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"Medical Journeys" is a set of clinical resources reviewed by doctors, meant for physicians and other healthcare professionals as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

Various treatment options exist for the patient with rheumatoid arthritis (RA) who has not had an adequate response to initial treatment with methotrexate, with choices dependent on factors such as comorbidities and risk factors.

But before moving on to additional therapies, it's advisable to ensure that methotrexate has been used optimally. "Methotrexate works best when we push the dose to 25 mg/week," said James R. O'Dell, MD, chief of the Division of Rheumatology at the University of Nebraska Medical Center in Omaha. "It also works far better if we use it subcutaneously rather than orally."

And if patients don't want to take methotrexate subcutaneously, the weekly dose can be split, with, for example, four pills in the morning and four in the evening on the day the drug is given. "It's very important to understand the nuances of dosing methotrexate, both with regard to having to use it orally and splitting the dose, particularly when we get up to 20 mg," said O'Dell.

The stresses that, for patients who don't adequately respond to a disease-modifying anti-rheumatic drug (DMARD) such as methotrexate, a treat-to-target approach is recommended, "because of the recognized importance of systematic monitoring and adjustment of treatment to minimize inflammation to prevent joint damage, as well as other long-term sequelae including cardiovascular disease and osteoporosis," the guideline authors wrote.

The decision on what specific approach to take following failure of methotrexate monotherapy remains a matter of some controversy.

Triple Therapy vs TNF?

The ACR guideline notes that the addition of a biologic DMARD or targeted synthetic DMARD is conditionally recommended over triple therapy (methotrexate plus sulfasalazine plus hydroxychloroquine) for patients receiving optimal methotrexate therapy who continue to have active disease.

"The panel vigorously debated whether to recommend addition of a biologic DMARD or targeted synthetic DMARD versus sulfasalazine and hydroxychloroquine (triple therapy) for patients with an inadequate response to methotrexate monotherapy in view of very low-certainty evidence favoring biologic DMARDs or targeted synthetic DMARDs, randomized controlled trials demonstrating equivalent long-term outcomes across both treatment strategies, and significantly less societal cost associated with triple therapy," the authors wrote.

A common approach when additional therapy is needed is to add a tumor necrosis factor (TNF) inhibitor to the methotrexate, which is usually effective in most patients, according to Elena Myasoedova, MD, PhD, of the Mayo Clinic in Rochester, Minnesota. "However, some providers and centers use triple therapy, which is not strictly suggested in the guidelines but which has been shown in to be noninferior to a TNF inhibitor."

But triple therapy "involves a lot of tablets, about 20 per week, so some patients find it cumbersome with regard to adherence, and it also takes time to start working," she explained. In one , treatment discontinuation was greater in patients receiving triple therapy, with hazard ratios of 2.17 (95% CI 1.63-2.88) among biologic-naive patients and 1.51 (95% CI 1.06-2.15) among those who were biologic-experienced.

O'Dell noted that depending on the clinical circumstances, he generally favors adding hydroxychloroquine or hydroxychloroquine plus sulfasalazine before going to a biologic. "That's what's done in almost every place in the world except for the United States, where people say give them a little methotrexate, maybe 15 mg orally, and if that doesn't work let's go ahead and rush them off to a biologic," he said.

The ACR guideline further states that the recommendation favoring a biologic or targeted synthetic DMARD rather than triple therapy was conditional and influenced by patient representatives who "strongly prioritized maximizing improvement as quickly as possible." The choice of triple therapy or a biologic "is highly preference sensitive, and decisions on how best to escalate care should incorporate patients' preferences," the guideline authors stated.

JAK Setbacks

The choice of specific agent to turn to after a patient continues to have active disease while on triple therapy or an initial TNF inhibitor depends on multiple factors, with the ever-broadening array of biologics and targeted synthetic DMARDs including Janus kinase (JAK) inhibitors such as tofacitinib (Xeljanz).

"It's a complicated question," O'Dell said. "We have to consider risks and concerns like infection, malignancy, travel exposures, and congestive heart failure. But everybody should be thinking about going to a biologic now before thinking about adding a JAK inhibitor."

"We had a lot of hopes for the JAK line of treatment," said Myasoedova. "The drugs are convenient; they are pills, so needle-averse patients can take them; and they are effective."

However, a multinational safety study known as began in 2014 after tofacitinib was approved in 2012. In the drug's pivotal trials, there had been suggestions of increased rates of infections and malignancies, and the FDA wanted the manufacturer (Pfizer) to provide additional risk details. The study included more than 4,000 patients receiving a TNF inhibitor or tofacitinib in dosages of 10 or 5 mg twice daily. An interim analysis in 2019 found an increased mortality rate in the higher-dose tofacitinib group, leading to termination of that treatment arm.

The final study analysis, published in the in Jan. 2022, found that the risk of major adverse cardiovascular events was increased among tofacitinib-treated patients (HR 1.33, 95% CI 0.91-1.94), as was the risk for incident cancer (HR 1.48, 95% CI 1.04-2.09).

