RA Treatment Safety & Efficacy: Where Are We in 2014?

March 19, 2014

No clear winner has emerged from all the recent research into rheumatoid arthritis treatment. But the vast bulk of the evidence, from systematic reviews of studies testing current therapies, is encouraging.

With the spate of new treatments for rheumatoid arthritis (RA), and the constant stream of new studies, it’s difficult to know exactly where we stand.

Is there good real-life data on the risks of biologics, TNF-alpha (TNF-α) inhibitors, interleukin-6 (IL-6), and the new Janus Kinase (JAK) inhibitors? How do they stack up against older, conventional disease modifying anti-rheumatic drugs (DMARDs)?

Can rheumatologists prescribe older and newer drugs with total confidence?

Real-life data from clinical practice is available mainly for older drugs. But the sheer numbers of studies and patients included in recent systematic literature reviews at least offer some reassurance.

Safety in Numbers

A safety review in the January 2014 Annals of the Rheumatic Diseases, encompassed 49 studies of currently approved biologics and DMARDs published through 2013, involving more than 87,000 registry patients. They looked at risks from infections to cancer. The analysis largely confirmed known safety data.1

The review included 9 biologics such as anakinra, etancercept, abatacept, tocilizumab, and certolizumab pegol, 15 synthetic DMARDs like leflunomide, azathioprine, tofacitinib, the old standards methotrexate (MTX) and sulfasalazine, and the glucocorticoid (GC) prednisone.1

Using the proposed new nomenclature,2 the review affirmed that biologicals (bDMARDs) and synthetics (sDMARDs) are all “relatively safe” for treating RA. But the authors cautioned “this does not mean that there are no risks at all.”1

For example:

•   TNF-α inhibitors are known to have a higher risk than sDMARDs of infections, including tuberculosis, that may not emerge immediately;

•   the limited safety information on tofacitinib is gleaned solely from randomized trials, not from real-life clinical practice;

•   while no new safety signals have emerged for conventional sDMARDs, “with a few exceptions, no high-quality studies were found either.”1

How Well Do Today’s Drugs Work?

An efficacy review by the same group surveyed data from 4 studies of conventional synthetic DMARDs (csDMARDs) and GCs (mostly prednisone) involving 980 patients, and 10 randomized controlled trials (RCTs) of tofacitinib among 5,563 patients. The analysis affirmed their effectiveness.

The report concluded that adding low-dose glucocorticoids to csDMARD therapy is beneficial in early RA. But it added that even “under tight control conditions, combination therapy with csDMARDs is no better than MTX monotherapy.”3

A third Annals report published online by the same group was an extended efficacy review of  data published only since January 2009, including EULAR and ACR meeting abstracts from 2011-2013 and ongoing phase III trials.4

The review of more than 100 studies, presentations, and publications confirmed the effectiveness of bDMARDs, csDMARDs, as well as new biosimilars and targeted synthetic DMARDs (tsDMARDS) like the JAK inhibitor tofacitinib (Xeljanz) and the IL-6 blocker tocilizumab (Actemra).4

The extended review also affirmed the efficacy of combinations such as biologicals and MTX.

The authors noted a dearth of quality RCTs that assessed the issue of switching bDMARDs. But they did find reassuring efficacy data for step-up therapy to improve responses when one therapy is inadequate or fails. Also, they concluded that the evidence suggests it is possible to reduce medication doses and safely maintain remission for patients who have achieved it.4

While these new reviews may provide some clinical comfort, the overall conclusion seems to be that no single treatment is dramatically different than others in safety or efficacy.

Rheumatologists are convinced of the efficacy of glucocorticoids (GCs) “and give them a prominent place in the treatment algorithms of RA, but still fear their safety profile,” the reviewers commented. “In part, this is due to the lack of robust safety data.”1

Where will we find new safety data for the older treatments? The authors strongly suggest that the methodology developed for biologic drug registries should be used to gain more insight into widely used older drugs, including GCs.

In its 2013 RA management recommendations, the European Union League Against Rheumatism (EULAR) stressed that being strategic about treatment is paramount. The extended review in the Annals also found that clinical and radiographic responses were greater with intensive and treat-to-target strategies.

Focus on Patients

Another important factor is the patients themselves. Several recent studies suggest that patient-specific factors such as longer disease duration, MTX intolerance, older age and co-existing conditions greatly impact treatment efficacy as well as survival.4

Drug efficacy needs to be measured by more than response rates, said Daniel Aletaha MD, a member of the EULAR guidelines task force, at the 2013 annual meeting of the American College of Rheumatology (ACR).

