Chronic cutaneous lupus erythematosus and the lupus erythematosus tumidus controversy

CCLE is a photosensitive dermatosis characterized by chronic lesions that may last for many months and produce scarring and atrophy. SLE and lupus-associated antibodies are uncommon in DLE. Classic DLE, which can be either localized (confined to head and neck) or generalized (above and below the neck), is the most frequent presentation of CCLE. Systemic symptoms and laboratory abnormalities occur more frequently in patients with generalized DLE than in patients with localized DLE. DLE lesions are typically erythematous indurated plaques with keratotic scale. Follicular plugging (dilated follicles plugged with keratin) is also characteristic. When lesions heal, they classically leave behind atrophic scars (scarring alopecia on the scalp) and dyspigmentation. Variants of DLE include hypertropic DLE (thick hyperkeratotic plaques, which may be confused with squamous cell carcinoma clinically and histologically), mucosal DLE (oral, conjunctival, nasal, and genital lesions), and lichenoid DLE (DLE and lichen planus overlap).

Other types of CCLE lesions include lupus panniculitis (lupus profundus) and chilblain (acral) LE. Lupus panniculitis manifests clinically as deep, tender subcutaneous nodules that heal with lipoatrophy. DLE lesions or ulceration may overlay the subcutaneous nodules. A biopsy is needed to exclude subcutaneous panniculitis-like T cell lymphoma from the clinical differential diagnosis. As with DLE, the risk of SLE in lupus panniculitis patients is low: In one case series of 40 lupus panniculitis patients, 10% fulfilled the criteria for SLE. Chilblain LE, a rare type of CCLE induced by cold temperatures, presents as erythematous papules localized to acral areas. In a series of 15 patients with chilblain LE, 20% had underlying SLE.

Most dermatologists also include LE tumidus (papulomucinous LE) in the CCLE category, but this is controversial. LE tumidus lesions are erythematous plaques with an urticaria-like morphology and no clinically visible epidermal changes. Like the other subtypes of CCLE, LE tumidus is a photosensitive dermatosis characterized by chronic or recurrent lesions and a low prevalence of lupus-associated autoantibodies and SLE. One study of 40 LE tumidus patients demonstrated a 10% prevalence of positive antinuclear antibody testing and a 0% prevalence of SLE. However, unlike other CCLE lesions, LE tumidus lesions heal without scarring and atrophy, and LE tumidus lesions are more photosensitive than other forms of CCLE. Furthermore, LE tumidus lesions lack the interface dermatitis that characterizes other LE-specific skin lesions. In a study of 91 LE tumidus biopsy specimens from 80 patients, vacuolar degeneration of the dermoepidermal junction was either absent or was slight and focal. The most frequent histopathologic findings were mucin deposition and a superficial lymphocytic perivascular and periadnexal infiltrate. Some suggest that LE tumidus should be classified as intermittent CLE to reflect the idea that LE tumidus is a distinct clinicopathologic entity with an intermittent, relapsing clinical course and a favorable prognosis. Others argue furthermore that, because LE tumidus lacks the characteristic interface dermatitis of LE-specific lesions and the association with SLE that defines LE-nonspecific lesions, LE tumidus should not be classified among the LE spectrum of skin diseases at all. LE tumidus patients share some clinical and histologic features with non-LE photosensitive skin diseases, such as polymorphous light eruption, lymphocytic infiltrate of Jessner, and reticular erythematous mucinosis, and it may be reasonable to classify LE tumidus within this clinical continuum. As new data enter the literature, the ideal classification of LE tumidus will become more apparent.

Subacute cutaneous lupus erythematosus

The term subacute CLE was chosen to reflect the observation that SCLE lesions last longer than the transient malar rash of ACLE but do not produce the chronic, destructive scarring and atrophy seen in CCLE. SCLE typically presents as photosensitive papulosquamous or annular-polycyclic plaques on the back, shoulders, extensor arms, and V-neck. The lesions lack the scale and follicular plugging that characterize DLE lesions. Vesiculobullous lesions can occur, especially around the annular plaques (vesiculobullous annular SCLE). Very rarely, a toxic epidermal necrolysis–like bullous eruption can evolve from otherwise typical SCLE lesions. Patients with SCLE often have the human histocompatibility antigen HLA-DR3 and high titers of antibodies to SSA and SSB. Approximately 50% of SCLE patients fulfill the criteria for SLE, but SLE patients with SCLE appear to have fewer organ systems involved than do SLE patients without SCLE. One study that compared inpatients with both SLE and SCLE to inpatients with only SLE found an increased prevalence of central nervous system disease, renal disease, arthritis, anemia, and pleuritis in the SLE-only group. Another study, which compared outpatients with SCLE (some also had SLE) to outpatients with SLE alone, found an increased frequency of serositis (pleuritis or pericarditis) and hematologic abnormalities (hemolytic anemia, thrombocytopenia, or leukopenia) in the SLE-only group.

