Neutrophilic Epitheliotropism is a Histopathological Clue to Neutrophilic Urticarial Dermatosis.

BACKGROUND: Neutrophilic urticarial dermatosis (NUD) comprises a particular autoinflammatory condition within the spectrum of aseptic neutrophilic dermatoses characterized by a distinct urticarial eruption clinically and a neutrophilic dermatosis histopathologically. OBJECTIVE: In this study, we reviewed skin biopsies of lesional skin of patients seen in our outpatient clinic for autoimmune dermatoses and in allergy department from 1982 to 2014 that fulfilled these criteria. METHODS: A total of 77 biopsies from 50 patients were analyzed histopathologically. Included were cases of Schnitzler syndrome, Still disease, systemic lupus erythematosus, Sjögren syndrome, cryopyrin-associated periodic syndrome, primary biliary cirrhosis, inflammatory bowel disease, and those that had signs of systemic inflammation not otherwise specified, that is, fever, arthritis, leukocytosis, and elevated erythrocyte sedimentation rate. A control cohort was defined as including a total of 70 biopsies from 50 patients comprising neutrophilic urticaria (pressure-induced and not pressure-induced), conventional urticaria, lupus erythematosus expressing neutrophils, and exanthematous drug reaction of macular type expressing neutrophils. RESULTS: Skin biopsies of NUD revealed a perivascular and interstitial neutrophilic infiltrate focally extending into the epithelia of epidermis, hair follicles, sebaceous and sweat glands, a feature which we termed neutrophilic epitheliotropism. This neutrophilic epitheliotropism proved to be of high sensitivity (83.1%) and lower specificity (74.3%). The histological findings could be substantiated by immunohistochemical markers for leukocytes (elastase and myeloperoxidase), in particular in cases where neutrophils showed uncharacteristic band-like nuclei. CONCLUSIONS: Neutrophilic epitheliotropism is a new sensitive and specific histopathological clue for NUD, a histopathological reaction pattern within the spectrum of neutrophilic dermatoses that needs to be differentiated from conventional urticaria.

The Diagnosis and Treatment of Systemic Lupus Erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease with a prevalence of 36.7/100 000 in Germany and a female/male ratio of 4:1. The clinical course is variable, with a broad spectrum of organ manifestations; lupus nephritis develops in about half of all patients. METHODS: This review is based on a selective search of PubMed and the Cochrane Library, including current guidelines and expert recommendations. RESULTS: Assessment of clinical symptoms, laboratory findings, and optional biopsy results are the basis for early diagnosis of SLE. All patients should be treated with antimalarials as soon as the diagnosis is confirmed. In particular, hydroxychloroquine is associated with a higher rate of remission, fewer relapses, and reduced damage in the course of the disease, even in lupus nephritis. High-dose glucocorticoids should be given only when acutely indicated; immunosuppressives such as azathioprine, methotrexate, or mycophenolate mofetil may be administered to reduce glucocorticoids, according to the EULAR recommendations. Belimumab was recently approved as add-on therapy in autoantibody-positive SLE patients with high disease activity unresponsive to standard treatment. Short-term induction pulse therapy with low-dose intravenous cyclophosphamide, as well as continued mycophenolate mofetil treatment are advances in lupus nephritis. CONCLUSION: The long-term prognosis for SLE has improved markedly in recent decades because of earlier diagnosis and optimized treatment. Further research and randomized controlled trials are needed for the development of specifically targeted therapies.

Early treatment with rutoside and ascorbic acid is highly effective for progressive pigmented purpuric dermatosis.

BACKGROUND AND OBJECTIVES: Progressive pigmented purpuric dermatosis (PPPD, Schamberg disease) is a rare benign, but chronic dermatosis frequently misdiagnosed as vasculitis or bleeding disorder. Although affected patients experience significant impairment in quality of life no effective treatment has been established. The aim of our two center case series was to evaluate efficacy and tolerability of the antioxidants rutoside and ascorbic acid as combination treatment for PPPD. PATIENTS AND METHODS: A retrospective review was performed on 35 patients with PPPD treated with 2 × 50 mg rutoside and 1,000 mg ascorbic acid daily between 2004 until 2011. The mean treatment duration was 8.2 months. RESULTS: 71.4% of the participants experienced complete clearance and 20.0% an improvement of more than 50%, accompanied by increased quality of life. Nine participants (25.1%) relapsed after discontinuation. In seven, rutoside and ascorbic acid was re-initiated, and all responded again. Only three participants reported mild adverse effects. Participants with shorter disease duration showed better therapeutic success, shorter time to response and lower risk of recurrence. CONCLUSION: Oral rutoside and ascorbic acid may be an efficient and well tolerated treatment for PPPD. Early treatment is recommended to achieve best clinical outcome.

