Lupus Erythematosus Tumidus

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In 1909, the term "lupus erythematosus tumidus" was first used by Hoffmann (Hoffmann 1909) at a meeting of the Berlin Dermatological Society, and, in 1930, five further patients were reported by Gougerot and Burnier (Gougerot and Burnier 1930, 1931,1932) to describe a disease with erythematous, indurated, nonscarring lesions on the face with minimal or absent surface changes. However, the next case reports of LET were not mentioned until 1965 in the German and French literature (Bazex et al. 1965, Casala et al. 1971, De Graciansky et al. 1965), and in the following years, only a few further cases were reported (Dekle et al. 1999, Mosquera Vieitez et al. 1984, Ruiz and Sanchez 1999). This might be due to the fact that other authors have not considered LET as a separate entity different from other variants of CLE, and it is likely that skin lesions described under different designations, such as "urticarial plaque lupus erythematosus," represent the same disease entity (Sontheimer and Provost 1996). Because some skin conditions share a variety of similar features, a correct diagnosis demands attention to rather subtle details and appreciation of the characteristic signs as well as the course of the disease. In 2000, our group (Kuhn et al. 2000a) analyzed 40 patients with LET and defined diagnostic criteria for the classification of this disease. Meanwhile, there is no doubt about LET being a separate entity, and further reports by other groups have been published indicating that the incidence of LET seems to be higher than found in earlier studies (Alexiades-Armenakas et al. 2003, Hsu et al. 2002,

Jolly et al. 2004, Pacheco et al. 2002). Interestingly, most case reports of LET in the literature are published by European countries indicating that many more patients are seen in the Caucasian population (Sontheimer 2000).

The importance of reevaluating this form lies in the characteristic clinical and histopathologic picture, in its remarkable photosensitivity, and in the course of the disease (Kuhn 2003). In several aspects, the cutaneous manifestations of LET differ from other variants of CLE. Scarring, the hallmark of DLE, does not occur in LET, even in patients with recurrent skin lesions at the same site for many years, and epidermal atrophy has not developed in any case. Follicular plugging and adherent hyperkera-totic scaling, which are further features of DLE, also have not been seen in any of the patients with LET. Hypopigmentation, frequently evident in patients with SCLE after the active phase with erythema and scaling, has never been detected in LET (David-Bajar and Davis 1997). Because some of the patients with LET present with annular skin lesions, there might be a possibility of developing annular erythema associated with Sjogren's syndrome; however, this rare entity has only been reported for Asian patients (Kuhn et al. 2000b). Furthermore, association with systemic disease seems to be very rare in patients with LET (Alexiades-Armenakas et al. 2003, Jolly et al. 2004); however, none of our patients fulfilled four or more ARA criteria for the diagnosis of SLE (Kuhn et al. 2000,Tan et al. 1982).Although joint symptoms occurred temporarily, no signs of inflammatory joint disease or rheumatoid arthritis have been detected, and further systemic manifestations, such as renal, central nervous system, or lung involvement, have not yet been appreciated in any of the patients. Therefore, the prognosis in patients with LET is generally more favorable than in those with other forms of CLE and several patients who had been followed for more than 15 years showed no recurrence after local or systemic treatment. However, this would need to be confirmed by long-term investigations in a greater number of patients.

LET is mostly found in males, and the mean onset of the disease is nearly the same as that described for DLE; therefore, compared with SCLE or SLE, patients with LET are older when the disease begins (Bangert et al. 1984). However, even children may be affected, and, interestingly, one boy had already developed LET skin lesions when he was 9 months old (Kuhn et al. 1997). LET in childhood seems similar to the adult form of the disease, with the same clinical and histologic features, but, to date, only three children with LET have been published in the literature (two boys and one girl aged 9 months to 3 years at disease onset) (Sonntag et al. 2003). Interestingly, photoprovocation tests, which had been performed in two of the young patients, demonstrated no characteristic skin lesions after UV irradiation, although the patients had a positive history of photosensitivity, and ANAs were not detectable. During 6-year follow-up, no signs of systemic involvement had developed in any of the three children.

