Manfred Uerlich

Scarring skin lesions of discoid lupus erythematosus are characterized by high numbers of skin‐homing cytotoxic lymphocytes associated with strong expression of the type I interferon‐induced protein MxA

Background  Infiltrating T lymphocytes are considered to play a major pathological role in skin lesions of cutaneous lupus erythematosus (CLE), a cutaneous autoimmune disease of unknown aetiology. Earlier histological studies revealed that the inflammatory infiltrate in CLE skin lesions is predominantly composed of T lymphocytes, with a slight predominance of CD4+ over CD8+ T cells, but failed to explain the development of scarring skin lesions, characteristic for chronic discoid lupus erythematosus (CDLE). Because recent investigations have highlighted the relevance of cytotoxic lymphocytes in autoimmune tissue destruction, we hypothesized that the scarring CDLE lesions might be caused by cytotoxic T lymphocytes.

Type I Interferon-Associated Recruitment of Cytotoxic Lymphocytes A Common Mechanism in Regressive Melanocytic Lesions

We studied 253 primary melanomas of the skin for histologic signs of regression. Detailed immunohistologic analyses, including expression of MxA (an antiviral protein specifically induced by type I interferons), the chemokine IP10/CXCL10, the chemokine receptor CXCR3, and the cytotoxic molecule granzyme B, were performed for 14 typical regressive tumors and 20 control samples (congenital nevi, halo nevi, unaffected skin). We found high expression of MxA, indicating local type I interferon production, in inflamed regressive melanocytic lesions, along with large numbers of natural interferon-producing plasmacytoid dendritic cells, CXCR3+ lymphocytes, and granzyme B+ lymphocytes. We also detected high expression of the interferon-induced chemokine IP10/CXCL10, linking type I interferon production and recruitment of CXCR3+ lymphocytes. Our results provide evidence that endogenous activation of type I interferons, infiltration of plasmacytoid dendritic cells, and recruitment of CXCR3+ and granzyme B+ lymphocytes are involved in spontaneous regression of melanoma and other melanocytic lesions. We believe this cytotoxic immune response represents an evolutionarily conserved pathway against intracellular pathogens.

Enhanced type I interferon signaling and recruitment of chemokine receptor CXCR3-expressing lymphocytes into the skin following treatment with the TLR7-agonist imiquimod.

Introduction:  Imiquimod (Aldara™) is an immune response modifier approved for the topical treatment of external genital and perianal warts which can mediate regression of several cutaneous malignancies [basal cell carcinoma (BCC), Bowens disease, actinic keratosis, and metastasis of malignant melanoma]. Recently, it was discovered that imiquimod acts through the toll‐like receptor (TLR) 7. We hypothesize that TLR7‐signaling strongly induces the production of interferon (IFN) α, which is able to enhance Th1‐mediated cellular antiviral and antitumor immunity.

Successful topical immunotherapy of bowenoid papulosis with imiquimod.