Cutaneous lupus erythematosus: first multicenter database analysis of 1002 patients from the European Society of Cutaneous Lupus Erythematosus (EUSCLE).

In this prospective, cross-sectional, multicenter study, we assessed clinical and laboratory characteristics from patients with cutaneous lupus erythematosus (CLE) using the Core Set Questionnaire of the European Society of Cutaneous Lupus Erythematosus (EUSCLE). 1002 (768 females, 234 males) patients with different subtypes of CLE, such as acute CLE (ACLE, 304 patients), subacute CLE (SCLE, 236 patients), chronic CLE (CCLE, 397 patients), and intermittent CLE (ICLE, 65 patients), from 13 European countries were collected and statistically analyzed by an SPSS database. The main outcome measures included gender, age at onset of disease, LE-specific and LE-nonspecific skin lesions, photosensitivity, laboratory features, and the criteria of the American College of Rheumatology (ACR) for the classification of systemic lupus erythematosus. The mean age at onset of disease was 43.0±15.7 years and differed significantly between the CLE subtypes. In 347 (34.6%) of the 1002 patients, two or more CLE subtypes were diagnosed during the course of the disease and 453 (45.2%) presented with LE-nonspecific manifestations. Drug-induced CLE and Sjögren's Syndrome had the highest prevalence in SCLE patients (13.1% and 14.0%, respectively). Photosensitivity was significantly more frequent in patients with ACLE, SCLE, and ICLE compared with those with CCLE. The detection of antinuclear antibodies such as anti-Ro/SSA and anti-La/SSB antibodies revealed further significant differences between the CLE subtypes. In summary, the EUSCLE Core Set Questionnaire and its database facilitate the analysis of clinical and laboratory features in a high number of patients with CLE and will contribute to standardized assessment and monitoring of the disease in Europe.

Therapeutic strategies evaluated by the European Society of Cutaneous Lupus Erythematosus (EUSCLE) Core Set Questionnaire in more than 1000 patients with cutaneous lupus erythematosus.

The aim of this prospective, cross-sectional, multicentre study performed by the European Society of Cutaneous Lupus Erythematosus (EUSCLE) was to investigate different therapeutic strategies and their efficacies in cutaneous lupus erythematosus (CLE) throughout Europe. Using the EUSCLE Core Set Questionnaire, topical and systemic treatment options were analysed in a total of 1002 patients (768 females and 234 males) with different CLE subtypes. The data were correlated with the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the criteria of the American College of Rheumatology (ACR) for the classification of systemic lupus erythematosus. Sunscreens were applied by 84.0% of the study cohort and showed a high efficacy in preventing skin lesions in all disease subtypes, correlating with a lower CLASI activity score. Topical steroids were used in 81.5% of the patients, with an efficacy of 88.4%, whereas calcineurin inhibitors were applied in 16.4% of the study population and showed an efficacy of 61.7%. Systemic agents including antimalarials and several immunomodulating/-suppressive drugs, such as systemic steroids and methotrexate, were applied in 84.4% of the 1002 patients. The CLASI activity and damage score was higher in treated CLE patients compared to untreated patients, regardless of therapy with topical or systemic agents. In summary, preventive and therapeutic strategies of 1002 patients with different subtypes of CLE were analysed in this prospective, multicentre, Europe-wide study. Sunscreens were confirmed to be successful as preventive agents, and topical steroids showed a high efficacy, whereas antimalarials were used as first-line systemic treatment.

Efficacy of tacrolimus 0.1% ointment in cutaneous lupus erythematosus: a multicenter, randomized, double-blind, vehicle-controlled trial.

BACKGROUND: Topical calcineurin inhibitors are licensed for the treatment of atopic dermatitis; however, the efficacy of tacrolimus in cutaneous lupus erythematosus (CLE) has only been shown in single case reports. OBJECTIVE: In a multicenter, randomized, double-blind, vehicle-controlled trial, we sought to evaluate the efficacy of tacrolimus 0.1% ointment for skin lesions in CLE. METHODS: Thirty patients (18 female, 12 male) with different subtypes of CLE were included, and two selected skin lesions in each patient were treated either with tacrolimus 0.1% ointment or vehicle twice daily for 12 weeks. The evaluation included scoring of clinical features, such as erythema, hypertrophy/desquamation, edema, and dysesthesia. RESULTS: Significant improvement (P < .05) was seen in skin lesions of CLE patients treated with tacrolimus 0.1% ointment after 28 and 56 days, but not after 84 days, compared with skin lesions treated with vehicle. Edema responded most rapidly to tacrolimus 0.1% ointment and the effect was significant (P < .001) in comparison to treatment with vehicle after 28 days. Clinical score changes in erythema also showed remarkable improvement (P < .05) after 28 days, but not after 56 and 84 days. Moreover, patients with lupus erythematosus tumidus revealed the highest degree of improvement. None of the patients with CLE demonstrated any major side effects. LIMITATIONS: The study was limited by the small sample size. CONCLUSION: Explorative subgroup analyses revealed that topical application of tacrolimus 0.1% ointment may provide at least temporary benefit, especially in acute, edematous, non-hyperkeratotic lesions of CLE patients, suggesting that calcineurin inhibitors may represent an alternative treatment for the various disease subtypes.

