[Head-to-head studies on psoriasis and psoriatic arthritis]. / Head-to-Head-Studien bei Psoriasis und Psoriasisarthritis.

Given the ever-increasing number of approved therapies for the treatment of psoriasis (PsO) and psoriatic arthritis (PsA), head-to-head (H2H) comparative studies are essential. These are aimed primarily at a comparative analysis of treatment effectiveness. In both PsO and PsA, biological disease-modifying antirheumatic drugs (bDMARD) have been shown to be superior to conventional therapies in H2H studies. In PsO interleukin 17 (IL-17) and IL-23 inhibitors proved superiority compared to tumor necrosis factor (TNF) inhibitors (etanercept and adalimumab) in several studies. Ustekinumab was more effective than etanercept, but less effective than IL-17 and IL-23 inhibitors. Only a few H2H studies have been published on the treatment of PsA. In the Spirit H2H study ixekizumab was superior to adalimumab using a combined endpoint of arthritis and psoriasis response (ACR-50 and PASI-100). When looking at arthritic symptoms only (ACR-20), secukinumab was not significantly superior to adalimumab in the EXCEED study but was superior in terms of the effect on skin involvement (PASI90). Other H2H studies focused on the treatment of enthesitis (ECLIPSA study), the efficacy of Janus kinase (JAK) inhibition (SELECT-PSA-1) or the additional administration of methotrexate to bDMARD treatment (MUST study). The H2H data have been incorporated into the treatment guidelines and have led to IL-17 and IL-23 inhibition being preferred over TNF inhibition in cases of relevant skin involvement in PsA.

The role of antidrug antibodies in ustekinumab therapy and the impact of methotrexate.

OBJECTIVE: We investigated the impact of concomitant MTX on ustekinumab (UST) levels and antidrug antibody (ADA) formation in PsA and evaluated consequences in pharmacodynamics and pharmacokinetics. METHODS: We conducted a post-hoc analysis on 112 PsA serum samples of subjects treated with open-label UST and either concomitant MTX (UST/MTX, n = 58) or placebo (UST/pbo, n = 54) obtained in a randomized (1:1), double-blind, multicentre trial. A validated antibody-binding-based multitiered testing was used to detect ADA and ADA with neutralizing capacity (nADA). The impact of MTX on UST immunogenicity was analysed by comparison of UST/pbo with UST/MTX cohorts at different time points. Patient- and disease-related predispositions for ADA formation were investigated with multiple linear regression analysis. Immunogenicity impact on pharmacokinetics, safety and efficacy was determined by cohort comparison between patients with and without ADA formation. RESULTS: Over 52 weeks, 11 UST/pbo- and 19 UST/MTX-treated patients developed ADA (P > 0.05). In the UST/pbo cohort, the visit-dependent UST levels were in the range of 0.047 (0.05) -0.110 (0.07) µg/ml overall, and 0.037 (0.04)-0.091 (0.08) µg/ml in ADA-confirmed subjects. In UST/MTX-treated patients, the UST levels exhibited an intervisit variation in the range of 0.0502 (0.04)-0.106 (0.07) µg/ml overall and 0.029 (0.03)-0.097 (0.07) µg/ml in ADA positive subjects (P > 0.05). At week 52, ADA-confirmed patients did not differ significantly (P > 0.05) in safety or clinical outcomes from ADA-negative patients. CONCLUSION: Concomitant MTX had no significant impact on UST immunogenicity. Furthermore, ADA formation was not associated with impairments in UST safety, efficacy or trough levels. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT03148860.

[Psoriatic arthritis : Clinical challenges and pharmaceutical management]. / Psoriasisarthritis : Klinische Herausforderungen und medikamentöses Management.

Psoriatic arthritis (PsA) is a systemic immune-mediated inflammatory disease of the musculoskeletal system, which is accompanied by a chronic and progressive course. It is characterized by different clinical manifestations and can severely impair the quality of life and function of patients due to the existing heterogeneity of the manifestations. The (early) diagnosis of PsA and individualized therapeutic management in routine clinical practice are difficult due to the enormous clinical variability. In addition to the appearance of arthritis of the peripheral joints, there can be involvement of the axial skeleton, skin psoriasis, nail psoriasis, enthesitis and dactylitis. The clinical appearance, course of the disease, risk factors and pathophysiological mechanisms of PsA have been extensively researched in recent decades. With the associated better understanding of the disease, new treatment options and goals for effective treatment have also been established.

