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Patients who have SCLE skin lesions in North America are predominately Caucasian females with a mean age in the 40s (Costner et al., 2004). However, the age range extends from as early as 18 months to the elderly. While other forms of cutaneous LE such as discoid LE are more common in African-Americans than Caucasians, SCLE is distinctly uncommon in African-Americans. In addition, SCLE has been found to be quite uncommon in Hispanics,Koreans and Chinese.

2.3. Environmental influences

Various environmental factors can induce or exacerbate SCLE skin lesions. Both natural (sunlight) and artificial forms of ultraviolet radiation routinely precipitate SCLE. However, it has been the author's personal experience that a small percentage of SCLE patients vehemently deny that their skin lesions are not photosensitive. Photo-testing studies have indicated that the action spectrum includes both UVB and UVA wavelengths (Kuhn et al., 2001). Photo-induction studies have suggested that 100% of SCLE patients have abnormal patterns of reaction to UV light that is typically observed beginning about 1 week after delivery of the photo-challenge (Sanders et al., 2003).

In the initial description of SCLE lesions, there was no indication that they could be induced by drugs. However, Reed et al. (1985) reported that SCLE skin lesions and Ro/SS-A autoantibodies could be precipitated by hydrochlorothiazide. When the hydrochlorothiazide was discontinued, the SCLE skin lesions spontaneously involuted. As can be seen in Table 1 there is now a rather long list of drugs that have been reported to or suspected of triggering otherwise typical SCLE skin lesions and Ro/SS-A antibody production (Costner et al., 2004; Pellowski et al., 2005). Is interesting how many of these drugs have been reported to produce photosensitivity skin reactions in the absence of evidence of LE. A possible explanation might be that an individual who is immunogenet-ically predisposed might experience a Koebnerizat-ion of SCLE skin lesions as a result of a phototoxic or photoallergic drug reaction.

Drug-induced SCLE should be differentiated from classical drug-induced SLE. The former is

Table 1

Drugs implicated in precipitating SCLE

Diuretics Thiazidesa Spironolactonea Calcium channel blockers Diltiazema Nifedipinea Nitrendipine ACE inhibitors Captoprila Cilazapril Acid blockers Ranitidine^ b Omeprazoleb Non-steroidal anti-inflammatory agents Naproxena Piroxicama b Blockers

Oxprenolol Lipid lowering Pravastatin1 Simvastatin1 Antimicrobials Griseofulvina Terbinafinea Antihistamines

Cinnarazine/triethylperazine Anti-convulsants

Phenytoina Antimalarials

Hydroxychloroquinea Sulfonylureas Glyburidea Chemotherapy

Taxotere (Docetaxel)a Tamoxifen Others

Leflunomidea Interferon-aa Procainamide D-penicillamineb Etanercept/infliximaba Insecticides Tetracycline derivatives (CO1-3)a a Drugs reported to be capable of producing photosensitivity skin reactions in individuals not having SCLE.

b Unpublished personal observation by author of SCLE induction with drug in question.

associated with Ro/SS-A autoantibodies and is defined by a characteristic photo-distribution of SCLE lesions. The latter is dominated by histone autoantibodies and systemic symptoms such as fever, arthritis, myalgias, and serositis. LE-specific skin changes of any type are rarely present in the classical form of drug-induced SLE. With exceptions, the medications that typically trigger SCLE lesions are distinct from those that trigger classical drug-induced SLE (e.g., hydralazine, procain-amide, isoniazid, minocycline, sulfasalazine), probably reflecting fundamentally different underlying disease mechanisms.

Cigarette smoking has been implicated as an eliciting/exacerbating factor for cutaneous and systemic LE (Costenbader et al., 2004). Curiously, several studies have also documented that cutaneous LE lesions, including SCLE, do not respond to antimalarials therapy in patients who smoke cigarettes compared to those who do not smoke (Rahman et al., 1998).

Experienced clinicians also recognize that psychological stress can precipitate/exacerbate cutaneous LE including SCLE skin lesions. However, this phenomenon has not been systematically studied. It has also been the author's personal experience long-term LE skin lesions, including SCLE, appear to be especially prone to clinical depression.