Cutaneous lupus erythematosus: update of therapeutic options part II.

In the first part of the review, topical agents and first-line systemic treatment options for cutaneous lupus erythematosus were discussed whereas in the second part, recent information on efficacy, dosage, and side effects for further systemic treatment options are described in detail. In contrast to other immunosuppressive agents, such as azathioprine, cyclophosphamide, and cyclosporine, methotrexate has recently received more attention in the treatment of the disease. Further second-line treatment includes retinoids, dapsone, and mycophenolate mofetil. Because of severe side effects or high costs, other agents, such as thalidomide or high-dose intravenous immunoglobulins, are reserved for severe recalcitrant CLE. Biologics, ie, rituximab, have been used to treat systemic lupus erythematosus; however, in CLE, most biologics have only been applied in single cases. In addition to successful treatment, induction of CLE subtypes by biologics has been reported. In conclusion, many treatment options exist for CLE, but not many are supported by evidence from randomized controlled trials.

Cutaneous lupus erythematosus: update of therapeutic options part I.

In patients with cutaneous lupus erythematosus (CLE), it is important to provide instructions concerning methods of protection from sunlight and artificial sources of ultraviolet radiation. Topical corticosteroids are the mainstay of treatment for patients with CLE; however, they are of limited value because of their well-known side effects. Recently, calcineurin inhibitors have been shown to be efficient as topical therapy in various CLE subtypes. The first-line treatment for severe and widespread skin manifestations is antimalarials; hydroxychloroquine or chloroquine can each be combined with quinacrine in refractory CLE. Systemic steroids can be used additionally in exacerbations of the disease. In the first part of this review, recent information on topical and first-line systemic treatment is described in detail while providing the reader with up-to-date information on efficacy, side effects, and dosage for the various agents. In the second part, additional systemic agents for the treatment of CLE will be discussed.

A database analysis of cutaneous lupus erythematosus with the EUSCLE Core Set Questionnaire.

The aim of this study was to determine whether the Core Set Questionnaire developed recently by the European Society of Cutaneous Lupus Erythematosus (EUSCLE) is a useful tool to evaluate clinical features and therapeutic strategies in cutaneous lupus erythematosus. Disease characteristics were analysed in 50 patients with different subtypes of cutaneous lupus erythematosus from two European centres (Germany and Sweden). Mean age at onset of disease was 42.0 +/- 13.3 years (range: 7-69 years) and this differed significantly between the cutaneous lupus erythematosus subtypes. Moreover, 22 (44.0%) of the patients with cutaneous lupus erythematosus fulfilled four or more of the American College of Rheumatology (ACR) criteria; however, only 7 (14.0%) had severe systemic organ manifestations, such as kidney involvement. The analysis of serological features, such as antinuclear antibodies, revealed further significant differences between the cutaneous lupus erythematosus subtypes. In conclusion, the EUSCLE Core Set Questionnaire provides a useful tool for standardized collection and statistical analysis of data on cutaneous lupus erythematosus in clinical practice.

The 100th anniversary of lupus erythematosus tumidus.

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.

Disseminated giant molluscum contagiosum in a patient with idiopathic CD4+ lymphocytopenia. Successful eradication with systemic interferon.

Idiopathic CD4+ lymphocytopenia is a rare disease without HIV infection or any other underlying immunodeficiency. Patients with this condition are predisposed to various opportunistic infections. We describe a 31-year-old woman with giant molluscum contagiosum disseminated over nearly the whole body. Immunologic analysis disclosed very low numbers of CD4+ lymphocytes (<11/microl, normal range: 240-3,100), an abnormal proliferative response of the patient's lymphocytes to artificial mitogens and specific antigens, and an anergic delayed-type hypersensitivity skin response. HIV serology was repetitively negative. The diagnosis of idiopathic CD4+ lymphocytopenia was established. Systemic treatment with pegylated interferon-alpha2b (50 microg/week) for 16 months resulted in complete eradication of her disseminated giant molluscum contagiosum. In this report we will further describe the nature of idiopathic CD4+ lymphocytopenia and emphasize its relevance to clinical dermatology.

