Key Research in Axial Spondyloarthritis Encapsulated

Adobe Stock | Sebastian Kaulitzki

10 abstracts from ACR Convergence 2024 stand out from the pack

WASHINGTON, D.C.—Our understanding of axial spondyloarthritis (axSpA) has really changed, especially with regard to male-female differences. In this report, we identify important research on axSpA presented at ACR Convergence 2024, summarize the abstracts and comment on why each is important, addressing the relevance for clinicians and the potential impact on future research.

Has the Pattern of axSpA Shifted?

Abstract 0558: Coates et al.¹

The diagnosis of axSpA is often delayed, as demonstrated clearly in this study from a large claims database. In this analysis, delay was considered as primary (i.e., the time from the earliest diagnosis of back pain until the first rheumatology visit) or secondary (i.e., the time from the first rheumatology visit to the diagnosis of axSpA). For the population as a whole, 41% had a total time to diagnosis of five years or more. Among those patients who saw a rheumatologist before diagnosis, the median primary delay was 2.62 years (1.07, 4.60) years while the secondary delay was 1.69 (0.24 to 3.72) years.

For a condition such as axSpA, delay may not be unexpected for important reasons: Back pain is common in the population; symptoms of axSpA are not well understood by the various providers who see patients with back pain; and imaging studies are often unrevealing. Delays by rheumatologists are perhaps more interesting and surprising because rheumatologists should be well aware of the complicated issues in diagnosis. Nevertheless, even rheumatologists may have difficulties in determining the presence of axSpA as the source of patient symptomatology.

One factor that may be contributing to delay relates to bias. The classic description of axSpA suggests a disease of young men. In this study, however, the mean age of axSpA diagnosis was 53.2 (14.9) years and 63.5% of the patients were women. These numbers are not far away from those of patients with rheumatoid arthritis (RA). Has the pattern of axSpA changed over the years, or is it our understanding of disease that has changed so that even rheumatologist may be uncertain about its presence?

The authors conclude, “This study highlights the need for medical education on inflammatory back pain and axSpA.” I agree, but for education to be effective, it is essential to know what should be taught.

The Importance of Study Populations

Abstract 0539: Puche-Larrubia et al.²

Rheumatic diseases are worldwide in prevalence, but important differences in clinical presentations can occur among patients in different countries, as well as racial and ethnic groups. These differences are important in understanding disease pathogenesis, as well as determining clinical outcomes. Using two large registries, this study compared clinical and demographic features of Ibero-American patients with radiographic axial SpA (r-axSpA) with those of European patients.

The study found that, compared with patients from Europe, Ibero-Americans patients showed more peripheral manifestations, more damage and worse function. The Ibero-Americans also had greater use of conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) and lesser use of biologic DMARDs. Disease manifestations also varied among racial groups. The obvious question relates to the origin of these differences and the respective roles of environment (including diet) and genetic factors in determining clinical manifestations because— part of the environment—access to medication also impacts outcomes, such as damage.

Although much research is needed to understand the interplay of the various factors in disease etiology and outcome, these differences are currently very relevant in interpreting clinical trials, which increasingly involve patients from all over the world. In discussing results of clinical trial, I have long believed that it is important to consider the composition of the study population in terms of the country of origin and region of the world of the trial sites. This study reinforces this view.

Sex-Related Differences in Biologic Efficacy

Abstract 0599: Chaudhary et al.³

axSpA comes in two main varieties (i.e., radiographic and non-radiographic) and affects both sexes, albeit with some differences. These differences include certain clinical findings and, possibly, pathogenesis because the frequency of HLA-B27 positivity is higher in men than women. To determine whether men and women also differ in their response to biologic therapy, Chaudhary et al. performed a systematic review and meta-analysis of the efficacy of tumor necrosis factor (TNF) inhibitors and IL-17 inhibitors in 11 studies, including clinical trials and registries, as well as retrospective and prospective cohort studies.

As expected, the frequency of HLA-B27 positive patients was higher in men than women. Overall, the studies indicated that men achieve higher response rates than women and that men are more likely to achieve a low disease activity state than women when treated with biologics.

Many explanations for these findings are possible (e.g., differences in sex-based responses to cytokine inhibition and the impact of HLA-B27 on underlying pathogenesis). Because dosing was not weight based, a difference in drug levels in men and women should not be an explanation unless female sex leads to differences in drug metabolism or clearance, including generation of anti-drug antibodies.

Although much further study of male-female differences in axSpA is indicated, it seems reasonable that reports of clinical studies should provide separate results on the basis of both HLA-B27 positivity and sex. Such an approach would be consistent with progress to personalized medicine which will be based on a host of biomarkers whose number will only increase in the future. Analysis of the impact of male-female differences seem an easy way to start.

A Uterine-Joint Axis

Abstract 1708: Mauro et al.⁴

This study combines three exciting areas of interest in rheumatology: male-female differences in disease manifestations; the role of the microbiome in immunopathogenesis; and the use of gene-expression analysis to elucidate underlying disease mechanisms.