Clinically, LET is characterized by succulent, urticaria-like, single or multiple plaques with a bright reddish or violaceous, smooth surface on sun-exposed areas, such as the face, upper back, V-area of the neck, extensor aspects of the arms, and shoulders (Fig. 6.17); the lesions spare the knuckles, inner aspect of the arms, and axillae, and have never been detected below the waist (Kuhn et al. 2000a). The swollen appearance of the lesions and the absence of clinically visible epidermal involvement are the most important clinical features of this subtype. The borders are sharply limited, and, in some cases, there is a tendency for the lesions to coalesce in the periphery,

Fig. 6.17. Lupus erythematosus tumidus (LET). Succulent, elevated, urticaria-like erythematous plaques on the right cheek

Tumidus Lesions Lupus

producing a gyrate configuration, or to swell in the periphery and flatten in the center (Fig. 6.18) (Mascaro et al. 1997). Some patients develop erythematous, annular lesions on the cheeks and upper extremities imitating the annular type of SCLE, and, recently, a patient with LET following the lines of Blaschko has been reported (Pacheco et al. 2002). LET lesions can also coexist with DLE lesions (Ruiz and Sanchez 1999) and have been reported to mimic alopecia areata when present on the scalp (Werth et al. 1992). However, other nonspecific LE lesions, such as hypopigmentation, mucous membrane ulcers, diffuse alopecia, livedo reticularis, and vasculitis, have never been seen in any patient.

It has long been suggested that this subset of CLE is characterized by a remarkable photosensitivity (Goerz et al. 1990). Provocative phototesting according to a standardized protocol revealed that patients with LET are more photosensitive than those with other forms of CLE. In a study by our group (Kuhn et al. 2001b), characteristic

Fig. 6.18. Polycyclic/annular form of lupus erythematosus tumidus (LET). Confluent, non-scarring lesions on the face with a tendency to coalesce in the periphery and flatten in the center

Fig. 6.18. Polycyclic/annular form of lupus erythematosus tumidus (LET). Confluent, non-scarring lesions on the face with a tendency to coalesce in the periphery and flatten in the center

Lupus Swollen Face

skin lesions were induced by UV irradiation in 43 (72%) of the 60 patients; 30 patients (50%) reacted to UVA and 29 (48%) to UVB irradiation. Combined UVA and UVB irradiation has been used in 30 patients; 19 of these patients (63%) reacted to this testing regimen. Interestingly, 19 (32%) of the 60 patients with LET reacted to more than one wavelength of UV irradiation. However, because of the latency period in developing positive phototest reactions, it may be difficult for patients to link sun exposure to their skin lesions. In contrast to the studies by Kind et al. (Kind et al. 1993) in 1993, our data further showed a positive photoprovocation test reaction in all 10% of the ANA-positive patients, and all 15% of the patients who had moderate ANA titers also developed skin lesions after UV irradiation. In addition, our data revealed a positive correlation of anti-Ro/SSA and anti-La/SSB antibodies and positive provocative phototest reactions, as has been described for patients with SCLE and neonatal LE.

Histologic analysis of skin lesions is necessary to confirm the diagnosis of LET, and, therefore, it represents one of the major criteria of this disease (Kuhn et al. 2003). The most frequent features in biopsy specimens from LET lesions are a moderate to dense, fairly well-circumscribed lymphocytic dermal infiltrate in a perivascular and periadnexal pattern and abundant interstitial mucin deposition. Occasionally, some neutrophils are present, and, in a few cases the dermis shows edema in its upper part; however, in contrast to other forms of CLE, epidermal changes, such as atrophy and follicular plugging, as well as vacuolar degeneration of the dermoepidermal junction or basement membrane thickening are absent. Skin biopsy specimens from UV-induced lesions of LET taken after provocative phototesting present with a similar pattern compared with primary lesions, but a more dense infiltrate of lymphocytes is seen, and interstitial mucin deposition is less prominent. Direct immunfluorescence staining of lesional skin specimens of LET has mostly been negative for immunoglobulin or complement components (Kind and Goerz 1988). In our recent study (Kuhn et al. 2003), biopsy specimens from primary skin lesions demonstrated immunoglobulin deposits (IgG, IgM) along the dermoepidermal junction in 24% of patients with LET, but IgA as well as complement components were not identified in any specimen from primary or UV-induced lesions.

In the past years, immunohistologic studies helped characterize the skin lesions of patients with LET and supported the clinical findings that LET represents a distinct subset of CLE with a similar immunopathomechanism rather than a different disease (Alexiades-Armenakas et al. 2003, Kuhn et al. 2002a, b). Epidermal surface molecules, such as intercellular adhesion molecule-1 (ICAM-1), histocompatibility class II molecule (HLA-DR), and 27E10, a distinct marker for cell activation and differentiation, were equally up-regulated in primary and UV-induced lesions of patients with LET, DLE, and SCLE (Kuhn et al. 2002b). Furthermore, skin specimens from patients with LET demonstrated an inflammatory infiltrate composed of more than 75% CD4+,CD8+, and HLA-DR+ cells; interestingly, CD45RO+ cells in contrast to CD45RA+ cells were the prevailing inflammatory cell population. Compared with skin specimens from patients with DLE and SCLE, the mean expression of CD4+ and CD8+ cells was higher (but not significant) in LET, and no differences were observed with the other three antibodies (Kuhn et al. 2002a). In contrast to controls, ICAM-1, vascular adhesion molecule-1, E-selectin, and P-selectin showed the same expression pattern in skin specimens from patients with DLE, SCLE, and LET.

