TNF inhibitors: First ‘fully effective’ treatment in ankylosing spondylitis
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While rheumatic diseases like ankylosing spondylitis confound clinicians, tumor necrosis factor inhibitors have shown consistent efficacy and safety to be a reliable tool for rheumatologists in this patient population.
“TNF inhibitors were the first treatment to be fully effective in ankylosing spondylitis,” Philip J. Mease, MD, from the Swedish Medical Center and the University of Washington in Seattle, told Healio in an interview. “It was found that the symptoms of the disease, including pain, stiffness, physical function and quality of life all improved with these drugs.”
Mease summed up the feelings of the rheumatology community on the five TNF inhibitors that are currently approved by the FDA to treat the spondyloarthropathies: Adalimumab (Humira, AbbVie), certolizumab pegol (Cimzia, UCB), etanercept (Enbrel, Amgen), golimumab (Simponi, Janssen) and infliximab (Remicade, Janssen).
“All five of these drugs are very similar in terms of efficacy and safety,” he said. “They are really interchangeable.”
Literature review
Wang and colleagues conducted a systematic literature review of 20 clinical trials involving six TNF inhibitors, 43 treatment arms, and 3,220 participants. The aim was to compare drugs in patients with active ankylosing spondylitis as assessed by efficacy data at 10 to 14 weeks (12-week analysis) and at 24 to 30 weeks (24-week analysis).
Disease activity was measured using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), along with Bath Ankylosing Spondylitis Functional Index (BASFI) and C-reactive protein (CRP) levels.
Results showed that all tested therapies demonstrated superiority over placebo in reducing both BASDAI and BASFI at the 12- and 24-week marks.
Infliximab yielded the strongest BASDAI response at 12 weeks but not 24 weeks. However, when one open-label trial was excluded, no differences were reported among the therapies in terms of BASDAI response at 24 weeks.
Other findings from the 12-week analysis showed that all therapies except certolizumab pegol bested placebo in reducing CRP. At 24 weeks, certolizumab pegol and infliximab-dyyb (Inflectra, Pfizer), a biosimilar formulation of infliximab, were the only drugs that failed to demonstrate superiority over placebo at reducing CRP.
“Sometimes, you can see benefit as early as 2 weeks, even though the typical primary endpoint is 12 to 16 weeks,” Mease said. “It is worth noting that the safety of TNF inhibitors is a bit better in spondyloarthritis than it is in rheumatoid arthritis.”
This improved safety profile may exist because spondyloarthritis patients tend to be younger and have less comorbid disease than their RA counterparts, according to Mease. “Also, spondyloarthritis is generally not treated with steroids,” he said. “Steroids can impact the safety profile of TNF inhibitors.”
Nonradiographic and radiographic disease
A consideration for clinicians treating the spondyloarthropathies is the rise of nonradiographic axial spondyloarthritis as an independent diagnosis. Previously, ankylosing spondylitis was only diagnosed if patients had radiographic evidence of sacroiliitis on imaging, but recent evidence has shown that individuals may experience spondyloarthropic inflammatory back pain without evidence appearing on radiography.
Mease noted that radiographic ankylosing spondylitis is predominantly a male condition, while nonradiographic disease includes a larger ratio of women, making the spondyloarthropathies more or less equivalent in terms of gender distribution.
Mease was clear that this has little impact on the use of TNF inhibitor therapy. “We treat the nonradiographic and radiographic patients largely the same,” he said.
This point highlights the aforementioned interchangeability. However, despite the consistency of TNF inhibitors in this population, switching or cycling through therapies is occasionally necessary, largely because patients with spondyloarthritis can have a variety of presentations, manifestations and comorbidities.
