The 2025 British Society for Rheumatology guideline for the treatment of axial spondyloarthritis with biologic and targeted synthetic DMARDs

Recommendations

• TNF, IL-17 or JAK inhibitors are recommended for people with active axSpA who have not responded adequately despite non-pharmacological and conventional pharmacological management (1A, SoA 97%) The currently licenced targeted therapies for axSpA in the UK include TNF inhibitors (TNFi: adalimumab, certolizumab pegol, etanercept, golimumab, infliximab and relevant biosimilars), IL-17 inhibitors (IL-17i: secukinumab, ixekizumab, bimekizumab) and JAK inhibitors (JAKi: tofacitinib, upadacitinib). Infliximab and tofacitinib are not licenced for non-radiographic axSpA. All targeted therapies have demonstrated an acceptable balance of efficacy and safety in axSpA RCTs (Supplementary Data S1, available at Rheumatology online). There is no evidence to support recommending one class or drug over another in terms of efficacy for musculoskeletal manifestations. The decision to escalate to targeted therapies and the choice of therapy should be made with the person with axSpA, taking into account prognostic factors, comorbidities (not discussed further, see [9]) and EMMs (summarized in Table 1 and discussed in subsequent recommendations). Not all people with axSpA will undergo structural progression detectable on radiographs (radiographic progression) [20]. However, observational studies have shown that certain groups (e.g. males, smokers, those with high baseline damage or high CRP [21]) have greater risk and rate of radiographic progression. These adverse prognostic factors should be considered as part of shared decision-making when initiating targeted therapies. Although generating RCT evidence for the effect of therapies on radiographic progression is challenging, current observational literature suggests that targeted therapies (specifically TNFi) are more likely to reduce radiographic progression compared with NSAIDs [22].
• Active disease should be determined by the treating clinician in the context of verified diagnosis and inflammatory disease activity, supported by validated indices such as the Axial Spondyloarthritis Disease Activity Score (ASDAS), BASDAI and spinal pain (1B, SoA 97%). For the purpose of escalation to targeted therapies, active disease should be defined after (1) appropriate use of non-pharmacological and conventional pharmacological therapies, and (2) verifying the diagnosis and inflammatory disease activity. The diagnosis of axSpA should be verified by a consultant rheumatologist, and includes ankylosing spondylitis (radiographic axSpA) and non-radiographic axSpA with objective features of inflammation (elevated CRP and/or MRI findings). Recommendations on diagnosis are beyond the scope of this guideline. However, the GWG emphasizes that the Assessment of Spondyloarthritis International Society (ASAS) classification criteria should not be used for diagnosis [23]. In the general population, most individuals positive for HLA-B27 will not develop axSpA [24], and non-pathological inflammatory changes on MRI can be highly prevalent (e.g. postpartum, among the physically active [25–27]). The necessary push to reduce diagnostic delay must be cautiously balanced against the potential for misdiagnosis. The decision to initiate therapy should be agreed upon with the person with axSpA, rather than being based solely on disease indices. Nevertheless, validated measures of disease activity should be documented at the time of treatment initiation and at each follow-up. The GWG recommends using the ASDAS, BASDAI and spinal pain for assessing disease activity (numerical rating scale preferred by ASAS over visual analogue scale [28]). Although BASDAI and spinal pain are included in NICE recommendations due to their use in historical clinical trials, their subjective nature means that scores can potentially be influenced by non-disease-specific factors such as comorbidities [29, 30]. ASDAS is the only instrument shown to correlate with radiographic progression [31, 32] and is included in almost all contemporary clinical trials in axSpA. Definitions of high disease activity using ASDAS ≥ 2.1 or BASDAI ≥ 4 usually coincide but, when discordant, the ASDAS definition better predicts treatment response [33, 34]. For these reasons, the GWG recommends transitioning towards regular inclusion of ASDAS in clinical practice (Table 2). Verifying diagnosis and assessing inflammatory disease activity can be clinically challenging. When there is doubt about the extent of inflammation, imaging such as MRI for axial and ultrasound for peripheral manifestations may be helpful. Detailed MRI recommendations have been provided by the British Society for Spondyloarthritis [35, 36] and ASAS [37] and will not be discussed further.
