Do Patients with Ankylosing Spondylitis in Remission Still Need TNF Inhibitors?

Patients with axial spondyloarthritis have a chronic, immune-mediated inflammatory disease that tends to localize to the sacroiliac joints and spine. Ankylosing spondylitis is, perhaps, the most representative of this group of diseases. Rheumatologists treat patients with axial spondyloarthritis with biologics, such as tumor necrosis factor inhibitors (TNFi’s), which can improve quality of life, activity and functionality. Unfortunately, TNFi treatment is expensive and is associated with the possibility of long-term side effects. Investigators thus seek a personalized medicine approach in which clinical and biological markers are used to identify those patients most likely to benefit from TNFi’s, while at the same time minimizing drug exposure to those who are not expected to benefit.

Can Treatment Dose Be Reduced?
Given the costs and potential long-term side effects of TNFi therapy, rheumatologists have wondered whether patients in remission require the full treatment dose. The answer from clinical practice and patient registries appears to be that patients with longstanding ankylosing spondylitis who achieve sustained clinical remission can reduce their treatment dose.

Unfortunately, rheumatologists lack both a uniform definition of reduced dose and a uniform definition of remission. Absent a uniform definition, a reduced dose is any dose below that indicated on the package insert. Likewise, absent a uniform definition of remission for patients with axial spondyloarthritis, physicians tend to rely upon the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the C-reactive protein.

In January, investigators from Spain published the results of the first randomized trial in support of the non-inferiority of reduced-dose TNFi therapy compared with full-dose TNFi’s in patients with spondyloarthritis.¹ They randomized patients who were in clinical remission into what they described as a conservative TNFi reduction schedule that brought the TNFi dose down to approximately 50% of the recommended dose, or into a standard dose cohort. The group defined clinical remission as BASDAI ≤2, no clinically active arthritis or enthesitis, and C-reactive protein within normal limits for ≥6 months.

The researchers in Spain found that patients in remission maintained low disease activity for a year equally well, whether they were randomized to reduced-dose TNFi’s or standard-dose TNFi’s. Moreover, the results suggested that serious adverse events, less serious events and infections occurred at only one-third the rate in the reduced-dose group compared with the full-dose group. This difference did not, however, reach statistical significance, probably due to the small sample size (i.e., 126 patients). Moreover, because the investigators were only able to obtain serum samples from half of the study population, their study was not powered to identify the patients who had a higher chance of maintaining a low disease activity after reduction of their TNFi dose.

Can Treatment Be Stopped?
With the knowledge that treatment can be successfully reduced in patients with ankylosing spondylitis who are in remission, some clinicians have proposed withdrawing treatment altogether from these patients. Unfortunately, although many patients can maintain low disease activity following TNFi dose reduction, complete treatment withdrawal in patients with ankylosing spondylitis appears to lead to relapse in most patients. This finding raises the question: How do patients with axial spondyloarthritis respond to retreatment after withdrawal of TNFi’s? The group in Spain has found the answer.

Mireia Moreno, MD, who serves in the rheumatology department of Parc Taulí Hospital Universitari of the Universitat Autònoma de Barcelona, and her colleagues first sought to determine how long patients with ankylosing spondylitis who were in persistent clinical remission would remain free of flares after withdrawal from anti-TNF therapy. They then evaluated the effects of treatment reintroduction and sought to identify any biomarkers that might predict response to reintroduction of therapy.

The REMINEA study group found that two-thirds of patients in clinical remission presented with clinical relapse shortly after infliximab withdrawal. Although the rheumatologists could safely reintroduce infliximab therapy to these patients, half of the patients did not experience the same clinical response to reinitiation they had achieved prior to treatment withdrawal.

Although many patients can maintain low disease activity following TNFi dose reduction, complete treatment withdrawal in patients with ankylosing spondylitis appears to lead to relapse in most patients.

The work, published April 5 in Arthritis Research & Therapy, represents the first prospective study to show that most patients with longstanding ankylosing spondylitis who are in persistent clinical remission experience relapse within 12 months of withdrawal from infliximab, and it suggests such relapse may have longstanding implications for patients.²

The investigators began with retrospective identification of 107 patients (72% male) with definitive ankylosing spondylitis who had received only infliximab treatment as a first-line TNFi therapy. The researchers defined persistent clinical remission as a BASDAI ≤2, normal C-reactive protein, and absence of active arthritis or enthesitis and/or any other extra-articular manifestations during the last six months in the absence of any additional steroid and/or non-steroidal anti-inflammatory drug treatment.

They used these criteria to identify a homogeneous cohort of 36 patients who presented with persistent remission. Retrospective analysis revealed that younger age, shorter disease duration and higher C-reactive protein at the start of infliximab treatment were all associated with clinical remission under treatment.

The prospective observational part of the study included the patients who were in remission and was performed in 23 hospitals with rheumatology services in Catalonia (northeastern Spain). The prospective study lasted 12 months and included an assessment every six to eight weeks for peripheral arthritis or enthesitis, BASDAI, C-reactive protein, erythrocyte sedimentation rate, Bath Ankylosing Spondylitis Functional Index (BASFI), and three visual analogue scales (spine global pain, spinal night time pain and patient’s global assessment). The investigators defined clinical relapse at any time period as newly appearing BASDAI ≥4 or C-reactive protein ≥0.8 mg/dL.

After treatment withdrawal, 58% of patients presented clinical relapse during follow-up. The researchers noted they were unable to determine any clinical or biological factors associated with the occurrence of relapse during follow-up. The investigators then reintroduced infliximab without an induction phase or any previous premedication to those patients who had relapsed. They found that only 52% achieved the clinical remission that they had achieved prior to the discontinuation of infliximab. Moreover, in 10% of patients, the reintroduction of infliximab was ineffective, and the rheumatologists had to turn to a new anti-TNF therapy for these patients.

“Overall, the results we reported here suggest the decision to withdraw treatment should be taken with considerable caution, and it seems unreasonable to propose withdrawal as an objective of the treatment strategy, at least at present, in the absence of any objective predictive factors of persistent clinical remission after treatment withdrawal,” concluded the authors.

Lara C. Pullen, PhD, is a medical writer based in the Chicago area.

References

1. Gratacós J, Pontes C, Juanola X, et al. Non-inferiority of dose reduction versus standard dosing of TNF-inhibitors in axial spondyloarthritis. Arthritis Res Ther. 2019 Jan 8;21(1):11.
2. Moreno M, Gratacós J, Torrente-Segarra V, et al. Withdrawal of infliximab therapy in ankylosing spondylitis in persistent clinical remission, results from the REMINEA study. Arthritis Res Ther. 2019 Apr 5;21(1):88.