The 100th anniversary of lupus erythematosus tumidus

Autoimmunity Reviews 8 (2009) 441–448

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Autoimmunity Reviews j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / a u t r e v

The 100th anniversary of lupus erythematosus tumidus☆ Annegret Kuhn ⁎, Dennis Bein, Gisela Bonsmann Department of Dermatology, University of Münster, Münster, Germany

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Available online 20 January 2009 Keywords: Lupus erythematosus tumidus Classification Intermittent cutaneous lupus erythematosus Photosensitivity

a b s t r a c t In 1909, the term “lupus erythematodes tumidus” was first introduced by the German Dermatologist E. Hoffmann. The next case reports of lupus erythematosus tumidus (LET) were not described until 1930, and in the following years, only a few further cases were reported. This might have been due to the fact that authors have not considered LET as a separate entity different from other variants of cutaneous lupus erythematosus (CLE), and it is likely that skin lesions described under different designations represent the same disease entity. Therefore, LET has been underestimated and neglected in the literature and has been characterized by clinical, histopathological, and immunohistochemical features only in recent years. In particular, phototesting has been crucial in defining LET as a very photosensitive entity of CLE. Up to now, more than 40 reports of LET have been published demonstrating that the course and prognosis of LET are generally more favorable than in other subtypes of CLE. A new classification system, including LET as the intermittent subtype of CLE (ICLE) has been suggested. On the occasion of the 100th anniversary of the first description of LET, we have reviewed the literature and provide here an overview on the different aspects of the disease. © 2009 Elsevier B.V. All rights reserved.

Contents 1. History . . . . . . . . . . . . . . . . . . 2. Epidemiology . . . . . . . . . . . . . . . 3. Clinical features . . . . . . . . . . . . . . 4. Photosensitivity . . . . . . . . . . . . . . 5. Histology and direct immunofluorescence . 6. Immunohistochemistry . . . . . . . . . . 7. Treatment . . . . . . . . . . . . . . . . 8. Course of the disease . . . . . . . . . . . 9. Separate entity in the classification of CLE . 10. Jessner's lymphocytic infiltration of the skin Take-home messages . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . .

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1. History ☆ The research was supported by a Heisenberg Scholarship from the German Research Foundation (DFG) to A. Kuhn (KU 1559/1-2). ⁎ Corresponding author. Department of Dermatology, University of Münster, Von-Esmarch-Straße 58, D-48149 Münster, Germany. Tel.: +49 251 83 52177; fax: +49 251 83 58947. E-mail address: [email protected] (A. Kuhn). 1568-9972/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2008.12.010

The term “lupus erythematodes tumidus” was first used by E. Hoffmann in 1909 [1] at a meeting of the Berlin Dermatological Society. Two patients presented with single round-shaped erythematous, elevated, tumorous lesions in

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the face without or with minimal scaling that vanished partly under pressure. Several years later (1930–1932) Gougerot and Burnier [2–5] reported five additional patients and described similar clinical features, such as erythematous, indurated, nonscarring lesions on the face with minimal or absent surface changes. However, the next case reports of LET were not described until the 1950s in the German and Spanish literature [6–8], and in the following years, only a few further cases were reported [9–13]. This might have been due to the fact that 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 [14]. In 2000, our group analyzed 40 patients with LET and defined diagnostic criteria for the classification of this disease [15]. We emphasized that a correct diagnosis demands attention to rather subtle details and appreciation of the characteristic signs as well as the course of the disease, because some skin conditions share a variety of similar features. Meanwhile, in our opinion LET is a separate entity

and more than 200 further patients have been published in the international literature indicating that the incidence of the disease seems to be higher than found in earlier studies (Table 1). 2. Epidemiology LET has been reported in women and men, which seem to be equally affected. In some studies a slight male predominance (22 males versus 18 females) was seen [15], whereas others reported a female:male ratio of 1:1 [16] or a slight female predominance (eight females versus seven males) [17]. Most case reports of LET in the literature are published by European groups indicating that many more patients are seen in the Caucasian population [18], however, no data with regard to the prevalence and incidence of LET are available in the literature. The mean age at onset of disease is nearly the same as that described for discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE) [19]. In our study [15], the mean age at onset of the disease in 40 LET