• Response to targeted therapies should be assessed using validated indices (e.g. ASDAS, BASDAI, spinal pain) 3–4 months after initiation, and every 6–12 months if treatment is continued1B, SoA 97%
• The absence of response to targeted therapies should prompt reassessment of the diagnosis and the extent of inflammatory disease activity (1B, SoA 100%). Once started, it is important to assess the effectiveness, tolerability, compliance and the appropriateness of continuing therapy. Follow-up assessment of disease activity should be holistic and supported by, but not solely reliant on, disease indices. The decision to continue therapy should be made jointly between the person with axSpA and the treating clinician. Treatment response should be evaluated at a minimum of 12 weeks after initiation. NICE recommends assessing response to TNFi after 12 weeks [38]; secukinumab, bimekizumab and JAKis after 16 weeks [39–42] and ixekizumab after 16–20 weeks [43]. The 2013 axSpA guideline recommended 6-monthly reviews. For the current guideline, the nature and interval of follow-up were debated after feedback from the public consultation. Concerns were raised that specifying assessments “every 6–12 months” might conflict with patient-initiated follow-up pathways. The GWG acknowledged that high-quality care can be maintained with longer intervals. However, removing the interval recommendation entirely could be open to misinterpretation that regular follow-up is optional and make auditing difficult. The GWG added that the nature and interval of follow-up can be adjusted based on individual circumstances but should be reviewed at each visit to ensure it remains appropriate. Patient-initiated follow-up or extended follow-up intervals may be considered if the condition is well-controlled and the person with axSpA has adequate education and access to a local rheumatology advice line or equivalent to promptly re-establish contact with the clinical team if necessary. Follow-up interval should not typically exceed 24 months. NICE recommends a BASDAI 50% or 2-unit reduction and 2-unit reduction in spinal pain [44] which, until revised, will continue to be the cornerstone of assessment. However, treatment response can be influenced by the presence of comorbidities, particularly for more subjective indices such as BASDAI and spinal pain [30, 45]. Moreover, BASDAI is not associated with radiographic disease progression [21, 46]. ASDAS disease activity states and improvement criteria are superior to BASDAI in differentiating levels of, and change in, disease activity [47]. Routine use of ASDAS is endorsed by ASAS-EULAR and OMERACT [48, 49]. For these reasons, the GWG recommends that assessments incorporate ASDAS. A reduction of ≥1.1 represents a clinically important response [50]. When using any index, assessments should consider whether residual symptoms are related to active inflammation; e.g. fibromyalgia may contribute to high tenderness and fatigue domains of BASDAI, while obesity may contribute to elevated CRP for ASDAS [51]. As discussed in recommendation (ii), repeat MRI of the whole spine and sacroiliac joints may help to assess inflammation and other causes of persistent symptoms. Diagnosing axSpA is challenging, and clinicians should remain open to re-evaluating the original diagnosis, particularly when there is (repeated) primary non-response to targeted therapies.
• An alternative targeted therapy is recommended for individuals with active disease who cannot tolerate, do not respond to, or lose response to the initial targeted therapy (1A, SoA 99%). As with overarching and treatment initiation recommendations, decisions for treatment switching should be shared and agreed upon with the person with axSpA. There is currently insufficient evidence to recommend a specific sequence of targeted therapies in the case of treatment failure in axSpA. TNFi are currently mandated as first-line by NICE, unless they are unsuitable [44]. In people with insufficient response to TNFi (TNFi-IR), a second TNFi has been shown in observational studies (but not RCTs) to be effective, albeit less so than the first [52]. The efficacy of IL-17i in those with TNFi-IR has been demonstrated in RCTs [53–58]. The efficacy of tofacitinib in TNFi-IR [59], and upadacitinib in TNFi-IR or IL-17i-IR [60], has also been shown in RCTs. Response to a second TNFi is lower in axSpA with primary non-response to the first TNFi, compared with those who switch because of secondary non-response [61, 62]. It is probable, as in other inflammatory arthritides, that people with axSpA who have primary non-response to one therapy are more likely to respond to a drug with a different mechanism of action. Switching from a bio-original drug to its equivalent biosimilar is not recommended when there is insufficient response to the former. In the context of verified diagnosis and inflammatory disease activity, the GWG suggests that there should not be a limit to the number of sequential therapies that any individual can have. This should include consideration of new therapies as they become available. Evidence for the safety and effectiveness of sequential therapy in axSpA is lacking and represents an important unmet research need. In axSpA, observational evidence is limited to cycling within the TNFi class, where the proportion achieving remission reduces across first-to third-line TNFi [62]. In PsA [63] and RA [64], responses reduce numerically across lines of therapy; however, an important proportion of participants were still able to achieve remission, up to the sixth-line in the case of RA.
