Pain is one of the main manifestations of axial spondyloarthritis (axSpA), which directly affects quality of life of patients.¹ In addition to inherent pain, some individuals with axSpA also develop pain that is more widespread, intense, or intolerable than suggested by the extent of their inflammatory disease. This is not rare; as many as approximately 49% of patients with undifferentiated axSpA and 45% with radiographic axSpA have reported chronic, widespread pain (CWP).²

To understand the presentation and impact of pain among patients with axSpA, we spoke with Sergio Schwartzman, MD, a clinical associate professor of medicine at Weill Cornell Medical College of Cornell University, the New York-Presbyterian Hospital, and the Hospital for Special Surgery (HSS) in New York City, and the emeritus Franchellie M. Cadwell chair at HSS.

He said, “The implications of pain in these patients are important. Patients do not perform their activities of normal daily living with comfort, and have difficulty participating in social and athletic activities. Increased incidences of depression³ and cognitive dysfunction⁴ are also associated with chronic pain.”

Statistical models have confirmed that the presence of CWP is an independent predictor of poorer quality of life in patients with axSpA.⁵ However, the relative contributions of disease activity and CWP disorders, such as fibromyalgia, can be difficult to distinguish in clinical practice.Symptoms of fibromyalgia can overlap with those of axSpA.⁶ Furthermore, these pain symptoms may fluctuate over time, possibly obscuring the effect of disease-modifying therapy.

Pain Presentations Across axSpA Subtypes

Although radiographic vs nonradiographic (nr) axSpA differ inherently in the extent of inflammatory spinal disease, Dr Schwartzman noted that the burden of both pain and fatigue are similar across these subtypes. This underscores that while pain can overlap with disease state, its time course, distribution, and intensity are not fully determined by inflammatory disease processes. However, central nervous processes may amplify and perpetuate the pain, as exemplified by fibromyalgia, which is a well-documented comorbidity in axSpA.⁷

Mogard and colleagues⁸ conducted a cross-sectional study of 175 patients enrolled in the SPARTAKUS cohort in Sweden, 43% of whom had CWP. Patients in the radiographic axSpA group tended to be older than those with nr-axSpA, were more often men, had a longer history of symptoms and poorer spinal mobility, and were twice as likely to have ever been smokers. Nevertheless, pain sensitivity, intensity, pain threshold and tolerance, and temporal summation index (reflecting increase in pain intensity during prolonged pressure stimulation) were all similar across radiographic and nr-axSpA; and patients with nr-axSpA had more entheseal tender points.

Dr Schwartzman emphasized, “One must not conceive of nr-axSpA as a more benign form of disease. It is just that it is an earlier form of the disease.”

The Time Course of Pain in axSpA

Knowledge regarding risks, incidence, and persistence of regional and widespread pain in axSpA is incomplete. Of 940 patients in the SpAScania cohort with radiographic axSpA and undifferentiated spondyloarthritis,⁹ more than 46% of patients reported CWP (defined as occurring for more than 3 of the previous 12 months, in a bilateral, upper- and lower-body, and axial distribution) at both baseline and follow-up; and 18% reported chronic regional (ie, less than widespread) pain at both baseline and follow-up. Greater pain intensity, worse fatigue, and poorer overall health status predicted incidence of CWP. Risk of remaining with CWP (rather than transitioning to regional or no pain) was greater in the presence of those 3 variables and also with higher age, the female sex, and higher reported anxiety.

However, further research suggests that pain presentations may vary over time. Widespread pain may be intermittent or unremitting in different periods in the same patient; regional distributions may become more widespread, and vice versa.^6,9 The driving factor behind such pain fluctuation is not yet understood. Patient-reported data on quality of life and sleep quality, fatigue, disease activity, and measures of function and overall activity impairment all predict development of chronic, rather than intermittent, widespread pain; however, the presence of the human leucocyte antigen (HLA)-B27 gene does not.⁶

Sex Differences in Patients With axSpA and Comorbid Pain Disorders

In Dr Schwartzman’s estimation, the burden of fibromyalgia plus axSpA is significantly more on women vs the general population. With regard to comorbid CWP, women with axSpA tend to report pain in more regions than do men,² despite similar C-reactive protein (CRP) levels. In addition, the female sex appears to predict persistence, though not incidence, of CWP.⁹

Furthermore, while radiographic axSpA is more common among men than women, the differences between the sexes is less significant in nr-axSpA. In fact, women appear more likely to develop nr-axSpA than radiographic disease.¹⁰ This is an important finding, in part, because CRP levels are less likely to be elevated in nr-axSpA (low baseline elevation is associated with poorer antitumor necrosis factor [TNF] treatment survival)¹⁰; and because, inherently, the most obvious radiographic evidence of disease is absent in nr-axSpA, often delaying diagnosis.

