The year saw fibromyalgia genes, TYK2 breakthroughs and in vivo CAR T-cell therapy shift the field toward mechanism-driven care.
If 2025 had a single defining rhythm for rheumatology, it was the steady shift from so-called care pathways to mechanism-first care, where genetics, cell lineage and pathway selectivity are starting to dictate what patients are offered and why.
Fibromyalgia was a hot topic for the year, headlined by a massive global study that linked the chronic pain condition to 26 genes associated with brain signalling.
It marks a turning point in understanding the syndrome and framed it as a central nervous system disorder with shared neural risk architecture across pain, fatigue and affective dysregulation, reframing conversations that for decades have been forced to hover around functional explanations.
The study, the largest of its kind, analysed genetic data from 11 international cohorts, including 54,629 individuals diagnosed with fibromyalgia and more than 2.5 million controls.
The researchers uncovered 26 genetic loci linked to fibromyalgia, providing the clearest biological basis yet for a condition long clouded by uncertainty and scepticism. Their findings are yet to be peer-reviewed by a journal but have been published as a pre-print on PubMed Central.
“This work provides the first robust genetic evidence defining fibromyalgia as a central nervous system disorder, thereby establishing a biological framework for its complex pathophysiology and extensive clinical comorbidities,” the researchers wrote.
The mechanistic re-anchoring arrived alongside a rare regulatory payoff in the form of the first new FDA-approved fibromyalgia therapy in more than 15 years.
Cyclobenzaprine HCl (Tonmya) is a first-in-class, non-opioid, once-daily skeletal muscle relaxant structurally related to tricyclic antidepressants, with a rapid-acting sublingual formulation designed for absorption directly into the bloodstream.
The approval was based on data from two pivotal Phase 3 trials, RELIEF and RESILIENT, which involved about 1000 adults.
Across both studies, cyclobenzaprine HCl significantly reduced daily pain scores at 14 weeks compared with placebo, and a higher proportion of patients achieved a clinically meaningful (≥30%) reduction in pain.
Conference coverage was also popular with RR readers this year. Among the best-read stories was a piece from the European Alliance of Associations for Rheumatology Congress detailing a selection of presentations that could help redefine the management of gout.
EULAR continues to recommend maintaining serum urate levels below 6 mg/dL (360 μmol/L), and even more stringently below 5 mg/dL (300 μmol/L) in severe cases.
However, the challenge of achieving these targets in clinical practice remains evident. New data presented at the congress in Barcelona offers hope for more effective and safer urate-lowering strategies, along with emerging insights into the broader health implications of gout control.
Lupus nephritis, historically a ‘choose your poison’ balancing act between renal preservation and steroid burden, also dominated the year’s most practice-changing headlines.
Related
At EULAR, comprehensive updated recommendations for managing lupus nephritis were released, offering a paradigm shift in approach to the complex autoimmune condition.
The recommendations landed as a broader clinical reset, most notably moving away from the old mycophenolate plus glucocorticoids as default framing toward a more nuanced, stratified toolkit aimed at preventing progression rather than just managing flares.
The recommended treatment duration has also been extended, with experts suggesting maintaining therapy for at least three years to prevent disease progression.
Earlier in 2025, we revealed details of the phase 3 REGENCY trial which positioned obinutuzumab added to standard therapy as meaningfully improving complete renal response rates at 76 weeks (with a design that explicitly tested tighter steroid tapering).
It reinforced B-cell depletion as more than a salvage strategy and nudging the field toward earlier, more decisive immunologic escalation when kidney outcomes are on the line.
“These findings are consistent with our current experience and will reiterate the utility of B cell depleting therapies,” said Associate Professor Alberta Hoi, a consultant rheumatologist and head of the lupus clinic at Monash Health.
“Ideally we will have access to obinutuzumab soon, but if not, these findings will consolidate the approach of using rituximab, another B cell depleting therapy,” said Professor Hoi, who was not involved in the study.
Just when lupus care might have felt incremental, an even more disruptive horizon appeared.
It came in the form of an in vivo CD19 CAR T-cell approach reported in NEJM correspondence, where the patient’s own immune system is effectively reprogrammed inside the body to ablate disease-driving B cells, giving rheumatologists a concrete preview of how cell therapy could migrate from oncology into refractory autoimmunity.
Traditional autologous CAR T-cell therapies targeting CD19 have shown promise in autoimmune diseases but are limited by high costs and the need for conditioning chemotherapy.
This novel approach employs cell-targeted lipid nanoparticles (LNPs) or lentiviral vectors to generate CAR T-cells directly in the patient, potentially circumventing these barriers.
CAR T-cell therapy was initially developed to treat certain kinds of tumour and blood diseases, such as lymphoma and leukaemia.
Professor Hoi told RR it was a novel study.
“mRNA technology is not that new, and most of us are familiar with its application in vaccinations, such as covid vaccines,” she said.
“But what is new in this setting is the specific delivery system, the LNP delivery system that has a target to CD8+ T cells, which then helps to offload the messenger package, to the right cellular type to convert them in vivo into CD19 targeting cells.
“I presume the main advantage is the manufacturing cost is significantly less than, say, a monoclonal antibody.”
Across the broader inflammatory spectrum, the year’s best stories clustered around two truths – that better targeting can expand the oral and biologic armamentarium; and that not every mechanism translates into clinical wins.
In psoriatic arthritis, zasocitinib emerged as the newest entrant in the TYK2 race.
