In spondyloarthritis (SpA), the wealth of biologic and disease-modifying anti-rheumatic drug (DMARD) options still leaves some patients unsatisfied with their treatment outcomes, most likely due to residual disease.
This year, the flurry of drug development in SpA continued, including promising phase II-III trial data released for the selective Janus kinase (JAK) inhibitor filgotinib and the anti-interleukin (IL)-17A monoclonal antibody vunakizumab in axial SpA (axSpA).
Assessment of SpondyloArthritis International Society (ASAS) improvements of 40% or better (ASAS40) occurred in 35% to 40% of filgotinib recipients versus 18% to 21% of placebo recipients, while ASAS improvements of 20% or better (ASAS20) were reported for 65.6% of vunakizumab patients versus 42.5% of placebo patients.
The trials were deemed successful despite ASAS responses falling well short of 100%, in line with what is acceptable for the many medications already on the market for varying subsets of SpA.
“It is common to have persistent symptoms despite treatment of inflammation. Firstly, when you look at the results from successful clinical trials for most DMARDs approved for axSpA … ASAS40 response is achieved by about 40% to 55% of patients,” Abhijeet Danve, MD, MHS, of the Yale School of Medicine in New Haven, Connecticut, told MedPage Today. “That informs us that patients will have residual symptoms despite treating the inflammation adequately.”
ASAS40 and ASAS20 are subjective measures of health recovery in terms of patient global assessment of the disease, spinal pain, function, and inflammation: ASAS40 is defined as a ≥40% improvement and an absolute improvement from baseline of two or more units in at least three of the four domains without any worsening in the remaining domain, and ASAS20 is defined as a ≥20% improvement and an absolute improvement from baseline of one or more units in at least three of the four domains and no major worsening in the remaining domain.
A major issue of tracking progress in SpA is the reliance on patient-reported outcomes and the lack of a good objective measure of disease activity.
“Frequently, there is contribution from the nociplastic pain,” Danve noted. “Some of the spinal symptoms can be from concomitant degenerative disc disease or facet arthritis, and distinguishing between the pain from the degenerative and inflammatory components is difficult owing to lack of specific monitoring biomarkers.”
Lianne Gensler, MD, of the University of California San Francisco, stressed that there will never be a physical exam that shows inflammation of axial joints of the spine and sacroiliac joints specifically. “It’s a huge problem in our field because we don’t have a physical exam … that really clearly says, ‘Oh, like rheumatoid arthritis, this patient has ongoing joint swelling.'”
“The closest you can come to that is an MRI,” she told MedPage Today, “but that one alone is not specific” and “you can’t do an MRI every time a patient has symptoms.”
SpA is itself a heterogeneous family of diseases characterized by inflammation in the spine and/or the entheses, the joint-like connective tissues where tendons and ligaments insert into bones. AxSpA is one manifestation affecting the spine, commonly causing lower back pain and stiffness, and can be split into radiographic (i.e., ankylosing spondylitis [AS]) or non-radiographic subsets, while peripheral SpA, a sister condition, can cause limb discomfort such as heel pain and plantar fasciitis.
Generally, pharmacological treatment of these sometimes-overlapping SpA conditions means initial therapy with nonsteroidal anti-inflammatory drugs, and in some cases glucocorticoids, before the patient resorts to the various DMARDs on the market. In a 2026 guideline update, the American College of Rheumatology endorsed tumor necrosis factor inhibitors and IL-17 blockers preferentially over JAK inhibitors for initial biologic DMARD treatment of AS and axSpA.
But what happens when patients still complain of residual symptoms after DMARD therapy?
“Many physicians who are treating patients don’t recognize that these symptoms are not necessarily driven by objective inflammation, and there’s a trigger response to change the treatment because a patient has residual symptoms. That’s a huge problem,” Gensler said.
“There’s certainly some patients who can be treatment refractory, but most patients that have ongoing symptoms actually [have] other factors, whether it’s damage, nociplastic pain, or comorbidities driving symptoms,” such as depression and obesity, she noted.
In these cases of residual symptoms, Danve suggested physical therapy and regular exercise, as well as use of medications such as gabapentin, selective serotonin reuptake inhibitors, and muscle relaxants to help the nociplastic pain.
“Having right expectations is important to avoid rapid cycling through DMARDs,” he said.
With residual disease being a major concern to researchers, several groups have recently tried to establish various terms to describe persistent symptoms and inadequate response to targeted therapies.
In 2025, ASAS released its consensus-based definition of difficult-to-manage (D2M) axial SpA: failure of at least two biologic or targeted synthetic DMARDs, suboptimal disease control, and the perception of problematic signs and symptoms by both rheumatologists and patients. Treatment-refractory disease is considered a subset within D2M that requires a history of treatment failure, the presence of objective signs of inflammatory activity, and the exclusion of non-inflammatory reasons for nonresponse.
Supporting the idea that many D2M symptoms are not coming from inflammation, Gensler cited her own group’s research and estimated that treatment-refractory patients, who do have objective signs of inflammation, make up just 10% of the D2M pool.
She urged rheumatologists to “take a step back and say, ‘Do I believe that the ongoing symptoms of disease activity are coming from inflammation?'”
They need to be “holistic” about assessing all the things that can drive symptoms and addressing them separately, she said, or getting patients to a clinician who will address them.
