be encountered varies between primary and secondary SjS. In addition, there is significant ethnic variation in patterns of skin disease seen in SjS. For example, the autoimmune annular erythema seen in Japanese SjS patients is extremely rare in patients from North America. Similarly, SCLE, a common skin feature among North American SjS patients, is unusual in SjS patients from Japan.

11.3Skin Changes Encountered in Primary SjS

Xerosis of both cutaneous and mucosal surfaces is a key manifestation of SjS [7]. Cutaneous xerosis may be characterized both on the basis of subjective symptoms (dryness, pinprick sensation) and objective findings (fine, dry scale; loss of light reflection from the skin surface; increased transepidermal water loss) [4]. Patients may report dryness and loss of luster of hair, as well as dryness and brittleness of the nails [1].

Cutaneous xerosis is generally reported in half to two-thirds of cases of SjS. In their classic paper, Bloch et al. [8] reported that 33/62 patients (53%) complained of dryness of the skin. Bernacchi et al. observed xerosis in 34/62 patients (55%) with primary SjS and found xerosis to be significantly higher in primary as opposed to secondary SjS [4]. In that study, patients with xerosis tended to be older (mean age 65 vs. 50) and were more likely to have circulating anti-Ro/SS-A or anti-La/ SS-B antibodies [4]. Skin dryness and pruritus are very common among healthy senior and elderly individuals who do not have SjS. Because SjS patients are often older than the mean population age, data describing the prevalence of dryness and pruritus in SjS should be viewed in this context.

The pathogenesis of xerosis in SjS is not completely understood. Dysfunction of the sebaceous and eccrine glands has been suggested because these organs are responsible for intrinsic skin lubrication [1]. A lymphohistocystic infiltrate within the eccrine glands has been demonstrated in some cases [1], supporting the hypothesis of loss of function secondary to an immune-mediated inflammatory process. However, a quantitative study of 12 patients with SjS (3 primary, 9 secondary), including eight patients who complained specifically of xerosis, failed to show diminished pilocarpine-induced sweat production compared to controls [9].

Altered function of the autonomic nervous system, both sympathetic and parasympathic, has been reported in SjS. Kovacs et al. reported a blunted response to cholinergic stimulation in SjS patients [10]. Mandl et al. reported abnormal responses for cutaneous vasoconstriction, orthostatic blood pressure, and deep breathing in patients with SjS compared to controls [11]. Xerosis in SjS may also relate to alterations in barrier function of the stratum corneum and to an altered keratinocyte pro- tein-expression profile [12].

The human stratum corneum plays a major role in limiting preventing transepidermal water loss and desiccation of the skin. However, there has been very little research on the biochemical integrity of the stratum corneum in SjS patients.

11.3.1Pruritus

Xerosis is often accompanied by pruritus. Pruritus was reported in 26/62 patients (42%) with primary SjS and associated with xerosis in 19 (73%) of those with pruritus [4]. Chronic rubbing and scratching may lead to hyperpigmentation and lichenification [1, 7, 13]. When pruritus is particularly intense, other incidental causes should be addressed (e.g., dermatitis herpetiformis, dermatographic urticaria, prodromal pemphigoid, and eczematous drug eruptions) [1].

Treatment of xerosis and pruritus in SjS can be challenging [1]. For xerosis, limiting daily bathing to 5–10 min with lukewarm (rather than hot) water can be helpful. Heat tends to soften and liquefy the natural skin oils, making them more likely to be removed by soapy water while bathing. Mild soaps or soapless cleansers should be used to cleanse dry areas such as the arms and legs while bathing. Strong antibacterial soaps and surgical scrubs (chlorhexidine) should be reserved for cleansing the body fold areas. Liquid body scrubs should be avoided while bathing. Colloidal oatmeal added to bath water can be soothing for dry, itchy skin.

After bathing, the patient should be directed to gently pat off excess water with a towel and to apply a bland emollient cream or ointment to damp skin. The emollient should be reapplied during the day as often as necessary and practical. When significant pruritus is present, topical corticosteroids (e.g., hydrocortisone, triamcinolone, fluocinonide, or clobetasol, in increasing order of potency) may be applied in ointments or creams once or twice daily for up to 2-week intervals. Ointments are preferred to creams because they trap water in the skin more effectively and are therefore more moisturizing. Nonsteroidal topical immunomodulators (tacrolimus, pimecrolimus) may be useful [14]. Oral antihistamines may provide relief of pruritis for some patients.

Caution should be observed with over-the-counter products alleged to treat dry skin. Ingredients such as neomycin and diphenhydramine (in rub-on or spray-on itch relief products) can cause cutaneous allergic reactions, often resulting in worsening of the itching and confusion about the correct diagnosis.

Two manifestations of SjS merit particular attention: eyelid dermatitis and angular cheilitis. Both commonly occur in association with regional mucosal dryness, though the cutaneous findings may not be attributably only to the xerophthalmia and xerostomia.

