Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease associated with a high disease burden and substantial impact on patients’ quality of life. Limited therapeutic options are available, with an unmet medical need for earlier diagnosis and treatment and more effective treatment options. Low awareness of HS amongst healthcare professionals (HCPs) leads to delayed diagnosis and a prolonged patient journey to HS-specific treatment. This article aims to describe the design of HELyx, an implementation science study in Germany, which aims to evaluate the effectiveness of an implementation strategy to improve screening and diagnosis of HS among HCPs (dermatologists and non-dermatologists) and timely referral to HS-treating dermatologists. HELyx is a hybrid, effectiveness-implementation science study with a pre-post design involving HCPs and is guided by the Consolidated Framework for Implementation Research. HELyx is being conducted in Germany over four consecutive phases (context analysis, pre-implementation, implementation, and post-implementation) in a sequential manner. A similar implementation science study is also being conducted in the United Arab Emirates (UAE) and Spain. HELyx aims to identify key unmet medical needs in the HS patient journey, to develop and implement a tailored medical education program, and to measure the effectiveness of the implementation. The primary endpoint is the change in the proportion of HCPs who used a diagnostic screening tool to identify patients with suspected HS during the 24 weeks of the post-implementation phase (assessed at Week 24) compared to the 24 weeks before implementation (assessed at baseline). Secondary endpoints include assessment of the use of HS disease severity assessment and patient-reported outcome tools and HCP referral behaviours.

[This corrects the article DOI: 10.3389/fimmu.2016.00557.].

Zusammenfassung Hintergrund Die chronisch‐entzündliche Hauterkrankung Hidradenitis suppurativa (HS) führt bei Betroffenen zu ausgeprägten Schmerzen und verminderter Lebensqualität. Trotzdem vergehen oft mehrere Jahre bis zur korrekten Diagnosestellung. In dieser Analyse sollten krankheitsbedingte Erfahrungen und Wege der Patienten mit HS untersucht und der ärztlichen Sicht gegenübergestellt werden. Patienten und Methodik Für die Studie wurden Ergebnisse einer Befragung von Dermatologen und deren Patienten zur Versorgungsrealität bei HS in Deutschland sowie öffentliche Beiträge auf Internet‐Foren und in sozialen Medien analysiert. Zusätzlich wurden Abrechnungsdaten deutscher Krankenkassen ausgewertet. Ergebnisse Patienten mit HS haben eine um 43,3% reduzierte Arbeitsfähigkeit. Die Dermatologie (26,5%) war der am häufigsten konsultierte Fachbereich, die Diagnose HS wurde dabei überwiegend im stationären Bereich (43,8%) gestellt. Als häufigste alternative Diagnose bei HS‐Patienten wurden Abszesse angegeben (53,2%). Die Analyse von Wechseln zu anderen Behandlern ergab, dass diese in der Dermatologie (34,1%) und der Chirurgie (42,4%) vorwiegend innerhalb des Fachbereiches erfolgen. Überweisungen erhielt die Dermatologie mehrheitlich aus dem hausärztlichen Bereich (67,1%) allerdings nur 12,1% von Chirurgen. Schlussfolgerungen Die Diagnoseverzögerung und die dadurch verlängerte Krankheitsbelastung von Patienten mit HS muss dringend reduziert werden. Dazu sollte, möglichst schon als Teil des Medizinstudiums, ein über die Dermatologie hinaus reichendes Bewusstsein für die Erkrankung, ihre Erkennung und Behandlung gefördert werden.

BackgroundThe chronic inflammatory skin disease hidradenitis suppurativa (HS) leads to severe pain and reduced quality of life. Nonetheless, it often takes years until a correct diagnosis is made. In this analysis, disease-related experiences and pathways of patients with HS were investigated and compared with the physicians' perspective.MethodsPublic posts on forums and social media as well as results of a survey conducted among dermatologists and their patients on the actual medical care reality of HS in Germany were analysed. Furthermore, claims data from German health insurance companies were evaluated.ResultsPatients with HS suffer from a 43.3% reduction in working ability. Dermatology (26.5%) was the most frequently consulted specialty, with HS diagnosed predominantly in the inpatient setting (43.8%). Abscesses were described as the most frequent alternative diagnosis in HS patients (53.2%). Patient-reported changes of physicians in dermatology (34.1%) and surgery (42.4%) occurred predominantly within the specialty. Dermatology received most referrals from general practitioners (67.1%), but only 12.1% from surgeons.ConclusionThere is an urgent need to reduce the delay in diagnosis and the prolonged burden of disease in patients with HS. Therefore, awareness of the disease, its detection and treatment which goes beyond dermatology should be promoted, if possible as part of medical studies.