Although drug-induced DLE is very rare, numerous drugs have been reported to induce SCLE. Drug-induced SCLE resembles idiopathic SCLE both clinically (papulosquamous or annular-polycyclic photodistributed lesions) and serologically (high prevalence of positive anti-SSA and positive anti-SSB). The medication classes that have been implicated most frequently in drug-induced SCLE are antifungals, calcium channel blockers, diuretics, antihistamines, beta-blockers, and chemotherapeutics. Previous reports have documented drug-induced SCLE occurring anywhere from weeks to years following initiation of the culprit drug, and the skin disease may persist for several months after stopping the offending medication.

Acute cutaneous lupus erythematosus

Of the LE-specific lesions, ACLE is most frequently associated with SLE. The usual clinical presentation of ACLE is a transient (hours to days) erythematous photosensitive rash on the malar area (butterfly rash). Less commonly, ACLE patients may have a generalized photosensitive morbilliform rash. ACLE rashes typically spare the nasolabial folds and knuckles, which helps distinguish ACLE from dermatomyositis. Rarely, patients present with a widespread subepidermal bullous eruption resembling toxic epidermal necrolysis, which evolves from otherwise typical photodistributed ACLE lesions.

Debate over the existence of Rowell syndrome

Rowell syndrome is a clinical entity that has been a source of confusion in the dermatology literature. In 1963, Rowell and colleagues defined a new syndrome based on four patients who had erythema multiforme–like lesions occurring in association with LE as well as the following immunologic serum abnormalities: speckled pattern of antinuclear antibody, anti-SjT antibody, and rheumatoid factor. Over the next 4 decades, several other investigators reported new cases of Rowell syndrome, but these cases did not meet the same immunologic serum criteria as Rowell’s initial patients, possibly because testing for SjT antibody became obsolete. In 2000, Zeitouni proposed new major and minor criteria for Rowell syndrome (diagnosis requires three major criteria and one minor criteria). The new major criteria were LE (systemic, discoid, or subacute), erythema multiforme–like lesions, and speckled antinuclear antibody; and the minor criteria were chilblains, anti-SSA or anti-SSB antibody, and positive rheumatoid factor.

Although dermatologists continue to publish reports of Rowell syndrome in the literature, some doubt that Rowell syndrome is a unique clinical syndrome. These investigators suggest that Rowell syndrome is merely erythema multiforme and LE coexisting in the same patient and that any common serologic abnormalities are likely coincidental. The lack of conservation of Rowell’s original serologic criteria in subsequent cases supports this contention. In addition, later reports of Rowell syndrome failed to fit the clinical and demographic profile described in Rowell’s original case series. Rowell’s patients were females in the third to seventh decade of life who suffered from DLE years before the onset of erythema multiforme lesions and rarely had mucosal erythema multiforme lesions. Later cases deviated from all of these commonalities. Furthermore, a recent report describes two patients who presented with clinical features of combined LE and erythema multiforme but were found to have LE-specific histopathology when the erythema multiforme–like lesions were biopsied. The authors of that report suggest that prior reports of Rowell syndrome may actually represent LE masquerading as erythema multiforme. Further studies will help clarify the significance of erythema multiforme–like lesions in patients with LE.

Lupus erythematosus–nonspecific skin lesions

The wide variety of lesions seen in patients with SLE which lack LE-specific histopathology have been previously divided into the following categories: cutaneous vascular disease, nonscarring alopecia, and miscellaneous other dermatoses. Cutaneous vascular diseases seen in SLE patients include vasculitis, vasculopathy, livedo reticularis, erythromelalgia, periungual telangiectasia, thrombophlebitis, and Raynaud phenomenon. In a recent study of 670 SLE patients, 11% had vasculitis. Of those with vasculitis, 89% had cutaneous manifestations. The most common vasculitis in SLE patients is small-vessel leukocytoclastic vasculitis, which frequently presents with palpable purpura or erythematous punctuate lesions on the hands (which may rarely enlarge and ulcerate). The small-vessel vasculitis may be associated with urticarial lesions lasting longer than 24 hours (urticarial vasculitis). Livedo reticularis is a nonspecific finding with an increased prevalence in several vascular diseases associated with SLE, including vasculitis, vasculopathy, and antiphospholipid antibody syndrome.

