Efficacy and safety of rituximab in pemphigus: experience of the German Registry of Autoimmune Diseases.

BACKGROUND: Rituximab has been reported to be effective in various small case series of patients with severe and/or refractory pemphigus. However, no systematic evaluation is available to corroborate this observation. The aim of this study was to systematically determine efficacy and safety of rituximab in treatment-resistant pemphigus. PATIENTS AND METHODS: Multicenter retrospective, observational study of 36 patients with severe pemphigus vulgaris (n = 33) and pemphigus foliaceus (n = 3) treated with rituximab before August 31(st) , 2008 and enrolled in a national observational registery between December 2008 and June 2009. RESULTS: Within a mean period of observation of 11 (1-37) months, 21 (58 %) pemphigus patients showed complete, 13 (36 %) partial, and 2 (6 %) no response to rituximab treatment. This correlates with a mean improvement of the visual analog scale for well-being of 34 (20-60) at baseline to 75 (40-95) at the last control visit. In 4 (11 %) patients, severe adverse events were recorded including 1 (3 %) serious infection. CONCLUSIONS: Data collected in this systematic registry indicate that rituximab is an effective and relatively safe adjuvant treatment option for refractory pemphigus. To further extend our knowledge on efficacy and safety of this drug, controlled prospective trials are required.

Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts.

Our scientific knowledge of bullous pemphigoid (BP) has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in BP. A major obstacle in sharing multicenter-based evidences for therapeutic efforts is the lack of generally accepted definitions for the clinical evaluation of patients with BP. Common terms and end points of BP are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. These recommendations from the International Pemphigoid Committee represent 2 years of collaborative efforts to attain mutually acceptable common definitions for BP and proposes a disease extent score, the BP Disease Area Index. These items should assist in the development of consistent reporting of outcomes in future BP reports and studies.

Efficacy of pimecrolimus 1% cream in the long term management of atopic hand dermatitis. A double-blind RCT.

BACKGROUND: Efficacy and steroid sparing effects of pimecrolimus 1% cream in atopic dermatitis have been shown recently, but there is no data on efficacy in long term management of atopic hand dermatitis. This study aims to investigate the efficacy of pimecrolimus 1% cream as maintenance therapy in patients suffering from atopic hand dermatitis. PATIENTS AND METHODS: A double-blind vehicle controlled study in 40 adult patients with atopic hand dermatitis (IGA ≤ 3) comparing the efficacy of twice daily application of pimecrolimus 1% cream given as maintenance treatment versus vehicle over a 8 week period after clinical response (IGA ≤ 2) to a 1-3 week pre-treatment with mometasone fuorate 0.1% was performed. Primary endpoint was the time to relapse (IGA ≥ 3). RESULTS: Thirty-six out of 40 patients were randomised to receive either pimecrolimus 1% (P) or vehicle cream (V). The number of patients with stable remission in patients randomised to pimecrolimus (53.8%) and vehicle (43.8%) did not achieve statistical significance between the groups (p = 0.41). Subgroup analysis of patients with initially moderate dermatitis (IGA = 3, n = 20) showed a trend towards a better outcome for the pimecrolimus group (stable remission P = 81.8% versus V = 55.6%) (p = 0.244). CONCLUSIONS: Pimecrolimus 1% cream twice daily was not superior to vehicle in the sequential maintenance therapy of atopic hand dermatitis, but efficacy in moderate forms should be investigated in further studies.

Immunosuppressive therapy for autoimmune bullous diseases.

Adjuvant immunosuppressive drugs are widely used to minimize corticosteroid-related adverse effects in the short-term and long-term management of cautoimmune bullous diseases. In bullous pemphigoid and pemphigus vulgaris, azathioprine and mycophenolate mofetil seem to be equally effective when used in combination with oral corticosteroids, but mycophenolate mofetil is less myelosuppressive and hepatotoxic. Due to a better safety profile, mycophenolate mofetil or enteric-coated mycophenolate sodium may gradually replace azathioprine as the first-line adjuvant of choice in the treatment of moderate to severe autoimmune bullous diseases, including epidermolysis bullosa acquisita and cicatricial pemphigoid. Cyclophosphamide still has a place in the treatment of severe relapsing autoimmune bullous diseases. Continuous oral cyclophosphamide provides optimal immunosuppression, but it also produces the highest cumulative dose. Several pulsed cyclophosphamide regimens have, therefore, been developed and are reported to be effective in severe forms of pemphigus. Randomized controlled studies are needed to compare the efficacy and safety of cyclophosphamide with newer treatment options, such as rituximab and immunoapheresis, and to define optimal dose ranges and duration of available immunosuppressive treatments in different stages of autoimmune bullous diseases.

