What are the 100 most cited fungal genera?

The global diversity of fungi has been estimated between 2 to 11 million species, of which only about 155 000 have been named. Most fungi are invisible to the unaided eye, but they represent a major component of biodiversity on our planet, and play essential ecological roles, supporting life as we know it. Although approximately 20 000 fungal genera are presently recognised, the ecology of most remains undetermined. Despite all this diversity, the mycological community actively researches some fungal genera more commonly than others. This poses an interesting question: why have some fungal genera impacted mycology and related fields more than others? To address this issue, we conducted a bibliometric analysis to identify the top 100 most cited fungal genera. A thorough database search of the Web of Science, Google Scholar, and PubMed was performed to establish which genera are most cited. The most cited 10 genera are Saccharomyces, Candida, Aspergillus, Fusarium, Penicillium, Trichoderma, Botrytis, Pichia, Cryptococcus and Alternaria. Case studies are presented for the 100 most cited genera with general background, notes on their ecology and economic significance and important research advances. This paper provides a historic overview of scientific research of these genera and the prospect for further research. Citation: Bhunjun CS, Chen YJ, Phukhamsakda C, Boekhout T, Groenewald JZ, McKenzie EHC, Francisco EC, Frisvad JC, Groenewald M, Hurdeal VG, Luangsa-ard J, Perrone G, Visagie CM, Bai FY, Blaszkowski J, Braun U, de Souza FA, de Queiroz MB, Dutta AK, Gonkhom D, Goto BT, Guarnaccia V, Hagen F, Houbraken J, Lachance MA, Li JJ, Luo KY, Magurno F, Mongkolsamrit S, Robert V, Roy N, Tibpromma S, Wanasinghe DN, Wang DQ, Wei DP, Zhao CL, Aiphuk W, Ajayi-Oyetunde O, Arantes TD, Araujo JC, Begerow D, Bakhshi M, Barbosa RN, Behrens FH, Bensch K, Bezerra JDP, Bilanski P, Bradley CA, Bubner B, Burgess TI, Buyck B, Cadez N, Cai L, Calaça FJS, Campbell LJ, Chaverri P, Chen YY, Chethana KWT, Coetzee B, Costa MM, Chen Q, Custódio FA, Dai YC, Damm U, de Azevedo Santiago ALCM, De Miccolis Angelini RM, Dijksterhuis J, Dissanayake AJ, Doilom M, Dong W, Alvarez-Duarte E, Fischer M, Gajanayake AJ, Gené J, Gomdola D, Gomes AAM, Hausner G, He MQ, Hou L, Iturrieta-González I, Jami F, Jankowiak R, Jayawardena RS, Kandemir H, Kiss L, Kobmoo N, Kowalski T, Landi L, Lin CG, Liu JK, Liu XB, Loizides M, Luangharn T, Maharachchikumbura SSN, Makhathini Mkhwanazi GJ, Manawasinghe IS, Marin-Felix Y, McTaggart AR, Moreau PA, Morozova OV, Mostert L, Osiewacz HD, Pem D, Phookamsak R, Pollastro S, Pordel A, Poyntner C, Phillips AJL, Phonemany M, Promputtha I, Rathnayaka AR, Rodrigues AM, Romanazzi G, Rothmann L, Salgado-Salazar C, Sandoval-Denis M, Saupe SJ, Scholler M, Scott P, Shivas RG, Silar P, Souza-Motta CM, Silva-Filho AGS, Spies CFJ, Stchigel AM, Sterflinger K, Summerbell RC, Svetasheva TY, Takamatsu S, Theelen B, Theodoro RC, Thines M, Thongklang N, Torres R, Turchetti B, van den Brule T, Wang XW, Wartchow F, Welti S, Wijesinghe SN, Wu F, Xu R, Yang ZL, Yilmaz N, Yurkov A, Zhao L, Zhao RL, Zhou N, Hyde KD, Crous PW (2024). What are the 100 most cited fungal genera? Studies in Mycology 108: 1-411. doi: 10.3114/sim.2024.108.01.

Metabolomic and lipidomic fingerprints in inflammatory skin diseases - Systemic illumination of atopic dermatitis, hidradenitis suppurativa and plaque psoriasis.