Introduction: Psoriasis is a chronic, inflammatory disorder with a physical and psychosocial burden. Recent epidemiological data on paediatric psoriasis in Germany is lacking. The aim of this study was to examine the prevalence, the incidence and associated epidemiological features of paediatric psoriasis in Germany using health claims data from a national health claims database.Methods: Continuously insured patients with paediatric psoriasis (2014-2017) from the Institute of Applied Health Research Berlin (InGef) database were included in this analysis. Between 2014 and 2017, we analysed the prevalence and incidence of paediatric psoriasis (aged < 17 years), relevant comorbidities, the most frequently attended and diagnosing medical specialties, and the number of systemic treatment prescriptions.Results: Overall, psoriasis prevalence (0.15-0.16%) and incidence (0.06-0.07%) remained stable between 2014 and 2017; both prevalence and incidence were higher in female patients. Psoriasis prevalence gradually increased with age between the age groups <6 years and 16-17 years. Obesity (11.5%) and somato-form disorders (7.0%) were the most common comorbidities identified. Overall, 90.4% of the psoriasis cases were diagnosed by either a dermatologist (50.9%), general practitioner (27.8%), or paediatrician (11.7%). Patients most frequently attended general practitioners (74.5%), dermatologists (57.9%) and paediatricians (56.5%). The use of systemic treatment(s) increased from 4.7% to 5.4% between 2014 and 2017.Discussion: The prevalence and incidence of paediatric psoriasis in Germany remained stable between 2014 and 2017, with a higher prevalence and incidence observed in females and older adolescents. Obesity and somatoform disorders were the most common comorbidities. General practitioners, dermatologists, and paediatricians were most often involved in the treatment of patients, highlighting the need for interdisciplinary management of paediatric psoriasis.

Background and objectives: Lichen planus (LP) is a chronic inflammatory skin disease and is a major burden for affected patients. However, data on this condition are scarce. This study aims to expand the knowledge on the epidemiology and treatment patterns of LP using German health claims data. Patients and Methods: This retrospective observational study was based on the In-Gef research database. Prevalent and incident LP patients were identified in the years 2015 and 2018. Descriptive statistics were calculated for demographic characteristics, treatment patterns, and comorbidity. Results: The prevalence of LP was 95.9 and the incidence was 20.1 per loo,000 individuals in 2018, corresponding to 79,605 prevalent LP cases in Germany. The first LP diagnosis was generally documented by a dermatologist or a primary care physician. Three-quarters of the incident and half of the prevalent patients received topical therapy, mostly without further systemic therapy. Comorbidity in LP patients was consistent with previously known associations. Conclusions: Available treatment options remain limited, underscoring the unmet need for safe and efficacious systemic treatment modalities. Lichen planus is frequently accompanied by clinically relevant systemic comorbidity. Taken together, these observations may improve our understanding of the burden of this disease and increase diagnostic awareness among clinicians.

ZusammenfassungHintergrund und ZieleLichen planus (LP) ist eine chronisch entzündliche Hauterkrankung, die eine große Belastung für die betroffenen Patienten darstellt. Es liegen jedoch nur wenige Daten zu dieser Erkrankung vor. Ziel dieser Studie ist es, das Wissen über die Epidemiologie und die Behandlungsmuster des LP anhand von Abrechnungsdaten deutscher Krankenkassen zu erweitern.Patienten und MethodenDiese retrospektive Beobachtungsstudie nutzte die InGef‐Forschungsdatenbank. Es wurden prävalente und inzidente LP‐Patienten aus den Jahren 2015 und 2018 identifiziert. Für demografische Charakteristika, Behandlungsmuster und Komorbidität wurden deskriptive Statistiken berechnet.ErgebnisseDie Prävalenz des LP lag bei 95,9 und die Inzidenz bei 20,1 pro 100 000 Personen im Jahr 2018, was 79 605 prävalenten LP‐Fällen in Deutschland entspricht. Die erste LP‐Diagnose wurde in der Regel von einem Dermatologen oder Hausarzt gestellt. Drei Viertel der inzidenten und die Hälfte der prävalenten Patienten erhielten eine topische Therapie, meist ohne zusätzliche systemische Therapie. Die Komorbidität des LP stand im Einklang mit bereits bekannten Assoziationen.SchlussfolgerungenDie verfügbaren Therapieoptionen sind nach wie vor begrenzt, was den ungedeckten Bedarf an sicheren und wirksamen systemischen Behandlungsmodalitäten unterstreicht. Der LP ist häufig mit klinisch relevanter systemischer Komorbidität verbunden. Zusammengenommen könnten diese Beobachtungen zu einem verbesserten Verständnis der Krankheitslast führen und das diagnostische Bewusstsein für diese Erkrankung unter Klinikern schärfen.