Nonscarring alopecia in SLE patients may have several causes, including lupus hairs (thinning at the frontal hairline; found during SLE flares), alopecia areata (patches of hair loss; has an increased incidence in lupus patients), and telogen effluvium (diffuse hair thinning). Other nonspecific skin lesions that may be observed in SLE patients include sclerodactyly, rheumatoid nodules, calcinosis cutis, urticaria, papulonodular mucinosis, cutis laxa, acanthosis nigricans, leg ulcers, lichen planus, and erythema multiforme.

Subclassification of bullous systemic lupus erythematosus (lupus erythematosus–nonspecific bullous lesions)

Bullous SLE (BSLE) is an autoantibody-mediated subepidermal vesiculobullous skin disease that is LE-nonspecific (does not occur as an extension of the skin lesions showing the interface dermatitis characteristic of LE). BSLE typically presents as a nonscarring generalized bullous eruption, which can be responsive to dapsone treatment. A diagnosis of BSLE requires (1) SLE, (2) vesiculobullous eruption, (3) histology showing subepidermal blister and neutrophilic upper dermal infiltrate, and (4) immunoglobulin and complement deposition at the basement membrane zone on direct immunofluorescence (immune reactants on or beneath the lamina densa ultrastructurally). Immunoblotting and indirect immunofluorescence on sodium chloride–split skin show that some BSLE patients have serum antibodies to type VII collagen and that their serum may react with a dermal epitope, an epidermal epitope, or both. The clinical, histopathological, and immunologic patterns seen in BSLE can resemble epidermolysis bullosa aquisita (EBA), dermatitis herpetiformis (DH), and bullous pemphigoid (BP), but BSLE patients have features that are not consistent with any single primary bullous disease.

A recent report argues that BSLE is a vague term that includes a heterogeneous group of vesiculobullous lesions and recommends using immunologic and histologic characteristics to divide BSLE into the following categories: DH-like vesiculobullous LE, EBA-like vesiculobullous LE, and BP-like vesiculobullous LE. Patients with DH-like vesiculobullous LE have histology showing neutrophilic microabscesses in dermal papillae, granular deposition of IgA or IgG at the basement membrane zone on direct immunofluorescence, and no evidence of serum basement membrane zone antibodies on indirect immunofluorescence. These findings are immunohistologically similar to those seen in idiopathic DH. In EBA-like vesiculobullous LE, there are serum antibodies to basement membrane zone type VII collagen (the EBA antigen), and serum binds a dermal epitope on sodium chloride–split skin (the same indirect immunofluorescence pattern seen in idiopathic EBA). BP-like vesiculobullous LE is characterized by the linear deposition of IgG and C3 at the dermoepidermal junction found in idiopathic BP. However, immunoelectron microscopy demonstrates that IgG deposits are largely below the basal lamina, and indirect immunofluorescence is negative for serum basement membrane zone antibodies. In contrast, idiopathic BP patients have IgG deposits that are localized to the lamina lucida area, and their serum frequently shows positive indirect immunofluorescence (binds to the epidermal portion of sodium chloride–split skin). BP-like, EBA-like, and DH-like vesiculobullous LE should be distinguished from the rare cases of otherwise typical primary idiopathic BP, EBA, and DH that have been reported in patients with SLE.

Cutaneous lesions and systemic lupus erythematosus criteria

The current American College of Rheumatology classification criteria for SLE include four cutaneous findings: malar rash, discoid rash, photosensitivity, and oral ulcers. Using these criteria, some patients with disease limited to the skin can be classified as having SLE. Other limitations of these criteria include (1) the association between the malar rash and photosensitivity, (2) the association between the discoid rash and oral ulcers, (3) the difficulty of definitively diagnosing the malar rash or discoid lupus without a biopsy, and (4) the lack of specificity of oral ulcers for LE. Integrating dermatologic input into the next revision of the American College of Rheumatology criteria for SLE would help to rectify the current limitations.