Auto-inflammatory skin diseases place considerable symptomatic and emotional burden on the affected and put pressure on healthcare expenditures. Although most apparent symptoms manifest on the skin, the systemic inflammation merits a deeper analysis beyond the surface. We set out to identify systemic commonalities, as well as differences in the metabolome and lipidome when comparing between diseases and healthy controls. Lipidomic and metabolomic LC-MS profiling was applied, using plasma samples collected from patients suffering from atopic dermatitis, plaque-type psoriasis or hidradenitis suppurativa or healthy controls. Plasma profiles revealed a notable shift in the non-enzymatic anti-oxidant defense in all three inflammatory disorders, placing cysteine metabolism at the center of potential dysregulation. Lipid network enrichment additionally indicated the disease-specific provision of lipid mediators associated with key roles in inflammation signaling. These findings will help to disentangle the systemic components of autoimmune dermatological diseases, paving the way to individualized therapy and improved prognosis.

Medium term (> 12 months) outcomes after laparoscopic hiatal hernia repair without conventional fundoplication using PH4B-mesh implant (Phasix™) in 176 reflux patients: experience and technique.

BACKGROUND: Hiatal mesh repair remains a controversial topic among anti-reflux surgeons. Biosynthetic mesh cruroplasty may prevent early recurrence while avoiding late esophageal erosion and strictures associated with non-resorbable materials. So far, medium-term results on hiatal PH4B (Poly-4-Hydroxybutyrate) mesh repair from high-volume centers are lacking. METHODS: We analyzed the medium-term efficacy and safety of PH4B mesh cruroplasty in 176 consecutive patients (≥ 18 years) with symptomatic hiatal hernias. Treatment failure was defined as the clinical recurrence of reflux symptoms. Patients could choose between mesh augmented hiatal repair (combined with a modified anterior hemifundoplication and fundophrenicopexy), Nissen fundoplication, and magnetic sphincter augmentation at their discretion. We also describe the surgical approach to mesh augmented hiatal repair used at our center. RESULTS: On average, patients were 55 (± 14) years old and followed up for 22 (± 7; sum: 3931) months. Treatment failed in 6/176 (3%, 95% CI: 2-7%) patients. The 24-month Kaplan-Meier failure estimate was 2.8% (95% CI: 0.4-5%). Each centimeter in hernia size increased the risk of failure by 52% (p = 0.02). Heavier patients (BMI > 27) had an 11% higher probability of clinical symptom recurrence (p = 0.03). The dysphagia and bloating/gas rate were 13/176 (7%), each. 8 (5%) patients required endoscopy due to dysphagia but without intervention. No serious complications, including mesh infection and erosion, or fatalities, occurred. CONCLUSION: Augmented PH4B mesh cruroplasty without conventional fundoplication shows excellent intermediate-term results in patients with reflux disease due to hiatal hernia. Around one in thirty patients experience treatment failure within 2 years of surgery. Hernia size and overweight are key determinants of treatment failure.

Small molecule biomarker discovery: Proposed workflow for LC-MS-based clinical research projects.

Mass spectrometry focusing on small endogenous molecules has become an integral part of biomarker discovery in the pursuit of an in-depth understanding of the pathophysiology of various diseases, ultimately enabling the application of personalized medicine. While LC-MS methods allow researchers to gather vast amounts of data from hundreds or thousands of samples, the successful execution of a study as part of clinical research also requires knowledge transfer with clinicians, involvement of data scientists, and interactions with various stakeholders. The initial planning phase of a clinical research project involves specifying the scope and design, and engaging relevant experts from different fields. Enrolling subjects and designing trials rely largely on the overall objective of the study and epidemiological considerations, while proper pre-analytical sample handling has immediate implications on the quality of analytical data. Subsequent LC-MS measurements may be conducted in a targeted, semi-targeted, or non-targeted manner, resulting in datasets of varying size and accuracy. Data processing further enhances the quality of data and is a prerequisite for in-silico analysis. Nowadays, the evaluation of such complex datasets relies on a mix of classical statistics and machine learning applications, in combination with other tools, such as pathway analysis and gene set enrichment. Finally, results must be validated before biomarkers can be used as prognostic or diagnostic decision-making tools. Throughout the study, quality control measures should be employed to enhance the reliability of data and increase confidence in the results. The aim of this graphical review is to provide an overview of the steps to be taken when conducting an LC-MS-based clinical research project to search for small molecule biomarkers.

