EULAR 2014: Research on Rheumatoid Arthritis, Spondyloarthritis

Light micrograph through the synovial membrane, which is thickened with layers of fibrin (bright pink), and fluid has leaked into the joint space.

PARIS, FRANCE—The past year’s research on rheumatoid arthritis (RA) largely reinforces the view that it’s okay to begin treatment with methotrexate with the option of stepping up treatment when necessary, said John Isaacs, MD, PhD, professor of rheumatology at Newcastle University, United Kingdom.

In a review of work on spondyloarthritis and ankylosing spondylitis, Dominique Baeten, MD, PhD, head of the Department of Immunology and Rheumatology at the University of Amsterdam, The Netherlands, said functional genomics has allowed the pathophysiology of the disease to be more fully explored, and he reviewed the latest treatment studies on TNF inhibitors and bone formation.

The experts made their remarks in a What Is New session at the Annual European Congress of Rheumatology (EULAR 2014) in June, essentially an expert’s guided tour through the literature since the last meeting of the European League Against Rheumatism in June 2013.

RA Research

Dr. Isaacs made these observations about the RA literature:

Anti-IL-6 drugs—sarilumab, olokizumab and sirukumab—all “look promising,” as does MOR103, a human monoclonal antibody to granulocyte-macrophage-colony-stimulating factor. But he stressed that they were all early-phase results.

Several studies—including the TEAR trial—showed that starting patients on methotrexate, then moving on to combination therapy when the response was insufficient, was a viable strategy.¹

Dr. Isaacs

“It is probably okay to start with methotrexate, as long as you’re prepared to step up fairly quickly, probably to combination DMARDs (disease-modifying antirheumatic drugs), at three months,” Dr. Isaacs said.

One study showed that gluco­corticoids in RA are associated with a dose-dependent increase in mortality rates, with a daily threshold at 8 mg, at which the dose-dependent mortality begins to be seen. This might help clinicians determine dosage.²

“We need to be aware of this when we use glucocorticoids in our daily practice,” he said. “They’re not benign drugs even though they’re very effective anti­inflammatory drugs.”

A head-to-head trial of subcutaneous abatacept, which blocks T-cell activity, and subcutaneous adalimumab, a TNF blocker, in biologic-naive patients with a background of methotrexate found the drugs to be equivalent at one and two years, with slightly more serious adverse events in the adalimumab group. The trial shows that patients don’t necessarily have to start biologic therapy with a TNF inhibitor.³

In the HONOR study, researchers looked at withdrawal from biologics once patients reach remission. Those with shorter disease duration were more likely to reach remission on adalimumab, and once withdrawn from the treatment, a post hoc analysis suggested that those in deep remission (with a DAS28-ESR of less than or equal to 1.98) showed similar rates of flares to those who were in remission but stayed on the drug.⁴

Dr. Isaacs also noted two editorials on the treat-to-target approach—they said it’s important to keep quality of life in perspective, rather than pursue a target blindly.^5,6

“Make sure we know what the incremental benefit is of pursuing remission—rather than low disease activity,” he said. “Or imaging remission rather than clinical remission.  Don’t forget quality of life, because if you’re pushing lots of pills into your patient, that might be having a negative effect [that] offsets the benefits.”

Spondyloarthritis Research

Dr. Baeten made these observations about the spondylo­arthritis (SpA) literature: Two studies found CD74 autoantibodies in patients with spondyloarthritis, challenging the notion that T cells and B cells may not play a major role in the disease.^7,8

Dr. Baeten said the studies mean the SpA community needs to revise their concept that T cells and B cells “are not important.”

“Clinically, if it holds true, then we have to go back to cohorts with early inflammatory back pain and test whether this would be a useful diagnostic biomarker, which would be obviously very important for this disease,” he said.

Dr. Baeten

Another study found that arthritis, spondylitis and enthesitis levels were all down in an anti-IL-23 mouse model, but with no effect on new bone formation. But the studies did little to shed light on the role of downstream cytokines IL-17 and IL-22, he said.⁹

“Clearly, we have more work to do even in an IL-23-dependent model, to understand which downstream cytokines are really key to the pathology,” Dr. Baeten said.

