Subacute cutaneous lupus erythematosus.

Gilliam recognized subacute cutaneous lupus erythematosus (SCLE) as a lupus-specific eruption that identifies a unique subset of lupus erythematosus. These patients were noted to have prominent photoaggravated skin disease and often had musculoskeletal complaints, but generally did not develop significant systemic disease. SCLE patients were later found to have other distinctive features, including the frequent presence of anti-Ro antibodies, and enrichment for the human histocompatibility antigens (HLA) B8 and DR3. In the 13 years of published reports of SCLE patients following the initial study by Sontheimer et al (Subacute cutaneous lupus erythematosus: a cutaneous marker for a distinct lupus erythematosus subset. Arch Dermatol 115:1409-1415, 1979) a number of additional observations regarding SCLE patients have been made. These have included the recognition that SCLE may be associated with other rheumatic diseases, and that photoactive medications may induce lesions of SCLE. Areas of controversy concerning SCLE include conflicting studies regarding the histopathology of SCLE as compared to discoid lupus erythematosus (DLE), as well as the frequency of detection of anti-Ro antibodies in SCLE patients. Recent interesting studies of SCLE include a description of a unique pattern of immunoglobulin G (IgG) deposition on direct immunofluorescence, which may indicate the binding of anti-Ro antibodies to keratinocytes in vivo.

Clinical, histologic, and immunofluorescent distinctions between subacute cutaneous lupus erythematosus and discoid lupus erythematosus.

Subacute cutaneous lupus erythematosus (SCLE) was originally described and distinguished from discoid lupus erythematosus (DLE) on the basis of clinical examination of the skin, but subsequent reports have questioned the concept of SCLE as a marker of a unique subset of LE patients. We classified 27 lupus patients, on the basis of cutaneous exam, as having discoid lupus skin lesions, subacute cutaneous skin lesions, or systemic lupus erythematosus (SLE) without DLE or SCLE lesions. Clinical features most characteristic of SCLE rather than DLE were superficial, non-indurated, non-scarring lesions, and photosensitivity, with lack of induration being the single most helpful finding. Histologic examination of lesional skin showed a relatively sparse, superficial infiltrate in SCLE and a denser, deeper infiltrate in DLE. A distinctive pattern of staining with direct immunofluorescence, particulate epidermal IgG deposition, was found in seven of seven SCLE patients (all anti-Ro/SSA positive) and none of the other patients. This distinctive pattern can be reproduced experimentally when anti-Ro/SSA autoantibodies are infused into human skin-grafted mice. Particulate dermal-epidermal junctional staining was the pattern seen in the patients who did not have SCLE. Clinically defining SCLE as a superficial inflammatory form of cutaneous lupus (i.e., considering lesions to be DLE if they are indurated) results in a meaningful segregation of SCLE and DLE patient groups. The epidermal IgG deposits unique to SCLE provide independent evidence that the clinical findings that were used to identify the patient groups actually identify distinctive cutaneous lupus subsets. The observation that antibodies are present in a different location in the skin in SCLE than in DLE indicates that SCLE and DLE are likely to have different pathomechanisms.

In three types of interface dermatitis, different patterns of expression of intercellular adhesion molecule-1 (ICAM-1) indicate different triggers of disease.