Genetic variants in FBLIM1 gene do not contribute to SAPHO syndrome and chronic recurrent multifocal osteomyelitis in typical patient groups.

BACKGROUND: Syndrome of synovitis acne pustulosis hyperostosis osteitis (SAPHO) and chronic recurrent multifocal osteomyelitis (CRMO) present two diseases of a dermatologic and rheumatologic spectrum that are variable in manifestation und therapeutic response. Genetic risk factors have long been assumed in both diseases, but no single reliable factor has been identified yet. Therefore, we aimed to clinically characterize a patient group with syndrome of synovitis acne pustulosis hyperostosis osteitis (SAPHO) (n = 47) and chronic recurrent multifocal osteomyelitis (CRMO)/ chronic non-bacterial osteomyelitis (CNO) (n = 9) and analyze a CRMO candidate gene. METHODS: Clinical data of all patients were collected and assessed for different combinations of clinical symptoms. SAPHO patients were grouped into categories according to the acronym; disease-contribution by pathogens was evaluated. We sequenced coding exons of FBLIM1. RESULTS: Palmoplantar pustular psoriasis (PPP) was the most common skin manifestation in CRMO/CNO and SAPHO patients; most SAPHO patients had sterno-costo-clavicular hyperostosis. The most common clinical category of the acronym was S_PHO (n = 26). Lack of pathogen detection from bone biopsies was more common than microbial isolation. We did not identify autosomal-recessive FBLIM1 variants. CONCLUSIONS: S_PHO is the most common combination of symptoms of its acronym. Genetic analyses of FBLIM1 did not provide evidence that this gene is relevant in our patient group. Our study indicates the need to elucidate SAPHO's and CRMO/CNO's pathogenesis.

Anti-TNFα-therapy as an evidence-based treatment option for different clinical manifestations of psoriatic arthritis.

The development programmes of different TNF-blocking agents in psoriatic arthritis (PsA) not only provided substantial evidence for the therapeutic benefits of the specific treatment options, but also enabled new insights into the differential treatment effects on distinct disease manifestations. For the first time, specific robust evidence for distinctive effects on different manifestations of PsA, as a distinct entity separate from rheumatoid arthritis (RA), has been generated in a standardized way. The clearest evidence was shown for an effect on peripheral arthritis (polyarticular) with ACR20 response rates from 45 up to 58% (vs. 9-24% for placebo), and an inhibition of radiographic progression demonstrated for the first time for a treatment principle in PsA. However, as PsA does not remain confined to the peripheral joints, it was necessary to address diverse patterns of PsA-subtypes in the outcome measurements of the anti-TNF trials. Accordingly, the results of the clinical studies on anti-TNF treatment also have demonstrated efficacy on enthesitis, dactylitis and skin psoriasis, either in sub analysis of results from phase III RCTs, or in additional prospective studies.

A Phase 1b PK/PD Study to Demonstrate Antigen Elimination With RLYB212, a Monoclonal Anti-HPA-1a Antibody for FNAIT Prevention.