3. Etiology/pathogenesis

Observations relating to the etiopathogenesis of a clinically complex, multigenic, environmentally exacerbated autoimmune disorder such as LE can be organized using a sequential stage framework: (1) inheritance of susceptibility genes, (2) loss of tolerance/induction of autoimmunity, (3) expansion/ maturation of autoimmune responses and (4) tissue injury/disease induction resulting from autoimmune effector mechanisms. While this paradigm can be useful in conceptualizing the etiopathogen-esis of LE in general and its subsets, in this example, it is used to outline observations relating to the etiopathogenesis of SCLE skin lesions. Table 2 provides an outline of the key etiopathogenetic elements of SCLE as they are currently understood. This paradigm has been discussed in depth elsewhere (Costner et al., 2004).

During characterization of the initial cohort of SCLE patients it was recognized that they were markedly enriched for the HLA-A1, B8, DR3

haplotype that is shared by approximately 25% of the North American Caucasian population (Sontheimer et al., 1981). The HLA-A1, B8, DR3 haplotype has subsequently been markedly extended and is now referred to as the 8.1 ancestral haplotype, i.e., the common Caucasoid haplotype (HLA-A1, Cw7, B8, TNFAB* a2b3, TNFN*S, C2*C, Bf*s, C4A* Q0, C4B*1, DRB1*0301, DRB3*0101, DQA1*0501, DQB1*0201) carried by most people who type for HLA-B8, DR3 (Lio et al., 2001). In addition, some SCLE patients have been reported to be partially or completely deficient in C2 and C4, the genes of which are located in the HLA region on chromosome 6. More recently, SCLE skin lesions have been significantly associated with a single nucleotide polymorphism (SNP) in the TNF-a gene promoter (-308A) (Werth et al., 2000; Millard et al., 2001). (The TNF-a gene is also located within the HLA region.) This TNF-a promoter in the presence of IL-1 alpha has been associated with exaggerated TNF-a expression in human epidermal keratinocytes following UVB exposure (Werth et al., 2000).

It is also possible that polymorphism in other pro-inflammatory cytokine/cytokine receptor genes, adhesion molecule genes, and chemokine/ chemokine receptor genes could play a predisposing role in SCLE. Meller et al. (2005) have recently suggested that the CXCR3 ligands, CXCL9 (interferon-g [INFg]-induced monokine), CXCL10 (INFg-inducible protein 10), and CXCL11 (INF-inducible T-cell a chemoattractant) are the most abundantly expressed chemokine family members in cutaneous LE lesions, including SCLE. CXCL9, CXCL10, and CXCL11 were observed to be expressed in cutaneous LE lesions at much higher levels than in disease controls (atopic dermatitis, psoriasis) and normal skin. In addition, the inflammatory infiltrate in cutaneous LE lesions was reported to be rich in CXCR3-expressing cells, especially skin homing T-cells and plasmacytoid dendritic cells. These findings were interpreted to suggest an amplification cycle in which UV light-induced injury induces cutaneous cell apoptosis, necrosis, and chemokine production (Meller et al., 2005). These mechanisms, in turn, mediate the recruitment and activation of autoimmune T-cells and INFa-producing plasmacytoid dendritic cells

Table 2

Sequential etiopathogenetic stages of SCLE skin lesions

Susceptibility stage (Genetic predisposition)

1. 8.1 ancestral HLA haplotype (A*01, B*08, DRB1*0301, DQB1*0201, TNFAB* a2b3, C2*C, C4 null) (syn. HLA A1, B8, DR3, DQ1/DQ2 of earlier nomenclature)

(a) C2, C4 deficiency

2. Partial C1q deficiency (C1qA gene SNP)

3. Sex hormone metabolism pathway polymorphism (?)

Induction phase (Loss of immune tolerance)

1 Environmental eliciting factors

(a) Ultraviolet light (UVB and UVA)

(b) Drugs/chemicals

(i) Photosensitizing drugs (see Table 1)

(ii) Cigarette smoking

(iii) Exogenous estrogens/estrogen mimics (?)