Frequency of disease-associated and other nuclear autoantibodies in patients of the German Network for Systemic Scleroderma: correlation with characteristic clinical features.

INTRODUCTION: In the present study, we analysed in detail nuclear autoantibodies and their associations in systemic sclerosis (SSc) patients included in the German Network for Systemic Scleroderma Registry. METHODS: Sera of 863 patients were analysed according to a standardised protocol including immunofluorescence, immunoprecipitation, line immunoassay and immunodiffusion. RESULTS: Antinuclear antibodies (ANA) were detected in 94.2% of patients. In 81.6%, at least one of the autoantibodies highly associated with SSc or with overlap syndromes with scleroderma features was detected, that is, anti-centromere (35.9%) or anti-topoisomerase I (30.1%), followed in markedly lower frequency by antibodies to PM-Scl (4.9%), U1-ribonucleoprotein (U1-RNP) (4.8%), RNA polymerases (RNAPs) (3.8%), fibrillarin (1.4%), Ku (1.2%), aminoacyl-transfer RNA synthetases (0.5%), To (0.2%) and U11-RNP (0.1%). We found that the simultaneous presence of SSc-associated autoantibodies was rare (1.6%). Furthermore, additional autoantibodies were detected in 55.4% of the patients with SSc, of which anti-Ro/anti-La, anti-mitochondrial and anti-p25/p23 antibodies were most frequent. The coexistence of SSc-associated and other autoantibodies was common (43% of patients). SSc-associated autoantibodies disclosed characteristic associations with clinical features of patients, some of which were previously not acknowledged. CONCLUSIONS: This study shows that five autoantigens (that is, centromere, topoisomerase I, PM-Scl, U1-RNP and RNAP) detected more than 95% of the known SSc-associated antibody responses in ANA-positive SSc patients and characterise around 79% of all SSc patients in a central European cohort. These data confirm and extend previous data underlining the central role of the determination of ANAs in defining the diagnosis, subset allocation and prognosis of SSc patients.

Up-regulation of the chemokine CCL18 by macrophages is a potential immunomodulatory pathway in cutaneous T-cell lymphoma.

Mycosis fungoides (MF) is the most frequent form of cutaneous T-cell lymphoma (CTCL), which can deteriorate from patch stage to dermal-based tumors and systemic involvement in years. The interaction of chemokines in the skin with CTCL cells might have implications for the pathogenesis of the disease. In this study, we show by PCR analysis and immunofluorescence staining that the chemokine CCL18 is present in skin biopsy specimens of patients with MF and its precursor form parapsoriasis en plaque but not in healthy tissue. In addition, the serum levels of CCL18 were increased threefold in MF patients compared with those in healthy controls. In skin, CCL18 was specifically expressed by CD163(+) CD209(+) macrophages at the invasive margin of the tumor and not expressed by mature CD208(+) dendritic cells in the center of the tumor. The chemokine CCL17 was, by contrast, ubiquitously expressed. Furthermore, CCL18 promoted the chemotaxis but not the proliferation of CTCL cells. CCL18 inhibited proliferation of tumor cells and abolished the CXCL12-induced growth of a CTCL cell line. These data link the increased expression of CCL18 with CTCL and suggest an immunomodulatory effect of the chemokine in the pathogenesis of CTCL.

Evaluation of the atrophogenic potential of hydrocortisone 1% cream and pimecrolimus 1% cream in uninvolved forehead skin of patients with atopic dermatitis using optical coherence tomography.

Topical corticosteroids are widely used to treat atopic dermatitis (AD), but their anti-inflammatory mode of action can be accompanied by several unwanted side effects including skin atrophy and telangiectasia. In this 8-week, investigator-blinded, intraindividual right-left comparison study with patients with mild-to-moderate AD, hydrocortisone 1% cream (HCT) was applied twice daily for 4 weeks on one side of forehead skin without clinical signs of AD and pimecrolimus 1% cream (PIM) on the other. Epidermal and dermal thickness were assessed by optical coherence tomography (OCT) and high-frequency ultrasound, respectively. Skin atrophy and telangiectasia were assessed by contact dermatoscopic photography (Dermaphot(®)). Treatment with HCT leads to a significant decrease in epidermal thickness after only 2 weeks of treatment, while the decrease in PIM-treated sites was less pronounced and was not statistically significant. By 4 weeks after the end of treatment, epidermal thickness returned to baseline values. No dermal thinning or development of telangiectasia could be observed by means of ultrasound or Dermaphot(®), respectively. In summary, this study indicates that a 2-week single course of topical treatment with a mildly potent steroid can cause transient epidermal thinning, an effect not seen in the PIM group. The slight decrease with PIM - although not significant - could be due to normalization of the increased skin thickness caused by a subclinical inflammation in AD. This study suggests that PIM may be safer for treatment of AD in sensitive skin areas like the face, especially when repeated application is required.

