Golden age of rheumatology: Comparing drug-associated risk in pre-biologic era vs. today
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By most metrics, modern rheumatology drugs are safer and more effective than those used in previous eras.
However, whether these therapies have fundamentally altered the everyday risk-benefit calculus for rheumatologists today, vs. the days of, for example, treating patients with gold, is a different story.
Source: Kathryn Dao, MD.
And there is perhaps no story that better characterizes how rheumatologists view risk today than the ongoing saga of the FDA and Janus kinase inhibitors. For 10 years, these drugs have dramatically improved the lives of countless patients. However, three high-profile FDA warnings over the last 2 years have given some experts pause.
“JAK inhibitors are incredible medications for multiple indications,” Kathryn Dao, MD, of the University of Texas Southwestern Medical Center, in Dallas, told Healio Rheumatology.
That said, Dao acknowledged the very real signals for cardiovascular outcomes and malignancies that led to the FDA warnings.
“The most recent warning for Xeljanz was a bombshell, not only because of the risk for [major adverse cardiac events], but because it applied to both the 10 mg and the 5 mg dose,” Dao said.
However, many rheumatology professionals, particularly those who have been practicing for a few decades, argue that the risks associated with current therapies should be viewed in the context of those from previous eras.
“In the ’70s and ’80s, the only options we had for treating rheumatoid arthritis were gold and NSAIDs,” Roy Fleischmann, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center, said in an interview. “These drugs were helpful in relieving pain and inflammation, but they do not prevent disease progression. And over the years, of course, we have come to realize that they come with many toxicities.”
According to Fleischmann, clinicians prescribing these treatments for patients had to manage a host of adverse effects and complications, including, but by no means limited to, gastrointestinal bleeding, nephrotoxicity, skin rashes and nausea.
“We also used steroids in much higher doses and for a much longer duration than today,” he said. “We know the multitude of effects of these drugs. The risk-benefit ratio is quite limited.”
Meanwhile, for Grace C. Wright, MD, PhD, president and CEO of Grace C. Wright, MD, PC, in New York, and president of the Association of Women in Rheumatology, the risk-benefit ratio for any individual drug is, in many ways, missing the point.
“Those who trained and cared for patients before we had effective therapies have a tangible and emotional sense of the risks that unchecked disease can pose,” she said. “We saw our patients crippled, disabled, their lives ruined, unable to work or stay in school or care for their families because of what their condition had done.”
It is for this reason that Wright believes placing the entire onus of risk and benefit on the drug itself — and not on the drug vs. these outcomes in an untreated, or inadequately treated, patient — creates a flawed equation.
However, because newer drugs are so effective, clinicians who began practicing after the biologic era may not have seen these crippling effects firsthand, and, consequently, may have a different perspective than older practitioners. That said, Wright said she does not necessarily see the value in trying to make young doctors understand the challenges of a previous generation.
“Discussion of risk for their patients has to be framed within their time period and their social collective,” she said.
This risk discussion also involves shared decision making with patients, who bring their own ideas and concerns to the clinic.
“It has been my experience over the years that when patients are first learning about the medications that can be used to treat their disease, they won’t ask which one works best — they will ask which one is safest,” Fleischmann said.
Walking the tightrope of history, disease progression and the risks and rewards of current therapies is a daily challenge for every rheumatologist. Understanding the recent history of JAK inhibitors may be the key to taking that first step.
Under ‘Surveillance’
Despite their efficacy, recent headlines associated with JAK inhibitors have not been positive.
In July 2019, the FDA issued a warning for an increased risk for blood clots and mortality with the 10 mg twice-daily dose of tofacitinib (Xeljanz, Pfizer) in ulcerative colitis.
That followed a previous FDA warning issued in February of that year for an increased risk of blood clots in the lungs and mortality associated with the 10 mg twice-daily dose of tofacitinib in RA. Importantly, this dose is not approved in RA, but it is approved for ulcerative colitis.
Two years later, on Feb. 4, 2021, the FDA issued the third of its three recent JAK warnings, based on the results of the ORAL Surveillance study.
“We have concluded there is an increased risk of serious heart-related events such as heart attack or stroke, cancer, blood clots, and death with the arthritis and ulcerative colitis medicines Xeljanz and Xeljanz XR (tofacitinib),” the FDA said in a statement at the time. “This trial compared Xeljanz with another type of medicine used to treat arthritis called tumor necrosis factor (TNF) blockers in patients with rheumatoid arthritis.”
The warnings — based on the ORAL Surveillance study examining tofacitinib and cardiovascular risk — implicated not only tofacitinib, but other JAK inhibitors as well, including baricitinib (Olumiant, Eli Lilly & Co.) and upadacitinib (Rinvoq, Abbvie), despite the fact these were not examined by the study or a comparable clinical trial.
