Disruption of placental ACKR3 impairs growth and hematopoietic development of offspring.

ACKR3 scavenges and degrades the stem cell recruiting chemokine CXCL12, which is essential for proper embryonic and, in particular, haematopoietic development. Here, we demonstrate strong expression of ACKR3 on trophoblasts. Using a maternally administered pharmacological blocker and Cre-mediated genetic approaches, we demonstrate that trophoblast ACKR3 is essential for preventing movement of CXCL12 from the mother to the embryo, with elevated plasma CXCL12 levels being detected in embryos from ACKR3-blocker-treated mothers. Mice born to mothers treated with the blocker are lighter and shorter than those born to vehicle-treated mothers and, in addition, display profound anaemia associated with a markedly reduced bone marrow haematopoietic stem cell population. Importantly, although the haematopoietic abnormalities are corrected as mice age, our studies reveal a postnatal window during which offspring of ACKR3-blocker-treated mice are unable to mount effective inflammatory responses to inflammatory/infectious stimuli. Overall, these data demonstrate that ACKR3 is essential for preventing CXCL12 transfer from mother to embryo and for ensuring properly regulated CXCL12 control over the development of the haematopoietic system.

Differences in transcriptional changes in psoriasis and psoriatic arthritis skin with immunoglobulin gene enrichment in psoriatic arthritis.

OBJECTIVES: Approximately 20% of people with psoriasis develop PsA. Although genetic, clinical and environmental risk factors have been identified, it is not known why some people with psoriasis develop PsA. The skin disease is traditionally considered the same in both. This study compares transcriptional changes in psoriasis and PsA skin for the first time. METHODS: Skin biopsies were collected from healthy controls (HC), and uninvolved and lesional skin from patients with PsA. Bulk tissue sequencing was performed and analysed using the pipeline Searchlight 2.0. Transcriptional changes in PsA skin were compared with existing sequencing data from participants with psoriasis without PsA (GSE121212). Psoriasis and PsA datasets could not be directly compared as different analysis methods were used. Data from participants with PsA in the GSE121212 dataset were used for validation. RESULTS: Skin samples from 9 participants with PsA and 9 HC were sequenced, analysed and compared with available transcriptomic data for 16 participants with psoriasis compared with 16 HC. Uninvolved skin in psoriasis shared transcriptional changes with lesional skin in psoriasis, but uninvolved skin in PsA did not. Most transcriptional changes in psoriasis and PsA lesional skin were shared, but immunoglobulin genes were upregulated in PsA lesional skin specifically. The transcription factor POU2F1, which regulates immunoglobulin gene expression, was enriched in PsA lesional skin. This was confirmed in the validation cohort. CONCLUSIONS: Immunoglobulin genes are upregulated in PsA but not in psoriasis skin lesions. This may have implications for the spread from the cutaneous compartment to other tissues.

Young-GRAPPA (Y-GRAPPA) at the 2022 GRAPPA Annual Meeting: One Year in Y-GRAPPA. Where Do We Stand, Where Do We Go?

Young-GRAPPA (Y-GRAPPA) was introduced at the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) annual meeting. Here we present the 1-year progress of Y-GRAPPA and future plans of this enthusiastic group of young clinicians and early career researchers interested in psoriasis and psoriatic arthritis.

Interleukin (IL)-17 Versus IL-23 Inhibitors: Which Is Better to Treat Patients With Moderate-to-Severe Psoriasis and Mild Psoriatic Arthritis in Dermatology Clinics?

Interleukin (IL)-17 and IL-23 inhibitors are both approved for the treatment of moderate-to-severe plaque psoriasis (PsO), as well as psoriatic arthritis (PsA). In the absence of head-to-head studies, it is not clear which agent is better suited to treat patients with moderate-to-severe PsO and mild PsA. During the 2022 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) conference, Dr. April Armstrong and Dr. Joseph Merola debated which of these 2 biologic classes should be used in this patient population. Armstrong argued in favor of IL-17 inhibition, whereas Merola presented reasons for IL-23 inhibition. An overview of their main arguments is described in this manuscript.

Cutaneous lesions in psoriatic arthritis are enriched in chemokine transcriptomic pathways.

OBJECTIVES: Skin from people with psoriasis has been extensively studied and is assumed to be identical to skin from those with psoriatic arthritis (PsA). Chemokines and the CC chemokine scavenger receptor ACKR2 are upregulated in uninvolved psoriasis. ACKR2 has been proposed as a regulator of cutaneous inflammation in psoriasis. The aim of this study was to compare the transcriptome of PsA skin to healthy control (HC) skin and evaluate ACKR2 expression in PsA skin. METHODS: Full-thickness skin biopsies from HC, lesional and uninvolved skin from participants with PsA were sequenced on NovaSeq 6000. Findings were validated using qPCR and RNAscope. RESULTS: Nine HC and nine paired PsA skin samples were sequenced. PsA uninvolved skin was transcriptionally similar to HC skin, and lesional PsA skin was enriched in epidermal and inflammatory genes. Lesional PsA skin was enriched in chemokine-mediated signalling pathways, but uninvolved skin was not. ACKR2 was upregulated in lesional PsA skin but had unchanged expression in uninvolved compared with HC skin. The expression of ACKR2 was confirmed by qPCR, and RNAscope demonstrated strong expression of ACKR2 in the suprabasal layer of the epidermis in PsA lesions. CONCLUSION: Chemokines and their receptors are upregulated in lesional PsA skin but relatively unchanged in uninvolved PsA skin. In contrast to previous psoriasis studies, ACKR2 was not upregulated in uninvolved PsA skin. Further understanding of the chemokine system in PsA may help to explain why inflammation spreads from the skin to the joints in some people with psoriasis.