On the nature of ‘switching’
Given the data, Deodhar and colleagues examined a number of parameters pertaining to TNF use. Outcomes of interest included switching, treatment failure and associations between failing on the drugs and health related QOL, work productivity and activity impairment (WPAI). The study population included 2,866 patients with ankylosing spondylitis from 18 countries. Complete treatment data were available for 2,795 of patients, of whom 32.8% had never undergone TNF inhibitor therapy, 58.1% were being treated with their first TNF and 7.2% had ever been treated with two or more TNF inhibitors. The latter group was defined as the treatment switch group.
The most common reasons for switching were primary or secondary lack of efficacy, according to the results. The mean duration for switching after the initial TNF inhibitor ceased to be efficacious was 11.1 months.
Other findings showed that 15.4% of patients were currently “failing” on a TNF inhibitor. Compared with patients who were benefitting from TNF inhibition, patients who were failing experienced poorer 5-dimension EuroQoL scores, 0.63 vs. 0.78. Similarly, failing patients also reported lower Medical Outcomes Study Short-Form Health Survey version 2 (SF-36v2) mental component summary scores, 41.8 vs. 46.3; physical component summary scores, 40.2 vs. 45.1; impaired work productivity, 46.4% vs. 25.0%; and activity, 44.5% vs. 29.6%; than those benefitting from the drugs (P<0.001 for all).
The researchers concluded that while switching TNF inhibitors is uncommon, those who do switch generally experience poorer outcomes overall.
Mease said it is difficult to predict who is going to fail on TNF therapy and require switching. “Some quite severe patients have a great response and sustained efficacy, while other severe patients burn through treatment benefit rapidly,” he said. “The same is true for patients with mild or moderate disease.”
As for which of the approved agents to choose as first-line therapy, Mease was pragmatic. “It comes down to what is first on the shelf at the insurance company formulary,” he said. “If there is another factor, it is that Medicare tends to treat the IV agents more favorably because they are economically better.”
There is no particular demographic or biomarker to determine likelihood of response or non-response, Mease added. “As a treating clinician, you just have to be aware that that efficacy can wane in a subset of patients.”
Long-term benefits
For patients who have failed multiple TNF inhibitors, rheumatologists managing the spondyloarthropathies now have options. “We are starting to increase the repertoire with interleukin (IL)-17 or a janus kinase (JAK) inhibitors,” Mease said. “But signs indicate that the overwhelming trend is that patients on TNF inhibitors can continue to do well over the long-term. We are starting to see data, particularly with certolizumab pegol, that these drugs can be effective going out to 5 years.”
Curtis and colleagues looked at more than 11,000 patients from 49 clinical trials of certolizumab pegol. While just one of the data sets included axial spondyloarthritis patients, the drug demonstrated a strong safety profile in infections, gastrointestinal outcomes and major adverse cardiac events. Looking to longer-term outcomes, mortality and malignancy rates were comparable to those observed in the general population.
While such large analyses of TNF inhibitors were previously limited to rheumatoid arthritis, Mease believes it is a good sign that researchers are turning their attention to spondyloarthritis. “We do not yet have the same depth of learning in ankylosing spondylitis registries that we do in RA, but we are getting there,” he said.
The data has forced clinicians to extrapolate data on TNF inhibitors from the RA registries to the spondyloarthropathies, which Mease acknowledged is not ideal. “Some of the extrapolation is reasonable,” he said. “But for some of it, we would be better served expanding spondylitis registries and learning that way.”
Looking ahead
If there is a new frontier for research in TNF inhibitors for the treatment of the spondyloarthropathies, it is in nonradiographic disease. “Recently, we have seen trials in this patient population that have led to approvals in Europe for nonradiographic axial spondyloarthritis,” Mease said. “At the moment, certolizumab is the only FDA-approved therapy for nonradiographic patients.”
Mease outlined another area for further research . “Once a patient is in deep remission for a long period of time, can you dose reduce or stop, and for how long might they remain in remission or not?” he said. “We are seeing these studies mostly in Europe at the moment. As a clinician and a researcher, I am very interested in what we are going to see from these controlled withdrawal studies.”
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