Katie Robinson

A method using solid-phase microextraction–liquid chromatography-mass spectrometry (SPME-LC-MS) was able to detect fatty acids and similar lipids that may help differentiate patients with psoriasis and 

. This is according to a small study published in

In this Q&A, corresponding author Vinod Chandran, MBBS, MD, DM, PhD, associate professor at the University of Toronto and director of the psoriatic arthritis program at the Schroeder Arthritis Institute in Toronto, discussed the research and its findings.

The researchers aimed to develop an LC-MS method to be used in combination with SPME to analyze fatty acids and similar molecules. They tested 25 chromatographic methods based on published lipid studies on two LC columns. As a proof of concept, serum samples from 27 patients with psoriasis (51% female, mean age 43 years), 26 patients with PsA (46% female, mean age 47 years), and 25 health controls (40% female, mean age 48 years) were processed using SPME and run on LC-MS. The best method for analyzing fatty acids and fatty acid-like molecules identified 18 compounds that were statistically significant between patients with psoriasis and those with PsA.

Approximately a quarter of patients with psoriasis have PsA. There is strong interest in discovering predictive biomarkers for patients with PsA among those with psoriasis, to shorten the time to diagnosis and management.

Metabolomics provides a powerful platform for identifying biomarkers for a complex, multifactorial disease such as PsA. Previous studies have reported examples of lipid dysregulation in serum taken from patients with PsA. Additionally, the high prevalence of metabolic syndrome and cardiovascular events in these patients makes lipids of key interest in psoriatic disease.

We sought to develop a metabolomics method using SPME-LC-MS to analyze serum lipids and identify any significant differences between patients with PsA and those with psoriasis.

What were the surprises from the findings?

The method we developed and optimized was capable of detecting lipids. Several classes of lipids such as acylcarnitines, lysophospholipids, and sphingolipids were significantly different between the patients with psoriasis and those with PsA. Specific focus was placed on valerylcarnitine, due to its confirmed identity using tandem mass spectrometry.

This is preliminary data that provides a good direction for future research in lipid biomarker discovery in psoriatic disease. We have developed and optimized a method that can be used on additional samples in a more expansive follow-up study.

What is the current practice and how could the findings possibly change things?

Currently, PsA is diagnosed in patients with evidence of an inflammatory articular disease, who meet certain clinical, laboratory, and imaging criteria. Patients with psoriasis are often screened at appointments with a dermatologist or general practitioner for signs of inflammatory arthritis.

Discovering accurate and reliable biomarkers for PsA could improve the ability of clinicians external to the field of rheumatology to identify patients with PsA. This may lead to prompt referral to a rheumatologist and early diagnosis and management of PsA by a rheumatologist.

What are the takeaway points for clinicians?

Emerging ‘omics’ sciences such as metabolomics have the potential to identify biomarkers that may aid in improving the diagnosis of PsA. Serum lipids such as valerylcarnitine have been found to be dysregulated in PsA. However, further research is needed to develop a biomarker panel to aid in clinical decision-making.

Koussiouris J, Looby N, Kulasingam V, Chandran V. A Solid-Phase Microextraction-Liquid Chromatography-Mass Spectrometry Method for Analyzing Serum Lipids in Psoriatic Disease. 

. 2023;13(8):963. Published 2023 Aug 20. doi:10.3390/metabo13080963

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In this Q&A, Vinod Chandran, MBBS, MD, DM, PhD, discussed a method to analyze biomarkers that may differentiate patients with psoriasis and psoriatic arthritis.

Q&A: The Role of Metabolomics in the Diagnosis of Psoriatic Arthritis

DNA methylation profiles in CD4+ T-cells differentiate patients with psoriasis from healthy individuals and skin psoriasis from patients with 

, according to a small study published in 

“DNA methylation may represent a stable and reliable biomarker candidate for predicting disease progression from skin psoriasis to PsA, monitoring disease activity, and evaluating treatment response,” wrote first author Valentina Natoli, MD, of the University of Liverpool in the UK, and the University of Genoa in Italy, and colleagues.