We found distinct patterns of intercellular adhesion molecule-1 (ICAM-1) expression in three diseases characterized by interface dermatitis with mononuclear infiltrates and keratinocyte cytotoxicity: lichen planus (LP), subacute cutaneous lupus erythematosus (SCLE), and erythema multiforme (EM). In LP, basal keratinocytes show strong ICAM-1 expression associated with a dermal infiltrate, but ICAM-1 expression in the rest of the epidermis is minimal. In SCLE, there is diffuse epidermal ICAM-1 expression, sometimes with accentuation on the cell surface of basal cells. In EM, there is strong basal cell expression of ICAM-1 with evident cell surface accentuation, and also pockets of suprabasal expression with cell surface accentuation. These patterns are associated with different factors that trigger cytokine release in different locations. Both tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) produce greater relative ICAM-1 expression in basal keratinocytes than in more differentiated keratinocytes. In LP, the pure basal keratinocyte expression of ICAM-1 appears to be caused by cytokines, predominantly IFN-gamma, released by dermal lymphocytes. The pattern of ICAM-1 in SCLE corresponds to the pattern induced by ultraviolet radiation (UVR): diffuse epidermal ICAM-1 expression, sometimes with basal accentuation. Some individuals are "responders" to TNF-alpha or UVR, showing high levels of ICAM-1 expression following UVR or TNF-alpha stimulation in vitro or UVR stimulation in vivo. We propose that the pattern of ICAM-1 induction in SCLE is dependent on UVR-induced TNF-alpha release. EM is associated with apparent latent Herpes simplex virus, and Herpes simplex virus (HSV)-infected keratinocytes show enhanced ICAM-1 expression. We propose that in EM suprabasal ICAM-1 expression may be induced directly by HSV infection or indirectly through TNF-alpha release induced by HSV reactivation. Induction of ICAM-1 within the epidermis is stratified and individually variable. Basal keratinocytes show maximal induction of ICAM-1 expression due to innate sensitivity to TNF and IFN-gamma stimulation, and to location adjacent to dermal sources of cytokines. Suprabasal ICAM-1 can be induced by UVR and epidermal TNF-alpha release, and by factors such as viral infection. Different triggers of cytokine release and adhesion molecule induction may influence the different patterns of inflammation seen in diverse inflammatory skin diseases.

Microscopic polyarteritis. Report of a case with cutaneous involvement and antimyeloperoxidase antibodies.

BACKGROUND: Microscopic polyarteritis is a systemic small-vessel vasculitis that primarily involves the kidneys but may also affect the skin and other organ systems. This unique vasculitis represents one of the vasculitides with antineutrophil cytoplasmic antibodies, usually of the perinuclear immunostaining pattern (P-ANCA, antimyeloperoxidase antibodies). The objective of this case report is to describe microscopic polyarteritis, the use of antineutrophil cytoplasmic antibodies, and the unique cutaneous histopathologic features of our patient. OBSERVATIONS: We describe a patient with clinical findings consistent with microscopic polyarteritis, the presence of antimyeloperoxidase antibodies, and a specific cutaneous leukocytoclastic vasculitis. This report further characterizes the histopathologic features by demonstrating that the anatomic location of the cutaneous vasculitic lesions is at the level of the dermal arteriolar vessels and postcapillary venules. CONCLUSIONS: Cutaneous arteriolar leukocytoclastic vasculitis may prove to be a histologic hallmark of microscopic polyarteritis when it presents in the skin. However, further case comparisons and histopathologic investigations are needed. The consequences of this systemic vasculitis, if not adequately treated, may be life threatening. Recognition of clinical features, use of antineutrophil cytoplasmic antibodies, and demonstration of a cutaneous arteriolar leukocytoclastic vasculitis may aid in the diagnosis and subsequent treatment of patients followed up by dermatologists for vasculitic ulcers.

Waldenström macroglobulinemia-induced bullous dermatosis.

BACKGROUND: Waldenström macroglobulinemia is a plasma cell dyscrasia of undetermined cause characterized by the monoclonal proliferation of lymphoplasmacytes in the bone marrow, lymph nodes, and spleen and elevated circulating levels and tissue deposition of monoclonal IgM produced by these aberrant cells. Rarely, cutaneous manifestations of this disease have been reported. OBSERVATIONS: We report the case of a patient with bullous dermatosis induced by Waldenström macroglobulinemia and demonstrate the subepidermal location of the separation and the presence of IgM and kappa light chains by immunoperoxidase, immunofluorescent techniques, and electron microscopy with immunogold staining. Immunoblotting revealed a strong band at the 290-kd area. CONCLUSIONS: The demonstration of the separation in the upper dermis at the site of IgM deposits suggests that these deposits may be an etiologic factor in this rare manifestation.

Esophagitis dissecans superficialis associated with pemphigus vulgaris.