11.3.2Annular Erythema of SjS

Annular erythema of SjS is comprised of erythematous skin lesions with indurated borders. These generally occur on the upper body and display mononuclear infiltrates in perivascular and periappendageal regions on skin biopsy. Annular erythema was first linked with primary SjS in Japanese patients in the 1980s [15]. This skin lesion was associated with the presence of circulating anti-Ro/SS-A and anti-La/SS-B autoantibodies but lacked the prominent interface dermatitis usually demonstrated by

Fig. 11.2 Annular erythema of SjS. These skin lesions are from the left thigh and palm of a 40-year-old Filipino woman with a history of parotid swelling, sicca symptoms, and arthralgias. She had a positive antinuclear antibody assay (1:640, speckled pattern) and anti-Ro/SS-A and anti-La/SS-B autoantibodies were present. Double-stranded DNA antibody assay was negative. The recurrent annular skin lesions with overlying mild scale that are shown had skin biopsy findings that were consistent with annular erythema of SjS. A mild degree of interface dermatitis on biopsy was likely responsible for the mild clinical scaling shown in the photos (potassium hydroxide exam of scraped scale was negative for dermatophytes). In addition to the upper trunk, neck and face, annular erythema of SjS skin lesions have also been described on the palms and soles (Clinical images were kindly provided by Dr. Jan P. Dutz, Department of Dermatology, University of British Columbia, Canada)

subacute cutaneous lupus erythematosus (SCLE). Moreover, SCLE lesions are quite rare among Japanese individuals. Annular erythema occurs in Caucasian SjS patients only rarely. Debate has existed about a potential relationship between annular erythema of SjS and SCLE. Some authors have speculated that annular erythema of SjS is the Japanese equivalent of lupus tumidus skin lesions in Westerners.

Katayama et al. have recently analyzed the clinical and laboratory findings in 28 of their own SjS patients with annular erythema. These cases were identified from a Japanese Dermatology Department and combined with data abstracted from 92 previously published cases [15]. Three clinical types of annular erythema have been identified: a doughnut-shaped, ring-like erythema with elevated borders: an SCLElike marginally scaled, polycyclic erythema; and a papular insect bite-like erythema. Each of the three morphologies displays the same set of histopathologic changes. In addition to the upper extremities and face, annular erythema has also been described on the soles of the feet (Fig. 11.2).

Three quarters of the annular erythema patients reported by Katayama et al. had circulating anti-Ro/SS-A and anti-La/SS-B autoantibodies. However, the presence

of annular erythema did not portend the occurrence of any specific SjS manifestations or complications. Annular erythema is very sensitive to systemic glucocorticoids and is typically controlled effectively with prednisone 10 mg/day.

11.3.3Eyelid Dermatitis

Eyelid dermatitis, common in SjS, can affect the upper or lower eyelids and is associated with pruritus or a foreign-body sensation. Three patterns of eyelid dermatitis are described: the slightly lichenified; the moderately lichenified and papular; and eyelid edema [13]. In a study of 52 Japanese patients with primary SjS, 22 (42%) had eyelid dermatitis. Patients with eyelid dermatitis tended to be older (mean age 61 vs. 49) and complain of ocular dryness (86% vs. 59%).

A study from Italy reported a somewhat lower prevalence of eyelid dermatitis among SjS patients [4]. Approximately equal percentages of primary and secondary SjS patients were described as having this condition: 15 of 62 patients (24%) and 8 of 31 (26%) patients, respectively. Of the patients with primary SjS, eyelid dermatitis was commonly associated with xerosis (13/15; 87%) and sicca symptoms (14/15; 93%). Only upper eyelid involvement was reported in this study.

Eyelid dermatitis may be managed with the intermittent use of low potency topical steroid creams (e.g., hydrocortisone, desonide). Nonsteroidal topical immunomodulators such as tacrolimus (0.03% or 0.1% ointment) and pimecrolimus (1% cream) are also useful.

Angular cheilitis. The xerostomia of SjS is associated with a number of intraoral consequences. These include a diminished rate of saliva secretion; a decreased buffering capacity of saliva; an increased risk of colonization by Candida, lactobacillus, or streptococcus species; and increased rates of dental caries [16, 17].

Angular cheilitis is a sign commonly associated with oral candidiasis. Both angular cheilitis and oral candidiasis have been correlated with the diminished salivary flow seen in SjS [17]. About a third of SjS patients will have difficulty with angular cheilitis.

A study from Italy found angular cheilitis to be more prevalent in patients with primary SjS (24/62; 39%) compared to secondary SjS (5/31; 16%). More than 95% of cases were associated with xerostomia [4].

Investigators from Sweden reported erythema or fissuring at the angles of the mouth in 28 (70%) of 40 patients with primary SjS and angular cheilitis in 14 (35%) of those same patients. In contrast, angular cheilitis is estimated to occur in about 3–5% of the general population [16].

In a study of 50 patients with SjS, three quarters were diagnosed with oral candidiasis and angular cheilitis was present in approximately one-fourth [18]. Oral candidiasis is more common in patients taking certain medicines such as prednisone or other immunosuppressives.

Angular cheilitis may be managed with topical antimycotic ointments (e.g., ketoconazole, miconazole, clotrimazole, or nystatin). Measures to increase salivary