Pre-analytical sample handling standardization for reliable measurement of metabolites and lipids in LC-MS-based clinical research.

The emerging disciplines of lipidomics and metabolomics show great potential for the discovery of diagnostic biomarkers, but appropriate pre-analytical sample-handling procedures are critical because several analytes are prone to ex vivo distortions during sample collection. To test how the intermediate storage temperature and storage period of plasma samples from K3EDTA whole-blood collection tubes affect analyte concentrations, we assessed samples from non-fasting healthy volunteers (n = 9) for a broad spectrum of metabolites, including lipids and lipid mediators, using a well-established LC-MS-based platform. We used a fold change-based approach as a relative measure of analyte stability to evaluate 489 analytes, employing a combination of targeted LC-MS/MS and LC-HRMS screening. The concentrations of many analytes were found to be reliable, often justifying less strict sample handling; however, certain analytes were unstable, supporting the need for meticulous processing. We make four data-driven recommendations for sample-handling protocols with varying degrees of stringency, based on the maximum number of analytes and the feasibility of routine clinical implementation. These protocols also enable the simple evaluation of biomarker candidates based on their analyte-specific vulnerability to ex vivo distortions. In summary, pre-analytical sample handling has a major effect on the suitability of certain metabolites as biomarkers, including several lipids and lipid mediators. Our sample-handling recommendations will increase the reliability and quality of samples when such metabolites are necessary for routine clinical diagnosis.

Magnetic resonance imaging characteristics in patients with spondyloarthritis and clinical diagnosis of heel enthesitis: post hoc analysis from the phase 3 ACHILLES trial.

OBJECTIVE: To investigate the imaging characteristics and clinically assess heel enthesitis in spondyloarthritis (SpA) by applying in a post hoc analysis the Heel Enthesitis Magnetic Resonance Imaging Scoring system (HEMRIS) in blinded and centrally-read MRI data from the ACHILLES trial (NCT02771210). METHODS: ACHILLES included patients (≥18 years) with active psoriatic arthritis or axial SpA with clinical and MRI-positive heel enthesitis refractory to standard treatment. Patients were randomized to receive subcutaneous secukinumab 150/300 mg or placebo. At week 24, patients on placebo were switched to secukinumab treatment. MRI-positive heel enthesitis was confirmed in all patients by local investigators. MRIs were performed at 3 timepoints: screening and weeks 24 and 52. In the present analysis, all MRIs were re-evaluated by 2 blinded central readers in a consensus read fashion for a priori defined MRI parameters based on HEMRIS. RESULTS: At screening, 171/204 (83.8%) of patients presented with entheseal inflammation and/or structural damage, considering both the Achilles tendon and plantar fascia. Pathologies were more evident in the Achilles tendon area compared to the plantar aponeurosis. The most frequent pathologies were intra-tendon hypersignal and retrocalcaneal bursitis. The mean total entheseal inflammation score at screening in the Achilles tendon area was 2.99 (N=204) and the mean change (standard deviation [SD]) from screening to weeks 24 and 52 was - 0.91 (1.99) and - 0.83 (2.12) in the secukinumab group vs - 0.48 (1.86) and - 0.80 (1.98) in the placebo-secukinumab group, respectively. The mean total structural damage score at screening was 1.36 (N=204) and the mean change (SD) from screening to weeks 24 and 52 was 0.00 (0.65) and - 0.06 (0.56) in the secukinumab group vs 0.08 (0.48) and 0.04 (0.75) in the placebo-secukinumab group, respectively. CONCLUSIONS: Based on the newly developed HEMRIS, entheseal inflammation and/or structural damage was confirmed in 83.3% of ACHILLES patients. Pathologies were more evident in the Achilles tendon area compared to plantar fascia, with the inflammatory parameters being more responsive with secukinumab treatment compared to placebo. The present analysis, with detailed information on individual MRI parameters, contributes to the scientific debate on heel enthesitis. TRIAL REGISTRATION: ClinicalTrials.gov NCT02771210 .

Physiological synchrony is associated with attraction in a blind date setting.