The extension of bullous lesions in pemphigus to the esophagus is relatively uncommon, especially in patients who appear to be in clinical remission. Very rarely, pemphigus vulgaris may affect the entire esophagus, resulting in complete sloughing of the mucous membrane. A 20-year-old man with pemphigus vulgaris presented to the emergency room with acute onset of dysphagia, odynophagia, and hemoptysis. There were no cutaneous or oral findings of pemphigus on presentation, since he was being maintained on corticosteroids and azathioprine with excellent results. During initial evaluation in the emergency room, the patient was observed to vomit a cast of the mucosal lining of the esophagus. The morphologic description of such an esophageal cast is termed esophagitis dissecans superficialis. This is the third case of esophagitis dissecans superficialis in pemphigus vulgaris recorded in the medical literature.

Azithromycin eruption in infectious mononucleosis: a proposed mechanism of interaction.

The penicillin family of antibiotics may induce drug eruptions when prescribed to patients with infectious mononucleosis. Very similar phenomena have also been cited with other antibiotic families. We report the first case of a cutaneous reaction in a patient with infectious mononucleosis treated with azithromycin. We propose an immune-based hypothesis to explain the transient sensitivity resulting in this secondary cutaneous eruption.

Rheumatoid neutrophilic dermatitis.

Rheumatoid neutrophilic dermatitis (RND) is a rare cutaneous finding in patients with severe rheumatoid arthritis or with high-titer rheumatoid factors. Most commonly, these lesions are erythematous papules or plaques distributed symmetrically on extensor surfaces. On histologic examination a dense dermal neutrophilic infiltrate without vasculitis is apparent. The pathogenesis of RND is unclear, and few treatments are known. With careful clinical and histologic examination, RND may be differentiated from the wide array of other cutaneous findings in rheumatoid arthritis.

The leukotriene antagonist montelukast as a therapeutic agent for atopic dermatitis.

BACKGROUND: Cysteinyl leukotrienes have been shown to be important in the pathogenesis of allergen-induced (atopic) asthma and rhinitis. Skin manifestations of atopic dermatitis have been reported to improve with leukotriene antagonists. Montelukast, a newer leukotriene antagonist, which is efficacious and safe in patients with asthma 6 years of age and older, has not been reported as therapy for atopic dermatitis. This article reports findings from a pilot study designed to determine whether montelukast is effective in decreasing the signs or symptoms of atopic dermatitis. OBJECTIVE: Our purpose was to compare the efficacy of montelukast with placebo as a treatment for patients with atopic dermatitis. METHODS: The study involved 8 adult patients (male and female) with at least 1 year of intermittent or persistent atopic dermatitis as determined by Hanifin criteria. Medication was given in a randomized, double-blind, placebo-controlled, crossover manner over 8 weeks as adjunctive treatment. Global evaluation of 6 signs (erythema, induration, excoriation, lichenification, scaling, erosion) were scored on a 0 to 3 scale each week, with a blinded investigator evaluating at the initiation, crossover, and final visit. A 30% decrease in total score was considered clinically significant. RESULTS: A significant difference in atopic dermatitis scores between placebo and active agent (P =.014) was recognized. There was no significant interaction between order and treatment. Atopic dermatitis scores tended to be higher with placebo. The mean standard deviation was 8.7 +/- 2.0. The mean for active agent was 6. 8 +/- 2.1. CONCLUSION: This study demonstrates that there is a modest, but significant, alleviation of atopic dermatitis with the use of the leukotriene antagonist montelukast used in an adjunctive manner over a 4-week period.

Occurrence of positive immunofluorescence in the dermo-epidermal junction of sun-exposed skin of normal adults.