Table 1 Reports of lupus erythematosus tumidus in the literature a. Author

Year

Country

Short title

Type of study

No. of LET patients

Hoffmann [1] Gougerot and Burnier [2–5] Freund [78] Vilanova [8] Rockl [7] Manok [6] Casala et al. [9] Mosquera Vieitez et al. [11] Kind et al. [38] Brown and Deng [34] Ruhdorfer et al. [12] Dekle et al. [10] Ruiz and Sanchez [13] Kuhn et al. [15] Rupec et al. [79] Alexiades-Armenakas [80] Hsu et al. [81] Kuhn et al. [37] Kuhn et al. [45] Kuhn et al. [46] Pacheco et al. [22] Alexiades-Armenakas et al. [17] Kuhn et al. [43] Bacman et al. [82] Sonntag et al. [21] Arfan-ul-Bari and ber Rahman [83] Chamberlain et al. [35] Choonhakarn et al. [41] Jolly et al. [52] Vasallo et al. [30] Di Cesare et al. [84] Roper et al. [85] Schneider et al. [33] Teixeira et al. [86] Vieira et al. [16] Hügel et al. [51] Zandman-Goddard et al. [32] Rémy-Leroux et al. [65] Stead et al. [23]

1909 1930–32 1932 1950 1954 1957 1971 1984 1993 1995 1998 1999 1999 2000 2000 2001 2002 2001 2002 2002 2002 2003 2003 2003 2003 2004 2004 2004 2004 2005 2006 2006 2006 2006 2006 2007 2007 2008 2008

Germany France Germany Spain Germany Germany Argentina Spain Germany USA Germany USA USA Germany Germany USA USA Germany Germany Germany USA USA Germany Germany Germany Pakistan UK Thailand USA Italy Italy USA Germany Portugal Spain Germany Israel France USA

First description of LET Single case reports of 5 LET patients Case report of LET compared with the description by Gougerot LET associated with LEP Case report of LET Case report of LET and successful therapy with chloroquine LET (JLIS) associated with CCLE Case report of LET Phototesting in CLE Thiazide-induced LET Differential diagnostic and pathogenetic aspects of LET Description of LET as a distinct form of CLE Concurrent manifestation of DLE/SLE and LET in the same patients Characterization of 40 patients with LET LET and DLE in carriers of X-linked chronic granulomatous disease Preliminary report to the LET study in 2003 Description of 4 LET patients with review of differential diagnosis Phototesting in LET Characterization of the inflammatory infiltrate of LET Upregulation of epidermal surface molecules in LET Unilateral LET following the lines of Blaschko Criteria for classification of LET with immunohistochemical analysis Histological characterization of LET Topical treatment with tacrolimus in LET LET in childhood Case report of LET LET following active antiretroviral therapy for HIV Study of 15 LET patients in Thailand, two of them with SLE LET in SLE with lesions progressing to DLE Monolateral eyelid erythema and edema as manifestation of LET Symmetric distribution of LET on the elbows Case report of LET mimicking scleroderma Infliximab-induced LET in a patient with rheumatoid arthritis Case report of LET Clinical and histological features of 26 patients with LET Resistance of LET to hydroxychloroquine due to smoking LET induced by exposure to significant doses of estrogens Comparison of clinical and histological features in JLIS and LET Coexistence of LET with SLE and DLE

Case report Case report Case report Case report Case report Case report Case report Case report Photot. study Case report Case report Case report Case report Retrosp. study Case report Prosp. study Case report Photot. study Research study Research study Case report Prosp. study Histol. study Case report Case report Case report Case report Retrosp. study Case report Case report Case report Case report Case report Case report Retrosp. study Case report Case report Retrosp. study Case report

2 5 1 1 1 1 1 1 32 1 1 4 4 40 2 15 4 60 b 10 b 15 b 1 15 b 80 b 1 3 1 1 15 1 1 1 1 1 1 26 1 1 18 2

Histol., Histological; Photot., Phototesting; Prosp., Prospective; Retrosp., Retrospective. a This list is not exhaustive. b The same patients have partly been included in previous studies.

