hypothesized that smoking might play a pathogenic role in cutaneous lupus erythematosus variants (DLE, tumid lupus) by inducing apoptosis, stimulating T-cell proliferation, and increasing photosensitivity. Another explanation might be that smoking provokes DNA damage, resulting in the formation of DNA adducts and the production of ds-DNA antibodies. Keratinocytes may also participate in lupus skin damage by increasing the apoptotic rate and the production of proinflammatory cytokines such as IFN-alpha and IL-6 for SLE and IFN-lambda for DLE.[9][10]

Histopathology

The findings of histopathologic examination in cutaneous lupus vary based on the subtype. Overlap can be seen in the histologic findings among the various clinical phenotypes, particularly ACLE, SCLE, and discoid lesions. In cutaneous LE, basal cell damage (also referred to as vacuolar degeneration, hydropic change, or interface dermatitis) and lymphohistiocytic inflammatory infiltrates are commonly seen. In discoid lupus lesions, periadnexal inflammation, follicular plugging, and hyperkeratosis are primarily seen in addition to the interface dermatitis.[11]Dermal mucinosis along with thickened basement membrane is usually noted. 

Examination of the skin for deposits of immunoreactants is called direct immunofluorescence (DIF). DIF of lesional skin can be useful in establishing a diagnosis of cutaneous LE in cases where routine histopathology is equivocal. DIF does not replace routine histologic staining as the method of choice for establishing a diagnosis. In active lesions of DLE, DIF of lesional skin is positive in the majority of cases. The most characteristic DIF finding in cutaneous LE is antibody deposition at the dermal-epidermal junction and around hair follicles. These deposits are typically granular, and they are composed primarily of IgG and/or IgM.[12][13]

The lupus band test (LBT) is a diagnostic procedure used to detect deposits of immunoglobulins and complement components along the dermo-epidermal junction in patients with lupus erythematosus (LE). LBT can help distinguish systemic lupus erythematosus from chronic lupus erythematosus because, in SLE patients, the LBT is frequently positive in both uninvolved and involved skin, whereas in CLE patients, only the involved skin is positive.[14][15] The LBT is positive on the lesional skin in 75% of patients. Ideal lesions for LBT for DLE are on the head and neck that have been present for at least a few months.

History and Physical

DLE is the most common form of chronic cutaneous erythematosus and can occur as localized form (80%) with lesions on the face, ears, and scalp or as disseminated DLE (20%) with lesions above and below the neck. The disseminated form of DLE, especially when involving the trunk, is associated with an increased risk of progression to SLE up to 28%.[16]

It is unusual for discoid lesions to present below the neck without lesions also being present above the neck. Occasionally, discoid lesions develop on mucosal surfaces, including the lips, nasal mucosa, conjunctivae, and genital mucosa.[5] Some patients with discoid lesions exhibit a photodistribution. Sun exposure seems to play a role in the development of lesions. However, patients can have discoid lesions on the sun-protected skin, and there is no clear association between sun exposure and their development.

The first morphological sign of DLE is a well-defined, annular erythematous patch or plaque of varying size followed by follicular hyperkeratosis, which is adherent to the skin. By removing the adherent scale, follicle-sized keratotic spikes similar to carpet tacks can be seen (“carpet tack sign”).[17] The lesions slowly expand with active inflammation and hyperpigmentation at the periphery, leaving depressed central atrophy, scarring, telangiectasia, and hypopigmentation.[18] DLE can progress to irreversible scarring alopecia on the scalp. Although uncommon, a squamous cell carcinoma can develop in a longstanding discoid lesion at 2 to 3 percent and is often associated with a poor prognosis.[19]

Patients who present with discoid lesions may have associated arthralgias, but, over time, only approximately 10% to 20% of these patients eventually meet the classification criteria for SLE. Hyperkeratotic plaques that are verrucous are noted in hypertrophic DLE, a rare entity of DLE.[20] 

Evaluation

In the evaluation of DLE, the dermatologist should take a directed history, perform a cutaneous examination looking for signs of possible systemic disease. The diagnosis of DLE is made based on clinical features, but histology may be required to confirm the diagnosis.[21][22] 

Autoantibodies to SSA/Ro, SSB/La, U1RNP, histones, and ssDNA, are common in patients with SLE, but they are not disease-specific. There are no other specific autoantibodies to differentiate the subtypes of CLE that are routinely used in practice. One further possible target of auto-antibodies is annexin 1, which has been suggested to play an important role in preventing autoimmune diseases. A recent study found a significantly higher level of anti-annexin 1 antibodies in DLE patients, suggesting that anti-annexin 1 antibodies might be a new diagnostic marker for DLE. Anti-annexin 1 antibodies level in the serum did not correlate with DLE activity.[23]