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare bleeding disorder of the fetus/newborn caused by development of maternal alloantibodies against fetal human platelet antigens (HPAs), predominantly HPA-1a. Currently there are no treatments available to prevent maternal alloimmunization to HPAs or FNAIT. METHODS: This proof-of-concept study (EudraCT Number: 2021-005380-49) was designed to assess the ability of subcutaneous (SC) RLYB212, a monoclonal anti-HPA-1a antibody, to eliminate HPA-1a positive platelets in an antigen challenge model of a 30 mL fetal-maternal hemorrhage. Subjects were randomized to receive a single SC dose of RLYB212 or placebo on day 1 in a single-blinded manner, followed by transfusion of 10 × 10^9 HPA-1a positive platelets on day 8. RESULTS: Four subjects received 0.09 mg SC RLYB212, 5 received 0.29 mg SC RLYB212, and 2 received placebo. RLYB212 achieved rapid elimination of HPA-1a positive platelets in a concentration-dependent manner, with concentrations as low as 3.57 ng/mL meeting the prespecified proof-of-concept criterion of ≥90% reduction in platelet elimination half-life vs placebo. Following HPA-1a positive platelet transfusion, a rapid decline was observed in the concentration of RLYB212 over a period of 2 to 24 hours, corresponding to the time needed for RLYB212 to bind to ~10% of HPA-1a on cell surfaces. RLYB212 was well tolerated with no reports of drug-related adverse events. CONCLUSION: The data from this study are consistent with preclinical efficacy data and support the potential use of RLYB212 as a prophylactic treatment for FNAIT that prevents maternal HPA-1a alloimmunization during at-risk pregnancies.

Combining seeded region growing and k-nearest neighbours for the segmentation of routinely acquired spatio-temporal image data.

PURPOSE: The acquisition conditions of medical imaging are often precisely defined, leading to a high homogeneity among different data sets. Nonetheless, outliers or artefacts still appear and need to be reliably detected to ensure a reliable diagnosis. Thus, the algorithms need to handle small sample sizes especially, when working with domain specific imaging modalities. METHODS: In this work, we suggest a pipeline for the detection and segmentation of light pollution in near-infrared fluorescence optical imaging (NIR-FOI), based on a small sample size. NIR-FOI produces spatio-temporal data with two spatial and one temporal dimension. To calculate a two-dimensional light pollution map for the entire image stack, we combine region growing and k-nearest neighbours (kNN), which classifies pixels into fore- and background by its entire temporal component. Thus, decision-making on reduced data is omitted. RESULTS: We achieved a [Formula: see text] score of 0.99 for classifying a data set as light polluted or pollution-free. Additionally, we reached a total [Formula: see text] score of 0.90 for detecting regions of interest within the polluted data sets. Finally, an average Dice's coefficient measuring the segmentation performance over all polluted data sets of 0.80 was accomplished. CONCLUSIONS: A Dice's coefficient of 0.80 for the area segmentation does not seem perfect. However, there are two main factors, besides true prediction errors, lowering the score: Segmentation mistakes on small areas lead to a rapid decrease in the score and labelling errors due to complex data. However, in combination with the light-polluted data set and pollution area detection, these results can be considered successful and play a key role in our general goal: Exploiting NIR-FOI for the early detection of arthritis within hand joints.

Machine learning identifies right index finger tenderness as key signal of DAS28-CRP based psoriatic arthritis activity.

Psoriatic arthritis (PsA) is a chronic inflammatory systemic disease whose activity is often assessed using the Disease Activity Score 28 (DAS28-CRP). The present study was designed to investigate the significance of individual components within the score for PsA activity. A cohort of 80 PsA patients (44 women and 36 men, aged 56.3 ± 12 years) with a range of disease activity from remission to moderate was analyzed using unsupervised and supervised methods applied to the DAS28-CRP components. Machine learning-based permutation importance identified tenderness in the metacarpophalangeal joint of the right index finger as the most informative item of the DAS28-CRP for PsA activity staging. This symptom alone allowed a machine learned (random forests) classifier to identify PsA remission with 67% balanced accuracy in new cases. Projection of the DAS28-CRP data onto an emergent self-organizing map of artificial neurons identified outliers, which following augmentation of group sizes by emergent self-organizing maps based generative artificial intelligence (AI) could be defined as subgroups particularly characterized by either tenderness or swelling of specific joints. AI-assisted re-evaluation of the DAS28-CRP for PsA has narrowed the score items to a most relevant symptom, and generative AI has been useful for identifying and characterizing small subgroups of patients whose symptom patterns differ from the majority. These findings represent an important step toward precision medicine that can address outliers.

GWAS meta-analysis of psoriasis identifies new susceptibility alleles impacting disease mechanisms and therapeutic targets.

Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci. To move towards a saturation map of psoriasis susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls and identified 109 distinct psoriasis susceptibility loci, including 45 that have not been previously reported. These include susceptibility variants at loci in which the therapeutic targets IL17RA and AHR are encoded, and deleterious coding variants supporting potential new drug targets (including in STAP2, CPVL and POU2F3). We conducted a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants and cross-referenced these against single cell expression profiles in psoriasis-affected skin, highlighting roles for the transcriptional regulation of haematopoietic cell development and epigenetic modulation of interferon signalling in psoriasis pathobiology.

Metabolic Profiling in Rheumatoid Arthritis, Psoriatic Arthritis, and Psoriasis: Elucidating Pathogenesis, Improving Diagnosis, and Monitoring Disease Activity.

Immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and psoriasis (Ps), represent autoinflammatory and autoimmune disorders, as well as conditions that have an overlap of both categories. Understanding the underlying pathogeneses, making diagnoses, and choosing individualized treatments remain challenging due to heterogeneous disease phenotypes and the lack of reliable biomarkers that drive the treatment choice. In this review, we provide an overview of the low-molecular-weight metabolites that might be employed as biomarkers for various applications, e.g., early diagnosis, disease activity monitoring, and treatment-response prediction, in RA, PsA, and Ps. The literature was evaluated, and putative biomarkers in different matrices were identified, categorized, and summarized. While some of these candidate biomarkers appeared to be disease-specific, others were shared across multiple IMIDs, indicating common underlying disease mechanisms. However, there is still a long way to go for their application in a routine clinical setting. We propose that studies integrating omics analyses of large patient cohorts from different IMIDs should be performed to further elucidate their pathomechanisms and treatment options. This could lead to the identification and validation of biomarkers that might be applied in the context of precision medicine to improve the clinical outcomes of these IMID patients.

An objective, automated and robust scoring using fluorescence optical imaging to evaluate changes in micro-vascularisation indicating early arthritis.

Fluorescence optical imaging technique (FOI) is a well-established and valid method for visualization of changes in micro vascularization at different organ systems. As increased vascularization is an early feature of joint inflammation, FOI is a promising method to assess arthritis of the hands. But usability of the method is limited to the assessors experience as the measurement of FOI is semi-quantitative using an individual grading system such as the fluorescence optical imaging activity score (FOIAS). The goal of the study was to automatically and thus, objectively analyze the measured fluorescence intensity generated by FOI to evaluate the amount of inflammation of each of the subject's joints focusing on the distinction between normal joint status or arthritis in psoriatic arthritis patients compared to healthy volunteers. Due to the heterogeneity of the pathophysiological perfusion of the hands, a method to overcome the absoluteness of the data by extracting heatmaps out of the image stacks is developed. To calculate a heatmap for one patient, firstly the time series for each pixel is extracted, which is then represented by a feature value. Secondly, all feature values are clustered. The calculated cluster values represent the relativity between the different pixels and enable a comparison of multiple patients. As a metric to quantify the conspicuousness of a joint a score is calculated based on the extracted cluster values. These steps are repeated for a total number of three features. With this method a tendency towards a classification into unaffected and inflamed joints can be achieved. However, further research is necessary to transform the tendency into a robust classification model.

Sensory testing and topical capsaicin can characterize patients with rheumatoid arthritis.