Young-GRAPPA at the Annual GRAPPA Meeting: Presentation of a New Group Within GRAPPA and Its Vision.

At the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) annual meeting, a separate group was created (Young-GRAPPA) to address the challenges of young researchers and physicians beginning their careers. This paper presents the initial organizational framework and different components and aims of this group. We were able to enroll over 50 young researchers as a result of this meeting.

GRAPPA Trainee Symposium 2020: A Summary of Oral and Poster Presentations.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) held a trainee symposium at its 2020 virtual meeting. Dermatology and rheumatology trainees presented their work on psoriasis and psoriatic arthritis. This report briefly reviews the 5 oral presentations and 25 posters presented at the event.

GRAPPA Trainee Symposium 2020: A Summary of Oral and Poster Presentations.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) held a trainee symposium at its 2020 virtual meeting. Dermatology and rheumatology trainees presented their work on psoriasis and psoriatic arthritis. This report briefly reviews the 5 oral presentations and 25 posters presented at the event.

Synovial biopsies in clinical practice and research: current developments and perspectives.

Synovial biopsy techniques have developed and widely expanded over the past few years, in particular due to the development of ultrasound-guided procedures. This article reviews the different techniques, clinical applications, and the latest advances in translational research as well as current challenges and perspectives. The first part focuses on different techniques available for biopsy, along with their feasibility, success rate, tolerance, and training requirements. In the second part, clinical applications are described. Data on diagnostic performances are reported, especially regarding septic arthritis. Translational research applications are described and explained in the final part, from the early histological studies and the first description of pathotype to more recent technologies involving -omics. Latest developments involving single-cell RNA sequence analysis have allowed the discovery of new cell subpopulations with remarkable roles in RA pathophysiology. These studies pave the ground for the discovery of new therapeutic targets and the implementation of personalized therapy in RA. Key Point •This review provides an overview of synovial biopsy techinques and applications especially in clinical and translational research.

Role of placental inflammatory mediators and growth factors in patients with rheumatic diseases with a focus on systemic sclerosis.

OBJECTIVES: Pregnancy in SSc is burdened with an increased risk of obstetric complications. Little is known about the underlying placental alterations. This study aimed to better understand pathological changes and the role of inflammation in SSc placentas. Leucocyte infiltration, inflammatory mediators and atypical chemokine receptor 2 (ACKR2) expression in SSc placentas were compared with those in other rheumatic diseases (ORD) and healthy controls (HC). METHODS: A case-control study was conducted on eight pregnant SSc patients compared with 16 patients with ORD and 16 HC matched for gestational age. Clinical data were collected. Placentas were obtained for histopathological analysis and immunohistochemistry (CD3, CD20, CD11c, CD68, ACKR2). Samples from four SSc, eight ORD and eight HC were analysed by qPCR for ACKR2 expression and by multiplex assay for cytokines, chemokines and growth factors involved in angiogenesis and inflammation. RESULTS: The number of placental CD3, CD68 and CD11 cells was significantly higher in patients affected by rheumatic diseases (SSc+ORD) compared with HC. Hepatocyte growth factor was significantly increased in the group of rheumatic diseases patients (SSc+ORD) compared with HC, while chemokine (C-C motif) ligand 5 (CCL5) was significantly higher in SSc patients compared with ORD and HC. CCL5 levels directly correlated with the number of all local inflammatory cells and higher levels were associated with histological villitis. CONCLUSIONS: Inflammatory alterations characterize placentas from rheumatic disease patients and could predispose to obstetric complications in these subjects.

In Human Autoimmunity, a Substantial Component of the B Cell Repertoire Consists of Polyclonal, Barely Mutated IgG+ve B Cells.

