Streptobacillus moniliformis and IgM and IgG Immune Response in Patient with Endocarditis1.

We describe a case of endocarditis caused by Streptobacillus moniliformis bacteria, a known cause of rat-bite fever, in a 32-year-old woman with pet rats in Germany. The patient had a strong serologic response, with high IgM and IgG titers. Serologic analysis is a promising tool to identify S. moniliformis bacterial infection.

Efficacy and safety of adjuvant immunoadsorption in pemphigus vulgaris and pemphigus foliaceus (IA-Pem Study): a multicentre randomized controlled trial.

BACKGROUND: Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are potentially life-threatening autoimmune blistering diseases. Treatment is based on long-term immunosuppression with high doses of glucocorticosteroids in combination with potentially corticosteroid-sparing agents and/or rituximab. Immunoadsorption (IA) has emerged as a fast-acting adjuvant treatment option. OBJECTIVES: To assess the clinical efficacy of IA in addition to best medical treatment (BMT). METHODS: We conducted a multicentre (26 centres from Germany and Austria) randomized controlled trial in 72 patients with newly diagnosed, relapsed or chronic active PV or PF (34 female patients and 38 male patients, aged 42-72 years) comparing BMT (prednisolone 1.0 mg kg-1 per day plus azathioprine or mycophenolate) with adjuvant IA (BMT + IA). Central 1 : 1 randomization was done at the coordinating centre for clinical trials (KKS Marburg). The primary endpoint was analysed using Kaplan-Meier and Cox regression methods. RESULTS: The study was ended prematurely owing to safety concerns after random allocation of 72 patients to BMT + IA (n = 34) or BMT (n = 38). The primary endpoint, time to complete remission on therapy, was not significantly different for the two groups [hazard ratio (HR) 1.35, 95% confidence interval (CI) 0.68-2.69; P = 0.39]. The cumulative dose of prednisolone was significantly lower in the BMT + IA group compared with BMT alone (difference -1214, 95% CI -2225 to -70; P = 0.03). In a post hoc analysis, patients with more extensive PV/PF showed a tendency towards a shorter time to remission in the BMT + IA group compared with the BMT group (HR 1.87, P = 0.17 in patients with baseline Pemphigus Disease Area Index ≥ 15). While more adverse events were observed in patients in the BMT group (29 vs. 25), severe adverse events were more frequent in patients in the BMT + IA group (17 events in 10 patients vs. 11 events in 8 patients). CONCLUSIONS: In this study, adjuvant IA did not demonstrate a shorter time to clinical remission, but a corticosteroid-sparing effect was observed. In patients with extensive PV/PF, post hoc analysis suggests that adjuvant IA may lead to earlier remission, but potential adverse events must be carefully weighed against the expected benefits.

Pemphigus vulgaris and pemphigus foliaceus are potentially life-threatening autoantibody-driven blistering diseases, which present with erosions or blisters on skin and/or mucous membranes. Treatment is based on long-term immunosuppressive agents. Immunoadsorption (IA) is a procedure that removes autoantibodies from the blood and has emerged as a fast-acting treatment option for pemphigus.We conducted a trial comparing best medical treatment (BMT) (prednisolone 1.0 mg kg per day plus azathioprine or mycophenolate) with best medical treatment plus IA (BMT + IA). A total of 26 centres from Germany and Austria recruited 72 patients with active pemphigus (34 women and 38 men, aged 42­72 years) who were randomly allocated in a ratio of 1 : 1 to the treatment groups.Following inclusion of 72 patients in the BMT + IA (n = 34) or BMT (n = 38) groups, the study ended prematurely owing to safety concerns. The main outcome, time to complete remission (relief of all symptoms) while still receiving therapy, was not significantly different for the two groups. In contrast, the cumulative dose of prednisolone was significantly lower in the BMT + IA compared with BMT alone. In an additional analysis, patients with more extensive pemphigus showed a tendency towards a shorter time to remission in the BMT + IA group compared with the BMT group. While more adverse events were observed in the BMT group (29 vs. 25), severe adverse events were more frequent in the BMT + IA group (17 vs. 11). In this study, IA did not show a shorter time to clinical remission, but a prednisolone-sparing effect was observed. In patients with extensive pemphigus, adjuvant IA may possibly lead to earlier remission, but potential adverse events must be carefully weighed against the expected benefits.

Increasing hospitalisation of patients with herpes zoster ophthalmicus-an interdisciplinary retrospective analysis.

