Safety and efficacy of pharmacological treatments for axial spondyloarthritis

Axial spondyloarthritis (ax-SpA) is a chronic inflammatory rheumatic disease with a variety of clinical presentations including chronic back pain, enthesitis, arthritis, and dactylitis. Occasionally, ax-SpA patients may present with extra-articular manifestations1-4 including anterior uveitis, psoriasis, and inflammatory bowel disease (IBD).5 The concept of ax-SpA includes both patients with definite structural damage on radiographs of the sacroiliac joints (according to 1984 New York criteria), (radiographic ax-SpA), and patients without structural damage, (non-radiographic ax-SpA). Non-radiographic ax-SpA is mostly considered an early stage of radiographic ax-SpA, but not all non-radiographic ax-SpA will develop structural damage in the axial skeleton.6 R-axSpA is largely equivalent to the classical ankylosing spondylitis (AS). These differences between r-axSpA and nr-axSpA are important for classification, not for diagnosis of axSpA. Ax-SpA is assessed clinically by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) or Ankylosing Spondylitis Disease Activity Score, the latter having shown a stronger longitudinal relationship with syndesmophyte formation than BASDAI.5 Smoking cessation,7 regular exercise,8 disease progression education, and physical therapy9 are non-pharmacological therapies recommended to all ax-SpA patients. To date, pharmacological treatments for ax-SpA include non-steroidal anti-inflammatory drugs (NSAID), tumor necrosis factor (TNF) inhibitors,10 interleukin-17 (IL-17) inhibitors, and potential Janus kinase (JAK) inhibitors. NSAID are the first-line treatment for ax-SpA patients suffering from pain and stiffness until the maximum dose is reached. It is effective in about 50%–60% of ax-SpA patients depending on which NSAID is used, but up to 20%–40% of patients have experienced from limited to no reduction in their pain.11 However, even with 4 weeks of effective NSAID treatment, the BASDAI scores of ax-SpA patients are still in the range of 4.0.12 The safety of NSAID treatment raises concerns about hypertension, renal impairment, cardiovascular diseases, hypersensitivity reactions or severe cutaneous adverse reactions such as Stevens-Johnson syndrome,13-15 and mortality. Hypertension is associated with continuous NSAID treatment and obesity.16 Moreover, there were some concerns about the association between NSAID usage and renal impairments in ax-SpA patients, but Couderc et al. demonstrated that the risk of renal impairment was significantly associated with age instead of with 3 months of NSAID intake.17 The safety of chronic NSAID usage in ax-SpA patients still requires further investigation. Furthermore, acute myocardial infarction risk is increased during the first month of NSAID treatment and is associated with a high dose of NSAID in the general population.18 However, NSAID treatment has been shown to reduce the cardiovascular and cerebrovascular risks of morbidity and mortality in ankylosing spondylitis patients who experience chronic systemic inflammation. Also, NSAID therapy has been found to improve the mobility of ankylosing spondylitis patients.19 Moreover, lower doses and lack of exposure to NSAID are associated with vascular mortality in patients with ankylosing spondylitis.19, 20 A meta-analysis indicates that short-term NSAID treatment does not show a significant increase in adverse events, and there are no notable differences in adverse events among different NSAID classes.21 As a result, short-term high-dose NSAID treatment effectively increases mobility, reduces pain, and mitigates the risk of cardiovascular events and mortality in ax-SpA patients. However, it is important to monitor for the potential risk of hypertension and reduced kidney function. TNF inhibitors are recommended for ax-SpA patients with high disease activity (BASDAI >4) with which non-pharmacological treatments and NSAIDs are not effective.5 It has been reported that patients treated with agents targeting the tumor necrosis factor (TNF)-alpha (a) infliximab,22 etanercept,23 adalimumab,24 golimumab,25 and certolizumab26 may achieve Assessment of Spondyloarthritis International Society 20 (ASAS20) response and improve bone marrow edema as visualised by magnetic resonance imaging (MRI). These are monoclonal antibodies