Treatment Recommendations & Guidelines

Introduction

Medical professional societies encourage development of treatment recommendations and/or guidelines that are based on current best evidence and represent a popular way of integrating evidence-based medicine into clinical practice. Thus the American College of Rheumatology (ACR) has current treatment guidelines available for several conditions that include rheumatoid arthritis (RA), osteoarthritis, juvenile idiopathic arthritis, gout, glucocorticoid-induced osteoporosis, lupus nephritis, perioperative management, Lyme disease, Polymyalgia rheumatica (PMR), psoriatic arthritis (PsA), reproductive health in rheumatic diseases, as well as for ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA). Such guidelines address treatment issues or questions and they do not deal with diagnosis. They use best evidence derived from systematic reviews of the medical literature and expert opinion (when the literature does not adequately address some aspects of management) is also utilized. The emphasis is on developing actionable recommendations that clinicians can readily utilize in their clinical practice.

In 2003, the Assessment of Spondyloarthritis International Society (ASAS) proposed recommendations for the use of tumor necrosis factor inhibitor (TNFi) in patients with AS, based on a Delphi questionnaire, published data, clinical expertise and a consensus meeting among experts. In 2006, the ASAS recommendations for the use of TNFi were updated, and the same year ASAS and European League Against Rheumatism (EULAR) published their joint recommendations for the management of AS on nonpharmacologic and pharmacologic treatment, including the use of TNFi. This was the first time that international recommendations for the management of AS had been proposed, and it was also the first official collaboration of ASAS and EULAR. The joint expert group proposed 10 recommendations that reflected the expert opinion based on research evidence and stated that these recommendations will be updated regularly to keep abreast of new developments in the management of AS, emphasizing that they have provided recommendations, not guidelines, for treatment and monitoring of patients with AS.

In 2010, both the ASAS/EULAR recommendations for the management of AS and the ASAS recommendations for the use of TNFis, which were complimentary to each other, were again updated. The 2010 update of the ASAS guidelines for the use of TNFis expanded its scope from AS to axial spondyloarthritis (axSpA). The two separate but complimentary recommendation sets were aggregated into the 2016 ASAS-EULAR management recommendations for axSpA, and updated in 2022 based on newly available evidence (see Figure 13-1 for the recommended treatment algorithm. The levels of evidence and grades of recommendation in the ASAS/EULAR recommendations were rated based on the assessments in the accompanying systematic literature reviews using the standards of the Oxford Centre for Evidence Based Medicine.

ACR released its first guidelines for the treatment of AS and nr-axSpA in 2015 in conjunction with Spondylitis Association of America (SAA) and Spondyloarthritis Research and Treatment Network (SPARTAN). A core group led the development of the recommendations, starting with 90 treatment questions, which were later reduced to 57. A systematic literature was conducted to address these questions covering central aspects of treatment of AS and nr-axSpA.

The quality of evidence was assessed by using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach already adopted by the Cochrane Collaboration because of its greater reliability for evaluating the quality of evidence for outcomes reported in systematic reviews than the Oxford Centre for Evidence Based Medicine evidence levels. In addition to appraising the quality of evidence in systematic reviews, GRADE method also includes other important aspects, such as identification of the most important treatment questions that need to be answered, specification of the important outcomes and use of a tested approach for deriving recommendations. A separate voting group reviewed the evidence and voted on all recommendations using the GRADE framework. Finally, 30 guidelines for AS and 27 for nr-axSpA on pharmacologic and nonpharmacologic treatment, including surgery, were proposed after integrating the results across all the relevant outcomes based not solely on the quality of the evidence. Selected comorbidities, disease monitoring, patient education and preventive care were also addressed.

The advent of new treatment modalities for patients with axSpA such as secukinumab, ixekizumab, tofacitinib and biosimilars, as well as evolving best practices for utilizing imaging (MRI and radiographs), led to the development of 2019 update of the ACR/SAA/SPARTAN guidelines using the same methodology. A team of experts performed a systematic literature review for 20 clinical questions on pharmacological treatment discussed in the 2015 guidelines, along with 26 additional questions on pharmacological treatment, treatment-to-target approach and the use of imaging. They were formulated to be either strongly for, conditionally for, conditionally against, or strongly against use of a treatment in a particular patient group.

