Maureen Dubreuil, MD, MSc - Rheumatology Advisor

Maureen Dubreuil, MD, MSc

Expert Perspectives
Maureen Dubreuil, MD, MSc

 

Expert Perspectives on Non-Radiographic Axial Spondyloarthritis

Maureen Dubreuil, MD, MSc

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Practice Community
Boston, Massachusetts
Hospital and Institutional Affiliations
Assistant Professor of Medicine, Section of Rheumatology, Boston University School of Medicine

 

Question

What are the limitations of the current Assessment of SpondyloArthritis international Society (ASAS) criteria for diagnosing nonradiographic axial spondyloarthritis (nr-axSpA)?

Answer

The ASAS criteria are for classification purposes, not for diagnostic purposes. This means that the criteria are intended to be applied to individuals who are being considered for inclusion in research studies, not patients being evaluated by their clinician. Classification criteria are used to establish a homogeneous population of people who theoretically would respond in a similar way to an intervention as part of a trial or would progress in a similar way as part of an observational study. Classification criteria do not include some of the less common manifestations of a disease that an individual patient might have, which a clinician could include in making his or her diagnosis.

The ASAS classification criteria for axSpA define axSpA using 2 groups: The imaging group identifies patients who have either radiographic or magnetic resonance imaging (MRI) demonstrating sacroiliitis combined with at least one other SpA feature. Patients defined by the clinical group are defined on the basis of the presence of HLA-B27 positivity with at least 2 other SpA features.

For inclusion in trials, in general, the individuals who are diagnosed as having nr-axSpA were assessed first to see whether they satisfied the clinical group, and only if they did not satisfy the clinical group did they go on to have an MRI. If the MRI showed sacroiliitis (and they had another axSpA feature), then they qualified via the imaging group. We have little published literature to date as to how similar subjects satisfying the clinical group are to those satisfying the imaging group, or to those who satisfy both. It is possible that people who meet on the clinical group but have completely normal MRIs, would have a different disease course or respond differently to treatment than those who have abnormal MRIs. Most trials to date have not reported results stratified by inclusion based on the clinical or imaging group of the ASAS criteria, so this would be an important next step: for investigators to consider these post hoc analyses, using existing trial data; for future studies to plan such analyses in advance; or for researchers to examine this question in observational cohorts.

Question

Imaging remains an important tool for the diagnosis of axSpA, but the role of imaging for monitoring disease activity is less well‐defined. Can you comment on the utility of spine and/or pelvis MRI for patients in whom the degree of active inflammation is unknown?

Answer

The most recent axSpA guidelines conditionally recommend use of a spine or pelvis MRI in patients who have unclear disease activity while receiving treatment with a biologic. The rationale behind this is that physical examination and laboratory measures are often normal despite active axSpA. In addition, symptoms of back pain may be nonspecific, so it may be difficult for clinicians to know whether a patient’s symptoms are the result of active inflammation and would therefore warrant a change in therapy. The guidelines cite the limited evidence regarding the role of MRI findings in changing treatment decisions.

However, the guideline report acknowledges that information from MRI may be useful for patients with axSpA in whom disease activity is unclear and in whom, after discussions with the patient, it was determined that MRI findings would influence the treatment decision. For patients with nr-axSpA, MRI imaging of the sacroiliac joints would be most appropriate, whereas for patients with ankylosing spondylitis (AS), imaging may focus on another spinal level (as indicated by the patient’s symptoms).

One caveat to the use of MRI is that abnormalities, including bone marrow edema or osteitis, can occur in people without axSpA and may not represent inflammatory disease.

In contrast to guidelines for those with unclear disease activity, the guidelines conditionally recommend against imaging in patients who have clinically stable disease solely to confirm inactivity. There is a lack of evidence that MRIs in clinically stable patients improve their clinical outcomes, and it is expensive. Another concern is that not all lesions seen on MRI are clinically significant, meaning that some abnormalities on MRI do not cause any pain. Therefore, seeing MRI lesions may result in overtreatment in people with stable axSpA. One exception to this recommendation is in cases in which the patient and the clinician have different opinions as to whether the axSpA is stable.

Question

The Ankylosing Spondylitis Disease Activity Score (ASDAS) has been used to assess disease activity in nr-axSpA. Can you discuss the limitations of ASDAS when applied to nr-axSpA?

Answer

ASDAS includes the domains of pain, inflammation, inflammation by labs, patient global assessment, peripheral signs (arthritis and enthesitis), and fatigue. Several of these items are reported by the patient (pain, inflammation, fatigue, and patient global assessment), which the ASDAS has in common with the Bath Ankylosing Spondylitis Disease Activity Index (another common disease activity measure). ASDAS also includes the clinician’s assessment of swollen joint count and tender enthesis count. Both the patient-reported items and the clinician’s assessment are easy to obtain within the context of the clinical encounter in the United States.