Diagnostic approach and treatment of cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (CLE) is a heterogeneous disorder with a wide range of skin manifestations. In the second part of this review, diagnostic procedures and treatment options in CLE are summarized.The diagnosis of the various subtypes of CLE is based on patients's history,clinical findings,laboratory features, and histological and immunofluorescent examinations of skin biopsies. In case of systemic organ involvement, further adequate technical investigations are necessary. The therapy has to be adjusted to the subtype of CLE and its inflammatory activity as well as the extent of skin involvement. The skin manifestations of CLE are primarily treated by topical therapy, such as glucocorticosteroids, in combination with antimalarials. The response of CLE to immunosuppressive drugs that control organ involvement in systemic lupus erythematosus is often disappointing. Recent advances in biotechnology resulted in the development of several novel systemic agents for the treatment of autoimmune diseases; however, controlled clinical trials are still necessary for the approval of new therapies in CLE.

A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of bullous pemphigoid.

OBJECTIVE: To investigate the safety and efficacy of oral methylprednisolone combined with azathioprine sodium or mycophenolate mofetil for the treatment of bullous pemphigoid. DESIGN: A prospective, multicenter, randomized, nonblinded clinical trial to compare 2 parallel groups of patients with bullous pemphigoid undergoing different treatments. SETTING: Thirteen departments of dermatology in Germany. PATIENTS: Patients with bullous pemphigoid (n = 73) as evidenced by clinical lesions suggestive of bullous pemphigoid, signs of subepidermal blistering on histologic analysis of skin biopsy specimens, linear deposition of IgG and C3 along the dermoepidermal junction, and deposition of autoantibodies at the blister roof in split-skin analysis. INTERVENTIONS: Treatment with oral methylprednisolone plus azathioprine (azathioprine group) or oral methylprednisolone plus mycophenolate mofetil (mycophenolate mofetil group). MAIN OUTCOME MEASURES: The cumulative total methylprednisolone doses and rates of remission. Secondary outcome measures were safety profiles and duration of remission. RESULTS: In 38 of 38 patients in the azathioprine group (100%), complete remission was achieved after a mean +/- SD of 23.8 +/- 18.9 days vs 42.0 +/- 55.3 days for 35 of 35 patients in the mycophenolate mofetil group (100%). In the azathioprine group, the median +/- SD total cumulative methylprednisolone dose used was 4967.0 +/- 12 190.7 mg vs 5754.0 +/- 9692.8 mg in the mycophenolate mofetil group. Nine of 38 patients in the azathioprine group (24%) experienced grade 3 or 4 adverse effects vs 6 of 35 patients in the mycophenolate mofetil group (17%). Azathioprine therapy induced significantly elevated liver function test results compared with mycophenolate mofetil (P < .001). Importantly, patients in the azathioprine group showed significantly higher toxicity grades for aspartate aminotransferase (P = .03), alanine aminotransferase (P = .03), and gamma-glutamyltransferase (P = .01) than did those in the mycophenolate mofetil group. CONCLUSIONS: Mycophenolate mofetil or azathioprine demonstrate similar efficacy during treatment of bullous pemphigoid, and similar cumulative corticosteroid doses were given in both treatment arms to control disease. However, mycophenolate mofetil showed a significantly lower liver toxicity profile than azathioprine therapy.

Clinical manifestations of cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (CLE) is a chronic inflammatory autoimmune disease with a broad spectrum of clinical manifestations and a variable course. In numerous investigations, it has been shown that exogenous factors, such as UV-light and drugs, can induce this disease. However, not all clinical aspects can be explained and therefore, the pathogenesis of CLE is currently under extensive research. The various cutaneous manifestations of LE are divided into LE-nonspecific and LE-specific skin disease based on histologic criteria. LE-nonspecific manifestations are mostly associated with systemic LE but can also occur in other diseases and include particularly vascular skin lesions such as pe-riungual telangiectases. LE-specific skin disease includes the subtypes of CLE such as acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE), chronic cutaneous LE (CCLE), and intermittent CLE (ICLE). The subdivision of these subtypes with different prognosis and course is supported by genetic, clinical, histologic, and immunoserologic findings. The subtypes of CLE require a specific morphological and clinical analysis, which is described in the first part of this review. In the second part of this review, further diagnostic procedures and therapeutic strategies in patients with CLE are discussed.

Topical tacrolimus as a therapeutic adjunct in patients with cutaneous lupus erythematosus. A report of three cases.

The topical therapy of cutaneous lupus erythematosus (LE) consists mainly of corticosteroids which may lead to significant side effects when overused. We report the efficacy of topical tacrolimus as a therapeutic adjunct in 3 patients with cutaneous LE of the face. All patients, 1 with systemic LE and a malar rash, 1 with annular subacute cutaneous LE, the other with a papular variant of subacute cutaneous LE, experienced significant improvement following application of tacrolimus ointment. Treatment with topical tacrolimus was tolerated well without major side effects in all patients. The presented cases are in line with recent reports that topical tacrolimus may be effective in facial LE.