Efficacy and safety of omalizumab in patients with chronic urticaria who exhibit IgE against thyroperoxidase.

BACKGROUND: A subgroup of patients with chronic spontaneous urticaria (CU) exhibits IgE antibodies directed against autoantigens, such as thyroperoxidase (TPO). We conducted this study to investigate whether such patients with CU with IgE against TPO benefit from treatment with omalizumab, a humanized anti-IgE mAb licensed for the treatment of severe persistent allergic (IgE-mediated) asthma. OBJECTIVES: We sought to assess the efficacy of omalizumab treatment in patients with CU with IgE autoantibodies against TPO. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study patients with CU (male/female, 18-70 years of age) with IgE autoantibodies against TPO who had persistent symptoms (wheals and pruritus) despite standard antihistamine therapy were randomized to receive either omalizumab (75-375 mg, dose determined by using the approved asthma dosing table) or placebo subcutaneously once every 2 or 4 weeks for 24 weeks. The primary end point was the change from baseline in mean weekly urticaria activity score after 24 weeks of treatment, as calculated from patients' diaries. The safety and tolerability of omalizumab were also assessed. RESULTS: Of the 49 randomized patients (omalizumab, n = 27; placebo, n = 22), 42 completed the study. At week 24, patients demonstrated a mean reduction in the weekly urticaria activity score from baseline of 17.8 with omalizumab and 7.9 with placebo (P = .0089). Complete protection from wheal development was observed in 19 (70.4%) patients in the omalizumab group compared with only 1 (4.5%) patient in the placebo group. The rate of adverse events was similar in both groups. CONCLUSIONS: The results of this study indicate that omalizumab is an effective treatment option for patients with CU with IgE autoantibodies against TPO who are refractory to conventional treatment.

Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID).

INTRODUCTION: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting. METHODS: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. RESULTS: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm). CONCLUSIONS: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.

Human slan (6-sulfo LacNAc) dendritic cells are inflammatory dermal dendritic cells in psoriasis and drive strong TH17/TH1 T-cell responses.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease that is considered to result from activated T cells stimulated by a population of inflammatory dermal dendritic cells (DCs). The origin and identity of these inflammatory dermal DCs are largely unknown. OBJECTIVE: We previously identified slanDCs (6-sulfo LacNAc) DCs as a rich source of TNF-α and as the early major source of IL-12. Here we studied the relevance of slanDCs as inflammatory dermal DCs in psoriasis. METHODS: Psoriasis skin samples were stained for the presence of activated slanDCs. Functional studies were carried out to determine the cytokine production of slanDCs, their T(h)17/T(h)1 T-cell programming, and their migration behavior. RESULTS: Large numbers of IL-23, TNF-α, and inducible nitric oxide synthase expressing slanDCs were found in psoriatic skin samples, which can be recruited by C5a, CX3CL1, and CXCL12. SlanDCs isolated from blood produced high levels of IL-1ß, IL-23, IL-12, and IL-6. Compared with classic CD1c(+) DCs, slanDCs were far more powerful in programming T(h)17/T(h)1 T cells that secrete IL-17, IL-22, TNF-α, and IFN-γ, yet CD1c(+) DCs induced a higher IL-10 production of T cells. Self-nucleic acids complexed to cathelicidin LL37 trigger endosomal Toll-like receptor (TLR) signaling (TLR7, TLR8, TLR9) and are key factors for the activation of DCs in psoriasis. We show that slanDCs respond particularly well to complexes formed of self-RNA and LL37. Similarly, slanDCs stimulated with a synthetic TLR7/8 ligand produced high levels of proinflammatory cytokines. CONCLUSION: Our study defines slanDCs as inflammatory dermal DCs in psoriasis and identifies their strong capacity to induce T(h)17/T(h)1 responses.