Despite the warnings, Dao stressed the positive impact JAK inhibitors have had for patients, noting these drugs are effective not only for treating RA, PsA and ulcerative colitis, but also for “something as simple as eczema.” They work quickly, with a short half-life, she said.
“Even if a patient does have an infection or side effect, the drugs are metabolized from the body very quickly,” Dao said.
“Even if a patient does have an infection or side effect, the drugs are out of the body very quickly,” Dao said.
According to Wright, appropriate interpretation of the ORAL Surveillance findings is critical to understanding the risk-benefit calculus involved with these drugs.
“The main finding from ORAL Surveillance is that the curves for JAK inhibitors and TNF inhibitors moved apart for these risks,” she said. “There was no placebo control arm.”
Although the risk for cardiovascular events may be present in JAK inhibitors, Wright suggested that another way to consider these findings is that TNF inhibitors may be protective of cardiovascular events — or at least more protective than JAK inhibitors.
“Also, it is important to consider the patient population,” she said. “How old were the patients, what level of disease activity did they have, how long had they had their disease? These are all contributing factors to the relevant comorbidities.”
Wright added that some of the “headlines” regarding FDA warnings have also been misleading.
“As we have seen throughout COVID, there is plenty of information available that is just completely incorrect,” she said. “But with JAK inhibitors, I would describe it as inadequate information.”
Wright noted “three-word headlines” that highlighted only the worst possible outcomes associated with the drugs.
“The headlines never talk about the diseases the drugs treat, or the patients whose lives they have improved,” she said. “But many people will see only the headlines and draw their conclusions.”
To that point, Wright offered an alternative conclusion one may draw from ORAL Surveillance.
“There is a risk of thrombosis in RA, period,” she said. “Now, there is also a risk for thrombosis in RA patients treated with a JAK. So, by treating you with a JAK inhibitor, although I have not changed your risk for thrombosis overall, I have altered the risk of a number of other things, because inflammation drives not only RA but also a host of comorbid conditions such as heart disease.”
According to Jon T. Giles, MD, MPH, associate professor of medicine in the division of rheumatology at the Columbia University Vagelos College of Physicians and Surgeons, ORAL Surveillance highlighted an important gap in rheumatology practice.
“Currently, there are no evidence-based guidelines to help us with CV risks associated with these medications,” he said.
Like his colleagues, Giles stressed the management of traditional cardiovascular risk factors in this patient population by controlling inflammation as well as minimizing steroid and NSAID use.
“Whether that paradigm needs to be different for people treated with JAK inhibitors, as opposed to those treated with TNF inhibitors, is not yet known, but my speculation is that those principles apply equally across all DMARD regimens,” he said.
Meanwhile, another practical lesson from ORAL Surveillance may be that patients with inflammatory autoimmune conditions demonstrate a higher cardiovascular disease risk in general, said Christina Charles-Schoeman, MD, MS, chief of the division of rheumatology at the University of California, Los Angeles, in an interview with Healio Rheumatology.
“This study has also brought to light the accelerated rate of cardiovascular disease in many patients with inflammatory autoimmune diseases,” she said. “This CVD awareness is critical for both patients and physicians, so that monitoring and primary prevention approaches are addressed in routine care, including attention to modifiable traditional CV risk factors and screening for CVD when appropriate.”
This lesson — staying ahead of potential complications — can and should be applied to the use of any medication, including another mainstay of rheumatology treatments — TNF inhibitors.
‘Safe Enough’ for Children and Pregnancy
Although the risk for infections like legionella and listeria are included in the warning label for TNF inhibitors, and reports of malignancy, particularly in pediatric and adolescent patients, must be reported, there is one key difference between these drugs and JAK inhibitors.
“With TNF inhibitors, we have had 20-plus years of experience with them on the market, for multiple indications,” Dao said. “We have safety data showing that they are safe in children, pregnant women, and breastfeeding mothers. When someone hears that a drug is safe enough for these populations, they feel confident about the safety of the drug.”
Regarding infections, Dao stressed that certain patients are at risk for these complications regardless of treatment.
“Often, we see these complications in older patients,” she said. “Every decade of age can impact infection risk, along with other factors like diabetes, disease activity and prednisone use.”
To contextualize risk, it is also worth looking at early warnings of lymphoma associated with TNF inhibitors, according to Dao.
“When the TNF inhibitors were first approved, due to cost and limited availability, the drugs were reserved for patients who were considered ‘worst case scenario’ with highly active disease,” Dao said. “We know that risk for lymphoma goes up with active disease. Hence, after some patients developed lymphoma on treatment, we were not sure if the drugs were to blame or the disease. Long-term follow-up of these medications in the real world found that the risk for lymphoma was not related to the drugs, but rather from highly active disease activity.”
However, this is also the real risk for skin cancer — TNF inhibitors can increase the risk for nonmelanomatous and melanomatous skin cancers, according to Dao.