• In the presence of moderate-to-severe or recurrent uveitis, a monoclonal TNFi is preferred over therapies with other mechanisms of action1A, SoA 98%
• A history of inactive uveitis is not an absolute contraindication to therapies with other mechanisms of action2B, SoA 97%
• If new uveitis develops in the context of well-controlled axSpA, decisions to change treatment should be made with an ophthalmologist where possible, taking into account the severity and/or frequency of uveitis flares and response to topical steroid (1B, SoA 97%). Acute anterior uveitis is the most common EMM that can occur in up to a quarter of people with axSpA [65]. In accordance with NICE, new presentations of uveitis should be assessed by an ophthalmologist within 24 hours [66]. The severity of uveitis can range from infrequent mild episodes to recurrent or sight-threatening disease. For moderate–severe or recurrent uveitis, the decision to commence a targeted therapy should be jointly made between rheumatology and ophthalmology as part of an MDT. Mild cases can be effectively managed with topical therapy and monitoring of side effects (e.g. steroid-induced ocular hypertension and cataract). Monoclonal TNFi are effective for the treatment of anterior uveitis in axSpA [67], although no targeted therapies are specifically licenced for this condition (adalimumab is licenced for non-infectious intermediate, posterior or panuveitis). Observational evidence suggests that etanercept and IL-17A inhibitors may be less effective at controlling uveitis than monoclonal TNFi [68]. In contrast to IBD, trial data do not suggest that IL-17Ais are harmful for uveitis [69]. A post hoc analysis of pooled axSpA trial data published after the full literature search suggested that bimekizumab may be superior to placebo for preventing uveitis flares [70]. A network meta-analysis of axSpA RCTs suggested that all targeted therapies are likely superior to placebo [71]. If uveitis develops or flares in individuals with well-controlled axSpA on etanercept or IL-17Ai, the severity and/or frequency of uveitis should be considered in consultation with an ophthalmologist before automatically switching therapy.
• IL-17 and monoclonal TNFi are preferred in the presence of extensive psoriasis (e.g. >10% body surface area) or severe localized psoriasis at sites associated with high functional impairment or impact (e.g. face, scalp, palms, soles, flexures, genital or nails), ideally in conjunction with a dermatologist (1A, SoA 96%). Among people with axSpA, psoriasis has a prevalence of ∼10% [65, 72] and is typically reported as being mild [73]. For mild cutaneous psoriasis, concomitant topical therapy can be recommended to and managed by the GP according to NICE guidance [74]. In people with well-controlled axSpA but inadequately controlled psoriasis, management should be discussed with a dermatologist and may not necessarily require a change in targeted therapy. For example, topical, photo, and systemic non-biologic therapies may provide sufficient control [74]. Where axSpA and psoriasis are both indications for targeted therapy, control of cutaneous psoriasis can be achieved by, in order of efficacy, IL-17i (bimekizumab was superior to secukinumab for skin control but increased incidence of candidiasis [75]), monoclonal TNFi or etanercept [76]. In dermatology settings, etanercept (though licenced) is used infrequently after monoclonal TNFi [77], while golimumab, tofacitinib and upadacitinib are not currently licenced for psoriasis. While detailed psoriasis assessment (e.g. Psoriasis Area and Severity Index) in rheumatology may be impractical outside academic settings, the GWG recommends using at least one objective measure for assessing and monitoring psoriasis. For example, body surface area can be estimated using the palm method, where the individual’s palm covers ∼1% of their body surface area. In people with psoriasis who subsequently develop axSpA, or in people with predominant skin involvement where targeted therapies have been led by dermatologists, decisions to switch therapy should consider that certain therapies used in psoriasis have no beneficial effect for axial symptoms (e.g. ustekinumab or IL-23p19 inhibitors), while other inhibitors of IL-17 signalling have (e.g. brodalumab [78]) or are likely to have therapeutic benefit despite not being licenced for axSpA.