Addition of pimecrolimus cream 1% to a topical corticosteroid treatment regimen in paediatric patients with severe atopic dermatitis: a randomized, double-blind trial.

BACKGROUND: Pimecrolimus and topical corticosteroids (TCS) combination therapy may provide an alternative treatment for patients with severe atopic dermatitis (AD), with faster clearance of disease flares, consequently reducing the duration of TCS treatment. OBJECTIVE: To assess the safety profile of pimecrolimus cream 1% combined with fluticasone versus fluticasone alone in paediatric patients with severe AD. METHODS: Patients (n = 376) were randomized to a combination of pimecrolimus cream 1% with fluticasone or vehicle plus fluticasone for 4 weeks. The primary outcome measure was the frequency of clinically relevant pre-defined adverse events (AEs) associated with the topical use of corticosteroids in patients with severe AD. RESULTS: Erythematous rash was the only AE, occurring more frequently in the combination group, while there were no noticeable differences in the frequency of other AEs of clinical interest between treatment groups. Efficacy variables were comparable between the two groups. A trend for greater time to relapse was observed for the combination of pimecrolimus cream 1% with fluticasone in patients who were clear at the end of treatment, with a marked improvement in facial AD. CONCLUSION: In paediatric patients with severe AD the overall safety profile of pimecrolimus cream 1% combined with fluticasone was similar to that of fluticasone alone.

Vitamin D metabolism.

Irradiation of human skin with ultraviolet B (280-320 nm) initiates the photochemical conversion of 7-dehydrocholesterol via previtamin D3 to vitamin D3. Vitamin D3 needs for its activation two hydroxylation steps in the liver and kidney. The final product, hormonally active 1alpha,25-dihydroxyvitamin D3 (calcitriol), arrives via the circulation to its target tissues and acts in a genomic or nongenomic manner. It has been found that human skin irradiated with ultraviolet B also is able to produce calcitriol in substantial amounts. This cutaneous vitamin D3 pathway is unique and, most likely, of considerable relevance for healthy and diseased skin. It is well known that topical application of calcitriol and its analogs can improve hyperproliferative skin diseases. Some studies have convincingly demonstrated that calcitriol and other vitamin D analogs may also be used for the treatment of immunological, inflammatory, and infectious skin diseases. More recently, it has been found that calcitriol or vitamin D analogs have photoprotective effects and can reduce UV-induced deoxyribonucleic acid damage.

Conversion of vitamin D3 to hormonally active 1alpha,25-dihydroxyvitamin D3 in cultured keratinocytes: relevance to cell growth and differentiation.

The regulatory potential of intracellularly generated calcitriol on growth and differentiation of cultured keratinocytes is determined by the degree of cell confluence and availability of the highly lipophilic substrate vitamin D3 to these cells. The enzymatic conversion of vitamin D3 to calcitriol is considerably elevated in the presence of the nontoxic surfactant copolymer pluronic F127 (120 microg/ml medium) compared to the control without this agent. We found a positive correlation between the formation rate of calcitriol and inhibition of the 3H-thymidine incorporation rate into the DNA of keratinocytes. Intracellularly generated calcitriol causes a clear increase of the cell diameter, and thus has a prodifferentiating effect on keratinocytes in vitro. These findings corroborate the hypothesis that UVB-induced production of vitamin D3 in human skin results in formation of substantial amounts of calcitriol in keratinocytes which suppress the growth and initiate differentiation of these cells.

Lipidome of narrow-band ultraviolet B irradiated keratinocytes shows apoptotic hallmarks.

BACKGROUND: UV light triggers a variety of biological responses in irradiated keratinocytes that might be associated with global perturbation of their lipidome. However, lipids that are specifically affected and the exact molecular mechanisms involved remain poorly understood. OBJECTIVES: To characterize time-dependent changes of the lipidome of cultured keratinocytes induced by narrow-band ultraviolet B (NB-UVB) irradiation. METHODS: Immortalized human keratinocytes (HaCaT) were cultured under standard conditions, irradiated with NB-UVB light (311 nm) at 400 and 800 mJ/cm(2) and collected 1, 2, 3, 6, 12 and 24 h later for lipid extraction. Lipid extracts were separated on silica plates in chloroform/ethanol/water/triethylamine (35:40:9:35) and in n-hexane/ethylacetate (5:1) followed by quantitative shotgun lipidomics analysis. RESULTS: Irradiation with 800 mJ/cm(2) of NB-UVB altered morphology and lipidome composition of HaCaT cells. Ceramide content increased two-fold 6- and 12-h postirradiation with 800 mJ/cm(2), followed by threefold increase in triacylglycerols (TAGs) that peaked at 24 h. In addition, we observed marked increase of various phosphatidylcholine and phosphatidylethanolamine ethers, whereas phosphatidylcholine-species with short-chain fatty acid moieties decreased. The abundance of other lipid species was altered to lesser extent or remained unchanged. CONCLUSIONS: NB-UVB affected the cellular lipidome of keratinocytes in strictly apoptosis-specific manner.