Humans are social animals whose well-being is shaped by the ability to attract and connect with one another, often through brief interactions. In addition to physical features, a choreography of movements, physical reactions and subtle expressions may help promote attraction. Here, we measured the physiological dynamics between pairs of participants during real-life dating interactions outside the laboratory. Participants wore eye-tracking glasses with embedded cameras and devices to measure physiological signals including heart rate and skin conductance. We found that overt signals such as smiles, laughter, eye gaze or the mimicry of those signals were not significantly associated with attraction. Instead, attraction was predicted by synchrony in heart rate and skin conductance between partners, which are covert, unconscious and difficult to regulate. Our findings suggest that interacting partners' attraction increases and decreases as their subconscious arousal levels rise and fall in synchrony.

[Development of quality standards for patients with axial spondyloarthritis for use in Germany]. / Entwicklung von Qualitätsstandards für Patient*innen mit axialer Spondyloarthritis zum Einsatz in Deutschland.

Quality standards (QS) are measurable constructs designed to quantify gaps in care and subsequently to improve quality of care. The Assessment of SpondyloArthritis International Society (ASAS) recently generated and published international QS for the management of patients with axial spondyloarthritis (axSpA) for the first time. The German Society of Rheumatology (DGRh) then decided to translate, review and possibly adopt these standards by a group of experts from different care settings. Against this background, national QS for the management of patients with axSpA for Germany were developed for the first time. The main focus was on feasibility and practical relevance. Ultimately, nine QS were defined with which the quality of care in Germany can and should be measured and improved.

Efficacy of secukinumab and adalimumab in patients with psoriatic arthritis and concomitant moderate-to-severe plaque psoriasis: results from EXCEED, a randomized, double-blind head-to-head monotherapy study.

BACKGROUND: Secukinumab [an interleukin (IL)-17A inhibitor] has demonstrated significantly higher efficacy vs. etanercept (a tumour necrosis factor inhibitor) and ustekinumab (an IL-12/23 inhibitor) in patients with moderate-to-severe plaque psoriasis. OBJECTIVES: To report 52-week results from a prespecified analysis of patients with active psoriatic arthritis (PsA) having concomitant moderate-to-severe plaque psoriasis from the head-to-head EXCEED monotherapy study comparing secukinumab with adalimumab. METHODS: Patients were randomized to receive secukinumab 300 mg via subcutaneous injection at baseline, week 1-4, and then every 4 weeks until week 48 or adalimumab 40 mg via subcutaneous injection every 2 weeks from baseline until week 50. Assessments in patients with concomitant moderate-to-severe psoriasis, defined as having affected body surface area > 10% or Psoriasis Area and Severity Index (PASI) ≥ 10 at baseline, included musculoskeletal, skin and quality-of-life outcomes. Missing data were handled using multiple imputation. RESULTS: Of the 853 patients [secukinumab (N = 426), adalimumab (N = 427)], 211 (24·7%) had concomitant moderate-to-severe psoriasis [secukinumab (N = 110, 25·8%), adalimumab (N = 101, 23·7%)]. Up to week 50, 5·5% of patients discontinued secukinumab vs.17·8% in the adalimumab group. The proportion of patients who achieved American College of Rheumatology (ACR) 20 response was 76·4% with secukinumab vs. 68·3% with adalimumab (P = 0·175), PASI 100 response was 39·1% vs. 23·8% (P = 0·013), and simultaneous improvement in ACR 50 and PASI 100 response at week 52 was 28·2% vs. 17·7%, respectively (P = 0·06). Secukinumab demonstrated consistently higher responses vs. adalimumab across skin endpoints. CONCLUSIONS: This prespecified analysis in PsA patients with concomitant moderate-to-severe plaque psoriasis in the EXCEED study provides further evidence that IL-17 inhibitors offer a comprehensive biological treatment to manage the concomitant features of psoriasis and PsA.

[Hospital paramedic. An interprofessional blended learning concept to qualify paramedics and medical personnel for deployment in intensive care units and emergency departments during the COVID-19 pandemic]. / Kliniksanitäter. Ein interprofessionelles Blended-Learning-Konzept zur Weiterqualifikation von Rettungsdienst- und medizinischem Personal zum Einsatz auf Intensivstationen und in Notaufnahmen während der COVID-19-Pandemie.