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patients was 36.4 years. Even children may be affected, and, interestingly, one boy had already developed LET skin lesions when he was nine months old [20]. LET in childhood seems similar to the adult form of the disease, with the same clinical and histopathologic features, but, to date, only one report of three children with LET have been published in the literature (two boys and one girl aged nine months to three years at disease onset) [21]. Interestingly, photoprovocation tests, which had been performed in two of the young patients, demonstrated no characteristic skin lesions after phototesting with UVA and UVB light, although the parents described a positive history of photosensitivity in their children; moreover, antinuclear antibodies (ANA) were not detectable in the sera of any of the children with LET. During a six-year followup, no signs of systemic involvement had developed in any of the three patients. Two children had a good response to topical treatment (corticosteroids, sunscreens), the eightyear old boy required antimalarial therapy. 3. Clinical features Clinically, LET is characterized by indurated, 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. The skin lesions mostly spare the knuckles, inner aspect of the arms, and axillae [15]. A patient with LET following the lines of Blaschko has been reported [22], and recently, one single case report demonstrated the rare occurrence of LET below the waist at a photo-protected site [23]. The swollen appearance of the LET lesions and the absence of clinically visible epidermal involvement are the most important 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, producing a gyrate configuration, or to swell in the periphery and flatten in the center [24]. It has been reported that LET can mimic alopecia areata when present on the scalp [25]; LE-non-specific lesions, such as livedo reticularis or leukocytoclastic vasculitis, have never been described in any patient with LET. Some LET patients develop erythematous, annular lesions on the cheeks and upper extremities imitating the annular type of SCLE, but never showing the characteristic collarette scaling of this subtype [26–28]. 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 LET skin lesions at the same site for many years, and epidermal atrophy has not developed in any case. Follicular plugging and adherent hyperkeratotic scaling, which are further clinical features of DLE, have not been seen in any of the patients either. Vitiligo-like hypopigmentation, frequently evident in patients with SCLE after the active phase with erythema and scaling, has not been detected in LET [29]. In 2005, an unusual case of LET presenting as unilateral eyelid erythema and edema was published in an 38-old caucasian men [30], as already described in LEP [31]. In the past, single case reports have been published demonstrating that LET can be induced by trigger factors, such as sex reassignment surgery with prolonged exposure to significant doses of estrogens [32]. Furthermore, druginduced LET is described in the literature in three cases. A