Hidradenitis suppurativa (HS) is a chronic, debilitating, and inflammatory skin disease. The epidemiology of HS varies greatly, with an estimated prevalence ranging from 0.03% to 4% worldwide. Similar to psoriasis (PsO), HS also exhibits a systemic inflammatory nature with a spectrum of systemic comorbidities. A large health insurance claims (HICs) database is analyzed to determine the demography and epidemiology of HS, PsO, and HS with concurrent PsO (HS-PsO) patients. Furthermore, the comorbidity profiles, including the comorbidity risk of these patient populations, are analyzed. This is a noninterventional retrospective analysis of anonymized HICs data using a subset of the Institute of Applied Health Research Berlin (InGef) database. The primary outcome is the prevalence and incidence of HS, PsO, and HS-PsO. Secondary outcomes include comorbidity profiles and a comorbidity risk analysis. The prevalence and incidence of HS were 0.0681% and 0.0101%, respectively. The prevalence of HS-PsO was 0.004% (6% of the total HS population). HS patients frequently suffered from arterial hypertension (45%), nicotine dependence (46%), obesity (41%), and depression (36%), which were more common in HS-PsO patients compared with HS alone. HS patients had an increased prevalence of metabolic, psychiatric, immune-mediated, and cardiovascular diseases, e.g., overweight/obesity [odds ratio (OR): 2.65, 95% confidence interval (CI) 2.37–2.96], depression (OR: 1.55, 95% CI 1.42–1.76), or seronegative rheumatoid arthritis (OR: 2.82, 95% CI 1.61–4.94) compared with the overall population. The increased risk of myocardial infarction in HS patients (OR: 4.1, 95% CI 3.5–4.8, adjusting for age/sex) was largely attributed to patient’s current smoking status (OR: 1.1, 95% CI 0.8–1.5, adjusting for smoking/age/sex). HS patients show a broad spectrum of inflammatory and metabolic syndrome-related comorbidities, with an increased risk by concurrent PsO. Important for clinical practice, the elevated cardiovascular risk of HS patients can be largely attributed to smoking.

Background: Relative Psoriasis Area and Severity Index (PASI) improvement, also called 'PASI response', is recommended in major guidelines for assessment of treatment response in psoriasis patients. However, under certain circumstances it has some limitations, e.g. when baseline values are missing or during long-term treatment. Improvement of health-related quality of life (HrQoL) can be measured by the Dermatology Life Quality Index (DLQI).Objective: To evaluate the association of HrQoL and relative and absolute PASI outcomes during therapy.Material and methods: Data of plaque psoriasis patients of two clinical trials (CLEAR and SCULPTURE) were pooled. The rates of patients achieving DLQI 0/1 at week 16 were compared for different categories of absolute PASI and PASI response values. The correlation of DLQI and absolute or relative PASI goals was assessed over 52 weeks.Results: One thousand and fifty-four patients with available assessments of PASI and DLQI were included. 76% of the patients with an absolute PASI ≤ 2 (N = 548) and patients with a 90% improvement in PASI (N = 559) achieved DLQI 0/1 at week 16. Achievement of DLQI 0/1 was equally reflected by absolute PASI and PASI response.Conclusion: Absolute PASI appeared to be a feasible alternative to PASI response for determining treatment success, reflecting HrQoL improvements in an equal manner.

Objective. Psoriasis is a systemic inflammatory disease often accompanied by comorbidities, including metabolic syndrome, cardiovascular diseases and depression. Up to 41% of psoriasis patients develop psoriatic arthritis (PsA), making it one of the most relevant manifestations. A large health claims data set was analysed to determine the rate of PsA development in psoriasis patients. Furthermore, comorbid disease profiles of psoriasis patients with or without PsA were compared, and potential risk factors for the development of PsA were identified. Methods. This was a non-interventional, retrospective analysis of anonymized insurance health claims data using a subset of the Institute of Applied Health Research Berlin (InGef) database. The primary outcome was the prevalence and incidence of diagnosed PsA among psoriasis patients in Germany. Risk factors for the development of PsA in psoriasis patients were determined by conditional logistic regression analysis. Results. The cumulative percentage of patients with existing psoriasis developing concomitant PsA over 4 years was 3.44%, with a mean time to diagnosis of PsA of 1.5 years. Psoriasis patients diagnosed with acute rheumatism (odds ratio: 2.93, 95% CI = 1.76, 4.86; P < 0.001) or pain in unspecific joints (odds ratio: 1.74, 95% CI = 1.01, 2.99; P = 0.047) showed an increased risk for development of PsA later on. Interestingly, fewer than half of the patients with concomitant PsA consulted a rheumatologist. Conclusions. Unspecific arthritic symptoms are likely to precede PsA diagnoses and can develop soon after onset of psoriasis, with accumulating risk over time. There is a high unmet need for early rheumatological assessment of psoriasis patients.