(c) Psychological stress (?)

2 Loss of tolerance to cutaneous autoantigens

(b) Keratinocyte-/melanocyte-specific antigens (?)

Possible mechanisms include: (i) dysregulation of UV light-induced keratinocyte apoptosis (ii) faulty disposal of autoantigen-bearing apoptotic keratinocytes, (iii) impaired induction of immune tolerance to cutaneous antigens following exposure to UV light

Expansion phase (Expansion of autoimmune effector mechanisms)

1. Autoantibodies (Ro/SS-A, La/SS-B) leading to immune complex formation, Partial C1q deficiency could exacerbate the biological impact of immune complex formation (C1q solubilizes and prevents immune precipitation of immune complexes)

2. Cutaneous autoantigen reactive T-cells (?) Currently, there is only indirect evidence supporting this possibility

Injury phase (Tissue injury resulting in clinical disease)

1. Autoantibody-mediated cutaneous injury (?)

2. Immune complex-mediated cutaneous injury (?)

a. Complement activation, membrane attack complex formation, cellular injury

3. Autoreactive T-cell-mediated cutaneous injury (?)

a. Direct T-cell-mediated cytotoxicity involving granzyme and perforin mechanisms b. Apoptosis resulting from local cytokine elaboration (e.g., TNF-a )

4. Mixed patterns of immunological cutaneous injury (?)

a. Antibody-dependent cell-mediated cytotoxicity

?-indicates author's speculation.

that subsequently release more effector cytokines, thus amplify chemokine production and leukocyte recruitment, finally leading to the development of a cutaneous LE phenotype. It would be interesting to know whether these chemokine abnormalities are specific for cutaneous LE or might be seen in other interface dermatidities such as cutaneous dermatomyositis.

Based on observations indicating that complete congenital deficiency of C1q is very strongly associated with photosensitive SLE (Botto and Walport, 2002), our lab has began to probe for more subtle forms of C1q deficiency as a predisposing factor for photosensitive cutaneous LE. Using a candidate gene approach, we recently identified what appears to be a association between the SCLE sub-phenotype and a newly described synonymous SNP in the second exon of the gene that encodes the A chain of C1q, the initial recognition molecule for the classical pathway of complement (Racila et al., 2003). In addition, SCLE patients who were found to be homozygous for this SNP were found to have lower serum levels of C1q antigen compared to SCLE patients not having this SNP. To date, this C1qA SNP is the only genetic association of SCLE that lies outside the HLA region.

4. Clinical manifestations

4.1. Clinical features

The original report of SCLE described it as a photosensitive, recurring, superficial, nonscarring type of cutaneous LE that occurred in a characteristic photo-related distribution including the V-area of the neck, upper trunk, and extensor aspects of the shoulders arms, forearms and the dorsal aspects of the hands and fingers relatively sparing the knuckles (Figs. 1-4). Curiously, it has been the author's experience that the central facial skin is less frequently affected by SCLE compared to other less photosensitive forms of cutaneous LE like discoid LE. It has always been curious that a photosensitive process like SCLE relatively spares a highly photoexposed area of skin - the central face. When SCLE does involve the face it typically is seen on the upper neck and mandibular areas of the lateral face, sparing the central aspects of the face. It is distinctly unusual to see SCLE lesions below the waist. It has been pointed out by others that the absence of induration in SCLE lesions can help to distinguish it clinically from discoid LE skin lesions (David-Bajar et al., 1992).

Because of the relatively strong association between the SCLE phenotype and production of Ro/ SS-A autoantibody, some physicians have come to require the presence of Ro/SS-A antibody for the diagnosis of SCLE. However, it should be remembered that in virtually all studies reported to date a certain percentage (10-35%) of otherwise typical SCLE patients have been negative for Ro/SS-A antibody by various assay methods. This observation raises concerns about the hypothesis that Ro/ SS-A antibody is directly involved in the patho-genesis of SCLE skin lesions.