BACKGROUND: The COVID-19 pandemic necessitated a time-critical expansion of medical staff in intensive care units (ICU) and emergency rooms (ER). OBJECTIVE: This article describes the development, performance and first results of an interprofessional blended learning concept called hospital paramedics, qualifying paramedics and additional medical personnel to support ICUs and ERs. MATERIAL AND METHODS: The Protestant Hospital of the Bethel Foundation (EvKB), University Hospital OWL, University of Bielefeld in cooperation with the Study Institute Westfalen-Lippe, developed a 2-stage blended learning concept (stage 1 e­learning with online tutorials, stage 2 practical deployment) comprising 3 modules: ICU, ER and in-hospital emergency medicine. At the beginning, the participants were asked about their sociodemographic data (age, gender, type of medical qualifications) and subjective feeling of confidence. At the end, a final discussion with the participant, the practice instructor and the supervising physician took place and an evaluation of the deployment by the head of the practice and the hospital paramedic was carried out using questionnaires. RESULTS: Within 6 weeks 58 (63%) of the 92 participants completed the online course and 17 (29%) additionally completed their traineeship. In the ICU they assisted with preparing catheter systems, medication and nursing, performed Manchester triage and initial care in the ER. After completion hospital paramedics were significantly more confident when working in a hospital, catheterization and tracheostoma care (p < 0.05). Of the supervisors 94% deemed the deployment as useful and 100% of the participants were prepared to be available at short notice in their areas as compensation for the COVID-19-pandemic in the event of a staff shortage. Through the provision of additional intensive care ventilators and monitoring units in the period from March to the beginning of May 2020 and the personnel management that was carried out, the EvKB was in a position to increase the number of previously provided ventilator beds by potentially >40 ventilation places. CONCLUSION: Blended learning concepts, such as hospital paramedics, can quickly qualify medical personnel for use in system-relevant settings, relieve nursing staff and thus create an expansion of intensive care capacities. Existing or pending pandemic and contingency plans should be complemented by such blended learning training so that they are immediately available in case of a second pandemic wave, future pandemics or other crisis situations.

Physiological synchrony is associated with cooperative success in real-life interactions.

Cooperation is pivotal for society to flourish. To foster cooperation, humans express and read intentions via explicit signals and subtle reflections of arousal visible in the face. Evidence is accumulating that humans synchronize these nonverbal expressions and the physiological mechanisms underlying them, potentially influencing cooperation. The current study is designed to verify this putative linkage between synchrony and cooperation. To that end, 152 participants played the Prisoner's Dilemma game in a dyadic interaction setting, sometimes facing each other and sometimes not. Results showed that synchrony in both heart rate and skin conductance level emerged during face-to-face contact. However, only synchrony in skin conductance levels predicted cooperative success of dyads. Crucially, this positive linkage was strengthened when participants could see each other. These findings show the strong relationship between our bodily responses and social behavior, and emphasize the importance of studying social processes between rather than within individuals in real-life interactions.

[Treatment of psoriatic arthritis : Are there differential indications?] / Therapie der Psoriasisarthritis : Gibt es eine Differenzialindikation?

Psoriatic arthritis (PsA) is a very heterogeneous immune-mediated disease that usually involves skin and joints but can also affect entheses and extra-articular structures during the disease course. Furthermore, it can also be linked with other associated diseases. Therefore, the individualized selection of an effective and patient-oriented treatment must be carried out taking the extent of various manifestations of the PsA itself and also of other influencing factors into consideration. Various recommendations for selection and control of the suitable treatment of PsA are available for clinical use. The recommendations of the European League Against Rheumatism (EULAR) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) are the two recommendations that are frequently used and internationally acknowledged. Both recommendations were updated in 2016. Specific German treatment recommendations are currently missing. In analogy to the treat-to-target strategy for rheumatoid arthritis, at least minimal disease activity (MDA) should be achieved in PsA patients with the use of specific therapeutic interventions if remission as the maximum therapeutic goal cannot be reached. New treatment options, which target different specific molecules, offer possibilities for a more differentiated personalized medicinal treatment for improvement of the care of PsA patients. This particularly applies to a focus on personalized strategies for optimal treatment of various manifestation forms and patterns.

Addition or removal of concomitant methotrexate alters adalimumab effectiveness in rheumatoid arthritis but not psoriatic arthritis.