BACKGROUND AND OBJECTIVES: Our study aimed at examining the long-time inflammatory effects of rheumatoid arthritis (RA) as chronic immune-mediated disease on pain sensation and neuropathy development compared to healthy subjects (HS). METHODS: We used the quantitative sensory testing (QST) protocol of the German Research Network on Neuropathic Pain and Electroencephalography (EEG)-based contact heat evoked potentials (CHEPs) before and after topical capsaicin application. We recruited 16 RA patients in remission or low disease activity state (mean age: 59.38 years [± 10.18]) and 16 healthy subjects (mean age: 56.69 years [± 8.92]). RESULTS: The application of capsaicin cream on the thigh provoked a stronger effect in HS for both mechanical and heat pain thresholds (MPT and HPT, resp.), according to the area under the receiver operation characteristic (AUROC) (HS: HPT: 0.8965, MPT: 0.7402; RA: HPT: 0.7012, MPT: 0.6113). We observed contrary effects regarding changes in CHEPs (HS: g*max = - 0.65; RA patients: g*max = 0.72). CONCLUSION: As the overall effect of topical capsaicin application was higher in HS for QST, we suggest the existence of a sensitization of TRPV1 channels in RA patients caused by long-time chronical inflammation, despite a lack of clinical signs of inflammation due to adequate treatment. The effect in CHEPs probably uncovers neuropathic symptoms. The effect of topical capsaicin on HPTs and CHEPs can act as a marker for the extent of sensitization and the development of neuropathic symptoms. Further studies are needed to prove if our proposed method can act as a marker for the success of anti-inflammatory treatment. Key Points • The effect of topical capsaicin may represent the extent of TRPV1 sensitization in rheumatoid arthritis. • The effect of topical capsaicin on the amplitude level of CHEPs can unmask neuropathic symptoms. • The effect of topical capsaicin on CHEPs and HPTs can show the long-term consequences and the treatment success of RA patients in remission.

[Treatment strategies in psoriatic arthritis]. / Therapiestrategien der Psoriasisarthritis.

Psoriatic arthritis is a heterogeneous immune-mediated disease that usually involves skin and joints but can also affect entheses and extraarticular structures in the disease course. In addition, associated diseases must be considered when choosing the appropriate therapeutic strategy. Different recommendations for treatment of psoriatic arthritis 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 internationally accepted guidelines frequently used to assist therapeutic decisions in clinical practice. New targeted treatment options developed based on a better knowledge of critical pathogenic pathways, will enlarge our armamentarium for optimized pharmacotherapy of psoriatic arthritis and improve personalized patient care.

Innovative Imaging Technique for Visualization of Vascularization and Established Methods for Detection of Musculoskeletal Inflammation in Psoriasis Patients.

Psoriasis (PsO) is one of the common chronic inflammatory skin diseases. Approximately 3% of the European Caucasian population is affected. Psoriatic arthritis (PsA) is a chronic immune-mediated disease associated with PsO characterized by distinct musculoskeletal inflammation. Due to its heterogeneous clinical manifestations (e.g., oligo- or polyarthritis, enthesitis, dactylitis, and axial inflammation), early diagnosis of PsA is often difficult and delayed. Approximately 30% of PsO patients will develop PsA. The responsible triggers for the transition from PsO only to PsA are currently unclear, and the impacts of different factors (e.g., genetic, environmental) on disease development are currently discussed. There is a high medical need, recently unmet, to specifically detect those patients with an increased risk for the development of clinically evident PsA early to initiate sufficient treatment to inhibit disease progression and avoid structural damage and loss of function or even intercept disease development. Increased neoangiogenesis and enthesial inflammation are hypothesized to be early pathological findings in PsO patients with PsA development. Different disease states describe the transition from PsO to PsA. Two of those phases are of value for early detection of PsA at-risk patients to prevent later development of PsA as changes in biomarker profiles are detectable: the subclinical phase (soluble and imaging biomarkers detectable, no clinical symptoms) and the prodromal phase (imaging biomarkers detectable, unspecific musculoskeletal symptoms such as arthralgia and fatigue). To target the unmet need for early detection of this at-risk population and to identify the subgroup of patients who will transition from PsO to PsA, imaging plays an important role in characterizing patients precisely. Imaging techniques such as ultrasound (US), magnetic resonance imaging (MRI), and computerized tomography (CT) are advanced techniques to detect sensitively inflammatory changes or changes in bone structure. With the use of these techniques, anatomic structures involved in inflammatory processes can be identified. These techniques are complemented by fluorescence optical imaging as a sensitive method for detection of changes in vascularization, especially in longitudinal measures. Moreover, high-resolution peripheral quantitative CT (HR-pQCT) and dynamic contrast-enhanced MRI (DCE-MRI) may give the advantage to identify PsA-related early characteristics in PsO patients reflecting transition phases of the disease.