BACKGROUND: The occurrence of herpes zoster is rising globally. Future trends will be influenced by changes in population demographics and the growing number of patients at risk. Overall this poses a challenge for healthcare systems. METHODS: In our interdisciplinary, single-centre retrospective analysis, we aimed to assess the burden of the disease within the Department of Dermatology and the Eye Centre from the Medical Centre, University of Freiburg from 2009-2022. We obtained data from 3034 cases coded using the ICD-10 B02.x. Patients were characterised by sex, age, year of treatment, and type of treatment (inpatient vs. outpatient). RESULTS: Overall we observed a 200% increase in the number of herpes zoster patients over the 13-year period. Upon closer analysis, this was mainly due to a rise in inpatient treatment for herpes zoster ophthalmicus. CONCLUSIONS: If the incidence of herpes zoster ophthalmicus continues to increase at the current rate the number of hospitalisations of zoster ophthalmicus would double by 2040, assuming guideline-appropriate treatment. Overall, the results show a growing need for inpatient ophthalmological care.

Remission of refractory esophageal lichen planus induced by tofacitinib.

As of now, there exists no established therapy for ELP. Retinoids, which are standard in treating cutaneous LP, do not exhibit positive effects in ELP. While topical glucocorticosteroids often yield favorable responses in esophageal inflammation, some cases prove recalcitrant or refractory. In such instances, various immunosuppressive therapies have been attempted with variable success.This report details a severe case of ELP that showed resistance to prednisolone, acitretin, alitretinoin, adalimumab, tacrolimus, hydroxychloroquine plus mycophenolate mofetil, and cyclophosphamide. The initiation of the JAK inhibitor tofacitinib induced an impressive clinical, endoscopic, and histological remission. This positive response to a JAK inhibitor is discussed in the context of our evolving understanding of the immune-mediated pathogenesis of this disease.

Efficacy and safety of Oleogel-S10 (birch triterpenes) for epidermolysis bullosa: results from the phase III randomized double-blind phase of the EASE study.

BACKGROUND: Epidermolysis bullosa (EB) is a heterogeneous group of rare, difficult-to-treat, inherited multisystem diseases affecting epithelial integrity. Patients with EB are affected by mechanical fragility of epithelial surfaces including the skin and, as a result, extensive recurrent blistering is a characteristic of the condition. Chronic wounds predispose patients with EB to the development of squamous cell carcinoma, which is a major cause of premature death. OBJECTIVES: EASE was a double-blind, randomized, vehicle-controlled, phase III study to determine the efficacy and safety of the topical gel Oleogel-S10 (birch triterpenes) in EB. EASE was funded by Amryt Research Limited. METHODS: Patients with dystrophic EB, junctional EB or Kindler EB and a target partial-thickness wound lasting ≥ 21 days and < 9 months that was 10-50 cm2, were enrolled and randomized via computer-generated allocation tables 1 : 1 to Oleogel-S10 or control gel - both with standard-of-care dressings. Study gel was applied to all wounds at least every 4 days. The primary endpoint was the proportion of patients with first complete closure of target wound within 45 days. RESULTS: A total of 223 patients were enrolled and treated (109 treated with Oleogel-S10, 114 with control gel). The primary endpoint was met; Oleogel-S10 resulted in 41·3% of patients with first complete target wound closure within 45 days, compared with 28·9% in the control gel arm (relative risk 1·44, 95% confidence interval (CI) 1·01-2·05; P = 0·013). Adverse events (AEs) occurred with similar frequency for Oleogel-S10 (81·7%) compared with control gel (80·7%). AEs were predominantly of mild-to-moderate intensity (4·6% were severe). CONCLUSIONS: Oleogel-S10 is the first therapy to demonstrate accelerated wound healing in EB. Oleogel-S10 was well -tolerated.

[Esophageal Lichen Planus - An Underdiagnosed Disease]. / Der Lichen planus des Ösophagus ­ Eine unterschätzte Erkrankung.

An involvement of the esophagus in patients with lichen planus was described for the first time in 1982. Ever since, it has been seen as a rarity. However, studies over the last 10 years have shown a higher prevalence than expected. It may even be supposed that esophageal lichen planus (ELP) is more common than eosinophilic esophagitis. ELP mostly affects middleaged women. The principal symptom is dysphagia. Endoscopically, ELP is characterized by denudation and tearing of the mucosa, trachealization and hyperkeratosis and esophageal stenosis may occur in patients with long courses of the disease. Histologic findings including mucosal detachment, T-lymphocytic infiltrate, intraepithelial apoptosis (civatte bodies) and dyskeratosis are crucial. Direct immunofluorescence shows fibrinogen deposits along the basement membrane zone. So far, there is no well-established therapy but a treatment with topic steroids is effective in 2/3 of the patients. Common therapy of lichen planus of the skin seems to be ineffective for treatment of ELP. Symptomatic esophageal stenosis should be endoscopically dilated. ELP joins the group of "new" immunologic diseases of the esophagus.