Treatment / Management

Early treatment of discoid lupus lesions may lead to the total clearing of skin lesions, but treatment failure results in permanent scarring. Hair loss, depressed scars, and pigmentary changes are often disfiguring, particularly in darker-skinned people. Some general measures, such as sun avoidance, avoidance of photosensitizing medications, and liberal application of sunscreen are encouraged because cutaneous lesions are known to be exacerbated by sunlight.[24] Smoking cessation is encouraged, as smoking can increase DLE disease activity. Studies demonstrate a statistically significant decrease in the efficacy of antimalarial medication in individuals who have currently or ever smoked.[25][26][27]

Current first-line treatment for DLE consists of photoprotection in conjunction with topical or intralesional corticosteroids and topical calcineurin inhibitors.[28] Chronic DLE lesions that are not responsive to topical therapy or have a widespread disease involvement are candidates for systemic therapy. When DLE is refractory to these measures, other agents with varying degrees of proven efficacy are used. Currently, no medications have been approved specifically, and many of the drugs described in the literature were developed for use in other autoimmune disorders.

Acute exacerbations of DLE are treated with the application of a super high or high potency topical corticosteroid.[29] Clinical improvement is usually observed within 2 weeks of therapy. Treatment can be stopped when lesions are erythema or scale-free (signs of disease inactivity). Cutaneous atrophy is the major adverse effect with chronic use of topical corticosteroids. If the DLE lesion is refractory to high potency topical corticosteroid use for 2 to 4 weeks, alternative therapy with intralesional corticosteroid or topical calcineurin inhibitor should be initiated. Topical calcineurin inhibitors such as tacrolimus 0.1% or 0.03% ointment, pimecrolimus 1% cream are mostly utilized for facial lesions, as they do not cause atrophy.[30] They are more expensive and have a slow onset of action. Clinical improvement is typically noted within 4 weeks of therapy. Low potency topical corticosteroids or topical calcineurin inhibitors are typically used to maintain the DLE lesions in remission once the acute flare resolves.[31] Burning sensation after application that resolves within 1 to 2 weeks is the most common adverse effect of topical calcineurin inhibitors. Topical lesions that do not respond to the above therapy are treated with intralesional triamcinolone acetonide of 0.1 ml (3 to 5 mg/ml strength). Multiple injections into the lesion 1 cm apart should be given. Injections can be repeated every 3 to 4 weeks. If there is no clinical improvement after 2 to 3 injections, alternative treatment should be initiated. Dyspigmentation and atrophy of the skin are the common side effects of intralesional corticosteroids.   

Antimalarials are immunotherapeutic and are considered first-line systemic therapy for CLE. Hydroxychloroquine (HCQ) and chloroquine with or without quinacrine are currently utilized in the treatment of DLE. HCQ is preferred over chloroquine due to the lower risk of side effects, specifically retinal toxicity. Quinacrine is known to cause hematological abnormalities. Hydroxychloroquine is usually started at 200 mg/day and increased to 200 mg two times a day in 1 to 2 weeks if there are no side effects. The maximum dose of hydroxychloroquine should not exceed 5 mg/kg of real body weight per day, given its association with retinal toxicity.[32] 6 to 8 weeks of therapy is required to assess the effectiveness. Quinacrine at a dose of 100 mg/day is added to hydroxychloroquine if no clinical improvement is noted with hydroxychloroquine alone.[33] Chloroquine dose should not exceed 2.3 mg/kg of real body weight per day due to the risk of retinopathy.[32]Hydroxychloroquine and Chloroquine should not be utilized together, given the cumulative retinal toxicity. Patients should receive baseline and periodic eye exams while on therapy. Blue-gray discoloration of face, shins, palate, and bleaching of light-colored hair may occur. Quinacrine use may lead to generalized yellow pigmentation of the skin, secretions, and sclera. 

Other treatment modalities, such as retinoids, vitamin A analogs with anti-keratinizing and anti-inflammatory effects, are sometimes used in CLE, but documentation in the literature is limited. Topical retinoids such as tretinoin 0.05% cream or tazarotene 0.05% gel are utilized to treat hypertrophic DLE.[34] Topical retinoids are pregnancy category X drugs, and cutaneous irritation is a commonly observed adverse effect. Immunomodulators and Immunosuppressive agents such as methotrexate, systemic retinoids, dapsone, mycophenolate mofetil, azathioprine, intravenous immune globulin (IVIG), cyclophosphamide, and cyclosporine, have all been trialed in the treatment of DLE but thought to be second-line when refractory to other treatments.[35]

Methotrexate at a dose range of 10 to 25 mg/week is utilized for DLE lesions. Clinical improvement is noted within 2 to 4 weeks of use, with the resolution of the lesions in about 6 to 8 weeks.[36] A dose of 5 to 10 mg of methotrexate is given as a test dose to assess if the patient can tolerate the drug. Liver function tests and complete blood count are followed 5 to 6 days after the drug administration to ensure no untoward side effects or intolerance to the medication. The most common side effects are gastrointestinal upset, hepatotoxicity, nephrotoxicity, teratogenicity, pulmonary fibrosis, bone marrow suppression, and oral ulcers. Folic acid supplements daily may minimize gastrointestinal side effects.[37] Mycophenolate mofetil is administered in doses of 1 to 3 gm/day. Gastrointestinal upset, cytopenias, and teratogenicity are some of the side effects of mycophenolate mofetil.