Therefore, given the increased proportion of nr-axSpA among women, both diagnosis and treatment may be challenging or delayed more often in women than men with axSpA.

Pain and Outcome Prediction

Dr Schwartzman noted, “We are only beginning to measure pain and use it in clinical trials to predict disease outcome or status. These relationships need to be better understood and researched.”

Pain exerts an important effect on health outcomes in axSpA, such as the additional impact of widespread pain and fatigue on quality of life.⁵ However, numerous symptoms of pain disorders, such as fibromyalgia, including entheseal pain and other tender points, fatigue, and stiffness, can overlap with those of axSpA,¹¹ obscuring the predictive value of pain in spondylopathies. Making a differential diagnosis is exacerbated by the paucity of biomarkers sensitive to disease activity for both axSpA and fibromyalgia.¹² Fluctuating pain symptoms may also complicate outcome assessment of disease-modifying antirheumatic drug (DMARD) treatment, reinforcing the need for careful verification of disease outcomes.

Data from a recent cross-sectional study⁸ points to an approach to address the ambiguity. In examining relationships between pain scores and clinical and health variables, study authors not only assessed pain using questionnaires but also measured pain sensitivity — threshold and tolerance — using cuff pressure algometry. Low pain tolerance was found to be associated with poor scores on a broad variety of measures of physical function, health-related quality of life, enthesitis, number of pain regions, fatigue, and anxiety, as well as Ankylosing Spondylitis Disease Activity Score using C-reactive protein (ASDAS-CRP). However, pain threshold and temporal summation scores were associated with fewer clinical variables. Given that pain tolerance may be especially closely associated with the affective component of pain, the researchers of the study⁸ drew attention to this link between centrally mediated pain and objective outcomes in axSpA. Delineating the association between separable pain measures and disease variables may likely inform future translational research to relieve comorbid pain and to distinguish between inflammatory vs central pain sources in axSpA.

Implications of Widespread Pain for Management of axSpA

Dr Schwartzman noted, “Physicians need to realize that there are different sources of pain in patients with axSpA. Clearly the pain can be related to the underlying condition — an inflammatory type of pain — and also to fibromyalgia and degenerative arthritis. Therefore, when evaluating patients with axSpA, physicians need to recognize that treating a causative element may not address all of the potential underlying causes of pain.”

A systematic review and meta-analysis indicated that approximately 1 in 6 patients with axSpA met criteria for comorbid fibromyalgia.¹³ Therefore, pain management in a large number of patients with axSpA requires care pathways beyond anti-inflammatory drugs and DMARDs. Of note, patients in the Bath Spondyloarthritis Biobank with axSpA, both with and without CWP, were likely to receive TNF inhibitors,⁶ suggesting that centrally mediated pain in a significant percentage of patients was nonresponsive to DMARD therapy.

Further, the question arises whether comorbid CWP and fibromyalgia in axSpA affect clinical response to DMARDs. Some studies suggest that drug effects on axSpA with or without comorbid CWP are not notably different¹⁴; however, others indicate poorer symptom and disease activity responses to TNF inhibitor therapy in the presence of CWP.¹⁵

Dougados and colleagues¹⁶ reported that patients with high Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores and enthesitis count — suggestive of (unconfirmed) fibromyalgia — did not have poorer treatment outcomes with etanercept, although they had worse depression. In contrast, a retrospective analysis demonstrated that TNF survival was lower in patients with both axSpA and fibromyalgia.¹¹

Therefore, knowledge gaps exist in terms of how fibromyalgia and other chronic pain disorders are linked mechanistically with axSpA, and to the extent that central and inflammatory pain processes are mutually isolated in axSpA.