Sir, Bowenoid papulosis is a disease presenting with fleshy, usually pigmented papules involving the genitalia of both sexes. In vulvar lesions, the term vulvar intraepithelial neoplasia (VIN3) is also used to describe the same condition. Histological examination reveals a picture consistent with carcinoma in situ, although the course of the disease appears to be benign. Association with oncogenic human papillomavirus (HPV 16, 18, 33) has been demonstrated. In the past, excisional surgery, electrocoagulation, cryotherapy and 5-fluorouracil have been used in the treatment of the condition with varying degrees of success. A 38-year-old woman was referred to our clinic with a 4-year history of pruritic skin lesions on her labia majora. She had previously been treated with podophyllin without any benefit. The molecular biological examination of the vaginal mucosa had been negative in terms of HPV typing (groups 6/11, 16/18, 31/33). However, HPV 31/33 was detected in the cervical smear (Hybrid Capture II test). Previous treatment with erbium laser, KTP 532 mm laser and podophyllin had been unsuccessful. On examination, erythema and numerous small papules were detectable on the labia minora and majora as well as in the clitoral and perianal area, each papule 1±3 mm in diameter (Fig. 1). The dermatohistopathological examination of several biopsies taken from these sites showed a uniform pattern with bowenoid epithelial changes, thus supporting the clinical diagnosis of bowenoid papulosis (Fig. 2). Treatment with imiquimod was initiated with a regimen different from that recommended for the treatment of genital warts. Imiquimod cream 5% was applied to affected areas on alternate days for 10 days until the skin became visibly irritated. The cream was now applied once daily for another 10 days, but washed off after 2 h each time. This treatment led towards complete clinical resolution within 8 weeks (Fig. 3). Histology performed 1 month, 6 months and 18 months after treatment demonstrated the absence of any precancerous epidermal changes (Fig. 4). The lympho histiocytic dermal infiltrate observed 1 month after treatment decreased in density in the control biopsies taken 6 and 18 months after treatment. Colposcopy performed 10 months after treatment showed minor acetic-white areas around the portio. No low-risk or high-risk HPV material was detected on the cervix (Hybrid Capture II test). More than 18 months after treatment the patient continues to be clinically clear. Imiquimod is a topical immune response modifier so far registered for the treatment of condylomata acuminata. Imiquimod directly induces antiviral and immunomodulating cytokines such as interferon-a, tumour necrosis factor-a and different interleukins from monocytes, macrophages and dendritic cells. Its effect on the innate immune response and the activation of Th1-immunity are responsible for its acute

Sporotrichoid phaeohyphomycosis due to Alternaria infectoria

We describe a cardiac transplant patient who had human cutaneous alternariosis with a sporotrichoid distribution of skin lesions. In this patient identification of the causative organism Alternaria infectoria was achieved by sequencing the rDNA internal transcribed spacer domain. Treatment with itraconazole led to clinical resolution within 4 months.

Topical Treatment of Pyoderma gangraenosum

The treatment of pyoderma gangraenosum (PG) is still a therapeutic challenge. Although several drugs such as corticosteroids, dapsone, clofazimine, azathioprine, tacrolimus and cyclosporine A have been shown to be effective in this disease, side-effects of these agents limit their systemic use in seriously ill patients. In recent years, topical treatment of the disease has gained attention. Several reports show an improvement of cutaneous lesions of PG following topical treatment. These earlier reports as well as our own observations suggest that topical therapeutic regimens can be a useful and safe alternative to systemic immunosuppressive therapy in the treatment of PG. We give a review about these topically used drugs and the mechanisms probably involved.

Selective Alterations in Natural Killer Cell Subsets in Patients with Atopic Dermatitis

We examined the immunophenotypic characteristics of natural killer (NK) cell subsets in patients with severe atopic dermatitis (AD), rhinitis allergica (RA) and in healthy controls. Expression of CD16, CD56 and CD57 antigens on peripheral blood lymphocytes was evaluated by simultaneous double immunocytofluorometry. Our results showed significantly lower percentages of cells with CD16, CD56 and CD57 surface antigens in patients with AD. Furthermore subdivision of the AD group into two subgroups, AD1 and AD0 (with and without antigen-specific IgE antibodies against potent inhalative allergens, i.e. mite, grass, rye, birch, cat) revealed that patients of subgroup AD1 showed a more prominent decrease compared to that of subgroup AD0. Moreover, we found a significant negative correlation between the percentage of CD56 + CD16 + NK cells and total IgE levels in serum, which were significantly higher in patients of subgroup AD1 than in AD0. NK cell activity was deficient in patients with AD but there was no difference between both subgroups. These data indicate that considerable heterogeneity in immunologic regulation may exist in patients with AD with regard to their NK cell subsets.

Rapid Improvement of Subacute Cutaneous Lupus erythematosus with Low-Dose Methotrexate