• Individuals with unexplained lower gastrointestinal symptoms should be assessed by a gastroenterologist, ideally before commencing targeted therapies1B, SoA 97%
• In the presence of active IBD, monoclonal TNFi or JAKi are preferred; IL-17 inhibitors should not be commenced1A, SoA 99%
• A history of inactive IBD is not an absolute contraindication to IL-17 inhibitors or etanercept (2B, SoA 97%). People with unexplained lower gastrointestinal symptoms suggestive of IBD (including Crohn’s disease and ulcerative colitis) should be referred to a gastroenterologist or an appropriate diagnostic pathway, before commencing targeted therapies. Faecal calprotectin can be a useful screening tool for gastrointestinal inflammation with high negative predictive value for IBD [79]. However, levels can be elevated due to NSAID use [80], which should be taken into account when considering gastroenterology referral. The prevalence of IBD among people with axSpA is ∼7% [65]. Coexisting IBD can influence multiple aspects of axSpA management, including NSAID use and choice of targeted therapies. IBD severity, relapse frequency and prognosis can vary substantially, and treatment decisions should be made in collaboration with gastroenterology where possible. In well-controlled axSpA, mild IBD may be managed by gastroenterology without a change in targeted therapy. Monoclonal TNFi or JAKi are preferred in people with active axSpA and IBD where advanced therapies are indicated. IL-17i should not be commenced in people with active IBD, as it may exacerbate intestinal inflammation (as demonstrated in the clinical trial of secukinumab in Crohn’s disease [81]). Given the relatively limited number of drug classes for axSpA, IL-17i can still be considered in the context of well-controlled IBD when no other options are available, but the balance of risk and benefit in these circumstances should be carefully considered with input from gastroenterology. If IL-17i is used, individuals and their clinicians should regularly monitor for symptoms compatible with IBD. In cases where gastroenterology is leading the use of targeted therapies, treatment decisions should consider the fact that some therapies (e.g. ustekinumab, IL-23p19 inhibitors or vedolizumab) lack evidence-base for treatment of axial inflammation.
• Treatment should aim to achieve predefined targets agreed upon with the individual living with axSpA, using individualized therapy adjustments that consider comorbidities and inflammatory disease activity (1B, SoA 99%). ASDAS is consistently associated with radiographic progression [31, 32]. However, the TICOSPA trial of treating to target (ASDAS < 2.1) in axSpA did not achieve its primary outcome (≥30% improvement in ASAS Health Index) or the majority of secondary outcomes [82]. Although all outcomes were numerically better in the treat-to-target arm, these differences are difficult to interpret in the context of an open-label trial. While there may be credible explanations for not meeting the primary end point (e.g. usual care being better than expected in academic recruiting centres), there is insufficient evidence to recommend treating to an index-based target. Furthermore, treating to target in the TICOSPA trial involved cycling through a greater number of biologics, albeit without incurring excess healthcare/economic costs. This is an important consideration because, unlike RA and PsA, pharmacological options for axial disease comprise only three classes of targeted therapies and no csDMARDs. The GWG recommends that, as with the decisions to initiate or switch therapy, therapeutic targets should be agreed upon with the person with axSpA and not solely based on disease indices. Treatment escalation should consider (1) the overall number of available therapeutic options, (2) adverse prognostic factors for disease progression and treatment response and (3) extent of inflammatory disease activity. Specific comorbidities or complications (e.g. osteoarthritis, fractures and fibromyalgia) and general comorbidity burden are all associated with higher axSpA disease indices independent of inflammatory disease activity, particularly subjective indices such as BASDAI and spinal pain [29, 83].
• Tapering of targeted therapies should be considered for individuals who have achieved sustained remission1A, SoA 98%
• Withdrawal of targeted therapies in the context of sustained remission is not recommended (1A, SoA 99%). Multiple RCTs, all investigating TNFi, have compared tapering (i.e. dose reduction without complete discontinuation) vs continuing the standard dose among those in sustained remission [84–87]. Overall, TNFi dose reduction was not inferior to continuing standard dose for maintaining response in both ankylosing spondylitis (i.e. radiographic) and non-radiographic axSpA, with a comparable risk of relapse. There was no clear difference in the risk of adverse events, although these trials were not powered to formally compare safety. People with axSpA in sustained remission should be offered therapeutic tapering, with the decision agreed upon between the person with axSpA and the clinician. ‘Sustained remission’ lacks formal definition but can be operationalized as low disease activity or remission for at least 6 months. Tapering is typically implemented by increasing dosing intervals, which (with the exception of certolizumab pegol) is an off-licence use of therapy. Withdrawal of targeted therapies among those in sustained remission was investigated in several RCTs of TNFi [84, 85, 88, 89] and one RCT of ixekizumab [90]. Flare rates were significantly higher in withdrawal arms compared with continuing standard dose or tapering arms. For example, 80% of participants who discontinued certolizumab pegol flared during the trial period, and not all were able to regain control [84]. Abnormal inflammatory response to biomechanical strain is considered part of axSpA pathology [91] and, because such stresses and strains are inevitable, flares are likely without ongoing disease suppression. Although complete withdrawal of targeted therapies is not recommended, people with axSpA, informed with these trial data, may nevertheless choose to discontinue therapy and should be supported with access to timely clinical review when needed.