Cutaneous lupus erythematosus

Epidemiology

Cutaneous manifestations occur in approximately 75% of patients with systemic lupus erythematosus (SLE) during the course of the disease and are the first sign in about 25% of patients. Epidemiological data of the different subtypes of cutaneous lupus erythematosus (CLE) have rarely been investigated, as most studies rather evaluate the incidence of SLE. In 2007, a study from Stockholm County, Sweden, reported that subacute cutaneous lupus erythematosus (SCLE) with anti-Ro/SSA antibodies has an incidence of 0.7 per 100,000 persons per year compared with an incidence of SLE of 4.8 per 100,000 persons per year.

Classification criteria for SLE

The criteria developed by the American College of Rheumatology (ACR) for the classification of SLE comprise 11 clinical and laboratory features and provide some degree of uniformity to the patient population of clinical studies. However, 4 of the 11 ACR criteria include mucocutaneous manifestations (malar rash, discoid lesions, photosensitivity, and oral ulcers) and therefore may result in an overestimation of SLE. In particular, the ACR criteria poorly define photosensitivity as “a result of an unusual reaction to sunlight by patient's history or physician's observation.” Furthermore, photosensitivity is not specific for SLE, as it is also observed in other photodermatoses, such as polymorphous light eruption.

To improve the clinical relevance and to incorporate new knowledge in SLE immunology, the Systemic Lupus Collaborating Clinics (SLICC) revised the ACR criteria in 2012. The SLICC criteria include 11 clinical criteria (e.g., nonscarring alopecia or synovitis) and 6 immunological criteria (e.g., decreased complement and antiphospholipid antibodies), whereas photosensitivity is no longer listed. The SLICC criteria have still to be assessed in routine clinical practice, and it is unclear how much impact these criteria will have on the validity of the diagnosis of SLE.

Photosensitivity

The importance of photosensitivity as one of the most common environmental triggers in lupus erythematosus (LE) has been outlined by different groups from Europe, Japan, and the United States. In SLE patients, even induction of systemic organ involvement, such as lupus nephritis, has been reported as a result of extensive sun exposure. Moreover, consistent sunscreen protection in patients with SLE is associated with better clinical outcomes, as well as a decreased need for immunosuppressive agents. In addition, several studies with a high number of CLE patients have been performed to show a clear relationship between ultraviolet (UV) radiation and disease-specific skin manifestations using a standardized photoprovocation protocol. Meanwhile, photoprovocation has been accepted as a diagnostic procedure to evaluate photosensitivity in CLE. In two retrospective studies of more than 400 patients with different subtypes of CLE, skin lesions induced by UVA and/or UVB radiation were observed in 54.0% and 61.7% of patients, respectively. The more recent analysis suggests that the reaction to UV light may change during the course of the disease and that photosensitivity should not be defined only on the basis of patients’ history. Moreover, a randomized, vehicle-controlled, intraindividual, comparative, double-blind study demonstrated that the application of a broad-spectrum sunscreen with a high protection factor prevented the appearance of disease-specific skin lesions in all tested patients with photosensitive CLE. A further study confirmed these results. In addition, immunohistological analysis of skin biopsy specimens taken from patients with CLE after UV exposure demonstrated that sunscreen protection reduces lesional tissue damage and inhibits the typical interferon-driven inflammatory response. The published studies imply that patients with CLE should receive thorough advice (i.e., information that UVA passes window glass) and instructions on photoprotective measures (i.e., information on suitable clothing). Sunscreens with a high sun protection factor (≥50) should be applied in a sufficient amount (2 mg/cm ² ) 20–30 minutes before sun exposure.

Cutaneous manifestations

Skin lesions associated with LE show great heterogeneity and have led to the differentiation into LE-specific and LE-nonspecific manifestations by clinical parameters and histological analysis of skin biopsy specimens. LE-nonspecific cutaneous manifestations, which may also appear in other diseases, are preferably associated with higher disease activity in SLE. These include cutaneous vascular lesions, such as periungual telangiectasia, red lunula, livedo racemosa, Raynaud's phenomenon, acral occlusive vasculopathy, thrombophlebitis, and leukocytoclastic vasculitis, which can occur as palpable purpura or urticarial vasculitis (especially hypocomplementemic urticarial vasculitis). Other nonspecific skin lesions include papular mucinosis, calcinosis cutis, nonscarring alopecia (i.e., “lupus hair”), and erythema multiforme, among others.

LE-specific cutaneous manifestations comprise the different subtypes of CLE, which are defined by a constellation of clinical and histological features, serological parameters, such as antinuclear antibodies, and the course of the disease. Since the first classification system of Gilliam including acute CLE (ACLE), SCLE, and chronic CLE (CCLE) more than 3 decades ago, several approaches have been made to further develop this system and to present a more detailed classification of the different CLE subtypes. For example, the subtype named LE tumidus (LET) with specific clinical, histological, and photobiological features has been analyzed and defined as a separate entity of CLE in the past years. Its course and prognosis is generally more favorable compared to other subtypes of CLE; therefore, a revised classification system, including LET as the intermittent, non-chronic subtype of CLE, was suggested as the “Duesseldorf Classification” ( Table 41.1 ).

In 2004, the European Society of Cutaneous Lupus Erythematosus (EUSCLE) was founded to further differentiate and assess the various subtypes of CLE and to achieve a general consensus concerning evidence-based clinical standards for disease evaluation. A study group of EUSCLE defined a core set of variables for the evaluation of the characteristic features of the disease and developed the EUSCLE Core Set Questionnaire, which includes various parameters considered the most relevant features of CLE. Data of 1002 patients with CLE from 30 centers in Europe were collected using the EUSCLE Core Set Questionnaire, and statistical analysis of clinical and laboratory features, as well as an evaluation of treatment options and their efficacies was performed. In addition, an analysis of the smoking behavior and the efficacy of antimalarials in part of the study population suggests that smoking is a risk factor for the disease, in particular for LET, and negatively influences CLE disease activity and the efficacy of antimalarial treatment.

Scores in cutaneous lupus erythematosus

To determine disease activity in everyday clinical practice and during clinical trials, several disease activity scores Systemic Lupus Erythematosus Disease Activity Index (SLEDAI); European Consensus Lupus Activity Measurement (ECLAM); British Isles Lupus Assessment Group (BILAG) have been established for SLE. In addition, the damage should be assessed once a year by the SLICC/ACR Damage Index. Although these scores include dermatological manifestations (e.g., butterfly rash, generalized erythema, oral ulcers), they are not suitable for evaluating the activity and damage of the different CLE subtypes. Therefore, the scoring system Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) has been developed for patients with cutaneous manifestations to assess disease activity and damage, taking into account anatomical regions (e.g., face, chest, arms) and morphological aspects (e.g., erythema, edema, infiltration, scarring, atrophy). By increasing the accuracy of existing parameters, such as scaling/hypertrophy and dyspigmentation, and by including several new parameters, such as edema/infiltration and subcutaneous nodule/plaque, the CLASI was revised in 2010. Thus, the revised CLASI is a validated scoring system for the clinical evaluation of activity and damage in different CLE subtypes, and is currently applied in several clinical trials.