The definitions of these and other key terms, such as active disease or stable disease are listed in Table 13-1. The guidelines were customized for patients with active or stable disease. NSAIDs in combination with physical therapy were recommended for first-line treatment, and TNFis were reserved for patients with persistently high disease activity despite conventional treatments, and switching to a second TNFi could be considered, especially in patients with loss of response (Figure 13-2).

There are now 86 recommendations for the management of AS and nr-axSpA, including new recommendations related to the use of newly available medications and for the use of imaging, as well as 36 recommendations from 2015 which were not re-examined. The first 41 items of the recommendations were focused on the treatment of adults with active AS (recommendations #1-22, Table 13-2), adults with stable AS (recommendations #23-29, Table 13-3) and adults with active AS or stable AS (recommendations #30-36, Table 13-4), as well as on the treatment of adult AS patients with comorbidities (recommendations #37-41, Table 13-5). The subsequent 10 recommendations addressed disease activity assessment, imaging and screening of adults with AS (#42-51, Table 13-6). The remaining 36 recommendations covered treatment of adults with active nr-axSpA (recommendations #52-73, Table 13-7), treatment of adults with stable nr-axSpA (recommendations #74-79, Table 13-8), treatment of adults with active or stable nr-axSpA (recommendation #80, Table 13-9), recommendations for disease activity assessment, and imaging of adults with nr-axSpA (recommendations #81-86, Table 13-10).

The summary of the recommendations for the treatment of active AS and stable AS are also summarized in Figure 13-2A (active diseases) and Figure 13-2B (stable disease), where the bracketed numbers represent the number preceding each recommendation in Tables 13-2-13-10. Ward and colleagues studied AS separately from nr-axSpA because these two entities have separate literatures, and treatments that may have been well studied in AS may not have been similarly studied in or applicable to the other. The level of evidence of these recommendations varied from very low to high (Tables 13-2-13-9). Due to a relatively limited literature on nr-axSpA, Ward and colleagues mostly relied on the AS literature and made the same recommendations for nr-axSpA as for AS, but with one exception, and that was addressed in recommendation #56 (Table 13-7), which reads “In adults with active nonradiographic axial SpA despite treatment with NSAIDs, we strongly recommend treatment with TNFi over no treatment with TNFi.”

It needs to be pointed out that as yet certolizumab is the only TNFi that has been approved by the FDA to treat nr-axSpA. Moreover, wording and the level of evidence of the recommendation #59 which reads “In adults with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with secukinumab or ixekizumab over no treatment with secukinumab or ixekizumab” is already outdated, because, as of now, both secukinumab and ixekizumab have been shown to be effective in the treatment of patients with nr-axSpA and been approved by the FDA and the EMA for this indication.

It should also be underlined that approvals of all biologics granted by both of these regulatory authorities restricted their treatment indications for nr-axSpA patients that show objective signs of inflammation indicated by elevated CRP or presence of active sacroiliitis on MRI. Evidence of objective signs of inflammation was a required criterion for inclusion to the pivotal trials of certolizumab, secukinumab and ixekizumab in patients with nr-axSpA. Moreover, the available evidence, from the results of randomized controlled trials of TNFis conducted in patients with nr-axSpA indicates that the TNFi treatment in the subgroup of nr-axSpA patients with the combination of negative MRI findings and normal CRP level at baseline do not exhibit a significantly better response than that observed with placebo. The 2019 guidelines do not take any position for such patients.

Lastly, it needs adding that application of the treat-to-target principle has recently been advocated in AS and related forms of SpA, and it was positively echoed in the 2016 ASAS/EULAR guidelines (and maintained in the 2022 ASAS/EULAR guideline update). However, the ACR/SAA/SPARTAN recommended conditionally against the adoption of treat-to-target approach for the treatment of AS and nr-axSpA (Table 13-5 and Table 13-9), in order to avoid imposing additional burdens on patients and providers, in the absence of sufficiently convincing evidence regarding its effectiveness. The choice of biologic in individual patients with axSpA are discussed in TNF Inhibitor Therapy , Biologics Targeting Interleukin-17 and Janus Kinse (JAK) Inhibitors.

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