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51-year-old woman with rheumatoid arthritis developed LET after 13 infusions with infliximab [33]. The patient had no previous history of skin disease or photosensitivity and showed erythematous, indurated plaques on her face and upper chest. The skin lesions persisted for eight months and serological evaluation revealed a high ANA titer of 1:2560 (HEp-2 cells) and low levels of anti-double-stranded (ds) DNA antibodies in the radioimmunoassay, but negative findings by ELISA and CLIFT indicating that the anti-dsDNA antibodies were not of the pathogenic IgG isotype. Results of an ANA screening test (including among others antibodies to SSA/Ro, SSB/La, Sm, U1-RNP) were negative. Histological analysis of a skin biopsy specimen was compatible with the diagnosis of LET. On discontinuation of treatment with infliximab, the skin lesions vanished within three weeks, the elevated ANA titer decreased within 10 weeks and the hypocomplementemia and the leukopenia returned to reference ranges. Because of the exacerbation of joint disease, treatment with etanercept was added to her drug regimen of low dose methotrexate and prednisolone. Subsequently, the patients' rheumatoid arthritis improved rapidly and no signs of LET recurrence could be detected. Moreover, one case report has been described in the literature that LET can be induced by thiazide diuretics [34]; furthermore, one LET occurred in a male HIV-positive patient as a manifestation of immune restoration following the initiation of highly active antiretroviral therapy (HAART) [35]. 4. Photosensitivity It has long been suggested that LET is characterized by a remarkable photosensitivity [36]. Provocative phototesting according to a standardized protocol revealed that patients with LET are more photosensitive than those with other forms of CLE. In our study from 2001 [37], characteristic skin lesions were induced by UV radiation 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. In contrast to the studies by Kind et al. in 1993 [38], our data showed a positive photoprovocation test reaction in all ANApositive patients (10%), and all patients having a moderate ANA titer (15%) also developed skin lesions after UV radiation. Furthermore, the data revealed a positive correlation of antiRo/SSA and anti-La/SSB antibodies and positive provocative phototest reactions, as has been described for patients with SCLE and neonatal LE [39,40]. In the study by Choonhakarn et al. [41], provocative phototest was positive in 5 (50%) of 10 tested LET patients. Four patients reacted to UVA and UVB and one patient to UVA radiation only. Positive phototest reactions in patients with LET appeared within 7.5 ± 4.9 days after the last irradiation [37]. Interestingly, 65% of the patients with a positive phototest result developed characteristic skin lesions between days 4 and 11, and 5% had a positive reaction more than 21 days after the last irradiation. However, the long latency period in developing positive phototest reactions makes it difficult for some patients to link sun exposure to their skin lesions and to answer the question about history of photosensitivity correctly. This might also be due to the fact that there is a

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variability of photosensitivity in relation to disease activity; moreover, patients usually avoid sun exposure after diagnosis of LET, because of their physician's recommendation. Nevertheless, not all patients with LET exhibit photosensitivity and not all cutaneous manifestations are related to sun exposure. The appearance in sun-protected areas suggests that UV exposure is unlikely to be always required for the development of skin lesions [42]. 5. Histology and direct immunofluorescence Histological analysis of skin lesions is necessary to confirm the diagnosis of LET, and, therefore, it represents one of the major criteria of this disease [43]. The most frequent features in biopsy specimens from LET lesions are a fairly wellcircumscribed lymphocytic dermal infiltrate in a perivascular and periadnexal pattern and abundant interstitial mucin deposition. The dermis shows edema in its upper part; however, in contrast to other subtypes 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 or show minimal and focal alterations [43]. Skin biopsy specimens from UVinduced lesions of LET taken after provocative phototesting presented with a similar pattern compared with primary lesions, but a more dense infiltrate of lymphocytes was seen, and interstitial mucin deposition was less prominent. Direct immunofluorescence (DIF) staining of lesional skin specimens of LET has previously been described as negative for immunoglobulin or complement components [44]. In the study by our group in 2002 [43], biopsy specimens from primary skin lesions demonstrated immunoglobulin deposits (IgG, IgM) along the dermoepidermal junction in 24% of patients with LET, but additional immunoglobulin classes (IgA) as well as complement components were not identified in any specimen from primary or UV-induced lesions. Moreover, Alexiades-Armenakas et al. [17] demonstrated in 2003 that in five out of 10 cases with LET, DIF analysis was negative. Among the five (50%) cases with deposited immunoreactants, four displayed linear deposits of IgG and granular deposits of IgM at the dermoepidermal junction. In one case, linear deposits of IgA, C3, and fibrin were also present, and one case showed granular deposits of IgM and fibrin alone. Vieira et al. [16] performed DIF in 15 of 26 patients with LET and 11 were negative. Two patients showed slight IgG deposition, one had moderate IgG and slight C3 deposition, and one patient had slight deposition of IgM, C3, and C1q at the dermoepidermal junction. However, Choonhakarn et al. [41] described a negative DIF in all 15 analyzed patients with LET. 6. Immunohistochemistry Immunohistological studies helped characterize 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. [17] performed a prospective study with 15 LET patients which were followed for a mean of seven years. Immunohistochemical findings showed that the majority of the cells in the inflammatory infiltrate reacted positively with an antibody to the pan-T cell marker