“Because I know that this small risk is present, if I am putting a patient on a TNF inhibitor, I recommend a regular skin surveillance by the dermatologist,” she said.
In fact, this is recommended for any drug and its attendant risks. Rheumatologists today will routinely comanage a patient with dermatology, oncology or cardiology, among others, or refer out to specialists as needed.
“The risks are well known to rheumatologists who treat patients with a variety of immunosuppressive agents beyond TNF and JAK inhibitors that also carry these safety concerns,” Charles-Schoeman said.
What may be less well-known to rheumatologists today, however, are the challenges faced by their predecessors in attempting to manage patients with inferior medications. Understanding this history may help put the real, but manageable, risks associated with TNF and JAK inhibitors into perspective.
Golden Age?
According to Fleischmann, treating RA in the 1970s meant, more often than not, using gold injections, which, although relatively effective by the standards of the time, would ultimately become known chiefly for its laundry list of adverse effects.
“In those days, gold was the most effective treatment we had for RA,” he said. “But it could cause nephrotoxicity, anemia, thrombocytopenia, and leukopenia.”
The monthly injections demanded regular assessments for protein in the urine and blood counts. Skin rashes were common.
“It was not an easy drug to use,” Fleischmann said.
These were also the days when rheumatologists might have used penicillamine for rheumatoid arthritis.
“It is an effective DMARD, but it fell out of favor due to multiple toxicities,” Fleischmann said.
In addition, although chemotherapeutics were effective, serious adverse events, such as in the bone marrow, made them challenging to use.
“Cyclosporine was also difficult to use,” Fleischmann said, noting that its use required regular serum level assessments. “We had to monitor for diabetes, nephrotoxicity and hypertension, among other adverse events.”
The 1980s brought the advent of methotrexate, which Fleischmann said was “far superior” to any other drug that had been used to that point.
“It became the cornerstone of treatment because one-third of patients went into full remission, with normalized function and no tender or swollen joints,” he said. “On top of that, another third felt much better, even if they did not reach remission.”
However, methotrexate also exemplifies the conundrum rheumatologists have long faced in managing risks and benefits. Nausea, fatigue and abnormalities in the liver and bone marrow, along with alopecia, occur with the drug.
“You can’t give this drug to people with significant renal compromise,” Fleischmann said.
According to Giles, rheumatologists in the pre-methotrexate era were often forced to make difficult decisions regarding potentially toxic treatments for patients who were generally sicker than those seen today.
“We had to give patients who were sicker, and had more comorbidities, drugs with a higher risk of toxicity,” he said. “This was not a great combination.”
All of this changed when the 1990s and early 2000s brought the development of biologics. Still, that did not mean that rheumatologists, or their patients, would be free from risk. In addition to the FDA warnings addressed above, JAK and TNF inhibitors have also been associated with tuberculosis, as well as reports of neurologic disease. Abatacept (Orencia, Bristol Myers Squibb) offers a “supposedly safer” profile, with no heart failure risk and lower risks for tuberculosis, according to Fleischmann.
Regarding interleukin (IL)-6 inhibitors, infections, neutropenia and elevated lipids have been reported, he added.
However, even with these risks and potential complications, Giles argued that the increased effectiveness, plus the overall lower number of side effects, associated with the drugs developed since the 1990s has greatly, unquestionably, improved patients’ lives.
“It is not to say that our current toolbox of drugs is risk-free, but being able to manage RA more effectively with drugs with fewer side effects means that overall quality of life is better for the average RA patient now compared with the ’70s and ’80s,” he said.
According to Wright, it is important to put this history — and comparisons between the pre- and post-biologic eras — into the proper context, and recognize how the relatively recent proliferation of data influences our understanding of risk.
“Today, we interrogate drugs differently than we did in the days of gold and NSAIDs,” she said. “We have so much more granular data on DMARDs and biologics.”
More data on efficacy will also, naturally, reveal more data on risk, she added.
“Current data may give us the sense that these therapies carry more risk, but that is different from saying that the risk is real,” Wright said.
It is critical for rheumatologists to understand the real and historical risks associated with the therapies they use. It is equally critical that they communicate all this information to their patients.
Trust vs. Fear
According to Wright, the cornerstone of any successful interaction between rheumatologists — or any physician — and their patients is trust.
“If I have sufficiently built trust with a patient, they will listen to my recommendations or when I separate fact from fiction,” she said. “But if they don’t trust me, they won’t.”
Meanwhile, Charles-Schoeman stressed that rheumatologists must also remember that no two patients are alike. This goes for their individual risk analyses as well as their knowledge regarding their own treatments.
“Patients may vary greatly in their risk tolerance and fears regarding medications in rheumatology,” Charles-Schoeman said. “They also vary in their degree of knowledge regarding safety profiles of specific therapeutics.”