In an , Jasvinder Singh, MBBS, of the University of Alabama at Birmingham, explained the clinical implications: "Recently, the FDA issued the black-box warning not just for tofacitinib but also for upadacitinib [Rinvoq] and baricitinib [Olumiant], the two other JAK inhibitors for which increased risks of MACE [major adverse cardiac events] and cancer are considered to be class effects," he wrote.

The FDA also tightened the eligibility for tofacitinib and upadacitinib from incomplete response to methotrexate to incomplete response to a previous TNF inhibitor.

"In patients with rheumatoid arthritis who have an incomplete response to methotrexate and have active disease, a TNF inhibitor will be preferred to tofacitinib for a new start, especially in persons 65 years of age or older," Singh concluded.

O'Dell added: "That's not to say the JAKS aren't very effective -- they are -- and they certainly would have a role, but wouldn't be the first thing to try after methotrexate failure."

Next Choices for Persistently Active RA

Multiple other options still exist for patients who have persistently active disease after having an inadequate response to a first TNF inhibitor. Choices among these newer agents reflect the patient's comorbidities, history, and risk factors, as well as the individual medications' risks and benefits.

"Depending on what the patient had going on, I would consider an IL [interleukin]-6 inhibitor, or abatacept [Orencia] to modify their T cells, or rituximab [Rituxan] to knock down their B cells," O'Dell said. "I have a tendency to go to IL-6 inhibition, but if there's a concern about bowel issues, maybe that's not the best choice. If there's concern about underlying infections, abatacept is a reasonable choice, and if there are concerns about malignancy, particularly lymphoma, then rituximab would be the right choice."

Myasoedova noted that rituximab also can be useful for patients who have severe extra-articular RA manifestations such as rheumatoid vasculitis or interstitial lung disease.

Abatacept is also a useful option rather than TNF inhibitors if the patient has a family history of demyelinating disease, but should probably be avoided for patients with chronic obstructive pulmonary disease, she said.

A caution with regard to rituximab, however, is that patients on this medication showed a two-fold or higher COVID-related mortality, "so we are trying to be sparing with that medication," she said.

The ACR guideline also weighed in on preferred choices for certain patient populations. For example, a non-TNF biologic agent or targeted synthetic DMARD was conditionally recommended over a TNF inhibitor for patients with class III or IV heart failure, and conventional DMARDs were recommended over biologics or targeted synthetic agents for patients who had had a serious infection within the previous year.

Tapering or Stopping?

Considerable interest exists among patients and clinicians alike with regard to cutting back on biologic medications for reasons including cost, convenience, and safety.

The ACR guideline advises that there is a moderate-to-high risk for disease flare and the potential for irreversible long-term joint damage when all DMARDs are withdrawn, and that the recommendation, therefore, is that a therapeutic dose of at least one DMARD be continued. In addition, treatment tapering should not be considered before patients are at their treatment target (remission or low disease activity) for at least 6 months.

"We have the luxury today of commonly seeing patients at our clinics whose disease is in remission, and we definitely think about lightening up on our therapies -- with the proviso that we should never think about discontinuing all DMARDs in an RA patient," said O'Dell. "If they have RA and you take them off all therapy, their RA is going to come back and it may be difficult."

"If a patient is on methotrexate plus a TNF inhibitor, it makes no sense to taper the methotrexate, because all our studies show that methotrexate helps the TNF inhibitors do a better job. So what we do is space out the interval for their TNF injections," O'Dell continued.

If the patient is on an every-2-week schedule, the interval can be increased to every 3 weeks, and if remission is maintained for 3 to 4 months, the interval could be spaced out further. "Patients will then find their happy spot -- the spot where they are taking their injections and they don't know it's time for their next injection except the calendar tells them it's time. If they start to feel they are missing the medication, that means it's time to go back to a shorter interval."

O'Dell also noted that in trials looking at whether patients were able to completely stop their biologic treatment, about 30% were able to do so -- "which is a big success," he said.

Looking Ahead

The challenge today is that, despite the increasingly wide array of therapeutic choices for RA, "we don't really know for individual patients which agents they are likely to respond to," said Myasoedova, who noted that finding predictors to response has been a focus of her research. In , she and her colleagues tested clinical and genomic biomarkers to predict response to methotrexate in patients with early RA. They found that combining factors such as age, sex, seropositivity, and baseline disease activity score plus 160 single nucleotide polymorphisms previously linked with RA accurately predicted a positive response at 3 months, with a sensitivity of 72% and specificity of 77%.

In another investigating the effects of the gut microbiome on treatment response, her group found significantly different microbiome patterns among patients with established disease who achieved minimum clinically important improvements over 6 months and those who did not. Those differences included taxonomic features, microbial taxa, and biochemical pathways. "Ultimately, modifying the gut microbiome to enhance clinical outcome may hold promise as a future treatment for RA," the authors wrote.

However, the research has not yet reached clinical relevance or possible implementation. "But we are working towards that, there is nothing to tell us at this time which treatments will be successful in individual patients," Myasoedova said. "But hopefully in the future there will be biomarkers that will help us understand this."

Read previous installments in this series:

Part 1: RA Beginnings: Before the Painful Joints

Part 2: RA: Still a Clinical Diagnosis

Part 3: RA: Choosing Initial Treatment

Part 4: Case Study: Patient With RA Develops Dangerous Symptoms