This week in Rheumatology

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This week: a weight-loss drug added to an IL-17 inhibitor keeps improving psoriatic arthritis at one year, new international treatment guidelines arrive for IgG4-related disease, and a type two anti-CD20 antibody beats placebo in active lupus.

Welcome to This Week in Rheumatology. We're covering 10 papers this week: 3 in depth, 4 in brief, 3 quick signals.

Merola and colleagues report the 52-week results of TOGETHER-PsA in Arthritis and Rheumatology [1]. This is a phase 3b randomised, open-label, assessor-blinded trial in 271 adults with active psoriatic arthritis and obesity or overweight with at least one weight-related comorbidity. It compares ixekizumab plus tirzepatide with ixekizumab alone. The abstract does not state the countries involved. The primary endpoint at week 36 combined an ACR50 response with at least ten percent weight loss, and it had already favoured the combination. By week 52, about 39 percent of patients on the combination met that composite, against under 2 percent on ixekizumab alone. ACR50 on its own kept diverging after week 36, reached by about 44 percent of patients on the combination and about 16 percent on monotherapy, a gap of 28 points. Minimal disease activity, DAPSA, patient-reported and metabolic outcomes also favoured the combination, and safety was consistent with what is known for each drug. The main limitation is that the week 52 outcomes were exploratory and not controlled for multiplicity, and the open-label design leaves room for bias in patient-reported measures. The evidence adds durability to the week 36 finding that treating weight alongside inflammation improves joint outcomes in this group.

In the Lancet Rheumatology, Perugino and colleagues publish the IgG4ward! Foundation treatment guidelines for IgG4-related disease, the first dedicated update since the 2015 international consensus [2]. Sixty-two investigators from 15 countries on six continents took part, including 52 physicians across specialties, eight patients, a caregiver and a medical reference librarian. The group consolidated 183 candidate questions into 40, and a librarian-led systematic literature search informed 28 treatment statements. Each statement was graded with the Oxford Centre for Evidence-Based Medicine levels of evidence. Consensus required more than 80 percent of physicians to agree, and it was reached on 22 of the 28 statements. The prompt for the update was the publication of two phase 3 placebo-controlled trials within the past two years. The main limitation is one the authors state themselves: most statements still rest on low-level evidence, and six statements did not reach consensus. The abstract does not list the individual recommendations, so their content cannot be summarised here. As evidence, the document gathers a fast-changing trial base into one graded framework and names the knowledge gaps that remain.

Also in the Lancet Rheumatology, Li and colleagues report a multicentre, double-blind, placebo-controlled phase 2 trial of obinutuzumab beta, a glycoengineered type two anti-CD20 antibody, in active systemic lupus erythematosus [3]. The trial enrolled 123 patients at 30 tertiary hospitals in China, with a mean age of 36. Ninety-three percent of participants were female and almost all were of Han Chinese ethnicity. Patients received 1000 milligram infusions or placebo on top of standard therapy. At week 12, an SRI-4 response occurred in 52 percent of patients on obinutuzumab beta and about a third of patients on placebo, a statistically significant difference of 19 percentage points. Serious adverse events were similar over 52 weeks, affecting about a fifth of patients in each arm, and the one death, from sepsis, occurred in the placebo group. The main limitations are the early primary endpoint at 12 weeks, the phase 2 size, and a single-country population of largely one ethnicity. The authors describe the findings as support for further evaluation and longer-term safety follow-up. The trial adds placebo-controlled evidence for a type two anti-CD20 approach in active lupus.

Now, four in brief.

Staying with lupus, Tayer-Shifman and colleagues, in Rheumatology, used a healthcare organization database to compare 3,692 adults with lupus against more than 380,000 matched controls over a median of about 13 years [4]. Vaccine uptake was higher in lupus: about three quarters of patients received influenza vaccine, against just over half of controls, and pneumococcal uptake was also higher. Despite this, patients with lupus had about four times the rate of pneumonia hospitalisation, along with higher rates of intensive care admission and death. Older age, comorbidity, higher socioeconomic status and glucocorticoid exposure were linked to uptake. As an observational study, it cannot separate vaccine effects from the risk carried by the disease and its treatment.