A bright, continuous, granular deposition of immunoreactants at the dermo-epidermal junction (DEJ) of lesional skin is highly suggestive of cutaneous lupus erythematosus (LE). A recent study of the direct immunofluorescence (IF) of sun-exposed skin in normal adults has demonstrated findings similar to the bright, continuous granular pattern found in cutaneous LE. This data suggests that positive IF from sun-exposed cutaneous lupus lesions is nonspecific. Forty-one healthy adults, without a history of dermatoses or photosensitivity, presenting to the dermatology clinic for the excision of skin cancers were studied. Excess non-lesional tissue, removed from Moh's excision sites (sun-exposed face and neck) in order to obtain appropriate cosmetic closure, was examined for the deposition of immunoreactants. The specimens were incubated with fluoresceinated monovalent anti-human immunoglobulin specific for IgG, IgA, IgM, C3, Clq, and fibrinogen and examined independently by 2 immunodermatologists without prior knowledge of patient or site. None of the samples demonstrated immunoreactant deposition consistent with cutaneous LE. IF of several specimens (21/41) had a weak (1+ or 2+), interrupted pattern of fibrinogen at the DEJ,--a common, non-specific finding. Weak, interrupted, linear and granular patterns were seen with IgM (10/41), Clq (9/41), IgG (2/41), IgA (2/41), and C3 (1/41). Fibrinogen was the only immunoreactant demonstrating a bright (3+), continuous, granular pattern (4/41). This data suggests that sun-exposure alone does not induce the deposition of immunoreactants at the DEJ in a pattern similar to that found in cutaneous LE.

Chronic herpes gestationis and antiphospholipid antibody syndrome successfully treated with cyclophosphamide.

Herpes gestationis shares many features with other bullous diseases, especially bullous pemphigoid. Treatments of benefit in bullous pemphigoid may also be effective for herpes gestationis. Cyclophosphamide, azathioprine, and other immunosuppressive agents have been used successfully in refractory cases of bullous pemphigoid. We describe a patient with severe and persistent herpes gestationis in the postpartum period and the antiphospholipid antibody syndrome, both of which were refractory to high-dose corticosteroid therapy. Treatment with pulsed-dose intravenous cyclophosphamide produced an excellent clinical response.

Human keratinocytes maintain reversible anti-apoptotic defenses in vivo and in vitro.

Human keratinocytes proliferate and differentiate in an epidermal environment where induction of apoptosis can be triggered by ultraviolet radiation (UVR), activated lymphocytes and cytokines. The purpose of this study was to determine whether keratinocytes were susceptible to apoptosis induced by ionophore, ultra-violet radiation, cytokines or crosslinking of CD95 (Fas/APO-1). In normal human skin exposed to two minimal erythema doses of ultraviolet radiation, suprabasal cells were the first keratinocytes to demonstrate apoptotic nuclei, and by 48 h apoptotic cells were identified throughout the mid to upper epidermis. However, most keratinocytes resisted apoptosis and UVR-induced apoptosis was not observed in basal cells, or in the most differentiated epidermis. Human keratinocytes and keratinocyte cell lines cultured in vitro developed maximal apoptosis 48 h after radiation. Human keratinocytes cultured in full growth factor supplements were resistant to UVR-induced apoptosis compared to keratinocyte cell lines or to a lymphoid cell line (HL60) susceptible to apoptosis. Keratinocyte cell lines were completely resistant to apoptosis induced by interferon-gamma, interferon-alpha, IL-2, IL-6, TNF-alpha, IL-1Ra, and GM-CSF. A subset of the cells in cultures of keratinocytes and transformed keratinocyte cell lines died by apoptosis in response to anti-Fas, IL-1alpha and TNF-alpha plus IFN-gamma and ionophore. Second passage freshly isolated human keratinocytes were much more resistant to apoptosis induced by ionophore, anti-Fas and cytokines than were transformed keratinocyte cell lines. Calcium shift to induce differentiation in second-passage keratinocyte cultures made keratinocytes even more resistant to UVR-induced apoptosis. This parallels the lack of UVR-induced apoptosis observed in the most differentiated keratinocytes in irradiated human skin. Both keratinocytes and keratinocyte cell lines express rather low levels of the anti-apoptotic proteins bcl-2 and bcl-x compared to other apoptosis-resistant cell types. The differences between keratinocytes and keratinocyte cell lines in susceptibility to apoptosis are not explained by difference in expression of bcl-2 or bcl-x. Finally, withdrawal of growth factors from keratinocytes decreased cell survival following UVR and increased the induction of apoptosis. Inhibition of protein synthesis with cyclo-heximide also made keratinocytes more susceptible to UVR-induced apoptosis, indicating that anti-apoptotic defences in cultured keratinocytes are dependent on active protein synthesis. These experiments show that the strong keratinocyte defences against apoptosis are stratified within the epidermis, and can be altered by differentiation and growth factor withdrawal.