except for etanercept which is a TNF receptor fusion protein. Golimumab had especially good treatment response rates, but this is most likely a result of better selection of ax-SpA patients.25 The treatment outcomes of TNF inhibitors in ax-SpA patients may be limited by obesity27 and fibromyalgia.28 Nonetheless, the TNF inhibitors' retention rate for ax-SpA patients with good functional status is 42% over 8 years of treatment.29 Also, the early efficacy of TNF inhibitors has been shown to enhance the prediction of improved treatment outcomes.29 Conversely, switching between different biologics due to a lack of treatment response significantly reduces the likelihood of responding to the new biologic.30 This is almost not the case for biosimilars. Moreover, when ax-SpA patients are in remission for 48 weeks, dose reduction seems to be acceptable with limited adverse events for most patients,31 but complete discontinuation of TNF inhibitor treatments would increase the risk of flare-up significantly. Nevertheless, if a relapse happens, TNF inhibitors have been safely readministered to ax-SpA patients.32 There are some concerns about the risks of severe infection and malignancy in ax-SpA patients receiving TNF inhibitor treatment, but studies have shown that the risks of severe infection and malignancy in ax-SpA patients treated with TNF inhibitors are not significantly elevated33-35 In cases of treatment failure with TNF inhibitors, it is recommended for ax-SpA patients to switch to another TNF inhibitor or IL-17 inhibitors such as ixekizumab, secukinumab, or bimekizumab. Currently, there are no predictive biomarkers for good response to IL-17 inhibitors, so therapy should be based on safety data, extra-articular manifestation presentation, and patient preferences. Clinical trials on secukinumab demonstrated that the patients achieved ASAS20 response compared with placebo, regardless of whether it was the first biological drug or was used after failing to respond to previous anti-TNF therapy.36-41 Close to 80% of ax-SpA patients show no radiographic progression for 2 years with good tolerance and low risks of malignancy, major adverse cardiac events, inflammatory bowel disease, and infections.42, 43 Real-life studies also support these findings, showing a significant reduction in Ankylosing Spondylitis Disease Activity Score and BASDAI scores over a 2-year study period.44 Furthermore, three phase III clinical trials have shown that ixekizumab-treated patients achieved an ASAS40 endpoint compared with placebo in both radiographic and non-radiographic ax-SpA patients.45-47 Yet, IL-23 is not recommended because no clinical benefit has been demonstrated in ax-SpA patients.48 Furthermore, there are sex differences between TNF inhibitor treatment outcomes, which show that male patients have better responses and lower pain levels than female patients. However, it is unclear if it is due to misdiagnosis or major differences between sexes and further research is required to confirm this phenomenon.49 Therefore, TNF inhibitors are effective treatments for ax-SpA patients, and dose reduction at the remission level is recommended to reduce the risk of flares from treatment discontinuation. In addition, IL-17 inhibitors are recommended if TNF inhibitors are not effective for ax-SpA patients. However, they can also be used as first line therapy, especially if skin involvement by psoriasis is present. This is not the case for IBD. For the past few years, the effect of JAK inhibitors on ax-SpA patients has been studied in several randomized controlled trials. Filgotinib was shown to be efficacious in ax-SpA patients who did not respond to first-line NSAID treatment, and it has limited treatment–emergent adverse effects with no previously reported safety issues in spermatogenesis.50 Upadacitinib is effective in ax-SpA patients, but currently only 15 mg is approved by the US Food and Drug Administration.51 The potential of using JAK inhibitors in the clinical setting has been researched extensively and tofacitinib and upadacitinib are approved by the FDA for r-axSpA and upadacitinib also for nr-axSpA. The addition of these therapeutic options will hopefully help to better treat ax-SpA patients. None. JB has no conflict of interest to report. The data that support the findings of this study are openly available in [Pubmed].