Early exposure to antibiotics and infections and the incidence of atopic eczema: a population-based cohort study.

It has been suggested that infants exposed to antibiotics are at increased risk for atopic eczema (AE), whereas the early exposure to infections might be protective. This study describes the complex relationship between early exposure to infections, anti-infectious treatment with antibiotics, and incident AE. Using a German population-based administrative health-care and prescription database, we established a cohort of 370 children not diagnosed as having AE during their first year of life. For each individual child we identified all infections and prescriptions of antibiotics within the first year as well as incident AE within the second year of life. Crude analyses suggested that early infections and exposure to antibiotics are risk factors for AE. However, stratified analyses indicated that early infections were only associated with a higher rate of AE when treated with broad-spectrum antibiotics such as cephalosporines or macrolides. The risk ratio (RR) of children with early respiratory tract infections not treated with antibiotics was 0.69 [95% confidence interval (95% CI) 0.39 to 1.24], whereas respiratory tract infections treated with macrolides (RR: 2.15, 95% CI: 1.18-3.91) or cephalosporines (RR: 1.93, 95% CI: 1.07-3.49) significantly increased the risk for AE. The results for other common childhood infections tended to be similar. Antibiotic treatment appears to modify the association between early infections and subsequent AE. We found no evidence that infections per se significantly alter the likelihood for subsequent AE.

Use of high-dose immunoglobulins in dermatology.

The treatment of severe autoimmune skin diseases and of toxic epidermal necrolysis (ICD: L51.2) with high-dose intravenous immunoglobulins (IVIg) is an established therapeutic procedure in dermatology. As IVIg are usually only administered in rare autoimmune diseases or in particularly severe disease courses, use of immunoglobulins in dermatology is commonly not based on experience from controlled and randomized studies typically demanded by evidence-based medicine. In face of the rarity of indications for IVIg it is improbable that such studies will be performed in the foreseeable future. Further, as the high costs of IVIg treatment limits its use as first-line therapy, no clear guidelines exist yet on IVIg use in skin diseases. The present recommendation is based on a consensus of the Working Group on European Guidelines of the EDF (European Dermatology Forum) and the EADV (European Association of Dermato-Venereology) and should provide aid in decision making for the use of IVIg in treating dermatologic diseases

Effects of the introduction of the German "Praxisgebühr" on outpatient care and treatment of patients with atopic eczema.

BACKGROUND: The introduction of a co-payment of 10 Euros per quarter and physician for adults (the so called "Praxisgebühr") as of January 01, 2004 was a significant health policy measure with unknown effects on medical care of patients with atopic eczema (AE). METHODS: Analysis of an administrative healthcare database from Saxony, Germany. Comparison of outpatient care and treatment of 11,036 patients with AE (6,696 adults) in the year before (2003) and after (2004) the introduction of the co-payment using descriptive statistics and logistic regression modeling. RESULTS: The proportion of adults with AE treated by dermatologists decreased from 52.8 % in 2003 to 42.3 % in the year after the co-payment was introduced. Consultations of general practitioners by adults and health services utilization by children/adolescents did not change. Treatment with topical calcineurin inhibitors in 2003 was an independent predictor for re-consultation in 2004 (p < 0.001). The proportion of adults receiving systemic steroids for AE significantly increased in 2004 (males: 2003: 5.9 %, 2004: 10.3 %, p < 0.001; females: 2003: 5.7 %, 2004: 8.2 %, p < 0.001). The risk for treatment with systemic steroids increased with the decrease in consulting frequency due to AE relative to 2003 (p = 0.006). CONCLUSIONS: After the introduction of the German "Praxisgebühr" fewer patients with AE received dermatological treatment. Simultaneously, an unexpectedly significant increase in the (non evidence-based) treatment of AE with systemic steroids was observed, of which patients with relatively lower consultation frequency after the introduction of the co-payment were particularly affected.