The prediction of joint disease in patients with psoriasis, as well as the early and correct diagnosis of PsA in the absence of skin disease are challenging. The pathophysiology of PsA and psoriasis is not fully understood, but the role of effector CD4+ T-cells has been recognized. Epigenetic modifications are believed to be involved in the molecular pathogenesis of PsA and psoriasis. DNA methylation has been linked with pathological effector T-cell phenotypes and inflammatory cytokine expression in psoriasis. In this study, the researchers aimed to identify disease-associated DNA methylation signatures in CD4+ T-cells from patients with PsA and psoriasis which could be used as diagnostic and/or prognostic biomarkers to inform treatment.

Peripheral blood mononuclear cells were collected from 12 patients with chronic plaque psoriasis (median age 41 years, 58% male, Psoriasis Area And Severity Index [PASI] score 41.0), 8 patients with PsA (median age 56.5 years, 50% male, PASI score 6.8) and 8 healthy controls (median age 27 years, 50% male). Patients developed skin psoriasis before the onset of PsA. At the time of enrollment, patients were not taking any relevant systemic immunomodulating therapy. CD4+ T-cells were separated by fluorescence-activated cell sorting. DNA methylation profiling and bioinformatic analyses were performed. The Interferome database was used to identify genes under interferon control, and DNA Methylation Scores were calculated.

The numbers and proportions of CD4+ T-cell subsets did not vary between patients with PsA, those with skin psoriasis, and controls. The researchers identified 883 differentially methylated positions (DMPs) affecting 548 genes between “all” patients with psoriasis and controls. Further analysis separated controls from skin psoriasis and PsA. When promoter DMPs were included, Gene Ontology enrichment analysis identified hypermethylation of genes involved in “regulation of wound healing, spreading of epidermal cells,” “negative regulation of cell-substrate junction organization,” and “negative regulation of focal adhesion assembly.” When controls and “all” patients with psoriasis were compared, 69.2% of DMPs mapped to interferon-related genes. DNA methylation profiles also distinguished patients with PsA from those with skin psoriasis (2949 DMPs/1084 genes) through genes affecting “cAMP-dependent protein kinase inhibitor activity” and “cAMP-dependent protein kinase regulator activity.” Treatment with cytokine inhibitors, including for Interleukin (IL-)17 and Tumor Necrosis Factor (TNF), corrected DNA methylation patterns of IL-17/TNF-associated genes, and methylation scores were linked to PASI scores.

The future application of DNA methylation in “clinical practice requires prospective validation in independent cohorts,” the authors concluded.

Limitations of the study include its small sample size and the age differences between patient groups. Normalization techniques were applied to reduce the impact of these age differences on DNA methylation. The study was not able to assess the effect of DNA methylation on active joint counts and joint disease activity in patients with PsA, as this information was lacking, or on gene transcription, as RNA sequencing was not performed. The authors noted patients with PsA without pre-existing skin involvement will need to be studied to further understand the transition from skin psoriasis to PsA.

Natoli V, Charras A, Hofmann SR, et al. DNA methylation patterns in CD4+ T-cells separate psoriasis patients from healthy controls, and skin psoriasis from psoriatic arthritis. Front Immunol. 2023;14:1245876. Published 2023 Aug 15. doi:10.3389/fimmu.2023.1245876

This small study found DNA methylation profiles in CD4+ T-cells may represent a stable and reliable biomarker.

DNA Methylation Discriminates Between Patients With Psoriatic Arthritis PsA, Skin Psoriasis

, overall adverse events (AE) with tofacitinib (Xeljanz, Pfizer) were consistent with that found in patients with 

. This is according to an analysis of post-marketing surveillance (PMS) data, published in 

, which were aligned with the established safety profile of tofacitinib.