CD3, with a mean of 78.0% CD3 positive cells, indicating a predominance of T lymphocytes. The majority of the inflammatory cells, with a mean of 82.7%, also reacted positively with an antibody to CD4, which labels helper T cells. A minority of the mean, 31.3% (±14.0), were CD8 positive cytotoxic T cells; the mean ratio of CD4:CD8 positive cells was 3.1 (±1.3):1. In a further immunohistochemical study by our group [45], the inflammatory infiltrate of 10 LET patients was characterized, demonstrating an 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, mean expression of CD4+ and CD8+ cells was higher (but not significant) in LET, and no differences were observed with regard to other T cell markers. In contrast to controls, intercellular adhesion molecule-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. In addition, epidermal surface molecules, such as histocompatibility class II molecules (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 [46]. 7. Treatment Due to the high photosensitivity, LET patients are recommended to avoid sun exposure in mid-day during summer and travel to sunny regions. Special consideration should be given to consistent UV protection through photoresistant clothing and application of light-shielding substances with highly potent chemical or physical UVA- and UVB-protective filters [47]. These substances should be applied in sufficient amount (ca. 2 mg/cm2) and with a high protection factor (SPF 50+) at least 15–30 min before sun exposure in order to avoid induction and exacerbation of cutaneous lesions [48,49]. In a recent vehicle-controlled, randomized, double-blind study, it has been demonstrated that the use of a broad-spectrum sunscreen with a high protection factor in both UVB and UVA can prevent skin lesions in all patients with photosensitive CLE [50]. Since the face is the most often affected area in LET, the disease obviously has a significant cosmetic implication. In our study from 2000 [15], a complete resolution of skin lesions was observed in 18 of 40 patients (45%) who had received only topical corticosteroids or sunscreens with a sun protection factor of 15 or greater. Twenty-two patients (55%) who had failed to respond to this regimen were treated with antimalarials. Chloroquine was successfully used at a daily dose of 3.5 to 4.0 mg/kg ideal body weight per day, and a complete resolution of the skin lesions was seen mostly after four to six weeks in treated patients. In three patients (8%) who did not respond to this treatment, hydroxychloroquine was successfully used at a daily dose of 6.0 to 6.5 mg/kg ideal body weight per day. Because of the rapid and effective improvement of the skin lesions after treatment with antimalarials, systemic corticosteroids or immunosuppressants were temporarily necessary in only two patients. Choonhakarn et al. [41] described 15 patients with LET; complete remission with topical corticosteroids was seen in only 1 patient. Eleven of 14