The oral agent engineered for sharper TYK2 selectivity than earlier JAK-pathway approaches delivered clinically meaningful improvements in joint and skin outcomes within 12 weeks in a phase 2b program.
Zasocitinib is already drawing comparisons with deucravacitinib – the first oral TYK2 inhibitor approved by the TGA in 2022 for the treatment of moderate to severe PsA.
Both drugs work by blocking TYK2 activity through the JH2 pseudokinase domain, making them more selective than traditional JAK inhibitors, which have been linked to serious safety concerns like cancer and cardiovascular events.
But zasocitinib may take TYK2 selectivity a step further. Developed through a computational design approach, it includes a unique methocyclobutyl ring that enhances its ability to specifically target TYK2 while avoiding similar enzymes like JAK1 and JAK2. This structural difference could translate to fewer off-target effects, potentially improving both safety and tolerability.
The study had some limitations, including a potential lack of statistical power and a lack of hierarchical testing approach for secondary and exploratory endpoints, owing to the small sample size.
“This was particularly evident for endpoints with impacts on domains only present in subsets of patients, such as dactylitis and enthesitis,” the researchers wrote.
“Larger studies are required to further assess the effect of zasocitinib on these disease domains.”
It won’t come as any surprise GLP-1 receptor agonists were another hot topic. One of the most read pieces on the topic was one in which researchers found semaglutide and tirzepatide may reduce RA disease activity and pain while improving metabolic risk profiles.
The findings open the door to a possible dual-purpose role for these drugs in treating both systemic inflammation and cardiovascular comorbidity in RA.
“To our knowledge, this is the first study to examine the effect of GLP-1 RA use on RA disease activity and cardiovascular risk profile in patients with RA and overweight or obesity,” the researchers wrote in ACR Open Rheumatology.
“We found that GLP-1 RA use was associated with significant improvement in RA disease activity, pain and cardiovascular risk profile. The presence of diabetes did not meaningfully affect these results, suggesting that these benefits were not unique to patients with diabetes.”
At the edges of classical rheumatology, the field also got a reminder of both opportunity and restraint.
ACR brought fresh evidence that a new VEXAS concept may be driven by IDH1/2 mutations in haematopoietic stem cells, pointing to actionable, oncology-derived targeted therapies for systemic autoinflammation.
The research included scientists from around the US, including New York University School of Medicine and Washington University School of Medicine, as well as Associate Professor Devendra Hiwase, a clinician‐scientist and consultant haematologist at the University of Adelaide’s Medical School, who also holds roles at the South Australian Health and Medical Research Institute and the haematology department at the Royal Adelaide Hospital.
The researchers have identified mutations in the IDH1 and IDH2 genes as potential drivers of inflammation in patients with systemic autoinflammatory disease (SAID) who test negative for UBA1 mutations – long known to cause the rare VEXAS syndrome.
VEXAS syndrome is a rare autoinflammatory disease first described in 2020 by researchers at the US National Institutes of Health, with the acronym reflecting key features of the disorder, including vacuoles, E1 enzyme, X-chromosome linked, autoinflammatory and somatic mutations.
Because the mutation is on the X chromosome, the syndrome predominantly affects men aged over 40 years. Women are rarely affected, but cases have been reported in those with X-chromosome monosomy, such as Turner syndrome or mosaicism.
VEXAS syndrome manifests with a combination of systemic inflammatory and hematologic features including recurrent fevers, skin rashes (especially red, painful nodules or vasculitic lesions), chondritis, lung inflammation, arthritis, venous thromboembolism, fatigue and weight loss, low blood counts (including anaemia, low platelets or white cells) and bone marrow with vacuoles in precursor cells.
Meanwhile, the secukinumab GCA trial underscored how even biologics with strong mechanistic plausibility can still stumble on primary endpoints, leaving only tentative steroid-sparing signals to justify another round of careful testing.
Pharma company Novartis announced that its phase 3 trial of secukinumab in patients with giant cell arteritis did not meet its primary endpoint of achieving sustained remission at 52 weeks.
The investigational use of secukinumab (Cosentyx) in patients with newly diagnosed or relapsing GCA, had generated high expectations following promising phase 2 data.
The randomised, double-blind, placebo-controlled, parallel-group study known as GCAptAIN, was conducted across 27 countries. It evaluated secukinumab in two dosing arms (300mg and 150mg), each paired with a 26-week glucocorticoid (GC) taper and compared them to a placebo group with a 52-week GC taper.
Secukinumab did not demonstrate a statistically significant improvement in sustained remission at Week 52 compared to placebo, Novartis said in a statement.
Despite the unmet primary and secondary endpoints, Novartis noted numerically favourable trends in the secukinumab arms, particularly regarding cumulative steroid dose and steroid-related toxicity. And importantly for clinicians, the safety profile of secukinumab remained consistent with its established record in other immune-mediated diseases, reinforcing confidence in its tolerability.
Novartis will complete a full evaluation of the GCAptAIN data and share the results at a later date.
This will be the last Rheumatology Republic e-news for 2025. We look forward to seeing you back here in 2026. If you have any story ideas or burning issues you think we should follow up, get in touch with us by email.
Wishing you all a safe, healthy and happy holiday season!
Amanda Sheppeard – editor, Specialist Titles and Clinical Update
amanda@medicalrepublic.com.au
Lincoln Tracy– deputy editor, Specialist Titles and Clinical Update
lincoln@medicalrepublic.com.au
Laura Andronicos – journalist, Specialist Titles and Clinical Update
laura@medicalrepublic.com.au