Objective: Randomized trials have shown that concomitant methotrexate (MTX) augments the effectiveness of tumour necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA), but its benefit in psoriatic arthritis (PsA) has not been demonstrated. The goal of this study was to examine whether the impact of concomitant MTX on therapeutic outcomes in patients with PsA was similar to its effects in RA. Methods: We used data from highly comparable and concurrent observational studies of patients with PsA (N = 1424) or RA (N = 3148) who initiated adalimumab therapy during routine clinical care. The 28-joint Disease Activity Score (DAS28) and patient-reported pain scores were evaluated in patients who received 24 months of continuous treatment with adalimumab monotherapy or adalimumab + MTX and in patients who initiated or stopped concomitant MTX during ongoing adalimumab therapy. Results: Twenty-four months of continuous treatment with adalimumab + MTX was superior to adalimumab monotherapy in RA patients, while no significant difference was observed in patients with PsA. RA patients who added MTX during the study showed significant individual improvements in DAS28 and pain scores at 6 months after the change in therapy, while those who removed MTX had slight increases in disease activity. In contrast, in patients with PsA, neither initiation nor removal of MTX during continuous adalimumab therapy had a significant effect on therapeutic outcomes. Conclusion: Addition of MTX to adalimumab confers further therapeutic benefit in patients with RA, but not in those with PsA, suggesting differences in MTX effects in these two patient populations. Clinicaltrials.gov NCT01078090, NCT01077258, NCT01111240.

[Medical care situation of patients with ankylosing spondylitis and psoriatic arthritis in Germany : Medical care situation of patients with spondyloarthritis (SpA): ankylosing spondylitis (AS) and psoriatic arthritis (PsA) from the perspective of rheumatologists in private practice and hospitals in Germany-Results of the research project "SpA Loop-Life of Outpatients"]. / Versorgungssituation von Patienten mit ankylosierender Spondylitis und Psoriasisarthritis in Deutschland : Versorgungssituation von Patienten mit Spondyloarthritis (SpA): Ankylosierende Spondylitis (AS) und Psoriasisarthritis (PsA) aus der Sicht von niedergelassenen und in Kliniken tätigen Rheumatologen in Deutschland ­ Ergebnisse des Forschungsprojekts "SpA Loop ­ Life of Outpatients".

BACKGROUND: The prevalence of spondyloarthritis (SpA) in Germany is approximately 1-1.4% and includes predominantly axial SpA (axSpA) and predominantly peripheral SpA. Ankylosing spondylitis (AS) belongs to the group of axial SpA but also exhibits peripheral manifestations. Psoriatic arthritis (PsA) can show purely peripheral or also axial manifestations. The total prevalence of SpA in Germany is approximately 1­1.4%, the prevalence of AS is ca. 0.5% and PsA 0.2-1.4%. Patients with AS are mainly treated by internal medical rheumatologists but in many places also basically treated by general practitioners and orthopedists. Patients with PsA are mainly diagnosed and treated by rheumatologists and dermatologists working in private practice or in clinical settings. Besides the control of inflammatory activity and prevention or slowing down of the characteristic disease progression, including irreversible structural changes, the main objectives of patients as well as treating physicians are particularly freedom from pain and a quality of life comparable to non-affected persons. Decisive for successful treatment are an early diagnosis and initiation of adequate therapy as well as regular monitoring of disease activity including treatment adjustment taking the needs of the patient into consideration; however, it is unknown how often this is actually successful in routine daily practice in Germany. OBJECTIVE: The aim of the SpA Loop research project was to display the current medical care situation of patients with AS and PsA treated in private practices and hospitals for rheumatology in Germany focusing on patient/physician profiles as well as the diagnostics and treatment. MATERIAL AND METHODS: The instrument for the survey was a standardized questionnaire with 29 multiple choice and perception questions that was distributed to medical specialists in the field of internal medicine and rheumatology. RESULTS: A high accordance between rheumatologists in private practice and in hospitals was observed with respect to the presentation and perception of the current medical care situation for patients with AS and PsA in Germany. Differences were only occasionally found. CONCLUSION: The results of this research project reflect the current status of the medical care situation of AS and PsA patients in Germany. They provide information on which areas of the medical care situation can selectively be improved as well as on interesting aspects and points of discussion with respect to the patient population treated.