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patients (79%) dramatically responded to chloroquine (250 mg/day). Methotrexate (7.5–10.0 mg/week) and systemic corticosteroids (10–30 mg/day) were beneficial in three patients who had failed to respond to chloroquine. In the report by Vieira et al. [16], 26 patients with LET were initially treated with sun protection and moderate potency topical corticosteroids with clearance of skin lesions in 21 patients. Only five required antimalarial agents. Recently, it has been reported that a patient with LET was resistant to hydroxychloroquine due to smoking and improved dramatically after reduction of smoking [51]. 8. Course of the disease The clinical features observed during exacerbations of the disease activity in LET occurred in most cases in summer due to sun exposure, and some patients reported that even after sitting behind glass windows, their skin disease had worsened. This was confirmed in the study by Vieira et al. [16]; the majority of the 26 LET patients had mild recurrences, usually during spring or summer, related to the first sun exposure. More than 50% of the patients remained aysmptomatic only with adequate sun protection. Association with systemic disease seems to be very rare in patients with LET, and in our study from 2000 [15], none of the patients fulfilled four or more ACR criteria for the diagnosis of SLE. 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 40 patients. Meanwhile, few cases have been published demonstrating that LET can be associated with SLE. Jolly et al. [52] reported that LET occurred in a patient with an established diagnosis of SLE. In other case reports, LET occurred concurrently with SLE [23]. SLE was present at the time of diagnosis in one of 15 patients with LET described by Alexiades-Armenakas et al. [17]; additionally, one patient developed SLE during the follow-up period. In a further study with 15 patients, SLE also appeared after the diagnosis of LET in one patient [41]. Few cases have been reported in the literature where LET is associated with DLE [13,15,17,23,41], and in two cases, it has also been described that LET lesions evolved over time into DLE [10,52]. However, detailed data are not available due to the low number of case reports published in the literature. In our experience, the prognosis in patients with LET is generally more favourable than in those with other forms of CLE and several patients who have been followed for more than 20 years show no recurrence after local or systemic treatment. Furthermore, once a lesion has developed, it persists in the same location, but may also disappear spontaneously with no scarring or dyspigmentation even if the disease relapses in these patients. 9. Separate entity in the classification of CLE In 1977, James Gilliam [53] initially proposed a nomenclature for the cutaneous manifestations of LE and soon thereafter, several refinements of this nomenclature were presented in collaboration with his colleague Richard Sontheimer [54,55]. This clinical-histopathologic classification system

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divided all skin lesions that have some form of relationship to LE into those that are histologically specific for LE (LE-specific skin disease) and those that do not share this pattern of histopathologic changes (LE-nonspecific skin disease). Three broad categories of LE-specific skin disease had been suggested: acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE), and chronic cutaneous LE (CCLE), including “classical” discoid LE (DLE), hypertrophic (verrucous) DLE, LE panniculitis (profundus), mucosal LE, lupus tumidus, Chilblain lupus, and DLE-lichen planus overlap [56]. The adjectives “acute,” “subacute,” and “chronic” used in these designations conform to the classic dermatologic definitions of these terms [57]. In contrast, LE-nonspecific skin manifestations, such as livedo reticularis, urticarial vasculitis, and Raynaud's syndrome, are often associated with SLE; however, they can also be encountered in other disease settings [58,59]. Since the initial formulation of the Gilliam nomenclature and classification system more than three decades ago, several attempts have been made to improve on this system or to provide altogether new approaches to the problem of classification of CLE. In the “Duesseldorf Classification 2004”, mucosal LE has not further been considered as a specific form of CCLE [26], since mucosal changes affecting the mouth, such as hard palate, buccal mucosa, gingiva, and uvula (rarely the nose, pharynx, and vagina) are also associated with other subtypes of CLE and especially SLE, often in relation to a worse outcome and systemic organ manifestations [60,61]. In addition, DLE-lichen planus overlap has also been excluded as a separate entity of CCLE. Although there are some case reports of this overlap syndrome, lichen planus may be associated with SLE and other autoimmune diseases [62]. Furthermore, diseases, such as erythema multiforme, toxic epidermal necrolysis, or autoimmune blistering disorders such as bullous pemphigoid, pemphigus vulgaris, and dermatitis herpetiformis Duhring as well as porphyria cutanea tarda have also been described in association with different subtypes of CLE and are not listed in the Gilliam's classification as separate forms [57,63]. Most importantly, LET has been included as a separate entity in the classification system (Table 2). Analysis in recent years has shown that this subtype has so many characteristic features [16,17,41] that it should be considered as a separate entity and differentiated from ACLE, SCLE, and CCLE [15,37,43,45,46]. Provocative phototesting has been crucial in defining LET as a very photosensitive entity of CLE in

Table 2 Classification of cutaneous lupus erythematosus. Acute cutaneous lupus erythematosus (ACLE) Localized form Generalized form Subacute cutaneous lupus erythematosus (SCLE) Annular form Papulosquamous form Chronic cutaneous lupus erythematosus (CCLE) Discoid lupus erythematosus (DLE) Localized form Disseminated form Lupus erythematosus profundus (LEP) Chilblain lupus erythematosus (CHLE) Intermittent cutaneous lupus erythematosus (ICLE) Lupus erythematosus tumidus (LET)