Subacute cutaneous lupus erythematosus Low-dose methotrexate Interleukin-1 blocking I. Böhm, MD, Department of Dermatology, University of Bonn, Sigmund-Freud-Strasse 25, D-53105 Bonn (Germany) When standard regimens fail in controlling cutaneous lupus erythematosus (LE), a variety of other therapeutics including azathio-prine, isotretinoin, interferon α2a, cyclophosphamide, dapsone, cyclo-sporin A or thalidomide have been used. Recently it has been shown that methrotrexate (MTX) is able to control rheumatoid arthritis with a low rate of adverse effects [1, 2]. Therefore, we treated with low-dose MTX once a week a female patient with subacute cutaneous LE who was refractory to systemic glucocorticosteroids; we could document an excellent clinical outcome without any side-effects. A 36-year-old female patient presented with a 10-year history of cutaneous LE with arthralgias. Erythematosquamous and papulosqua-mous lesions were seen mainly on the trunk, the arms and upper legs (fig. i). Skin biopsy revealed hyperkeratosis, focal thinning of the epidermis and some scattered colloid bodies. The basal cells showed minimal hydropic degeneration and the basement membrane was slightly thickened. Lymphocytic infiltration was seen in the upper dermis with a perivascular pattern and showed particular invasion into the epidermis. Focal extravasation of erythrocytes was present. Direct immunofluorescence showed only perivascular deposits of the complement component C3. Routine laboratory findings were normal except for the erythrocyte sedimentation rate (62/72 mm), dsDNA antibodies (ELISA) 534.0 U/ml (normal 9-40) and antinuclear antibodies (Hep2 cells) 1:2,560 (normal < l :80) with a homogeneous fluorescence pattern. Antibodies against Ro (SSA), La (SSB), Ul-snRNP and RNP-SM complex were detected. Anticardiolipin antibodies were 34.8 U/ml (normal 0-12.0). Other systemic LE symptoms could be excluded. Based on these findings, the diagnosis of subacute cutaneous LE with systemic involvement was made. Before admission she had been treated for 10 years with systemic glucocorticosteroids with a daily dose of up to 20 mg. Initially, she noticed improvement, but later the skin lesions were refractory to steroid therapy and she had developed Cushing’s symptoms. We started MTX therapy with 25 mg/week i.v. (first injection with 12.5 mg/week). Two weeks after starting

Antibodies targeting extractable nuclear antigens: historical development and current knowledge

The extractable nuclear antigens (ENA) are a heterogeneous group of ribonucleoproteins and non-histone proteins with different functions in nuclear metabolism. The detection of antibodies targeting ENA is a well-established tool in the diagnosis of autoimmune diseases such as lupus erythematosus (LE), progressive systemic sclerosis (PSS), polymyositis (PM), dermatomyositis (DM), mixed connective tissue disease (MCTD), SjoÈgrens syndrome (SS) and overlap syndromes. Descriptions of precipitin reactions between soluble tissue components and sera of patients suffering from these diseases, as well as identification of the antigen± antibody reactions, have been the subject of a large number of investigations in recent years. Most of the corresponding antigens have been identified (over 20 antigen systems) and knowledge about the clinical and genetic association of the antibodies detected has improved. Antibodies targeting ENA were first described in 1959, when Holman et al. recorded a precipitin reaction of sera from systemic LE (SLE) patients with extractable antigens isolated from crushed calf thymus. This observation was interpreted as an antigen± antibody reaction of autoantibodies in the SLE sera with soluble nuclear antigens. The nomenclature of an autoantibody to ENA depended on the group first describing it, and was made corresponding to the nuclear function of the antigen (RNP), the name of the patient providing the prototype serum (Ro, La, Sm, Jo, Mi) or the disease from which the serum donor suffered (SSA, SSB, SSC, Scl-70, PM-1, PM-Scl). The historical development of antigen±antibody systems lends a depth of understanding to the current knowledge we hold of them. This is particularly true for the systems discussed in this review: Sm, RNP, Ro/SSA, La/SSB, SSC, Scl-70, PM-1, PM-Scl, Ku, Mi and Jo-1. See Table 1 for an overview

Systemische Therapie des kutanen Lupus erythematodes

Die Behandlung des kutanen Lupus erythematodes (CLE) stellt oft eine therapeutische Herausforderung dar, vor allem bei Patienten, die auf eine rein topische Therapie nicht ansprechen oder zusätzliche systemische Manifestationen zeigen. Hier muß vielfach auf eine systemische Therapie zurückgegriffen werden. Zwar werden einige Substanzen erfolgreich in der systemischen Therapie des CLE eingesetzt, diese sind jedoch häufig nicht für diese Indikation zugelassen.