“While these results should be interpreted in the context of the limitations of PMS studies and spontaneous AE reporting, these data provide insight to the clinician regarding expected real-world safety outcomes in patients with PsA treated with tofacitinib,” noted Gerd R Burmester, MD, professor of medicine at the Charité University Hospital in Berlin, Germany, and colleagues.

The safety of tofacitinib, an oral Janus kinase (JAK) inhibitor approved for the treatment of PsA and RA, has been shown in clinical trials of up to 4 years in PsA and 9.5 years in RA. PMS data using AE reports have been previously published for tofacitinib in RA, but not PsA, and there are limited reports of the real-world safety profile of tofacitinib in PsA.

This retrospective analysis included spontaneous AE reports submitted to Pfizer’s safety database from December 2017 — when 5 mg twice daily (immediate release [IR]) and 11 mg once daily (modified release [MR]) doses of tofacitinib were approved for PsA in the US — to November 2021 for PsA, and from November 2012 — when the 5 mg twice daily IR dose was approved for RA in the US followed by the 11 mg once daily MR dose on in February 2016 — to November 2021 for RA.The endpoints included AEs; serious AEs (SAEs); AEs of special interest (AESIs), comprising serious infections, herpes zoster, cardiovascular events, malignancies and venous thromboembolism; and fatal cases. IQVIA global commercial sales data was used to estimate drug exposure. The number, frequency (number of events/100 patient-years' exposure), and reporting rates (RRs) were summarized by indication and formulation.

A total of 73,525 case reports were reviewed, of which 5394 were for PsA and 68,131 were for RA, with 20,706 and 439,370 patient years of exposure, respectively. Of the case reports, 6.8% for PsA and 6.2% for RA did not report a tofacitinib formulation and were excluded. For both PsA and RA, a higher number of AEs were reported for tofacitinib IR than MR (IR/MR: PsA = 8349/7602; RA = 137,476/82,153). However, the RRs for AEs (IR/MR: PsA = 59.6/113.4; RA = 44.0/64.8) and SAEs (PsA = 8.1/13.6; RA = 8.0/9.5) were higher with MR than IR.

The frequency of SAEs, AESIs and fatalities was largely similar across formulations and indications. The most frequently-reported AE preferred terms for PsA and RA, respectively, included drug ineffective, at 20.0% and 17.8%; pain, at 9.7% and 10.6%; condition aggravated, at 9.9% and 10.5%; and headache, at 8.8% and 7.9%. Off-label use was the second most frequently reported AE for PsA, at 10.5% compared with 3.4% in RA. Investigators explained this might be attributable to use of tofacitinib as monotherapy or at a higher dose.

Limitations of the PMS data analysis include the potential for reporting bias, with higher RRs observed in females and in younger patients, and the exposure estimation from commercial sales data. Additionally, more data were available for RA than for PsA, and for IR than for MR tofacitinib. Further, most patients would have received concomitant medication per regulatory labeling, which may have contributed to the AE risk.

The difference in RRs may relate to “differences in cumulative exposure, regional reporting trends or different patient populations,” investigators noted. “Potential trends in reporting by sex and age require further assessment.”

Burmester GR, Coates LC, Cohen SB, et al. Post-Marketing Safety Surveillance of Tofacitinib over 9 Years in Patients with Psoriatic Arthritis and Rheumatoid Arthritis [published online ahead of print, 2023 Jul 17]. Rheumatol Ther. 2023;10.1007/s40744-023-00576-8. doi:10.1007/s40744-023-00576-8

Researchers report on the global real-world safety profile of tofacitinib in psoriatic arthritis. 

Tofacitinib Shows Similar Safety Profile in PsA, RA Post-Marketing Data 

For patients with spondyloarthritis (SpA), including psoriatic arthritis (PsA), and axial SpA (axSpA), 26 disease-modifying anti-rheumatic drugs (DMARDs) are currently in clinical development, including 15 molecules for PsA and 18 for axSpA. This is according to a systematic review published in RMD Open, which found that the target diversity of these molecules was low.