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contrast to all other subtypes of CCLE [37]. Only the distinct subtype of SCLE has a nearly comparable photosensitivity as LET [64]. Moreover, LET does never lead to long-term sequelae, such as permanent scarring, hypo- and hyperpigmentation, or lipatrophy as the other subtypes of CCLE. In addition, histopathological analysis of skin biopsy specimens of LET show characteristic perivascular and periadnexal lymphocytic infiltrate and abundant interstitial mucin deposition [16,17,43]. In the typical case of LET, there is absence of epidermal involvement; however, minimal epidermal changes, such as focal, slight vacuolar degeneration of the dermoepidermal junction, may be seen. The prognosis in LET is generally more favourable than in those with other forms of CLE and skin lesions may show an intermittent course with relapsing lesions after disease-free periods, but can also display long-term remission with the use of sunscreens. In the literature, LET is mostly seen as CCLE; however, in our opinion there is no doubt about LET being a separate entity due to the characteristic features described above. Therefore, based on the nomenclature by Gilliam in 1977 [53], we modified the classification system in 2004 including LET as the intermittent subtype of CLE (ICLE) (Table 2) [26].

fied as having LET demonstrating the difficulty in separating these two diseases. After the reclassification according to histological features, JLIS and LET showed only slight clinical differences (more frequent nasal bridge lesions in LET and annular lesions in JLIS). The authors of this study favoured the hypothesis of a continuous spectrum covering both diseases [65]. Moreover, the observation of effective treatment with hydroxychloroquine [15] and thalidomide [76,77] in JLIS actually suggests that the two diseases, LET and JLIS, may belong to the same entity of CLE. In conclusion, LET is a highly photosensitive disease with characteristic clinical and histological features and has long been neglected and underestimated in the literature. The 100th anniversary of the first description of LET was used as an occasion to review the reports of LET. It can be summarized that LET is a distinct subtype of CLE with an intermittent course, which should be included as a separate entity, named ICLE, in the classification of CLE. If JLIS is a disease within the spectrum of CLE and also belongs to the same entity as LET needs to be further analyzed.

10. Jessner's lymphocytic infiltration of the skin

• LE tumidus (LET) has been characterized in the past by several groups demonstrating characteristic features different from other subtypes of cutaneous LE (CLE); in particular, phototesting has been crucial in confirming LET as a separate entity of the disease spectrum. • Clinically, LET is characterized by succulent, urticaria-like, single or multiple plaques with a bright reddish or violaceous, smooth surface on sun-exposed areas. This subtype does never lead to long-term sequelae, such as permanent scarring, hypo- and hyperpigmentation or lipatrophy. • Provocative phototesting revealed that patients with LET are more photosensitive than those with other subtypes of CLE. Characteristic skin lesions were induced by UV radiation in 72% of 60 patients with LET; 30 patients (50%) reacted to UVA and 29 (48%) to UVB irradiation. • The most frequent histological features in skin biopsy specimens from LET lesions are a fairly well-circumscribed lymphocytic dermal infiltrate in a perivascular and periadnexal pattern and abundant interstitial mucin deposition. In contrast to other subtypes of CLE, epidermal changes and vacuolar degeneration of the dermoepidermal junction or basement membrane thickening are absent or show minimal alterations. • In addition to acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE), and chronic cutaneous LE (CCLE), LET has been included in the “Düsseldorf Classification of Cutaneous Lupus Erythematosus 2004” as a separate entity designated as “intermittent cutaneous lupus erythematosus (ICLE)”.