[Esophageal Lichen Planus - an Underdiagnosed Disease]. / Der Lichen planus des Ösophagus ­ Eine unterschätzte Erkrankung.

An involvement of the esophagus in patients with lichen planus was described for the first time in 1982. Ever since, it has been seen as a rarity. However, studies over the last 10 years have shown a higher prevalence than expected. It may even be supposed that esophageal lichen planus (ELP) is more common than eosinophilic esophagitis. ELP mostly affects middle-aged women. The principal symptom is dysphagia. Endoscopically, ELP is characterized by denudation and tearing of the mucosa, trachealization and hyperkeratosis and esophageal stenosis may occur in patients with long courses of the disease. Histologic findings including mucosal detachment, T-lymphocytic infiltrate, intraepithelial apoptosis (civatte bodies) and dyskeratosis are crucial. Direct immunofluorescence shows fibrinogen deposits along the basement membrane zone. So far, there is no well-established therapy but a treatment with topic steroids is effective in 2/3 of the patients. Common therapy of lichen planus of the skin seems to be ineffective for treatment of ELP. Symptomatic esophageal stenosis should be endoscopically dilated. ELP joins the group of "new" immunologic diseases of the esophagus.

Use and importance of different information sources among patients with rare diseases and their relatives over time: a qualitative study.

BACKGROUND: Finding reliable information on one of more than 7000 rare diseases is a major challenge for those affected. Since rare diseases are defined only by the prevalence criterion, a multitude of heterogeneous diseases are included. Common to all, however, are difficulties regarding information access. Even though various quantitative studies have analyzed the use of different information sources for specific rare diseases, little is known about the use of information sources for different rare diseases, how users rate these information sources based on their experiences, and how the use and importance of these information sources change over time. METHODS: Fifty-five patients with a variety of rare diseases and 13 close relatives participated in qualitative interviews. For these interviews, a semi-structured guideline was developed, piloted, and revised. Data analysis involved a qualitative content analysis developed by Philipp Mayring. RESULTS: The participants considered internet as the most important and widespread information source, especially for early information. Although patients have difficulty dealing with information obtained online, they consider online searching a quick and practical option to gather information. During the course of the disease, personal contact partners, especially self-help associations and specialized doctors, become more important. This is also because information provided online is sometimes insufficiently detailed to answer their information needs, which can be complemented by information from doctors and self-help. CONCLUSIONS: People rarely use just one type of source, but rather refer to different sources and informants. The source used depends on the type of information sought as well as other person-related factors such as preexisting knowledge and the disease stage. To improve people's information searching and connect them with medical specialists in rare diseases, a central information portal on rare diseases might be a suitable access point to provide free and quality assured information for patients, caregivers, and physicians. This would allow not only patients but also doctors to find quality assured information on symptoms and therapies as well as patient associations and specialized doctors.

Esophageal lichen planus: towards diagnosis of an underdiagnosed disease.

Background: Although lichen planus (LP) is a common skin disorder, the prevalence of esophageal involvement (ELP) and its clinical manifestations are poorly defined. We aimed to establish diagnostic criteria and characterize disease outcomes of ELP.Methods: Clinical, endoscopic, histological, and immunofluorescence data from consecutive patients with known LP between 2013 and 2018 were analyzed. We established endoscopic (denudation and tearing of the mucosa, hyperkeratosis and trachealization) and histological criteria (mucosal detachment, T-lymphocytic infiltrate, intraepithelial apoptosis, dyskeratosis, and fibrinogen deposits along the basement membrane) to grade disease severity. Endoscopic findings were correlated with clinical symptoms. Response to medical therapy was monitored.Results: Fifty-two consecutive patients (median age 59.5 years) were analyzed. According to our grading system, 16 patients were considered as severe and 18 as mild ELP. Dysphagia was the only symptom which differentiated patients with severe (14/16) or mild ELP (8/18) from patients without ELP (1/18). Concomitant oral and genital involvement of LP was associated with the presence of ELP, while oral involvement alone was not. Follow-up of 14/16 patients with severe EPL for at least one year revealed that most of these patients responded to topical corticosteroids (budesonide: n = 9/10 or fluticasone n = 2/2). Three budesonide patients experienced a resolution of symptomatic esophageal stenosis.Conclusions: Esophageal involvement of LP is frequent, but may be asymptomatic. ELP can be diagnosed using the diagnostic criteria proposed here. Dysphagia and combined oral and genital manifestation are associated with ELP. Therapy with topical corticosteroids appears to be a prudent therapeutic approach for ELP.