General principles

The design of the CLASI was based on guidelines established by Finlay for the development of an outcome instrument for atopic dermatitis. Each criterion is discussed in greater detail below. According to the guidelines, instruments should:

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  Be easy to administrate

  
  
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  Clearly separate scores assigned by the clinician from scores assigned by the patient

  
  
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  Ensure that the signs graded are unambiguous and amenable to change; and make clear that, if there is a high correlation between the presence of two different signs, only one is recorded

  
  
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  Base areas of involvement on assessments of the sites involved rather than on estimates of total surface area involvement

  
  
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  Make certain that validity testing should demonstrate good intra- and inter-rater reliability.

Ease of administration

The CLASI can be used even in a busy clinical practice. The layout is easy to follow, and the scoring is self-explanatory. It can be completed without disrupting office routine and without the use of invasive tests. The average time needed to complete the CLASI is 5.25 minutes, ranging from 1 to 11 minutes.

Separation of patient and physician scores

The CLASI includes only those scores determined by the clinician, all of which are based on clinical signs. Patient-derived scores are recorded on separate visual analog scales that measure subjective symptoms, including pain, itch, and fatigue.

Clinical signs: activity and damage

As discussed earlier, the clinical signs that comprise the activity score include erythema, scale, mucous membrane lesions, and inflammatory alopecia. The clinical signs that comprise the damage score include dyspigmentation, scarring, and scarring alopecia. The erythema score is considered a particularly reliable reflection of disease activity because it is easily identified in most skin types. Physiologically, erythema mirrors disease activity well because it results directly from the hyperemia associated with inflammation. The physician’s visual estimation of erythema is considered an accurate measurement of activity because several studies have demonstrated a good correlation between subjective visual assessments of erythema and objective laser Doppler assessments of blood flow.

Following a common trend in rheumatology, the CLASI clearly differentiates between activity and damage, providing two independent summary scores. This distinction is seen in other outcomes measures for SLE. For example, the SLEDAI and SLAM-R specifically measure activity, whereas the Systemic Lupus International Collaborative Clinics–American College of Rheumatology Damage Index specifically measures damage. This separation is critical because activity and damage embody two different aspects of the disease. The activity score reflects ongoing inflammation, which has the potential to decrease with treatment. The damage score represents the aftermath of inflammation, which cannot itself be treated, only prevented. As such, the activity score is most appropriate for short-term drug studies, whereas the damage score is helpful in long-term preventative studies.

There is little clinical utility in combining scores because of the potential for scores that are deceptively stable despite significant clinical changes. Clinical experience has shown that patients who respond to therapy can have a simultaneous decrease in the activity score and increase in the damage score, reflecting the alleviation of active inflammation amidst organ damage caused by previous inflammation. Thus, it is most appropriate to treat each score as a separate indicator of disease burden.

Area of involvement

An important decision in the development of any outcome measurement for cutaneous diseases is how best to capture the extent of the disease. One method considered was lesion counting, as is commonly used in acne. This system was rejected for two reasons. First, the interrater reproducibility is poor. Second, the lesions in CLE tend to range in size, and improvement can lead to a paradoxic increase in the number of lesions, as large confluent lesions fragment into smaller lesions.

Another popular method is the estimation of surface area involvement, as has been used in the PASI (Psoriasis Area and Severity Index) and the SCORAD (Severity Scoring of Atopic Dermatitis). This method was rejected for two reasons. First, studies have shown that area assessments are difficult to perform, resulting in poor interrater reproducibility and a high incidence of errors. Second, this method fails to account for the particular concern that patients have about noticeable lesions, regardless of the total surface area involved.

Cutaneous lupus tends to affect photo-exposed areas, such as the face, V-neck area, scalp, and extensor surfaces of the arms—the areas most visible to others. Studies in psoriasis have shown that patients with visible lesions who feel stigmatized by their disease suffer from impaired quality of life. Furthermore, it has also been shown that patients with visible skin lesions suffer from more psychiatric symptoms than patients with lesions in unexposed areas. As such, these areas require special attention and aggressive treatment, even if the area of involved skin is small. To account for this, the CLASI separates exposed areas into a number of distinct categories, thereby effectively weighing those areas more heavily in the total score. The head, for example, is divided into the scalp, ears, nose, and rest of face. Each of these individually carries the same weight as much larger areas of the body, such as the back/buttocks and abdomen.

Inter- and intra-rater reliability

Inter- and intra-rater reliability is discussed in detail in the following section on validation.

