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.

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.

[Imaging of psoriatic arthritis and aspects of radiographic progression]. / Bildgebung bei der Psoriasisarthritis und Aspekte der röntgenologischen Progression.

Psoriatic arthritis (PsA) is a heterogeneous multifactorial disease with musculoskeletal involvement, which can be manifested as monoarthritis, oligoarthritis or polyarthritis and in some patients can also affect the axial skeleton. The most frequent indications of inflammation are bone marrow edema and enthesitis. The early and differential diagnosis of PsA is a clinical challenge, particularly as a differential diagnosis from other inflammatory or degenerative diseases of joints. Inflammatory joint and tendon alterations in the region of the extremities and the spine can be visualized with high sensitivity by the use of magnetic resonance imaging (MRI), musculoskeletal sonography (US) and fluorescence optical imaging (FOI). The use of MRI has a prognostic value with respect to the further radiographic course of the disease, particularly in the initial stages of the disease. Structural damage can be specifically and also partially demonstrated 3­dimensionally in peripheral joints and the spine by the use of computed tomography (CT) and conventional X­ray imaging. High-resolution peripheral quantitative CT (HR-pQCT) in particular, can visualize pathophysiological processes and the morphological consequences even in early stages of the disease. The values of conventional X­ray diagnostics, CT, MRI, musculoskeletal US and alternative imaging procedures are presented with respect to the diagnostics and prognosis of the progression of patients with PsA.

[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.

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.

[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.

[Do we still need clinical studies in rheumatology?]. / Brauchen wir noch klinische Studien in der Rheumatologie?

Despite a large number of approved therapies demonstrating efficacy in the treatment of rheumatic diseases, only 60-85 % of patients with the indications for rheumatoid arthritis are adequately treated in Germany. Additionally, approved therapies for other immune-mediated diseases are often entirely lacking, indicating the great medical need for the development of new innovative therapies in this specialized field. The development of new drugs is expensive due to the high costs of conducting clinical trials in all phases of development up to obtaining approval; therefore, pharmaceutical companies are looking for ways to save costs in the particular developmental stages. Although the classical regions for drug development (i.e. western Europe, the USA and Japan) offer both a high level of data quality and a good infrastructure to conduct clinical trials due to high standards of education and quality, clinical trials are expensive in these regions. Beside high costs, the comparatively low recruitment rates in these regions are one of the main reasons for the shifting of drug developmental stages from classical regions to eastern European, Latin American and Asian countries, which provide services for drug development and high recruitment rates for comparatively less money. However, there are many strong arguments for the participation of regions in western Europe, especially German sites in clinical trials. In this article these arguments are discussed and possible solutions and strategies for conducting and compensation of study centers in Germany for clinical trials in the field of rheumatology are provided.

Increased Serum Levels of the IL-33 Neutralizing sST2 in Limited Cutaneous Systemic Sclerosis.

The pathophysiology of both limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous SSc (dcSSc), representing two subtypes of an autoimmune disease of the connective tissue, is still enigmatic. Life-limiting, progressive fibrotic changes as a consequence of vasculopathy and autoimmunity are characteristic in varying extent for lcSSc and dcSSc. Previously, an increased IL-33 serum concentration in early phase SSc patients and an elevated tissue expression of its receptor, ST2L, on endothelial cells (EC) were described. While suggested as a biomarker for fibrotic diseases, for example liver fibrosis, the role of soluble ST2 (sST2) in the pathological processes and its contribution to vascular fibrosis in SSc has not been investigated. Here, we showed that sST2 is elevated in late phase limited cutaneous SSc (lcSSc) as compared to patients with shorter disease duration or with the diffuse subtype of SSc. We demonstrated that sST2, not IL-33, is significantly increased in serum of lcSSc patients with disease duration over 9 years. Soluble ST2 was not elevated in healthy controls or in SSc patients with early skin involvement or disease duration shorter than 9 years. Furthermore, we observed that sST2 serum levels were lowered by iloprost (prostacyclin) treatment. After 5 days of iloprost infusion, sST2 serum levels fell in 6 of 7 patients. Therefore, we not only like to propose sST2 as a biomarker for progressive vascular fibrosis, but moreover, suggest that the involvement of sST2 in the pathogenesis of lcSSc may be exploited therapeutically.

[Pharmacotherapy of psoriatic arthritis. Treatment recommendations against the background of limited evidence]. / Pharmakotherapie der Psoriasisarthritis. Behandlungsempfehlungen vor dem Hintergrund limitierter Evidenzen.

International treatment recommendations for assisting the choice of pharmaceutical treatment of psoriatic arthritis are currently available in two different versions. While the group for research and assessment of psoriasis and psoriatic arthritis (GRAPPA) recommendations mainly focus on both the description of treatment options for the different phenotypes of psoriatic arthritis and the listing of evidence grades, the European League against Rheumatism (EULAR) recommendations try to implement the knowledge about drugs into an algorithm for the different treatment steps. However, the presentation of a treatment algorithm suggests comparable evidence levels for the individual treatment steps, which is at present not the case for psoriatic arthritis. This should be borne in mind for each individual treatment option and treatment step when using a predetermined therapy algorithm and in view of the heterogeneous study results (or no study results available). Both recommendations are currently being revised and will allow the latest evidence trends to be included in the updated version.

[Personalized medicine in cytokine-targeted therapy]. / Personalisierte Medizin bei Zytokin-gerichteten Therapien.

Personalized healthcare tries to predict the effectiveness and safety in individual therapeutic approaches by defining individual patient characteristics (biomarkers), while stratification uses diagnostic patterns for groups of patients for prediction of therapeutic response with less adverse reactions caused by the drugs applied. Both methods are implemented in oncology and infectiology and in the therapy of rheumatological diseases there is a need for both. Cytokine-directed therapies are important for the treatment of rheumatological diseases, especially when therapy with conventional disease-modifying antirheumatic drugs (DMARD) has failed. Despite the high potency of these drugs for inhibiting pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin 1 (IL-1) and IL-6, sufficient responses are only seen in some of the patients. Therefore, stratification and personalized medicine are ways to optimize efficacy and tolerability of biologic therapies. Some initial evidence is available for potential future strategies using molecular and genetic markers for stratified cytokine inhibition.

[Diagnosis and therapy of early psoriatic arthritis]. / Diagnostik und Therapie der frühen Psoriasis-Arthritis.

Early diagnosis of psoriatic arthritis is of importance because an erosive disease is already detectable after a 2-year duration of symptoms. Often psoriatic arthritis cannot easily be detected because of the diversity of disease manifestations in early stages. As up to 30% of psoriasis patients develop psoriatic arthritis an interdisciplinary dermatologic/rheumatologic approach to diagnose findings and treatment decisions would be desirable. Screening tools, such as validated questionnaires allow an early detection and selection of patients with a high probability of psoriatic arthritis even in dermatological care or on a house physician basis. The implementation of the CASPAR criteria as a classification tool for psoriatic arthritis has also improved the diagnosis finding in patients with a recent onset of active musculoskeletal disease. Data from early psoriatic arthritis cohorts illustrate that drug-free remission is rare. An adequate treatment is of importance. The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has developed treatment recommendations based on the available evidence for different treatment modalities.