The presence of gallstones (cholelithiasis) is a highly prevalent and severe disease and one of the leading causes of hospital admissions worldwide. Due to its substantial health impact, we investigated the biological mechanisms that lead to the formation and growth of gallstones. We show that gallstone assembly essentially requires neutrophil extracellular traps (NETs). We found consistent evidence for the presence of NETs in human and murine gallstones and describe an immune-mediated process requiring activation of the innate immune system for the formation and growth of gallstones. Targeting NET formation via inhibition of peptidyl arginine deiminase type 4 or abrogation of reactive oxygen species (ROS) production, as well as damping of neutrophils by metoprolol, effectively inhibit gallstone formation in vivo. Our results show that after the physicochemical process of crystal formation, NETs foster their assembly into larger aggregates and finally gallstones. These insights provide a feasible therapeutic concept to prevent cholelithiasis in patients at risk.

Immunoglobulin G (IgG) harbors a conserved N-glycosylation site which is important for its effector functions. Changes in glycosylation of IgG occur in many autoimmune diseases but also in physiological conditions. Therefore, the glycosylation pattern of serum IgG is well characterized. However, limited data is available on the glycosylation pattern of IgG in cerebrospinal fluid (CSF) compared to serum. Here, we report significantly reduced levels of bisected glycans in CSF IgG. Galactosylation and sialylation of IgG4 also differed significantly. Therefore, we propose a common mechanism mediating glycosylation changes of IgG at the transition from serum to CSF in steady state conditions.

Deficient clearance of apoptotic cells reportedly contributes to the etiopathogenesis of the autoimmune disease systemic lupus erythematosus (SLE). Based on this knowledge, we developed a highly specific and sensitive test for the detection of SLE autoantibodies (AAb) utilizing secondary NEcrotic cell (SNEC)-derived material as a substrate. The goal of the present study was to validate the use of SNEC as an appropriate antigen for the diagnosis of SLE in large cohort of patients. We confirmed the presence of apoptotically modified autoantigens on SNEC (dsDNA, high mobility group box 1 protein, apoptosis-associated chromatin modifications, e.g., histones H3-K27-me3; H2A/H4 AcK8,12,16; and H2B-AcK12). Anti-SNEC AAb were measured in the serum of 155 patients with SLE, 89 normal healthy donors (NHD), and 169 patients with other autoimmune connective tissue diseases employing SNEC-based indirect enzyme-linked immunosorbent assay (SNEC ELISA). We compared the test performance of SNEC ELISA with the routine diagnostic tests dsDNA Farr radioimmunoassay (RIA) and nucleosome-based ELISA (anti-dsDNA-NcX-ELISA). SNEC ELISA distinguished patients with SLE with a specificity of 98.9% and a sensitivity of 70.6% from NHD clearly surpassing RIA and anti-dsDNA-NcX-ELISA. In contrast to the other tests, SNEC ELISA significantly discriminated patients with SLE from patients with rheumatoid arthritis, primary anti-phospholipid syndrome, spondyloarthropathy, psoriatic arthritis, and systemic sclerosis. A positive test result in SNEC ELISA significantly correlated with serological variables and reflected the uptake of opsonized SNEC by neutrophils. This stresses the relevance of SNECs in the pathogenesis of SLE. We conclude that SNEC ELISA allows for the sensitive detection of pathologically relevant AAb, enabling its diagnostic usage. A positive SNEC test reflects the opsonization of cell remnants by AAb, the neutrophil recruitment to tissues, and the enhancement of local and systemic inflammatory responses.

The production of reactive oxygen species (ROS) via the oxidative burst has been connected with promotion of inflammation and tissue damage, but in recent years has been implicated in regulation of inflammation. We investigated the effects of ROS on the murine model of lupus and in patients (SLE).