[Autoimmune blistering dermatoses in children]. / Bullöse Autoimmundermatosen im Kindesalter.

Autoimmune blistering skin disorders represent a rare group of autoantibody-induced dermatoses against desmosomal and hemidesmosomal molecules. The common age of onset for pemphigus and pemphigoid, as well as dermatitis herpetiformis, encompasses the adult age, but all these disorders can be observed neonatally and/or during childhood. If the disease occurs postpartum or neonatally, physicians should consider transplacental transmission of pathogenic maternal immunoglobulin G (IgG)-autoantibodies, and both mother and child should be included in the diagnostic work up. If the disorder is suspected in childhood, early immunoserological testing and skin biopsies for direct immunofluorescence analyses are recommended for the correct diagnosis and subsequently for the right choice of treatment. First-line recommendations are nonhalogenated topical steroids, followed by oral dapsone. All therapies require preliminary examinations, e. g. enzyme-activity testing (as is glucose-6-phophate dehydrogenase in dapsone treatment). In refractory cases, further treatment choices like high-dose intravenous immunoglobins, plasmapheresis/immunoadsorption or targeted therapies like anti-CD20 autoantibody therapies are indicated. An intense dermatological support and good medical care are essential for an age-appropriate development of the child and to lower possible treatment-associated adverse events.

Skin inflammation associated with arthritis, synovitis and enthesitis. Part 2: rheumatoid arthritis, reactive arthritis, Reiter's syndrome, Lyme borreliosis, dermatomyositis and lupus erythematosus.

Syndromes associated with concurrent skin and joint inflammation frequently pose a therapeutic challenge for both dermatologists and rheumatologists. In part 1 of this review, we discussed psoriatic arthritis as well as the autoinflammatory disorders SAPHO syndrome, Still's disease and Behçet's disease. Part 2 will address rheumatoid arthritis, reactive arthritis, Reiter's syndrome and Lyme borreliosis. In addition, we will discuss dermatomyositis and lupus erythematosus, two common autoimmune disorders that frequently present with both cutaneous and joint involvement. For each of the aforementioned disorders, we will highlight aspects of epidemiology, pathogenesis, clinical presentation, diagnosis and treatment.

Skin inflammation associated with arthritis, synovitis and enthesitis. Part 1: psoriatic arthritis, SAPHO syndrome, Still's disease, Behçet's disease.

The coincidence of skin and joint inflammation poses a challenge for both dermatologists and rheumatologists. Adequate management of such disorders requires that physicians of both specialties have sound knowledge of the other discipline. In case of suspected joint involvement, familiarity with the diagnostic options available to rheumatologists enables dermatologists to selectively refer their patients for a rheumatology consult. The objective of the present review is to familiarize the reader with the stepwise diagnostic workup performed by rheumatologists today, including laboratory tests, musculoskeletal ultrasound, X-ray studies, and magnetic resonance imaging. Subsequently, we will discuss a number of disorders characterized by the concurrence of skin and joint inflammation, highlighting aspects of epidemiology, etiology and pathogenesis, clinical presentation, diagnosis and treatment. These disorders include psoriatic arthritis as well as autoinflammatory disorders such as SAPHO syndrome, Still's disease and Behçet's disease.

Everolimus-associated perianal ulcers in an eight-month-old heart transplant recipient.

mTOR inhibitors have a wide spectrum of therapeutic applications in adults and children. Little is known, however, about serious adverse effects in children undergoing mTOR inhibitor therapy. Oral ulcers are common and sometimes severe, but no other gastrointestinal involvement has been reported so far. Here we present a case of everolimus-associated perianal ulcers in an eight-month-old infant, 3 months after heart transplantation, which necessitated the drug's discontinuation. In a thorough series of diagnostic tests, we identified no other cause for the progressive perianal ulceration. The recognition and appropriate management of mTOR inhibitors' adverse effects in pediatric patients are essential and remain challenging.