Immunogenicity assay development and validation for biological therapy as exemplified by ustekinumab.

Introduction of biotherapeutics has been a major milestone in the treatment of different chronic diseases. Nevertheless, the immune system can recognize the administered biological as non-self and respond with generation of anti-drug antibodies (ADA), including neutralizing ADA (nADA). Immunogenic responses may result in altered drug dynamics and kinetics leading to changes in safety and efficacy. However, there are several challenges with standard techniques for immunogenicity testing. Ustekinumab (UST), used in different inflammatory diseases, is a therapeutic antibody directed against the shared p40 subunit of interleukin (IL)-12 and IL-23, interfering in the pathogenically crucial T helper type 1 (Th1)/Th17 pathway. We established and validated different approaches for detection and quantitation of UST, UST-specific ADA and nADA. Addressing the obstacle of complex formation of UST with nADA, we developed an acidification assay to approach the total amount of nADA. Validated methods were based on surface plasmon resonance spectroscopy (SPR), enzyme-linked immunosorbent assay (ELISA) and a cell-based approach to characterize neutralizing capacity of nADA. Parameters assessed were determination and quantitation limits, linearity, range, precision, accuracy and selectivity. Quantitation of ADA and UST was feasible at lower concentrations using ELISA, whereas SPR showed a wider linear range for determination of ADA and UST. Accuracy, precision and linearity for quantitation were comparable using ELISA, SPR and the cell-based approach. All validated parameters fulfill the requirements of regulatory agencies. A combination of the testing approaches could address the increasing demand of precision medicine as it can be suitable for capturing the whole spectrum of immunogenicity and is transferable to other biologicals.

[Value of combining biologics with methotrexate for treatment of psoriatic arthritis-questions remain]. / Stellenwert der Kombination von Biologika mit Methotrexat in der Behandlung der Psoriasisarthritis ­ Fragen bleiben offen.

BACKGROUND: Concomitant methotrexate (MTX) improves the therapeutic effect of biologic therapies in rheumatoid arthritis treatment. However, the influence of MTX on biologic therapy in psoriasis arthritis (PsA) has not yet been fully clarified, as data from randomized clinical studies are lacking. So far, it is only known, that PsA patients with inadequate response to MTX or non-steroidal anti-inflammatory drugs alone respond equally well to a subsequent biologic therapy. OBJECTIVES: The aim of this study is to investigate whether MTX-naive patients achieve greater disease improvement with the combination of MTX and a biologic than with biologic monotherapy alone, and whether patients on MTX in whom a biologic therapy is additionally started would worsen if MTX is discontinued. METHODS: The current data situation and its limitations are presented. Furthermore, an investigator-initiated multicenter randomized clinical study in patients with active PsA is introduced (MUST study), which investigates the influence of placebo-controlled MTX combination therapy with the interleukin 12/23 inhibitor ustekinumab (UST) in order to close the existing evidence gap. RESULTS: The primary objective of the study is to demonstrate the non-inferiority of UST monotherapy compared to MTX/UST combination therapy as measured by mean DAS28 values at week 24. Of 196 planned patients, 77 have been included so far. Recruitment is still open. CONCLUSION: The MUST study offers the ideal opportunity to investigate the influence of concomitant MTX in a controlled study design and to assess whether the addition of MTX to UST therapy or its continuation is beneficial for PsA patients.

[S2e guideline: treatment of rheumatoid arthritis with disease-modifying drugs]. / S2e-Leitlinie: Therapie der rheumatoiden Arthritis mit krankheitsmodifizierenden Medikamenten.

