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Currently, treatment options for patients with peripheral spondyloarthritis, which includes psoriatic arthritis and non-psoriatic types, are limited. Philippe Carron, MD, Department of Rheumatology, Ghent University Hospital, Belgium, says, “One of the problems we encounter in the daily management of peripheral spondyloarthritis is that we have no other therapeutic options in patients refractory to NSAIDs [non-steroidal anti-inflammatory drugs], sulfasalazine and methotrexate. Most of these patients are young and experience a high burden of disease. We know that TNF inhibitors are efficient, but they are not reimbursed unless there is concomitant psoriasis or sacroiliac involvement, which is not always present.”
The CRESPA Study
Dr. Carron is also the first author of a paper published in Arthritis & Rheumatology.1 The CRESPA study (clinical remission in peripheral spondyloarthritis) analyzed patients diagnosed with peripheral spondyloarthritis (as fulfilled by the Assessment of SpondyloArthritis International Society [ASAS] classification criteria) who had experienced symptoms for fewer than 12 weeks.1 The randomized, placebo-controlled phase was followed by an open-label phase from Weeks 24–48. The study included 60 patients, 40 of whom received 50 mg of the TNF inhibitor golimumab subcutaneously every four weeks until Week 20 and another 20 patients who received placebo.
Golimumab was stopped in patients in sustained clinical remission. This was defined as complete absence of peripheral arthritis, enthesitis and dactylitis at two consecutive visits (at Weeks 12, 24, 36 and 48). Patients with sustained disease activity at the end of Week 24 received 50 mg golimumab every four weeks through Week 48. In the open-label extension, patients restarted 50 mg golimumab for a total of 104 weeks if they developed a clinical relapse (at least one swollen joint plus enthesitis or dactylitis) after an initial remission. Those showing partial response (at least 40% improvement from baseline as defined by the Peripheral Spondyloarthritis Response Criteria) also received golimumab for the extension period.
Eighty-two percent of patients (49/60) achieved sustained clinical remission following induction of golimumab. Of the 49 responders, 30 were in remission by Week 24 and another 11 by Week 35; eight more were in remission by Week 40. No significant response occurred in placebo-treated patients, ruling out spontaneous remission. The researchers followed patients from a range of 23 months to five years after golimumab cessation. At that time, 53% of the responders (26 of 49) were still in sustained and drug-free remission.
The researchers also analyzed factors that predicted relapse after drug withdrawal. Both polyarticular disease and pre-existing psoriasis were strong predictors for relapse. In patients with psoriasis, the estimated odds for sustained drug-free remission was 80% lower (OR=0.2, 95% CI 0.06 to 0.65, P=0.008), and patients with polyarticular disease had odds 83% lower (OR=0.17, 95% CI 0.03 to 0.84, P=0.03) than for patients without polyarticular disease or psoriasis.
Discussion
Dr. Carron
Dr. Carron notes, “This is the first study of the impact of first-line anti-TNF therapy in very early peripheral spondyloarthritis to achieve clinical remission after which a withdrawal was performed. This study indicates drug-free remission is an achievable target in early spondyloarthritis in at least 50% of patients.” The study extends and confirms earlier published results from the study that initiation of TNF inhibitors in very early peripheral spondyloarthritis yields remarkably high rates of remission.2
Earlier work demonstrated most patients with more long-standing forms of the disease quickly relapse after withdrawal of TNF-inhibitor therapy.3 In this study as well, patients with more established forms of disease did not respond as consistently, as indicated by the greater relapse rates in patients with oligoarthritis and patients with pre-existing psoriasis (which on average had been present for four years). Dr. Carron and colleagues speculate that in the early phase of the disease, aggressive therapy may lead to disproportionate benefits, with patients having a good chance for achieving drug-free remission. In this phase, immune dysregulation may be reversible in some patients.
“Since autoimmunity is characterized by the loss of tolerance toward self-structures, drug-free remission at the molecular level probably means not only complete suppression of disease activity, but also the reestablishment of tolerance,” Dr. Carron explains.
“Later, in the progressive phase of the disease, autoimmunity is no longer reversible,” Dr. Carron continues. “In this late phase, adequate therapy leads to moderate benefit, and patients have a low chance of remission. And it looks like there is no chance for drug-free remission. This hypothetical model suggests that, among other known and unknown factors, disease duration is a crucial risk factor for progressive disease.”
He says this hypothesis might explain the high rates of drug-free clinical remission observed in this study, in which the mean disease duration had been only five weeks.
Dr. Carron notes we don’t know the precise time frame in which the disease might become more refractory to drug withdrawal strategies. However, he believes all patients with spondyloarthritis, both axial and peripheral, might benefit from treatment during this early period when the disease appears to be more susceptible to treatment—the earlier, the better.
“Collectively, these data establish a novel therapeutic framework in defined subsets of early peripheral spondyloarthritis. This can help clinicians make the right therapeutic decisions,” says Dr. Carron.
Overall, this research can be contextualized in terms of a larger body of work studying treatment withdrawal strategies in early forms of axial spondyloarthritis. Dr. Carron notes a number of reasons may incite interest in this topic. These include introduction of the treat-to-target principle in axial spondyloarthritis, better ability to diagnose the disease in its early forms, the new use of the Ankylosing Spondylitis Disease Activity Score to evaluate scores of clinical remission and an increased interest in exploring biomarkers. Cost effectiveness also plays a role, due to the expense of TNF inhibitors.
Dr. Carron explains that such approaches, “try to reach the ultimate goal in treatment—recovery.” He also notes that in this setting TNF inhibitors are treated as class agents, because there are no head-to-head trials showing that some TNF inhibitors may be better than others.
Further Study
Moving forward, Dr. Carron and colleagues are also looking at patients who completed the original CRESPA extension. “After those two years (Week 104), patients were offered an additional 12 weeks of golimumab treatment, but now in combination with methotrexate 15 mg weekly,” explains Dr. Carron. “At Week 116, patients in clinical remission continued methotrexate, but discontinued golimumab.”
The researchersfollowed the patients prospectively to assess rates of sustained clinical remission without golimumab.
It was restarted if the patients relapsed under the methotrexate monotherapy. In September, the data from this follow-up study were shared at the International Spondyloarthritis Congress of Ghent.
Ruth Jessen Hickman, MD, is a graduate of the Indiana University School of Medicine. She is a freelance medical and science writer living in Bloomington, Ind.
References
- Carron P, Varkas G, Renson T, et al. High rate of drug-free remission after induction therapy with golimumab in early peripheral spondyloarthritis. Arthritis Rheumatol. 2018 May 27. doi: 10.1002/art.40573.
- Carron P, Varkas G, Cypers H, et al. Anti-TNF-induced remission in very early peripheral spondyloarthritis: The CRESPA study. Ann Rheum Dis. 2017 Aug;76(8):1389–1395.
- Paramarta JE, Heijda TF, Baeten DL. Fast relapse upon discontinuation of tumour necrosis factor blocking therapy in patients with peripheral spondyloarthritis. Ann Rheum Dis. 2013 Sep 1;72(9):1581–1582.