Extending ideas on the gut-joint axis in the pathogenesis of axSpA, Mauro et al. explored a uterine-joint axis by assessing the microbiota in vaginal, cervical and uterine swabs using 16 rRNA sequencing. The study found evidence of genital dysbiosis in axSpA patients. A reduction in Lactobaccilli and an increase in Gardnerella vaginalis were both observed. Further, single-cell RNA sequencing of menstrual blood from patients with axSpA showed a strong imbalance of monocytes and IL-7R positive cells compared with those of healthy controls.

A companion study in SKG mice also showed evidence of genital inflammation and specific gene clustering in genital tract tissues compared with those of control BALB/c mice.

Although this study involved only a small number of patients, the results are nevertheless provocative. They are a reminder that the gut represents only one microbiome and that the study of the uterine microbiome may provide essential data to elucidate male-female differences in inflammatory disease.

Vitamin D Supplementation

Abstract 0565: Lichaa et al.⁵

axSpA has gone by other names, including Bechterew’s disease, Marie-Strumpell disease and, of course, ankylosing spondylitis (AS). AS is, in fact, a misleading term because most patients don’t ankylose and, indeed, many do not show any radiographic findings. The study by Lichaa and colleagues investigates determinants of ankylosis based on imaging by an experienced radiologist, comparing those with ankylosis and those without matching for relevant factors. As a possible determinant for ankylosis, serum vitamin D levels were assessed after occurrence of ankylosis.

In the patient cohort studied, 16% had ankylosis and were more likely to have low vitamin levels compared to matched controls (18.63 vs 24.36 ng/ml). This finding is interesting although the mechanisms by which a low vitamin D level would affect bony ankylosing is speculative. Given the simplicity of vitamin D supplementation and possible other health benefits, a trial of vitamin D supplementation is certainly warranted, but likely difficult to conduct because of the length of the study and uncertainty in level of vitamin D that should be targeted. Nevertheless, it seems very reasonable to assess vitamin D levels as part of the evaluation of patients with axSpA and consider supplementation with the chance that it reduces the progression to AS.

Potential New Biomarker

Abstract 0580: Talukdar et al.⁶

Transcriptomic analysis of peripheral blood cells is a powerful biomarker approach that can generate an abundance of information on the transcriptomic profile of lymphocyte and monocyte populations. The amount of data is truly “big.” One goal of transcriptional analysis is the development of predictive biomarkers to characterize treatment responders and non-responders, with the eventual goal of matching the patient to the most effective drug. The study by Talukdar is a step in this direction for patients with axial spondyloarthritis. Although the study involved only 21 patients, the use of single-cell RNA-seq and a Nanostring gene expression array showed some notable findings. Among biologic naive patients, non-responders had a lower proportion of T cells and higher proportion of monocytes than responders. Other notable differences related to the relative upregulation of interferon-regulated genes in non-responders. After treatment, a decrease in chemokines and cytokines levels was observed in responders.

As in the case of all new biomarkers, validation is essential and only time will tell how immunophenotyping will fit into personalized medicine approaches to optimize therapy.

Axial Spondyloarthritis Patients with Comorbid Fibromyalgia

Abstract 0561: Brink et al.⁷

Just about every form of inflammatory arthritis has a significant proportion of patients who fail to respond to conventional therapy and display persistent generalized pain and impaired quality of life. In these patients, fibromyalgia (FM), a condition of nociplastic pain with central sensitization, is a possible cause. In a cohort of axSpA patients, both radiographic and non-radiographic variants, Brink et al. assessed the prevalence of FM and its impact of patient outcomes.

As the data indicated, the prevalence of FM was 9% overall, with 17% in women and 2% in men. FM was also associated with a higher BMI and HLA-B27 negativity. Those with FM also showed more tender joints, worse disease activity, more functional limitations, less employment and lack of treatment response to more DMARDs. Although FM can be designated as a co-morbidity, its frequency among patients with inflammatory arthritis is so high that it appears to be an intrinsic feature of disease. Assessing FM can be accomplished by questionnaires, physical findings and quantitative sensory testing. These are straightforward approaches that seem very worthwhile to personalize the treatment approach using both pharmacologic and non-pharmacologic means.

Spinal & Hip Mobility in Patients with axSpA & Chronic Back Pain

Abstract 0544: Bento da Silva et al.⁸

Although imaging often dominates the discussion of axSpA, physical findings are nevertheless important for assessing diagnosis, outcomes and treatment effects. Bento da Silva and colleagues, therefore, assessed measures of spine and hip mobility in patients with axSpA and non-axSpA chronic back pain with two or fewer years of symptoms. The measures assessed included such classics as occiput-to-wall (OWD), chest expansion and the modified Schober (mShober) tests. Data were available both at baseline and after two years.

For both groups, about 50% of patients had one or more measure of impaired spinal mobility, with overall poorer mobility in the non-axSpA patients except for OWD. After two years, mobility remained largely unchanged in both groups although axSpA was associated with larger improvements in mSchober but higher odds of OWD impairment.

These are very interesting findings and raise the question of the origin of mobility impairment in both populations. A comparison with radiographs would be important especially among the patients with non-axSpA. As someone who has often used mobility measures to screen for axSpA, I will be mindful in the future of the limitation of the physical findings in clinical assessments.