Thalidomide, a potent teratogen, has been used in the treatment of DLE. An early report of its use in treating DLE of 60 individuals treated with 50 to 100 mg per day found complete or marked regression in 54 individuals (90%) with disease relapse in 71% of individuals with medication discontinuation.[38] Side effects apart from teratogenicity include drowsiness, constipation, rash, edema, xeroderma, peripheral neuropathy, and thromboembolism.[39] Lenalidomide is a thalidomide analog that may also prove useful in the treatment of DLE. Evidence suggests lenalidomide effectively treats DLE and has a less severe side effect profile than thalidomide but may be similarly limited by a tendency to relapse once discontinued. IVIG is given at a 2 g/kg dose and repeated every 4 to 8 weeks.[40] IVIG is expensive, and CLE lesions tend to recur with its use. Headache, renal failure, hypersensitivity reactions, thrombosis, vasculitis, and aseptic meningitis are some of the adverse effects of IVIG therapy.

Differential Diagnosis

Differential diagnoses of DLE include granuloma faciale, tinea faciei, cutaneous tuberculosis, cutaneous leishmaniasis, lymphoproliferative disorders, and sarcoidosis. DLE-induced scarring alopecia can be confused with lichen planopilaris, tinea capitis, and central centrifugal cicatricial alopecia. Hypertrophic DLE may be confused with keratoacanthoma, squamous cell cancer, hypertrophic lichen planus, and prurigo nodularis.

Prognosis

DLE lesions heal with scarring, atrophy, and dyspigmentation, causing more morbidity than mortality. Psychological functioning is affected by DLE lesions.[41] Exacerbations are associated with sun exposure and often occur in spring and summer. Localized DLE involving the scalp may lead to cicatricial alopecia. Generalized DLE is associated with the risk of progression to SLE in about 28 percent.[16] Chronic DLE lesions in about 2 to 3 percent can progress to squamous cell carcinoma, which is usually associated with a poor prognosis.[19] Early detection and treatment of DLE lesions can minimize the associated morbidity. 

Complications

DLE and progression to SLE are associated with complications like

• Cicatricial alopecia
• Pancytopenia
• Thromboembolism
• Arthritis
• Myositis
• Hypertension
• Renal failure
• Neuropsychiatric manifestations like seizures, depression
• Pleuropericarditis
• Pancreatitis, mesenteric vasculitis
• Optic neuritis
• Therapy-related adverse effects
• Vitamin D deficiency 

Periodic surveillance of DLE lesions and therapy-related side effects is crucial to avoid complications and promote clinical resolution.

Deterrence and Patient Education

Patients should be educated about photoprotection and the possibility of developing skin lesions up to 3 weeks after sun exposure.[42] Using protective clothing and wide-brimmed hats, avoiding sun exposure in peak hours of 10:00 AM to 2:00 PM, generous application of sunscreen with at least sun protection factor of 30 against both UVA and UVB solar light, avoidance of photosensitizing medications, and avoiding outdoor occupations are highly recommended. Cessation of smoking and avoidance of alcohol is encouraged. Educating patients that nicotine interferes with antimalarial therapy uptake and hastens their metabolism helps them understand the rationale behind tobacco cessation.[43] Smoking cessation without nicotine replacement therapy is ideal. Patients are prone to vitamin D deficiency by minimizing sun exposure and sunscreen application; hence, it is recommended to counsel them on annual screening for vitamin D deficiency.[44] 

Enhancing Healthcare Team Outcomes

Lupus is best managed by an interprofessional team of healthcare workers because the disorder can affect almost every organ in the body. Besides physicians, the role of the nurse, pharmacist, therapist, social worker, and mental health counselor is vital. The key is to stress the importance of medication compliance. Patients should be educated about the importance of seeking help early when symptoms arise. At the first sign of renal dysfunction, medical help should be sought. Once renal failure is established, the only treatment is transplantation or dialysis. Patients should be told to avoid sunlight, stop smoking, eat healthily and remain active. Women of childbearing age should consult with an obstetrician before getting pregnant. Finally, joining a support group and/or following up with a mental health counselor is highly recommended.[45][46] [Level 5]

Outcomes

Discoid lupus is an unpredictable and highly variable disorder. While the condition is benign, it can cause devastating complications, often leading to high morbidity and a poor quality of life. The disorder frequently waxes and wanes. The outcome is much improved for patients with only skin and musculoskeletal involvement. The outcomes are worst for patients with CNS and renal involvement. Today, with treatment, there is an 80% survival at ten years, but failure to comply with treatment can lead to early death. At some point in time, the majority of lupus patients will develop hypertension, lipid disorders, diabetes, infections, osteoporosis, and malignancies like lymphomas and liver cancer. [47][48] [Level 5]