The Position of Targeted Next-generation Sequencing in Epidermolysis Bullosa Diagnosis.

The precise classification of epidermolysis bullosa (EB) into 4 main types and more than 30 subtypes is based on the level of skin cleavage, as well as clinical and molecular features, and is crucial for early prognostication, case management, genetic counselling and prenatal or pre-implantation diagnosis. We report here the molecular pathology of 40 consecutive cases of suspected EB, which were investigated by immunofluorescence mapping (IFM) and/or by a targeted next-generation sequencing (NGS) multi-gene panel. IFM correctly established the EB subtype in 76% of cases, while the molecular pathology was completely elucidated in 90% of cases by the targeted NGS multi-gene panel. Thirteen previously unreported mutations in EB genes were identified. In cases with unclear clinical and IFM findings, mutations were found by NGS in previously unexpected genes. IFM was useful in delivering fast results in newborns, and in indicating the consequences of the variants of uncertain significance on protein level. This study underscores the efficacy of the strategy of combining targeted NGS with IFM in resolving unusual EB phenotypes. It also suggests that, despite technological advances, careful clinical evaluation and deep phenotyping remains a crucial factor that dictates successful diagnosis of EB.

Telephone health services in the field of rare diseases: a qualitative interview study examining the needs of patients, relatives, and health care professionals in Germany.

BACKGROUND: Rare diseases are, by definition, very serious and chronic diseases with a high negative impact on quality of life. Approximately 350 million people worldwide live with rare diseases. The resulting high disease burden triggers health information search, but helpful, high-quality, and up-to-date information is often hard to find. Therefore, the improvement of health information provision has been integrated in many national plans for rare diseases, discussing the telephone as one access option. In this context, this study examines the need for a telephone service offering information for people affected by rare diseases, their relatives, and physicians. METHODS: In total, 107 individuals participated in a qualitative interview study conducted in Germany. Sixty-eight individuals suffering from a rare disease or related to somebody with rare diseases and 39 health care professionals took part. Individual interviews were conducted using a standardized semi-structured questionnaire. Interviews were analysed using the qualitative content analysis, triangulating patients, relatives, and health care professionals. The fulfilment of qualitative data processing standards has been controlled for. RESULTS: Out of 68 patients and relatives and 39 physicians, 52 and 18, respectively, advocated for the establishment of a rare diseases telephone service. Interviewees expected a helpline to include expert staffing, personal contact, good availability, low technical barriers, medical and psychosocial topics of counselling, guidance in reducing information chaos, and referrals. Health care professionals highlighted the importance of medical topics of counselling-in particular, differential diagnostics-and referrals. CONCLUSIONS: Therefore, the need for a national rare diseases helpline was confirmed in this study. Due to limited financial resources, existing offers should be adapted in a stepwise procedure in accordance with the identified attributes.

Use of Complementary and Alternative Medicine in Patients with Autoimmune Bullous Dermatoses: A Cohort Study Analysis of a Rare Disease Group.

INTRODUCTION: Autoimmune bullous diseases (AIBD) are a heterogeneous group of rare autoantibody-mediated blistering dermatoses of the skin and/or mucous membranes. Their incidence is around 20 new cases per million inhabitants per year in Germany. Patients with chronic, oncological, or rare diseases often urge for a holistic therapeutic approach that includes complementary and alternative medicine (CAM). So far, only few contradictory reports on CAM in pemphigoid or pemphigus disease exist. The purpose of this study was to determine the frequency, motives, and satisfaction with the use of alternative treatments in patients with AIBD and to provide a basis for further investigation. METHODS: We used a structured online questionnaire, consisting of 20 questions to survey patients with AIBD and their relatives. The German pemphigus and pemphigoid self-help groups were responsible for distributing anonymized questionnaires. In total, we recovered 97 questionnaires, 63 of which met full inclusion criteria (24 males and 39 females). RESULTS: Of the included participants, more than half had a currently active disease. Of all patients, 58.7% stated that they had used CAM at least once. Women were more likely to use CAM, whereas age and education showed no association to CAM use. The main motives for using CAM were "doing something for oneself" and "opportunity to contribute to treatment" (38.1% each). The internet (23.8%) was the most common source of information, and vitamins were the most frequently used therapy (49.2%). CONCLUSION: Our results provide new insights into the demand for CAM within this rare disease patient group. Physicians should be aware of these methods to meet patient needs but also be able to identify potential barriers such as risks and interactions.