AMH Titers in Women with axSpA

Abstract 0577: Franc et al.⁹

Perhaps the largest genetically determined factor in inflammatory disease relates to male-female differences, which can impact clinical manifestations, disease outcomes and treatment responses. Further, with women, inflammatory disease can influence fertility and pregnancy outcomes, issues for which new data are urgently needed as the treatment armamentarium changes. Franc et al. studied the expression of anti-Mullerian hormone (AMH), an indicator of ovarian reserve, in 381 women in the DESIR cohort over 10 years. Overall, AMH levels in the cohort were significantly lower than those of the controls for all age groups. Further, the study showed two trajectories of AMH decrease: a lower AMH level at age 18 with a slow decline to age 45 and a higher AMH level at age 18 followed by a steeper decline.

Although many factors could influence these trajectories (e.g., inflammation, treatment), the study highlights the need to understand better the interplay of disease and fertility; it also suggests the value in clinical studies as well as routine care to assess markers such as AMH.

NSAIDs & Incident Hypertension

Abstract 0540: Meade Aguilar et al.¹⁰

Non-steroidal anti-inflammatory drugs (NSAIDs) are effective agents for the treatment of axSpA, with a response to NSAIDs one of the indicators for the presence of inflammatory back disease. The toxicity of these agents (e.g., gastrointestinal, cardiovascular) has always been a concern and has constrained chronic usage. Meade Aquilar and colleagues revisited this issue by assessing hypertension in a longitudinal cohort (DESIR) of patients with early axSpA, determining hypertension by patient self-report, medication usage or blood pressure measurements at two visits. Of the patients, two-thirds were on NSAIDs at the time of baseline, and incident hypertension occurred in 11%. Nevertheless, the analysis failed to find a relationship between high-dose NSAID use and incident hypertension after adjustment for confounders.

These are interesting and, perhaps, unexpected findings that can be considered in choosing therapies for axSpA. Gastrointestinal side effects and the effects of NSAIDs in older patients and those with cardiovascular risk factors remain important concerns. Still, the data are valuable in assessing benefits and risks of the ever-increasing number of agents for axSpA.   

David S. Pisetsky, MD, PhD, is a professor of medicine and immunology at Duke University School of Medicine, Durham, N.C., and a staff rheumatologist at the Durham VA Medical Center. He also served as the first physician editor of The Rheumatologist.

References

1. Coates L, Selmi C, Mease P, et al. Sex-related differences in baseline patient and disease characteristics: Post hoc analyses of three phase 3, randomized, double-blind, placebo-controlled studies in patients with active psoriatic arthritis [abstract]. Arthritis Rheumatol. 2024;76(suppl 9).
2. Puche-Larrubia M, Ladehesa-Pineda M, Font P, et al. Clinical expression of radiographic axial spondyloarthritis and its association with HLA-B27 in European and Ibero-American populations: Data from the REGISPONSER and RESPONDIA registries [abstract]. Arthritis Rheumatol. 2024;76(suppl 9).
3. Chaudhary H, Pamuk O, Abi Doumeth S, et al. Sex-related differences in efficacy of biologics in axial spondyloarthritis: A systematic review and meta-analysis [abstract]. Arthritis Rheumatol. 2024;76(suppl 9).
   
4. Mauro D, Vecellio M, Bergot A, et al. Unveiling the uterine-joint axis: Dysbiosis and subclinical uterine inflammation in female axial spondyloarthritis pathogenesis [abstract]. Arthritis Rheumatol. 2024;76(suppl 9).
5. Lichaa A, KRUG P, Nzeusseu Toukap A. Low vitamin D serum level is a risk factor for ankylosis in axial spondyloarthritis: Evidence from a nested-case-control study [abstract]. Arthritis Rheumatol. 2024;76(suppl 9).
6. Talukdar A, Ibeh N, Machhar R, et al. Cellular immune activation signatures at baseline predict response to TNF inhibitors in axial spondyloarthritis [abstract]. Arthritis Rheumatol. 2024;76(suppl 9).
7. Brink A, Mogard E, Lindqvist E, et al. Axial spondyloarthritis patients with comorbid fibromyalgia feel worse, work less and more often try multiple biological DMARDs—Results from a population-based cohort [abstract]. Arthritis Rheumatol. 2024;76(suppl 9).
8. Bento da Silva A, Ramiro S, van Lunteren M, et al. A two-year comparison of spinal and hip mobility between axial spondyloarthritis and chronic back pain patients in the spondyloarthritis caught early (SPACE) cohort [abstract]. Arthritis Rheumatol. 2024;76(suppl 9).
9. Franc M, Guibourdenche J, Tournadre A, Molto A. AMH titers in women with axial spondyloarthritis are significantly lower compared to the general population: An analysis of the 10-year follow-up of the DESIR cohort [abstract]. Arthritis Rheumatol. 2024;76(suppl 9).
10. Meade Aguilar J, Liew J, Stovall R, et al. Nonsteroidal anti-inflammatory drug use and incident hypertension among patients with axial spondyloarthritis [abstract]. Arthritis Rheumatol. 2024;76(suppl 9).