B cells are critical for promoting autoimmunity and the success of B cell depletion therapy in rheumatoid arthritis (RA) confirms their importance in driving chronic inflammation. Whilst disease specific autoantibodies are useful diagnostically, our understanding of the pathogenic B cell repertoire remains unclear. Defining it would lead to novel insights and curative treatments. To address this, we have undertaken the largest study to date of over 150 RA patients, utilizing next generation sequencing (NGS) to analyze up to 200,000 BCR sequences per patient. The full-length antigen-binding variable region of the heavy chain (IgGHV) of the IgG B cell receptor (BCR) were sequenced. Surprisingly, RA patients do not express particular clonal expansions of B cells at diagnosis. Rather they express a polyclonal IgG repertoire with a significant increase in BCRs that have barely mutated away from the germline sequence. This pattern remains even after commencing disease modifying therapy. These hypomutated BCRs are expressed by TNF-alpha secreting IgG+veCD27-ve B cells, that are expanded in RA peripheral blood and enriched in the rheumatoid synovium. A similar B cell repertoire is expressed by patients with Sjögren's syndrome. A rate limiting step in the initiation of autoimmunity is the activation of B cells and this data reveals that a sizeable component of the human autoimmune B cell repertoire consists of polyclonal, hypomutated IgG+ve B cells, that may play a critical role in driving chronic inflammation.

Interleukin-12 and interleukin-23 inhibition in psoriatic arthritis.

The cytokines interleukin (IL)-12 and interleukin (IL)-23 have been implicated variously in the pathogenesis of psoriasis and psoriatic arthritis (PsA). By corollary, the IL-12/23 inhibitor, Ustekinumab has been developed as an approved therapeutic for the skin and musculoskeletal syndrome of psoriasis / PsA. This review describes briefly the role of IL-12 and IL-23 in the pathophysiology of psoriatic arthritis and evaluates trial data that support its clinical use in psoriasis and different manifestations of psoriatic arthritis. The next steps towards targeting this pathway also are discussed.

Identification of urinary peptide biomarkers associated with rheumatoid arthritis.

Early diagnosis and treatment of rheumatoid arthritis are associated with improved outcomes but current diagnostic tools such as rheumatoid factor or anti-citrullinated protein antibodies have shown limited sensitivity. In this pilot study we set out to establish a panel of urinary biomarkers associated with rheumatoid arthritis using capillary electrophoresis coupled to mass spectrometry. We compared the urinary proteome of 33 participants of the Scottish Early Rheumatoid Arthritis inception cohort study with 30 healthy controls and identified 292 potential rheumatoid arthritis-specific peptides. Amongst them, 39 were used to create a classifier model using support vector machine algorithms. Specific peptidic fragments were differentially excreted between groups; fragments of protein S100-A9 and gelsolin were less abundant in rheumatoid arthritis while fragments of uromodulin, complement C3 and fibrinogen were all increasingly excreted. The model generated was subsequently tested in an independent test-set of 31 samples. The classifier demonstrated a sensitivity of 88% and a specificity of 93% in diagnosing the condition, with an area under the receiver operating characteristic curve of 0.93 (p<0.0001). These preliminary results suggest that urinary biomarkers could be useful in the early diagnosis of rheumatoid arthritis. Further studies are currently being undertaken in larger cohorts of patients with rheumatoid arthritis and other athridities to assess the potential of the urinary peptide based classifier in the early detection of rheumatoid arthritis.

Analysis and modelling of cholesterol and high-density lipoprotein cholesterol changes across the range of C-reactive protein levels in clinical practice as an aid to better understanding of inflammation-lipid interactions.

OBJECTIVES: Raised total cholesterol (TC) and reduced high-density lipoprotein (HDL) cholesterol levels are established cardiovascular disease (CVD) risk factors. However, in autoimmune conditions the lipid-CVD association appears paradoxical, with inflammation as a potential confounding factor. We therefore sought to model the relationship between systemic inflammatory illness and lipid levels using C-reactive protein (CRP) as the prototypical marker of inflammation. Our hypothesis was that there would be an inverse association between raised CRP levels and both TC and HDL-cholesterol levels. METHODS: Results from samples analysed simultaneously for CRP and lipids in a 6-month period were collected retrospectively from a large city hospital laboratory database that collates results from both primary and secondary care. The relationships between CRP and lipids were determined using graphical techniques and empirical, non-parametric, best fit models. RESULTS: A total of 11 437 blood samples was included. We identified a significant (p<0.001) biphasic relationship between TC and CRP: TC increased within the healthy CRP range of less than 5 mg/l, but decreased with CRP levels above 10 mg/l. The two effects approximately cancelled each other out in the intermediate CRP range of 5-10 mg/l. There was an inverse relationship between HDL-cholesterol and CRP. CONCLUSIONS: Lipid levels change significantly during inflammatory illness in a population with both acute and chronic conditions. These results provide a strong epidemiological basis for the better understanding of lipid changes in inflammatory conditions and with anti-inflammatory therapies.

Cardiovascular and metabolic risks in psoriasis and psoriatic arthritis: pragmatic clinical management based on available evidence.

Several studies suggest that patients with psoriasis and, in particular, psoriatic arthritis (PsA) are at increased risk of cardiovascular disease. These patients are also more likely to be obese and to have diabetes and fatty liver disease. This article discusses the association between psoriasis and PsA and cardiometabolic disorders, emphasising the need for better consideration of simple lifestyle interventions. It also highlights areas for future research and proposes a simple and pragmatic test portfolio to screen for cardiovascular risk and metabolic disorders in patients at higher risk.