“When we talk about drugs to treat RA, we more or less find out that everything seems to work in the same proportion of patients," said Aletaha, who is an associate professor of rheumatology at the University of Vienna. "And that it’s not so much the drug that’s ruling the response rates, but the population that we study the drug in.”

It’s well established that older age and comorbid conditions increase the risk for adverse events and death among patients on medications.5 One newly published analysis of patient responses in randomized trials of biologics plus MTX or MTX montherapy found that one key predictor of good ACR responses is shorter disease duration.6

Also, upwards of 11% of RA patients may be MTX intolerant. Severe side effects including gastrointestinal problems (so bothersome that merely anticipating MTX treatment makes some patients feel sick) must surely affect adherence and therefore efficacy.7

Newer Options

As for new agents, there are encouraging data for Janus Kinase inhibitors.

Tofacitinib, the first JAK inhibitor approved in 2012 to treat moderate to severe RA, and the newer agents baracititinib and ruxolitinib, are currently in ongoing clinical trials, as is an experimental selective JAK-1 inhibitor, GLPG0634.8

Data reported at the 2013 ACR meeting show that high, medium, and low doses of tofacitinib are all effective for RA patients who have an inadequate response (or intolerance) to MTX. The risks do not increase for those who continue the drug for up to five years, either as monotherapy or in combination with cDMARDs.9

However, patients over age 65 appear to be at greater risk for adverse events and drug discontinuation.10

No Clear Winner

At present, apparenly, no old or new RA drug has emerged a clear winner.

“A significant proportion of patients may still not reach the desired therapeutic target. Therefore new therapies are still needed and, indeed, are on the horizon,” concludes the 2013 EULAR RA management recommendations.

Unless one or more RA therapies clearly prove a more effective treatment, strategy will remain key.

For EULAR task force member Daniel Aletaha, the winning strategy is treat-to-target, which assures that patients won’t remain on less effective therapies – because if one treatment fails, clinicians now know they can safely switch to another.


 

 

References:

1.  Ramiro S, Gaujoux-Viala C, Man JL, et al., Safety of synthetic and biological DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis. (2014) 73:529-535. [published online first 8 Jan 2014] doi: 10.1136/annrheumdis-2013-204575. Published Online First: 8 January 2014]. Including online supplementary data.

2.  Hackethal V, A DMARD by Any Other Name: New Classifications Proposed.” Rheumatology Network, October 7, 2013.

3.  Gaujoux-Viala C, Nam J, Ramiro S, et al., Efficacy of conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids and tofacitinib: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis.Ann Rheum Dis. (2014) 73:510-515. [Published Online First: 6 January 2014] doi:10.1136/annrheumdis-2013-204588.
 
4.  Nam JL, Ramiro S, Gaujoux-Viala C, et al., Extended report: Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis.  Ann Rheum Dis (2014) 73:516-528. [Published Online First: 7 January 2014] doi:10.1136/annrheumdis-2013-204577.

5.  Listin J, Kekow J, Manger B, et al., Mortality in rheumatoid arthritis: the impact of disease activity, treatment with glucocorticoids, TNFα inhibitors and rituximab.Ann Rheum Dis. (2013)  doi:10.1136/annrheumdis-2013-204021 {Online first Nov 29-13].

6.  Kanters S, Druyts E, Mills EJ, Thorlund K. What drives the comparative effectiveness of biologics vs methotrexate in rheumatoid arthritis? Meta-regression and graphical inspection of suspected clinical factors. Rheumatology (2014) doi: 10.1093/rheumatology/ket492 [Published online first 5 March 2014.]
 
7.  Alasan MB, van den Bosch OF, Creemers MC, et al., Prevalence of methotrexate intolerance in rheumatoid arthritis and psoriatic arthritis.Arthritis Res Ther. (2013) Dec 18;15(6):R217. [Epub ahead of print].

8.  Tasset C, Harrison P, Van der Aa A, et al., The JAK1-Selective Inhibitor GLPG0634 Is Safe and Rapidly Reduces Disease Activity In Patients With Moderate To Severe Rheumatoid Arthritis; Results Of a 4-Week Dose Ranging Study. ACR 2013 Abstract #2381

9. Wollenhaupt J, Silverfield J, Lee EB, et al., Tofacitinib, An Oral Janus Kinase Inhibitor, In The Treatment Of Rheumatoid Arthritis: Open-Label, Long-Term Extension Safety and Efficacy Up To 5 Years. ACR 2013 Abstract: #2328.

10.  Schulze-Koops H, Curtis JR; Takiya L, et al., Efficacy and Safety of Tofacitinib In Older and Younger Patients With Rheumatoid Arthritis. ACR 2013 Abstract: #2331.