Papillon-Lefèvre syndrome (PLS) is characterized by nonfunctional neutrophil serine proteases (NSPs) and fulminant periodontal inflammation of unknown cause. Here we investigated neutrophil extracellular trap (NET)-associated aggregation and cytokine/chemokine-release/degradation by normal and NSP-deficient human and mouse granulocytes. Stimulated with solid or soluble NET inducers, normal neutrophils formed aggregates and both released and degraded cytokines/chemokines. With increasing cell density, proteolytic degradation outweighed release. Maximum output of cytokines/chemokines occurred mostly at densities between 2 × 107 and 4 × 107 neutrophils/cm3. Assessment of neutrophil density in vivo showed that these concentrations are surpassed during inflammation. Association with aggregated NETs conferred protection of neutrophil elastase against α1-antitrypsin. In contrast, eosinophils did not influence cytokine/chemokine concentrations. The proteolytic degradation of inflammatory mediators seen in NETs was abrogated in Papillon-Lefèvre syndrome (PLS) neutrophils. In summary, neutrophil-driven proteolysis of inflammatory mediators works as a built-in safeguard for inflammation. The absence of this negative feedback mechanism might be responsible for the nonresolving periodontitis seen in PLS.-Hahn, J., Schauer, C., Czegley, C., Kling, L., Petru, L., Schmid, B., Weidner, D., Reinwald, C., Biermann, M. H. C., Blunder, S., Ernst, J., Lesner, A., Bäuerle, T., Palmisano, R., Christiansen, S., Herrmann, M., Bozec, A., Gruber, R., Schett, G., Hoffmann, M. H. Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases.

Verschiedene Formen der Pankreatitis sind gekennzeichnet durch eine Infiltration mit Granulozyten, nehmen jedoch unterschiedlichste klinische Verläufe (Schwere akute Pankreatitis vs. Autoimmune Pankreatitis Typ 2). Eine kürzlich beschriebene Funktion neutrophiler Granulozyten besteht in der Bildung aggregierter extrazellulärer Fallen („neutrophil extracellular traps“).

Many effector mechanisms of neutrophils have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Neutrophil extracellular traps (NETs) have been assigned a particularly detrimental role. Here we investigated the functional impact of neutrophils and NETs on a mouse model of lupus triggered by intraperitoneal injection of the cell death-inducing alkane pristane. Pristane-induced lupus (PIL) was aggravated in 2 mouse strains with impaired induction of NET formation, i.e., NOX2-deficient (Ncf1-mutated) and peptidyl arginine deiminase 4-deficient (PAD4-deficient) mice, as seen from elevated levels of antinuclear autoantibodies (ANAs) and exacerbated glomerulonephritis. We observed a dramatically reduced ability to form pristane-induced NETs in vivo in both Ncf1-mutated and PAD4-deficient mice, accompanied by higher levels of inflammatory mediators in the peritoneum. Similarly, neutropenic Mcl-1ΔMyelo mice exhibited higher levels of ANAs, which indicates a regulatory function in lupus of NETs and neutrophils. Blood neutrophils from Ncf1-mutated and human individuals with SLE exhibited exuberant spontaneous NET formation. Treatment with specific chemical NOX2 activators induced NET formation and ameliorated PIL. Our findings suggest that aberrant NET is one of the factors promoting experimental lupus-like autoimmunity by uncontrolled release of inflammatory mediators.

The goal of this study was to investigate the glycosylation profile of native immunoglobulin (Ig)G present in serum immune complexes in patients with rheumatoid arthritis (RA). To accomplish this, lectin binding assays, detecting the accessibility of glycans present on IgG-containing immune complexes by biotinylated lectins, were employed. Lectins capturing fucosyl residues (AAL), fucosylated tri-mannose N-glycan core sites (LCA), terminal sialic acid residues (SNA) and O-glycosidically linked galactose/N-acetylgalactosamine (GalNac-L) were used. Patients with recent-onset RA at baseline and after 3-year follow-up were investigated. We found that native IgG was complexed significantly more often with IgM, C1q, C3c and C-reactive protein (CRP) in RA patients, suggesting alterations of the native structure of IgG. The total accessibility of fucose residues on captured immune complexes to the respective lectin was significantly higher in patients with RA. Moreover, fucose accessibility on IgG-containing immune complexes correlated positively with the levels of antibodies to cyclic citrullinated peptides (anti-CCP). We also observed a significantly higher accessibility to sialic acid residues and galactose/GalNAc glyco-epitopes in native complexed IgG of patients with RA at baseline. While sialic acid accessibility increased during treatment, the accessibility of galactose/GalNAc decreased. Hence, successful treatment of RA was associated with an increase in the SNA/GalNAc-L ratio. Interestingly, the SNA/GalNAc-L ratio in particular rises after glucocorticoid treatment. In summary, this study shows the exposure of glycans in native complexed IgG of patients with early RA, revealing particular glycosylation patterns and its changes following pharmaceutical treatment.