However, a laboratory assessment of inflammation using either C-reactive protein (CRP) or erythrocyte sedimentation rate cannot be performed within a clinical encounter in most US outpatient practices. This testing requires the patient to go to a phlebotomy site to have the blood sample drawn, and generally the sample is then tested in an approved clinical laboratory. Results are typically reported to the clinician at least a few hours later. This is in contrast to the process in other countries, in which point-of-care testing is available for CRP, which allows the ASDAS to be calculated in real time to inform shared decision-making. The delay in CRP or erythrocyte sedimentation rate reporting make the use of ASDAS challenging for clinicians in the United States because the calculation requires the laboratory result.

Another minor challenge is that the ASDAS is calculated using a fairly complex formula (including a natural logarithm or a square root) and several weighted features, so the clinician cannot easily calculate without a web-based or local computer application.

In spite of these challenges to its use, ASDAS remains the global standard for assessing disease activity in axSpA. ASDAS was developed by axSpA experts using rigorous methodology, and it has undergone extensive testing and validation globally. ASDAS is highly correlated with the Bath Ankylosing Spondylitis Disease Activity Index, CRP, inflammation scores on MRI, and physician global assessment. Still, ASDAS remains a topic of ongoing study, including regular assessments of its components and cut points defining different levels of disease activity.

Question

Skeletal disease in axSpA can be accompanied by extra-articular disease including uveitis, psoriasis, and inflammatory bowel disease. Can you discuss changes in treatment regimens when these specific comorbidities arise?

Answer

Uveitis (iritis) is the most common extra-articular manifestation of axSpA, affecting up to one-quarter of patients during their lifetime. Acute treatment of uveitis involves topical or systemic glucocorticoids. Long-term management, especially of recurrent uveitis, is recommended to include tumor necrosis factor (TNF) inhibitors. There is evidence that monoclonal antibody TNF inhibitors are effective in preventing recurrent episodes of uveitis. The guideline panel did not recommend any specific monoclonal antibody TNF inhibitor over another, although the majority of evidence supporting TNF inhibitors has included adalimumab or infliximab. There are few data supporting the use of certolizumab or golimumab. In contrast, etanercept, a fusion protein inhibitor of TNF, does not improve outcomes in uveitis, and there are even case reports of uveitis flares with etanercept treatment, so it is not recommended for treatment of uveitis. Data for secukinumab show that rates of uveitis were not different in those treated with drug vs placebo, but these data are limited. There is also insufficient evidence as to whether ixekizumab has any effect in treating uveitis.

In people who have both axSpA and inflammatory bowel disease (IBD), the recommendation is for treatment with a monoclonal antibody TNF inhibitor over treatment with other biologics. This recommendation was based on limited data that incident IBD or flares of IBD were lower among patients with axSpA treated with TNF inhibitors, and a large body of literature on the treatment of isolated IBD. Just as with the treatment of uveitis, for patients with concurrent axSpA and IBD, the recommendation is to use a monoclonal antibody TNF inhibitor and not to use etanercept. Notably, etanercept is not approved for the treatment of either Crohn disease or ulcerative colitis.

It is also important to note that although secukinumab is effective for treatment of axSpA, its use has been associated with the development of Crohn disease. An increased risk for IBD flare has also been reported with ixekizumab. So it seems that biologics directed at inhibition of interleukin-17 (IL-17) have differential effects on axSpA and IBD.

Tofacitinib, a Janus kinase inhibitor, is approved for the treatment of ulcerative colitis but not for Crohn disease. Tofacitinib had promising results in the treatment of axSpA in a phase 2 study and is currently in phase 3 study, but it is not currently approved for axSpA and is not addressed in the most recent guidelines. Notably, a black box warning was recently issued for tofacitinib because of increased concern for risk for thrombotic events including pulmonary embolism and deep venous thrombosis. Treatment of psoriasis when it co-occurs with axSpA can include use of ultraviolet therapies, topical therapies, and other oral small molecules directed solely at the treatment of psoriasis, or therapies can be selected to treat both psoriasis and SpA. As with the treatment of uveitis and IBD, TNF inhibitors are effective for managing both psoriasis and axSpA. Any of the TNF inhibitors, including etanercept, can be used. In addition, for treatment of psoriasis in axSpA, IL-17 inhibitors including secukinumab and ixekizumab have demonstrated efficacy for both skin and spinal disease. It is important to note that IL-12/23 inhibitors (ustekinumab and guselkumab) are approved for psoriasis but not for axSpA.