There are two major morphological varieties of fully expressed SCLE lesions - annular and pap-ulosquamous (Figs. 1-4). Both of these types of SCLE begin with the same primary lesion - a non-indurated papulosquamous papule or small plaque. In some patients, these primary lesions expand to produce multiple discrete papulosquamous plaques that can merge together to produce a retiform array (Figs. 1 and 2, panel B). In other patients, for unknown reasons, the primary lesions expand and

Figure 1. A fully developed flare of SCLE lesions on the chest, V-area of neck, and deltoid areas. (A) annular SCLE. Note the polycyclic array produced by merging of the individual lesions. (B) papulosquamous/psoriasiform SCLE. Note the reticulated, retiform array produced by merging of the individual lesions.

Figure 1. A fully developed flare of SCLE lesions on the chest, V-area of neck, and deltoid areas. (A) annular SCLE. Note the polycyclic array produced by merging of the individual lesions. (B) papulosquamous/psoriasiform SCLE. Note the reticulated, retiform array produced by merging of the individual lesions.

Lupus Erythematosusarthritis

Figure 3. Annular SCLE on the chest, back, and neck. (A) Note the trailing scale at the borders of the annular lesions. Rarely, the active advancing edge of annular SCLE lesions will undergo a vesiculobullous change as a result of epidermal basal layer apoptotic disruption resulting from a highly intense form of interface dermatitis. (B) Note the marked postinflammatory hypopigmentation at the center of the annular lesions

Figure 3. Annular SCLE on the chest, back, and neck. (A) Note the trailing scale at the borders of the annular lesions. Rarely, the active advancing edge of annular SCLE lesions will undergo a vesiculobullous change as a result of epidermal basal layer apoptotic disruption resulting from a highly intense form of interface dermatitis. (B) Note the marked postinflammatory hypopigmentation at the center of the annular lesions

Annular Polycyclic
Figure 4. SCLE on the extensor aspect of the arms. (A) Note the erythema multiforme-like morphology of the smaller early lesions and the typical annular SCLE appearance of the single more advanced lesion. (B) Note the psoriasiform appearance of this example of papulosquamous SCLE.

clear in the center to produce annular lesions that can merge together to produce a polycyclic array (Figs. 1 and 2, panel A). Annular SCLE typically displays postinflammatory depigmentation at the center of lesions that distinguishes it from other types of annular erythema reactions that are not related to LE.

While most patients exhibit one or the other of these two major morphological variants of SCLE, some display both elements concurrently. To date, there has been no convincing significant differences reported in the clinical, genetic, immunologic, and other laboratory features of patients who display only annular or papulosquamous SCLE skin lesions. However, it has been suggested anecdotally by the author (Sontheimer, 1989; Costner et al., 2004) and others (Cohen and Crosby, 1994) that the papulosquamous variant of SCLE, especially in males, might carry a higher risk for features of more severe systemic LE (e.g., nephritis).

Since the original description of SCLE, a number of morphological variants have been described including pityriasisiform, exanthematous, erythrodermic, erythema multiforme-like, po-ikilodermatous, annular-vesiculopustular, and toxic epidermal necrolysis-like among others (Costner et al., 2004; Pellowski et al., 2005). However, it should be emphasized that each of these variants is quite rare.

The relationship between SCLE and erythema multiforme deserves separate consideration. Neville Rowell and coworkers (Rowell et al., 1963) described erythema multiformly like lesions occurring in LE patients who produced autoantibodies to the Sjogren's syndrome autoantigen Sj-T. The Sj-T autoantibody specificity is now thought to be immunologically identical to the La/SS-B autoantibody specificity. La/SS-B autoantibodies are closely linked to Ro/SS-A autoantibodies and are present in one-third to one-half of SCLE patients depending on the method of assay. Other features in the original description of Rowell's syndrome include the presence of antinuclear antibodies in a speckled pattern and a positive test for rheumatoid factor. There continues to be debate concerning the relationship between the skin lesions seen in Rowell's syndrome and erythema multiforme-like variant of annular SCLE with some workers suggesting that they are identical (Vassileva, 2004; Roustan et al., 2000). The author has recently presented his views on this subject within the framework of a conceptual discussion of all vesicular-bullous skin lesions that can be seen in the context of LE (Ting et al., 2004).

