Targeted synthetic DMARDs

8 minute read

The run of synthetic DMARDs in RA therapy looks set to go for a while yet, and bring with it even more targeting capability Changes in treatment of RA since the early 1980s have been profound.  Led initially by the introduction of methotrexate, and then followed by the development of biologics and most recently, targeted […]

The run of synthetic DMARDs in RA therapy looks set to go for a while yet, and bring with it even more targeting capability

Changes in treatment of RA since the early 1980s have been profound.  Led initially by the introduction of methotrexate, and then followed by the development of biologics and most recently, targeted synthetic DMARDs, has meant a plethora of options now exist for RA patients, including those who don’t respond to the primary therapies.

The biggest step change, perhaps underlined by their commercial success as the most profitable drug class in history, has been the introduction of biologic disease-modifying antirheumatic drugs (bDMARDs), and specifically, the TNF-alpha inhibitors, at the beginning of the century.1

In some respects, the bDMARDs may have lulled the profession into a sense of complacency. The TNF-alpha inhibitor step change was so big, that subsequent improvements in therapy, even though they have often significantly expanded treatment options for RA patients have seemed small developments by comparison.

However, bDMARDs are only effective in about two thirds of RA patients and are contraindicated in some circumstances.2

So the need has been there for some time to look at more specific therapies which target certain classes of patients.

There are a range of different drug classes within the bDMARD group. TNF-alpha inhibitor represents just one but the most used. Others include IL-6 inhibitors,  rituximab and abatacept.

Janus kinase (JAK) inhibitors first appearing a few years ago, are now considered a potential new wave of treatment options for patients who fail to respond to bDMARDs. For many, these new agents will be first line options after failure of the conventional DMARDs.3

In Australia, after just a few years, tofacitinib (Xeljanz)  already accounts for nearly one third of RA patient initiations if conventional DMARDS have proven inadequate or not been tolerated and up to one third of switches off TNF inhibitors when they have proven inadequate.3

Early this year baricitinib (Olumiant) was approved for use in Australia. It’s introduction may signal that the TNF-alpha inhibitor revolution has some way to run yet. 

Baricitinib is a once daily oral JAK1 and JAK2 inhibitor versus twice daily tofacitinib, but in addition, early data from a study recently published in the New England Journal of Medicine suggests it might offer significant clinical improvement over the TNF-alpha inhibitor adalimumab (HUMIRA) which has probably been a defining standard of care for bDMARDs for the last 15 years.4

The RA-BEAM study was a 52-week, randomised trial of 1,307 patients with active RA who were receiving therapy with methotrexate and were randomly assigned either placebo, 4mg of baricitinib once daily, or 40mg of adalimumab every other week.

The study was conducted at 281 centres across 26 countries, was designed by the sponsor, Eli Lilly, and an academic advisory board who were not employees of Lilly. Patients in the study had had RA for an average of 10 years and about 75% had three or more erosions.

The researchers found that baricitinib had significant clinical benefits compared with placebo at week 12 and greater efficacy than adalimumab. Based on radiographic evidence, both baricitinib and adalimumab significantly inhibited progression of the disease at week 24 compared with placebo.

To week 24 serious adverse events were observed to be more frequent with baracitinib and placebo than with adalimumab. Other effects of both baricitinib and adalimumab included reduced neutrophil count, increased aminotransferase and creatinine levels, and increased LDL and HDL cholesterol levels.

The authors summarised their paper as follows:

“… in patients with active rheumatoid arthritis despite receiving therapy with methotrexate, the addition of once-daily oral baricitinib was associated with improvements in signs and symptoms, physical function, patient reported outcomes, and progression of structural joint damage as compared with placebo and with improvements in ACR20 response and DAS28-CRP as compared with adalimumab.”

Secondary analysis of the RA-BEAM study via patient reported outcomes (PROs) was completed in late 2017 and found that “baricitinib provided significantly greater improvement in most PROs compared with placebo and adalimumab, including physical function MJS, pain, fatigue and quality of life. Improvement was maintained to the end of the study (week 52)”.5

Nearly 3000 patients with RA who completed a previous baricitinib trial will be part of an ongoing long-term safety data study called RA-BEYOND.6

It is probably important to note here that although biologics have had a ground breaking effect on RA treatment, the future of RA treatment is clearly not solely dependent on this drug class. With both biologics and the new non-biologic targeted synthetic DMARDs, the establishment of national registers is thought important in eventually understanding more fully the real-world effectiveness of RA therapies beyond that observed in randomised clinical trials.7

One key safety area researchers investigating the JAK inhibitors will be focusing on, is the possible venous thromboembolism (VTE) risk.