“The identification and development of specific molecular targets and intracellular pathways lead to new therapeutic strategies and will probably improve our therapeutic armamentarium for personalized patient treatment,” wrote Renaud Felten, MD, associate professor at Strasbourg University Hospital in France, and colleagues.

Treatment for SpA has advanced with the introduction of tumor necrosis factor (TNF), interleukin 17 (IL-17), IL-12/IL-23, IL-23, and Janus kinase (JAK) inhibitors. However, a proportion of patients remain non-responders and some DMARDs are ineffective for certain disease manifestations. To find the most suitable treatment for each patient, new molecules and therapeutic strategies are needed.

This systematic review included 17 international clinical trial databases that were searched in February 2023, using 3 keywords “spondyloarthritis,” “ankylosing spondylitis,” and “psoriatic arthritis.” The researchers aimed to provide an overview of potential therapeutic options for the SpA spectrum in the coming years by identifying all DMARDs currently marketed, in clinical development or withdrawn for PsA and axSpA.

Overall, the search identified 3574 trials, with 63 DMARDs evaluated for PsA and axSpA, including 9 conventional synthetic DMARDs (csDMARDs), 37 biological DMARDs (bDMARDs), and 17 targeted synthetic DMARDs (tsDMARDs). Of the 63 DMARDs, 17 were already marketed and 26 were in clinical development.

For PsA, a total of 44 DMARDs were identified, including 5 csDMARDs, 27 bDMARDs, and 12 tsDMARDs. Among the 15 molecules in development, 8 reached phase 2 trials and 7 reached phase 3 trials, while 6 were JAK inhibitors, 6 were IL-17 inhibitors, and 1 was an IL-23 inhibitor.

For axSpA, a total of 44 DMARDs were identified, including 6 csDMARDs, 27 bDMARDs and 11 tsDMARDs. Among the 18 treatments in development, 1 reached phase 1 trials, 10 reached phase 2 trials and 7 reached phase 3 trials. Ten molecules were IL-17 inhibitors, 2 were JAK inhibitors and 2 were granulocyte-macrophage colony-stimulating factor inhibitors.

Of the IL-17 inhibitors in development, netakimab and brodalumab have shown promising phase 3 study results, while bimekizumab is under review by the European Medicines Agency for approval in Europe. Meanwhile, izokibep, a bispecific fusion protein, and sonelokimab, a trivalent nanobody specific to IL-17A, IL-17F and serum albumin, may offer new ways to target IL-17. Among the most advanced JAK inhibitors in clinical development are ivarmacitinib, filgotinib, and deucravacitinib. Four of the 6 JAK inhibitors evaluated for PsA inhibit TYK2, which mediates signaling by cytokines, such as IL-12 and IL-23, that are involved in the pathogenesis of PsA. Meanwhile, new targets are also in development. Zunsemetinib and CC-99677 are oral selective covalent MK2 inhibitors being evaluated in phase 2 trials for PsA and axSpA, respectively.

Limitations to the study included its reliance on a time-dependent update of the DMARD development pipeline and the use of keywords from the description of clinical trials.

“IL-17 inhibitors represent 56% of the DMARDs in development for axSpA and 40% for PsA, whereas JAK inhibitors represent 40% of the DMARDs in development for PsA,” the investigators noted. “With so many new DMARDs in development for SpA, but low target diversity, we will need to develop new strategies or biomarkers to help clinicians make informed treatment decisions.”

Denis A, Sztejkowski C, Arnaud L, Becker G, Felten R. The 2023 pipeline of disease-modifying antirheumatic drugs (DMARDs) in clinical development for spondyloarthritis (including psoriatic arthritis): a systematic review of trials. RMD Open. 2023;9(3):e003279. doi:10.1136/rmdopen-2023-003279

This systematic review found 26 DMARDs in clinical development for spondyloarthritis, including psoriatic arthritis, but their target diversity was low.