4.2. Association with other forms of cutaneous LE and LE nonspecific skin disease

SCLE lesions can occur in the same patient in association with other forms of LE-specific skin disease such as chronic cutaneous LE (discoid LE) or acute cutaneous LE. It has been suggested that approximately 20% of SCLE patients will develop typical chronic cutaneous LE lesions and (e.g., classical discoid LE) or acute cutaneous LE lesions (e.g., nonscarring malar butterfly erythema) at some point in the course of their illness. In addition, SCLE patients can also develop one or more types of LE-nonspecific skin disease (e.g., small vessel leukocytoclastic vascultis, Raynaud's phenomenon, finger nailfold telangiectasias, livedo reticularis) (Sontheimer, 1989). These LE-nonspecific skin disease findings have been reported in 10-20% of SCLE patient cohorts (Sontheimer, 1989). It has been the author's experience that grossly visible finger nailfold telangiectasia are seen much less commonly in SCLE patients compared to patients having either clinically amyopathic dermatomyositis or classic dermatomyositis.

It has been the author's personal experience that SCLE patients who develop either acute cutaneous LE or a form of LE-nonspecific skin disease might have a higher risk of developing clinically significant SLE. This is not surprising as both acute cutaneous LE and LE-nonspecific skin disease are known to be associated with a higher risk of clinically significant SLE compared to other forms of LE skin disease such as the various clinical varieties of chronic cutaneous LE.

4.3. Association with SLE

SCLE patients in the original cohort were observed to frequent display symptoms of a mild systemic illness marked predominately by lethargy, easy fatigability, and musculoskeletal complaints (Sontheimer et al., 1979). While 48% had four or more of the American Rheumatism Association classification criteria for SLE, none had serious central nervous system or renal disease (the American Rheumatism Association is now known as the American College of Rheumatology). The American Rheumatism Association classification criteria for SLE that were fulfilled in these patients related predominately to cutaneous and musculo-skeletal manifestations and mild serological and other laboratory changes. A review of published cases of SCLE in 1989 revealed that severe systemic manifestations of SLE (e.g., central nervous system disease, nephritis) appeared to occur only infrequently in patients presenting with SCLE skin lesions (Sontheimer, 1989). Subsequent longer-term all want studies have revealed that only about 10-15% of patients whose presenting illness includes SCLE skin lesions go on to develop severe clinical manifestation of SLE (Sontheimer, 1989; Chlebus et al., 1998; Costner et al., 2004; Pellowski et al., 2005). The clinical and/or laboratory features that might identify the small percentage of SCLE patients who at risk for developing more severe manifestations of SLE over time have yet been systematically examined.

4.4. Association with other autoimmune diseases

SCLE skin lesions can occur in other clinical settings in which Ro/SS-A autoantibody is seen such as Sjogren's syndrome and rheumatoid arthritis (Costner et al., 2004; Pellowski et al., 2005). The association with Sjogren's syndrome might be expected from the 8.1 ancestral haplotype immuno-genetic background and Ro/SS-A autoantibody production that it shares. In some studies involving prolonged follow-up intervals, as many as 43% of SCLE patients have been observed to also develop features of Sjogren's syndrome (Black et al., 2002).

Indurated annular erythematosus plaques have been described predominately in Asian patients (especially Japanese) having Sjogren's syndrome in association with the presence of Ro/SS-A and La/ SS-B antibodies (Miyagawa, 1994; Watanabe et al., 1997; Yamamoto and Nishioka, 2004). The histopathology of such lesions reveals prominent dermal mucin accumulation and perivascular mononuclear cell inflammation but no interface dermatitis that would be typical of SCLE. There has been some debate over the possibility that annular erythema of Sjogren's syndrome represents an ethnic variant of SCLE. However, several Caucasian patients with annular erythema of Sjogren's have recently been reported suggesting that these two clinical entities might be distinct (Haimowitz et al., 2000).

