Triple therapy for early RA: there and back again

The turn of the century was a time of great strides in the management of rheumatoid arthritis.

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Leflunomide was PBS approved, becoming the first new treatment option for RA in decades, and robust, systematic investigation into optimising the management of RA was ongoing. With a retrospect-o-scope, these advances may seem to be minimal compared to the impact of biological therapy, but they were actually game changers.  

In 1997, the landmark COBRA study demonstrated the efficacy of a “step-down” approach to therapy, initiating high dose oral steroids, methotrexate (MTX) and sulfasalazine (SSZ) and withdrawing slowly over time. This statement grossly oversimplifies the study, it’s findings, legacy and impact. Several studies of early aggressive therapy followed.

In 1999, the FinRACo study demonstrated that the combination of MTX, SSZ, hydroxychloroquine (HCQ) and steroids was superior to SSZ monotherapy.

In 2002, James O’Dell published a paper entitled “Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: results of a two-year, randomized, double-blind, placebo-controlled trial”.

Rapidly nicknamed “triple therapy”, the combination of MTX, SSZ and HCQ saw a higher percentage of people meet ACR 20 improvements compared to MTX and HCQ, with the MTX and SSZ combination performing more poorly.

In 2004, the TICORA study demonstrated the efficacy of a “step-up” approach to therapy, with treatment escalation driven by an algorithm focusing on tight control. Therapy was initiated with SSZ, with MTX, HCQ and steroids added if the DAS was >2.4 at frequent study visits.

By this time, the first TNF inhibitors had been shown to be safe and efficacious, although expense prohibited routine use. Thus began a well-orchestrated, largely pharma funded, campaign marketing the “treat to target” principle.

To summarise, a huge body of evidence drove paradigm shifts in the management of RA to ensure early identification of RA (“window of opportunity”) and aggressive, outcomes-driven therapy (“treat to target”).

My recollection is that some Australian rheumatologists embraced triple therapy, while others focused more on the principles of tight control than the details of the drugs.

Meanwhile, the PBS approved the use of bDMARDS and the management of RA in Australia became then less influenced by the evidence and more reflective of PBS requirements to access bDMARDs. These rules have changed over the last 20 years, and this is reflected in the prescribing habits of Australian rheumatologists.

So, fast forward to 2022 and the Australian Living Guideline for the pharmacological management of inflammatory arthritis.

The guidelines are created by an expert advisory team of Australian rheumatologists, consumers and allied health professionals. They recognise that traditional guidelines quickly become outdated and aim to frequently revise their recommendations, incorporating up-to-date evidence to ensure the guidelines remain high quality and relevant.

In addressing the question of initial management of RA, the guidelines conditionally recommended: methotrexate in combination with other DMARDs as initial therapy in people with rheumatoid arthritis. For most people this implies triple therapy (methotrexate + sulfasalazine + hydroxychloroquine). While the combination of methotrexate and most b/tsDMARDs is also effective, this is currently not a feasible option for most people.

It is important to note, this guideline does not address the role of steroids in the management of early RA.

The recommendation draws on evidence from a 2016 network meta-analysis, in which methotrexate in combination with other drugs was found to achieve significantly better ACR50 response rates than monotherapy. The only combination not involving b/tsDMARDS was triple therapy, and triple therapy performed as well as those involving b/tsDMARDS. The probability of ACR50 response was similar among combination therapies (range 56-67%) compared with 41% for methotrexate alone. 

The guidelines then go on to reference a 2016 discrete choice analysis finding that patients with rheumatoid arthritis would be happy to take triple therapy if it presented them with a 5% absolute increase in the chance of achieving an ACR50, noting that the evidence shows an almost 20% absolute increase in ACR50 response rate with triple therapy.

The guidelines have drawn a strong reaction from the Australian rheumatology community. In response, the ARA hosted a debate to address the issue in June.

Professor Lyn March presented the affirmative case, addressing the evidence of efficacy and patient preferences. Ben Horgan, a consumer, then reminded us to talk to our patients. Dr Helen Cooley present the negative argument, addressing practicalities, tolerability, cost to the patient and feasibility. Ben again reminded us to talk to our patients.

I’ve reflected on the debate and reviewed the evidence. It’s made me ponder what happened to triple therapy. Maybe the Australian PBS rules discouraged its use. But it’s not unique to Australia.

A 2007 study aimed to address why Dutch rheumatologists didn’t use the COBRA strategy. A mentor of mine says that good clinicians will adopt management strategies if there are strong scientific principles, consistency of evidence and a positive clinical experience. I think that the scientific principles and evidence are hard to dispute, the missing element is a positive clinical experience.

What I did take from the debate was Ben Horgan’s voice. Talk to our patients. So for the last two weeks, I’ve talked about the guidelines to my patients with early rheumatoid arthritis, and none of them have opted for triple therapy. Which is OK, because ultimately, it’s their choice. The reality is that triple therapy is about 37 tablets a week, as opposed to two with MTX monotherapy, and that is a hard sell.

So in 2022, the best available evidence suggests the optimal therapy for people with RA (in a fiscally restrictive health care system) is a 20-year-old management strategy that many us found impractical in the first place. Is this a disappointing statement in how far our craft has come? Maybe.

Alternatively, if we read the guidelines in full, and consider their development and the context, maybe we can see progress. The guidelines were developed with patient research partners, strongly address the evidence regarding patient preferences and implore us to work with the person with rheumatoid arthritis. We need to partner with our patients, present them with the evidence and allow them to choose.

So triple therapy may be an old management strategy, but if we apply it in a modern way, with the patients squarely at the centre, then perhaps we have come a long way.