In a 325-patient, 24-week trial of the anti-TNF certolizumab pegol (CZP), now indicated for RA, CZP rapidly reduced axial SpA signs and symptoms, with a safety profile similar to that seen in RA patients.¹⁰

A trial on infliximab and naproxen shed light on how early, aggressive treatment might allow for treatment withdrawal. Patients with early axial SpA were treated with naproxen and infliximab or with naproxen and placebo. Those getting the combination were twice as likely to meet partial remission criteria.¹¹ When treatment was stopped, 60% lost the partial remission, but many stayed in remission. Keeping patients on naproxen didn’t make a difference.¹²

In a bone formation study on ankylosing spondylitis (AS) patients, researchers found a correlation between disease activity scores and mSASSS scores, an index characterizing radiologic changes in the spine in AS patients. Dr. Baeten stressed that doesn’t mean there’s a causal link, but said it’s a line of inquiry worth pursuing more.¹³

Two other trials, he said, showed that TNF inhibitors slowed radiographic progression in AS patients. The studies “re-open the debate” on whether TNF blockers affect new bone formation, but they were troubled by methodological problems, including different baseline characteristics of patient groups and the use of historical controls, rather than simultaneous controls, Dr. Baeten said.^14,15

“If the effects are there, they’re not very large and there is still a debate [about] whether there really is any effect at all,” he said. “For me, the main question is, how can we address [this] in the next year and come up with cleaner designs, cleaner studies, that will help us?”

Thomas R. Collins is a freelance medical writer based in Florida.

References

1. Moreland LW, O’Dell JR, Paulus HE, et al. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: The treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum. 2012 Sep;64(9):2824–2835.
2. del Rincon I, Battafarano DF, Restrepo JF, et al. Glucocorticoid dose thresholds associated with all-cause and cardiovascular mortality in rheumatoid arthritis. Arthritis Rheumatol. 2014 Feb;66(2):264–272.
3. Schiff M, Weinblatt ME, Valente R, et al. Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: Two-year efficacy and safety findings from AMPLE trial. Ann Rheum Dis. 2014 Jan;73(1):86–94.
4. Tanaka Y, Hirata S, Kubo S, et al. Discontinuation of adalimumab after achieving remission in patients with established rheumatoid arthritis: 1-year outcome of the HONOR study. Ann Rheum Dis. 2013 Nov 28 [Epub ahead of print].
5. Solomon DH, Bitton A, Katz JN, et al. Review: Treat to target in rheumatoid arthritis: Fact, fiction, or hypothesis? Arthritis Rheumatol. 2014 Apr;66(4):775–782.
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7. Baraliakos X, Baerlecken N, Witte T, et al. High prevalence of anti-CD74 antibodies specific for the HLA class II-associated invariant chain peptide (CLIP) in patients with axial spondyloarthritis. Ann Rheum Dis. 2014 Jun; 73(6):1079–1082.
8. Baerlecken NT, Nothdorft S, Stummvoll GH, et al. Autoantibodies against CD74 in spondyloarthritis. Ann Rheum Dis. 2014 Jun;73(6):1211–1214.
9. Benham H, Rehaume LM, Hasnain SZ, et al. IL-23 mediates the intestinal response to microbial beta-glucan and the development of spondyloarthritis in SKG mice. Arthritis Rheumatol. 2014 Mar 24. [Epub ahead of print]
10. Landewe R, Braun J, Deodhar A, et al. Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled Phase 3 study. Ann Rheum Dis. 2014 Jan;73(1):39–47.
11. Sieper J, Lenaerts J, Wollenhaupt J, et al. Efficacy and safety of infliximab plus naproxen versus naproxen alone in patients with early, active axial spondyloarthritis: Results from the double-blind, placebo-controlled INFAST study, Part 1. Ann Rheum Dis. 2014 Jan; 73(1):101–107.
12. Sieper J, Lenaerts J, Wollenhaupt J, et al. Maintenance of biologic-free remission with naproxen or no treatment in patients with early, active axial spondyloarthritis: Results from a 6-month, randomised, open-label follow-up study, INFAST Part 2. Ann Rheum Dis. 2014 Jan;73(1):108–113.
13. Ramiro S, van der Heijde D, van Tubergen A, et al. Higher disease activity leads to more structural damage in the spine in ankylosing spondylitis: 12-year longitudinal data from the OASIS cohort. Ann Rheum Dis. 2014 May 7 [Epub ahead of print].
14. Haroon N, Inman RD, Learch TJ, et al. The impact of tumor necrosis factor α inhibitors on radiographic progression in ankylosing spondylitis. Arthritis Rheum. 2013 Oct;65(10):2645–2654.
15. Baraliakos X, Haibel H, Listing J, et al. Continuous long-term anti-TNF therapy does not lead to an increase in the rate of new bone formation over 8 years in patients with ankylosing spondylitis. Ann Rheum Dis. 2014 Apr;73(4):710–715.