With variable levels of knowledge comes varying degrees of fear, according to Giles.
“A good starting place is to try to understand where the patient’s fears are coming from and not necessarily dismiss them out of hand,” he said. “Then, it is possible to tailor treatment around what is acceptable and help them to understand absolute risk.”
Wright explained that rheumatologists can effectively tailor treatment by emphasizing how a given medication will impact a patient’s individual situation and needs.
“I try not to say, ‘Everyone should be treated with a JAK inhibitor,’ because that is not true,” she said. “I tell a patient, ‘I think a JAK inhibitor is the right choice for you,’ and then I explain the reasons why, based on their disease activity, comorbidities and other factors.”
In fact, Wright has developed a term for these myriad factors that can impact patient outcomes: Stacked risk.
“Stacked risk is when you walk in with an inflammatory disease, and then you are a smoker, and then you are 65 years old, and then you have hypertension and your cholesterol is 300,” she said.
Her message is that, when viewed in totality with these factors, the possible adverse events associated with a DMARD or biologic pale in comparison.
“Patients with these underlying factors almost invariably have worse outcomes,” Wright said. “Once they understand this concept of stacked risk, they are open to my suggestions for minimizing those risks.”
Rheumatologists interacting with patients today must also consider the prevalence of misinformation. For Dao, it is critical to stress to patients that when it comes to risk, they must weigh the odds of active disease vs. the odds of medication side effects.
“Patients basing their opinions and actions on flawed information are gambling with their health,” she said. “They need to be talking to their doctors. Their doctors are the card counters who will give them the best advice to beat the odds.”
The good news is that with so many drugs available to clinicians, it is possible to achieve a wide variety of treatment goals. As the next generation of rheumatology providers rises to prominence, that trend is likely to continue.
Choice of a New Generation
“Newer generations of providers are more safety conscious,” Fleischmann said. “If there is any question of safety signal, they may not even use the drug.”
However, Fleischmann acknowledged that most rheumatologists have historically been careful with newer medications.
“Thinking back to the mid-1980s, it probably took 10 or 15 years for people to start using methotrexate regularly and effectively,” he said. “Even then, many started using it at 7.5 mg per week, which is a subtherapeutic dose.”
It is with this in mind that Giles believes that the risk calculus for currently used biologics is “very firmly in place” and unlikely to change with the next generation of providers. “Biosimilars are also not likely to change this, given how uniform the biosimilar studies are in relation to safety for the biosimilar products relative to their originator drugs,” Giles said.
In addition, younger rheumatologists may have an advantage regarding risk assessment through the use of modern technology and social media, according to Dao.
“They can find what they need on PubMed immediately,” she said. “They are able to connect with experts in the field through social media and crowdsource information via Twitter polls. With social media at their fingertips, the world has become a much smaller place.”
Although some clinicians may be wary of using a vehicle like Twitter to gather input about a drug, or a particularly challenging patient, Dao suggested that reading the opinions of dozens or hundreds of doctors around the country — or around the world — is far superior to the most common option available to rheumatologists a generation or two ago, which was to call one or two colleagues on the phone.
A larger and more sophisticated body of data will also inform decision-making, according to Charles-Schoeman.
“The next generation of rheumatologists are hopefully learning a good balance between understanding medication risks as well as disease risks,” she said. “As new clinical trial and real-world observational data continue to emerge with newer therapies, they will need to continue to update their safety monitoring as well as discussions with patients.”
However, for Charles-Schoeman, the risk-benefit conversation ultimately comes back to one important consideration — the consequences of uncontrolled disease.
“They will also need to continue to remember the complications of unchecked systemic inflammation so that they do not shy away from using agents,” she said. “These are agents which may lead to disease remission and substantial improvement in long-term outcomes.”
- References:
- FDA warning on JAK inhibitors: www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death.
- FDA warning on TNF blockers: www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-update-tumor-necrosis-factor-tnf-blockers-and-risk-pediatric.
- For more information:
- Christina Charles-Schoeman, MD, MS, can be reached at 200 Medical Plaza Suite 365, Los Angeles, CA 90095; email: ccharles@mednet.ucla.edu.
- Kathryn Dao, MD, can be reached at 9900 N Central Expy. Suite 550, Dallas, TX 75231; email: kathryn.dao@utsouthwestern.edu.
- Roy Fleischmann, MD, can be reached at 5939 Harry Hines Blvd. #400, Dallas, TX 75235; email: rfleischmann@arthdocs.com.
- Jon T. Giles, MD, MPH, can be reached at 161 Ft. Washington Ave., New York, NY, 10032; email: jtg2122@columbia.edu.
- Grace C. Wright, MD, PhD, can be reached at 345 East 37th St., Suite 303C, New York, NY 10016; email: gcwright.md@gmail.com.
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