In Seminars in Arthritis and Rheumatism, Pichon and colleagues retrospectively studied 465 patients with giant cell arteritis across several centres [5]. About a third of patients relapsed within five years, and headache, jaw claudication and aortic uptake on PET-CT at diagnosis were linked to higher relapse risk. In a subset of 135 patients with serial measurements, normalisation of plasma fibrinogen at one month was associated with roughly a seventh of the relapse risk over two years. A month-one fibrinogen cut-off of 3.77 grams per litre gave a specificity of 90 percent. The cut-off was derived exploratorily in a retrospective cohort, and the authors state it needs external validation.

In Arthritis and Rheumatology, Lee and colleagues used the CARRA Registry, covering 8,093 children with non-systemic juvenile idiopathic arthritis, to build dynamic machine learning models that predict inactive disease about six months ahead, updated at each visit [6]. Three structurally different algorithms performed similarly on an independent test cohort, with moderate discrimination, an area under the curve just under 0.8, and good calibration. Prior disease activity, enthesitis and uveitis were the strongest predictors. The Bayesian network suggested that treatment decisions were mostly reactive to disease activity and shaped by step-therapy requirements. Discrimination is moderate, and the models have not been tested prospectively or outside this registry.

Osteoarthritis and Cartilage carries the ACTIVE trial from Straat and colleagues, a single-blind randomised trial at eleven Dutch centres in 287 working-age, employed patients awaiting total or unicompartmental knee arthroplasty [7]. The personalised eHealth program iRecover, with an activity tracker, a case-manager consultation and goal attainment scaling, was compared with usual care that itself included an eHealth component. Median time to return to self-selected daily activities was 52 days with the program and 75 days with usual care, a median of 23 days sooner. The trial is randomised and multicentre, but its population was restricted to employed patients willing to return to work.

Three quick signals.

In the Annals of the Rheumatic Diseases, Lu and colleagues gave low-dose blinatumomab, a CD19 by CD3 bispecific T-cell engager, to one patient with anti-Mi-2-positive dermatomyositis and one with refractory ANCA-associated vasculitis [8]. Both patients improved, with marked B-cell depletion and no cytokine release syndrome over 14 months. With two patients, this is hypothesis-generating only.

Parikh and colleagues, in Seminars in Arthritis and Rheumatism, scoped 58 studies of anti-phosphatidylserine/prothrombin antibodies in antiphospholipid syndrome [9]. Most studies reported links with thrombosis and with lupus anticoagulant, but assays, cut-offs and persistence testing varied widely. The authors see a selective adjunct role in difficult cases rather than a fourth criterion antibody, and a scoping review cannot weigh effect sizes.

Finally, Ye and colleagues, in Nature Reviews Rheumatology, review checkpoint inhibitor-associated inflammatory arthritis, the most common rheumatic immune-related adverse event [10]. It is mostly seronegative, often persists after immunotherapy stops, and is increasingly managed with conventional and biologic DMARDs to limit glucocorticoids while preserving cancer therapy. This is a narrative review without new data.

Stepping back across this week's papers, the randomised evidence came with early or exploratory endpoints: one trial's longer follow-up was not controlled for multiplicity, and another measured response at an early timepoint. Much of the remaining evidence was retrospective, registry-based or drawn from a handful of patients, and even the new guidelines rest mainly on low-level evidence. Signals of association were common across the week, while prospective validation remained the missing step for most of them.

If you only have time for one paper this week, make it the 52-week TOGETHER-PsA results [1]. It extends the question of treating obesity alongside inflammation in psoriatic arthritis from a single primary timepoint to a full year, while leaving confirmation of the exploratory endpoints to further trials.

That's your roundup for This Week in Rheumatology. The full transcript and references are available on the episode page. See you next week.

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