LET bears striking similarities to PLE, Jessner's lymphocytic infiltration of the skin, reticular erythematous mucinosis (REM), and pseudolymphoma (Ruhdorfer et al. 1998). The clinical distinction between PLE and LET can be difficult; however, LET shows a much more delayed reaction after sun exposure, and healing of skin lesions takes much longer, even when sun exposure is avoided and a sun block is applied daily (Holzle et al. 1987,Lehmann et al. 1986). Furthermore, in contrast to LET, desen-sitization phototherapy or photochemotherapy are the most effective forms of preventive treatment in PLE (Bilsland et al. 1993, Ortel et al. 1986). Histologic investigations provide further criteria to differentiate PLE from LET, both showing a superficial and deep lymphocytic infiltration and no changes at the dermoepidermal junction (Ackerman 1997). However, in contrast to LET, a marked edema is seen in the papillary dermis and interstitial mucin deposition is not detectable, which is best accomplished by colloidal iron staining. Interestingly, in two studies determining ANAs in patients with PLE, 10%-14% also showed titers of 1:80 or higher, correlating positively in one study with a longer duration of skin lesions (Murphy and Hawk 1991, Petzelbauer et al. 1992)

Jessner's lymphocytic infiltration of the skin is a relatively uncommon disorder with asymptomatic, papulonodular, nonscarring lesions most often located on the face that has not always been considered a specific disease entity. Until today, no unanimity exists concerning its nosology (Weyers et al. 1998). Several studies demonstrated that clinical and histopathologic criteria are insufficient to distinguish Jessner's lymphocytic infiltration of the skin from different subtypes of CLE (Akasu et al. 1992, Bonczkowitz and Weyers 1996). In a more recent report (O'Toole et al. 1999), the occurrence of these two conditions in one family further supports the theory that Jessner's lymphocytic infiltration of the skin is in the same disease spectrum as CLE. In addition, Weber et al. (Weber et al. 2001) supposed by provocative phototesting that Jessner's lymphocytic infiltration of the skin might be a photosensitive variant of LET. Histologically, Jess-ner's lymphocytic infiltration of the skin shows a patchy perivascular and sometimes periadnexal infiltrate consisting of lymphocytes, few histiocytes, and plasma cells. The infiltrate often shows a tendency to arrange itself around cutaneous appendages and blood vessels, and it may extend into subcutaneous fat (Ash-worth and Morley 1988, Bonczkowitz and Weyers 1996). However, in contrast to LET, mucin deposition seems not to be a major histologic criteria in patients with Jessner's lymphocytic infiltration of the skin and was not described in the original report by Jessner and Kanof in 1953 (Jessner and Kanof 1953).

Reticular erythematous mucinosis is a further rare disease with skin lesions ranging from erythematous, indurated papules to reticulated, macular erythema on the central chest or upper back. In contrast to LET, young to middle-aged women are mostly affected. Interestingly, some authors also consider REM to be a variant of CLE because antimalarial agents have been reported to be the most effective therapy, and patients with REM have shown aggravation of the rash on exposure to sunlight (Brad-dock et al. 1993, Cohen et al. 1990). However, only a few attempts have been made to quantify the light intolerance or to provoke the skin by phototesting in this disease (McFadden and Larsen 1988), and, in addition, treatment of REM with a large dose of UVB radiation has even been suggested (Yamazaki et al. 1999). Histologic analysis of REM shows no or minimal vacuolar degeneration at the dermoepidermal junction and a mild to dense perivascular and perifollicular infiltrate of lymphocytes with abundant mucin deposition in the dermis (Vanuytrecht-Henderickx et al. 1984). Furthermore, pseudolymphoma can also clinically simulate LET; however, in most cases, histologic analysis shows a top-heavy, usually wedge-shaped infiltrate of small lymphocytes as well as plasma cells and eosinophils and no interstitial mucin deposition (Ploysangam et al. 1998, Weinberg et al. 1993).

In summary, LET is a distinct subset of CLE with characteristic clinical features requiring correlation with photobiologic, serologic, histologic, and immunohisto-logic findings because, taken in isolation, other diagnoses can be indicated. The reported data emphasize the importance of defining LET as a separate entity with an intermittent course and demonstrate that this disease has been neglected in the literature since first mentioned in 1909.

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