Five patients (0.5%) treated with baricitinib 4mg reported a VTE event during the 24-week, randomised, placebo-controlled time period. Notably, no events were reported with the 2mg dose or placebo during this time period.

On further analysis of data from all those RA patients who took baricitinib, 3492 patients (6726 patient-years of observation), 31 patients experienced a VTE with an exposure-adjusted incidence rate of 0.5 per 100 patient years.8

They are all small numbers so the data is not clear, but despite this, there has been some discussion in the US about the risk of VTE associated with JAK inhibitors, possibly as a class effect.

Commenting on this possibility in Medscape Medical News recently chief of rheumatology research at Swedish Hospital Medical Center and clinical professor of Medicine at University of Washington in Seattle, Philip J. Mease, MD, said.

“I certainly don’t dismiss the question or potential concern…but to lump agents together as a class effect, especially since there may be real biological differences between the various JAK inhibitors, is too sweeping and potentially inaccurate. It is reminiscent of how celecoxib got stained when the rofecoxib myocardial infarction data came out, only to be exonerated years later by the PRECISION trial.” 9

Associate Professor Peter Nash, from the Department of Medicine at the University of Queensland told Rheumatology Republic that the RA-BEAM study is significant given its potential impact on the current, long-term gold standard treatment of RA  namely the combination of a TNF inhibitor with methotrexate.

A JAK inhibitor/methotrexate combination showing superior efficacy, particularly on pain measures, compared with TNF inhibitors with methotrexate is an important step in RA treatment, said Professor Nash who is also Director of the Rheumatology Research Unit on the Sunshine Coast in Queensland.

He says the step change here is important enough to suggest that this JAK inhibitor class will likely keep expanding, representing a new era of RA therapy. He noted that there are two new JAK inhibitors currently in phase three trials, upadacitinib (late phase 3) and filgotinib, both of which are showing promise.

Dr Mona Marabani, past president of the Autralian Rheumatlogy Association and current vice president of Arthitis Australia, is enthusiastic about the developments.

“It is fantastic to have another option for treating our RA patients. Oral therapies have great appeal and, coupled with its excellent efficacy data, would provide a good therapeutic choice for patients,” she told Rheumatology Republic.

“[But], patients on these drugs will need their lipids monitored, and there may be a signal for venous thromboembolism, so as with all treatments, optimal patient selection is important.”

Depending on the long-term safety data (and between tofacitinib and now baricitinib) the JAK Inhibitor class seems to have created a feasible option for RA patients who aren’t responding well to methotrexate and TNF-alpha inhibitors such as adalimumab. And there are more currently under investigation such as filgotinib and upatacitinib which may offer further enhancements to targeted therapy past the baseline therapies on offer.10

Another therapeutic option currently under investigation with possibly a less toxic profile is the proteasome inhibitor. Proteasome inhibitors are molecules whose mode of action is to induce an unfolded protein response.


Aggarwal, S & Abraham, Rheumatoic Arthritis Treatments: A Historical Perspective, JSM Arthritis, 28 July, 2016 (1) 2

PBS Data, 2016/17. Collated & Analysed

Dillhon S, Tofacitinib: A Review in Rheumatoid Arthritis, Drugs, Dec 2017 (18)

Taylor PC, et al, Baracitinib Versus Placebo or Adalimumab in Rheumatoid Arthritis, New England Journal of Medicine, 2017, 3376 (7)

Keystone ED, et al, Patient Reported Outcomes from Phase 3 Study of Baracitinib or Adalimumab in Rheumatoid Arthritis, Annals of Rheumatic Diseases, Sept 5, 2017, (76)


Elena Nickphorou, et al, Biologics Registers in RA:methodological aspecs, current role and future applications, Nature Reviews: Rheumatology, 2017, MacMillan (13)

Australian PI, Olumiant,

Kelly, Janis C, RA: Do JAK Inhibitors Increase Blood Clot Risk? , Medscape medical news, December 22, 2017

Nakayamada S, et al, Recept Progress in JAK Inhibitors for the Treatment of Rheumatoid Arthritis, BioDrugs, Oct 2016, 30 (5)

This article was made possible by an independent educational grant from Ely Lily Australia. It was written by Rheumatology Republic staff.

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