Content validity

Content validity refers to the inclusion of essential features of the disease in the outcome instrument. This was accomplished by collaborating with a group of seven dermato-rheumatologists with expertise in CLE during the development of the CLASI. The instrument was further assessed by a group of dermatologists and rheumatologists at the American College of Rheumatology Response Criteria Committee on SLE at a meeting in Germany in 2004. Finally, during the initial testing of the CLASI, the raters were interviewed extensively, and their feedback was used to make several improvements to the instrument.

Inter-rater reliability

Interrater reliability refers to the similarity between measurements made by two different observers on the same subject. For both activity and damage scores, the interrater reliability was high: Eleven physicians scored nine different patients and achieved intraclass Pearson’s correlation coefficients of 0.86 (95% CI, 0.73–0.99) and 0.92 (95% CI, 0.85–1.00) for the activity and damage scales, respectively.

Intra-rater reliability

Intra-rater reliability refers to agreement of multiple measurements made by one observer on a single subject. For this assessment, eight physicians scored four patients, one of whom was evaluated twice. The intra-rater reliability was also found to be quite high. For the activity score, the Spearman’s correlation coefficient was 0.96 (95% CI, 0.89–1.00), with a mean difference between scores of two points. For the damage score, the Spearman’s correlation coefficient was 0.99 (95% CI, 0.97–1.00), with a mean difference between scores of zero points.

Clinical responsiveness

To assess clinical responsiveness, changes in the CLASI were monitored for 2 months (56 days) following initiation of a new therapy. These scores were correlated with changes in other clinical outcome instruments, including the physician’s global skin assessment, the patient’s global skin assessment, and the patient’s assessment of pain and itch. Eight subjects with CLE (four DLE, two SCLE, and two DLE/SLE) were included. The results indicated a high correlation between changes in the CLASI activity score and in the physician’s global skin assessment (r _p = 0.97, P = .003, n = 7), the patient’s global skin assessment (r _p = 0.85, P = .007, n = 8), and the pain score (r _p = 0.98, P = .004, n = 5). These early findings suggested that the CLASI is responsive to changes in disease activity.

Recent studies performed by other groups have further validated the clinical responsiveness of the CLASI. Kreuter and colleagues showed that CLASI activity scores in patients with tumid LE decreased significantly after 3 months of therapy with an antimalarial medication. In another study, Kreuter and colleagues illustrated that CLASI activity scores decrease significantly after 3 months of therapy with mycophenolate sodium, which correlated with improvements on ultrasound and colorimetry. A third study, by Erceg, demonstrated that CLASI activity scores in patients with DLE decreased significantly after 6 to 18 weeks of pulsed dye laser therapy.

Extension to rheumatology

Because rheumatologists frequently encounter patients with CLE, further validation studies were performed to assess the CLASI when used by rheumatologists rather than dermatologists. Internal structure reliability (inter- and intra-rater reliability) and diagnostic skill were evaluated. Diagnostic skill was assessed to ensure that the CLASI is used for CLE to the exclusion of mimicker skin diseases. Fourteen subjects were enrolled, including 10 with CLE, 3 with CLE plus a mimicker disease, and 1 with a mimicker disease only. The subjects were evaluated by five rheumatologists and five dermatologists.

The results indicated that the CLASI has high reliability when used by rheumatologists. The interrater reliability correlation coefficients were 0.83 (95% CI, 0.70–0.96) for activity and 0.86 (95% CI, 0.75–0.97) for damage. The intrarater reliability correlation coefficients were 0.91 (95% CI, 0.71–1.00) for activity and 0.99 (95% CI, 0.94–1.00) for damage. The diagnostic skill assessment, however, suggested that rheumatologists may not have the training to reliably distinguish between CLE and mimicker diseases. Several mimicker lesions were misdiagnosed as CLE, resulting in poor specificity compared with dermatologists (0.46 vs 0.74, respectively). These results indicate that it may be prudent for rheumatologists to consult with dermatologists when recruiting patients for studies using the CLASI.

Severity

Many clinical trials only enroll patients with moderate or severe disease. It is therefore important to have a standardized method of assessing disease severity to ensure that that the patient populations included in different trials are comparable. This was accomplished by categorizing 37 patients (45 visits) as “mild,” “moderate,” or “severe” based on the principal investigator’s subjective assessment. Corresponding CLASI activity scores were also calculated and analyzed with crosstab row percents and receiver operating characteristic curves. The results indicated that mild, moderate, and severe disease corresponded with CLASI activity score ranges of 0 to 9 (sensitivity 93%, specificity 78%), 10 to 20, and 21 to 70 (sensitivity 80%, specificity 95%), respectively ( Table 1 ).

Table 1

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