By virtue of their Ro/SS-A autoantibody production, women with SCLE lesions are at a small degree of risk for delivering an infant affected by neonatal LE. However, this risk (<0.5%) appears to be no greater than for Ro/SS-A autoantibody-positive pregnancies occurring in other clinical settings (Sjogren's syndrome, rheumatoid arthritis, SLE). SCLE skin lesions have also been reported to occur in patients with autoimmune thyroiditis, hereditary angioedema, and autoimmune polyglandu-lar syndrome Type II (Schmidt's syndrome).

4.5. SCLE as a paraneoplastic phenomenon

In addition, there has been the suggestion that SCLE skin lesions can occur as a paraneoplastic phenomenon. Approximately 10 cases have been reported to date in which SCLE skin lesions appeared to relate to the presence of various types of internal malignancy (lung and breast being the most common) (data reviewed in Dawn and Wainwright (2002)). The significance of this association is currently uncertain. It has not been the author's habit to evaluate all new SCLE patients for internal malignancy.

5. Diagnostic investigations

5.1. Serology/immunology

Sixty-three percent of the original cohort of SCLE patients tested had positive antinuclear antibody assays using human tumor cell substrates (Sontheimer et al., 1979). In addition, 62% of the initial cohort of SCLE patients tested had Ro/SS-A autoantibodies by Ouchterlony double immunodiffusion analysis (Sontheimer et al., 1982). Other autoantibodies seen in SLE patients such as double-stranded DNA and Sm were seen much less commonly than Ro/SS-A autoantibodies in the original cohort of SCLE patients (Sontheimer et al., 1982). Subsequent studies by others employing the same assay techniques found similar results (Sontheimer, 1989). When more sensitive solid phase immunoassays such as ELISA have been employed, higher rates of Ro/SS-A autoan-tibody have been observed (up to 90%) (Lee et al., 1994). However, with such sensitive assays the clinical utility of Ro/SS-A autoantibody decreases since up to 10% of normal individuals have been found to have "abnormal" levels of anti-Ro/SS-A by solid phase immunoassays.

Twenty-five percent of the initial cohort of SCLE patients tested was positive for La/SS-B autoanti-bodies by Ouchterlony double immunodiffusion (Sontheimer et al., 1982). As with Ro/SS-A antibody, higher percentages of La/SS-B antibody have been observed in SCLE patient cohorts using solid phase immunoassays. Ro/SS-A and La/SS-B autoantibodies have been observed to be a linked set of autoantibodies. That is to say, they are frequently seen to be present in association with each other. This is due to the fact that the two separate proteins that bear Ro/SS-A and La/SS-B auto-antigenic determinants are components of the same ribonucleoprotein particle that is identified by the presence of small uridine-rich hYRNA molecules that were initially thought to be restricted to the cytoplasm. Experimental work has shown that when an autoantibody response is generated against one component of a cellular ribonucleo-protein particle autoantibodies are subsequently produced against antigenic determinants on other molecular components of the same ribonucleopro-tein particle via a mechanism of epitope spreading (Kinoshita et al., 1998).

As the molecular identity of the various components of the Ro/SS-A ribonucleoprotein particle became known there was hope that qualitative difference in the autoantibody response to these various components of the Ro/SS-A ribonucleo-protein particle might correlate with the various clinical phenotypes that have been associated with Ro/SS-A antibody production (i.e., SCLE, Sjog-ren's syndrome, SLE, rheumatoid arthritis, neonatal lupus). However, for the most part, this has not been found to be the case (McCauliffe et al., 1996).

A biologic false positive test for syphilis has been reported in 7-33% of SCLE cases (Sontheimer, 1989). Follow-up studies have revealed elevated levels of anti-cardiolipin antibody in 16% of SCLE patients (Fonseca et al., 1992). The author has personally observed several SCLE patients that developed deep-vein thrombosis who were subsequently found to be positive for high levels of IgG anti-cardiolipin antibodies.

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