LET bears striking similarities to “Jessner's lymphocytic infiltration of the skin” (JLIS) and its variant the “palpable migratory arciform erythema”, which are the most important differential diagnosis of LET. JLIS is a relatively uncommon relapsing disorder with asymptomatic or pruritic, papulonodular, nonscarring lesions without epidermal involvement that most often is located on the face (especially, on the zygomatic arch area) or upper back that has not always been considered a specific disease entity [9,15,65–69]. Until today, no unanimity exists concerning its nosology [70]. Over the past few decades, several studies have reported that clinical and histological analysis of JLIS show only slight differences compared to LET or are insufficient for distinguishing from the spectrum of CLE [65,71,72]. In one report, JLIS and “probable” DLE were described separately in two sisters supporting the theory that JLIS may be in the same disease spectrum as CLE [73]. Otherwise, familial occurrence of JLIS has been reported in several patients, in particular in three brothers of one family [74,75]. To our knowledge, in contrast to JLIS no publication to date regarding familial LET exists in the literature. In 2001, Weber et al. [69] suggested by provocative phototesting that JLIS might be a photosensitive variant of LET. In a recent analysis of 210 cases, Lipsker et al. [67] raised the question as to whether JLIS may be a dermal variant of CLE. They found that 9.5% of the investigated JLIS patients had a positive direct immunofluorescence and that 45.7% of the patients had significant titers of ANA. In addition, in their study, 7.6% of patients with typical JLIS also showed characteristic findings of different subtypes of CLE. The group concluded that JLIS “could be a specific cutaneous manifestation of LE, namely a poor dermal variant of LE”. In a recent retrospective multicenter study from 2008, RémyLeroux et al. [65] further recorded clinical, histological, serological, and phototesting characteristics of patients with JLIS and LET who had been consulted during the past 15 years. Interestingly, in the two groups, nine patients were reclassi-

Take-home messages

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Rituximab in idiopathic inflammatory myopathy Rituximab, an antibody to CD20 cells, is largely used to treat rheumatoid arthritis and systemic lupus erythematosus. In a recent paper, Sultan et al. (Clin Exp Rheumatol 2008;26:887–93) have administered 1 g of rituximab, at days 0 and 14, to eight patients with refractory idiopathic myopathy. After infusion, all except one patient had adequate B cell depletion and a repopulation after 3 to 42 months. Only two patients observed a clinical response, both had dermatomyositis with positive anti-Jo-1 antibodies. The levels of CPK were reduced at least 30% during 10 to 36 months. However, muscle strength did not achieve 15% of improvement. Importantly, re-evaluation of the patients showed that one had inclusion body myositis, another one presented muscular dystrophy, and the last one developed nodular sclerosing lymphoma. This study suggests an inadequate response to rituximab in inflammatory myopathies, and claim to attention to differential diagnostic that could explain refractory clinical pictures.

Ro/SSA and la/SSB, apoptosis and autoimmunity Ro/SSA and La/SSB proteins have been linked to autoimmunity in systemic lupus erythematosus and Sjogren’s syndrome. Apoptotic cells may present on their surface these proteins (“apotopes”). In a recent article, Reed et al. (J Autoimmun 2008;31:263–7) reviewed the role of Ro/SSA and La/SSB proteins as apotopes in patients with autoimmunity. The authors also suggests that mapping of B cell apotopes might be better than standard epitope mapping due to the ability to identify novel pathways of autoantibodies production as well as new species of autoantibodies.

Autoantibodies and subtypes of autoimmune hepatitis Autoimmune hepatitis is related to the production of autoantibodies. In a very recent paper, Mehendiratta et al. (Clin Gastroenterol Hepatol 2009;7:98–103) have studied the association among clinical, laboratory, histopathological findings, and response to therapy with the presence of antinuclear and anti-smooth muscle antibodies in 52 patients with autoimmune hepatitis. The authors found that 81% of the group had at least one autoantibody. All variables analysed were comparable in the patients with and without autoantibodies, such as therapeutics, demographics, clinical, amminotransferase levels and histopathological features. This study was able to demonstrate the presence of antinuclear or anti-smooth muscle antibodies does not discriminate subgroups of patients with autoimmune hepatitis, in respect to therapy.