BACKGROUND: Medication-based strategies to treat rheumatoid arthritis are crucial in terms of outcome. They aim at preventing joint destruction, loss of function and disability by early and consistent inhibition of inflammatory processes. OBJECTIVE: Achieving consensus about evidence-based recommendations for the treatment of rheumatoid arthritis with disease-modifying anti-rheumatic drugs in Germany. METHODS: Following a systematic literature research, a structured process among expert rheumatologists was used to reach consensus. RESULTS: The results of the consensus process can be summed up in 6 overarching principles and 10 recommendations. There are several new issues compared to the version of 2012, such as differentiated adjustments to the therapeutic regime according to time point and extent of treatment response, the therapeutic goal of achieving remission as assessed by means of the simplified disease activity index (SDAI) as well as the potential use of targeted synthetic DMARDs (JAK inhibitors) and suggestions for a deescalating in case of achieving a sustained remission. Methotrexate still plays the central role at the beginning of the treatment and as a combination partner in the further treatment course. When treatment response to methotrexate is inadequate, either switching to or combining with another conventional synthetic DMARD is an option in the absence of unfavourable prognostic factors. Otherwise biologic or targeted synthetic DMARDs are recommended according to the algorithm. Rules for deescalating treatment with glucocorticoids and-where applicable-DMARDs give support for the management of patients who have reached a sustained remission. DISCUSSION: The new guidelines set up recommendations for RA treatment in accordance with the treat-to-target principle. Modern disease-modifying drugs, now including also JAK inhibitors, are available in an algorithm.

[Safety and efficacy of off-label use of biologic therapies in patients with inflammatory rheumatic diseases refractory to standard of care therapy : Data from a nationwide German registry (GRAID2)]. / Sicherheit und Wirksamkeitshinweise zum Off-label-Einsatz von Biologikatherapien nach Versagen konventioneller Therapien bei Patienten mit entzündlich rheumatischen Erkrankungen : Ergebnisse eines nationalen Registers (GRAID2).

BACKGROUND: The German Registry of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry study collecting data from patients with inflammatory, mainly rheumatic diseases refractory to standard of care therapy and treated with an off-label biologic therapy. The retrospective documentation comprised case history, diagnosis, course of disease (including safety and global efficacy). The objective was to evaluate the global clinical outcome and safety of off-label biologic therapy in clinical practice. RESULTS: Data from 311 patients with an overall observation period of 338.5 patient-years were collected. The mean patients age was 47.8 years with 56.9% females. The most frequently documented diagnoses comprised rejection prophylaxis/therapy after renal transplantation (NTX, 18.3%), ANCA-vasculitides (17.4%), systemic lupus erythematosus (SLE, 10.3%), autoinflammatory fever syndromes (8.4%), autoimmune myositis (7.4%) and pemphigus (5.8%). Documented biologic therapies included rituximab (RTX, 70.1%), tocilizumab (TCZ, 9.3%), infliximab (IFX, 7.1%), anakinra (ANK, 5.5%), adalimumab (ADA, 3.5%), etanercept (ETA, 2.3%) and certolizumab (CTZ, 0.6%). After initiation of off-label biologic treatment, tolerability was assessed by the physicians as "very good"/"good" in 95.5%. Altogether, 275 adverse events were documented and of these, 104 were classified as serious adverse events and occurred in 62 patients. In 19 of these patients severe infections (30.6%) were documented, resulting in a rate of 5.6 severe infections per 100 patient years. A total of six deaths were documented, while five of these cases were rated as not related to the biologics treatment. Notably, the use of RTX in patients with small vessel vasculitides and of TCZ in patients with large vessel vasculitides prior to their approval support their relevance in clinical management of patients with severe diseases. CONCLUSION: The results of this registry together with data of GRAID1 provide evidence that use of off-label biologic therapies in patients with inflammatory rheumatic diseases refractory to conventional treatment did not result in any new safety signal already known for these compounds or subsequently shown by clinical trials in certain entities.

[Psoriatic arthritis : Current therapeutic standards]. / Psoriasisarthritis : Aktuelle therapeutische Standards.

Psoriatic arthritis (PsA) is a heterogeneous immune-mediated disease that usually involves the skin and joints but can also affect the entheses, spine and other extra-articular structures. Furthermore, it can be coupled with associated comorbidities. The selection of a patient-oriented and effective therapy is based on the extent of various manifestations of the disease as well as further influencing factors. Various recommendations for selection and control are available for deciding on a suitable treatment. The recommendations of the European League Against Rheumatism (EULAR) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) are most frequently used and are internationally acknowledged. Both recommendations were updated in 2016. German treatment recommendations are currently lacking. In analogy to the treat-to-target strategy in the treatment of rheumatoid arthritis, minimal disease activity should at least be achieved with the therapeutic intervention used if remission as the therapeutic target cannot be reached. New treatment options, which target different molecules, provide possibilities for a more differentiated therapy for improvement in the treatment of PsA patients.