To control rheumatoid arthritis and its symptoms, it's the ends and not the means that matter.
“The most important thing about taking care of patients with rheumatoid arthritis is not the therapy that's used,” said James O’Dell, MD, FACP. “It's not so important that I use drug A versus B versus C. But it's very important to get the patient under good control.”
To squelch the inflammatory discomfort of rheumatoid arthritis, doctors should move quickly to start drugs with related disease activity targets in mind, ideally focused on remission, according to the latest guidelines from the American College of Rheumatology (ACR).
The concept of treating to a specific disease target—as determined by the doctor and patient—isn't new but now is being further emphasized, said Dr. O’Dell, vice-chair of internal medicine and chief of the division of rheumatology at the University of Nebraska Medical Center in Omaha.
The ACR guidelines, published in January in Arthritis & Rheumatology, are the first to update management since 2012 and encapsulate the latest insights into drug treatment in the rapidly moving field, said Dr. O’Dell, who was a coauthor. For example, the first Janus kinase (JAK) inhibitor that inhibits cellular production of inflammatory mediators, tofacitinib, was approved after the prior guidelines had been finalized, he said. Also in recent years, several studies have shown that the older drug combination of methotrexate plus hydroxychloroquine and sulfasalazine might help some patients as much as the newer biologic drugs, he said.
“We now have good trial evidence that a significant percentage of patients that many people had previously felt needed biologics in fact don't,” said Dr. O’Dell, thus enabling them to avoid the associated toxicity risks and higher costs.
Whether the new guidelines, which lay out a systematic approach to drug treatment beginning with monotherapy, open the door to a greater role for primary care remains to some degree in dispute. Dr. O’Dell feels that the risks and subtleties involved with even long-standing drugs like methotrexate warrant instead fast tracking a patient to a rheumatologist. But several other doctors maintain that primary care doctors can and should handle the initial treatment of these patients, particularly in areas of the country where there is a shortage of rheumatologists.
One Arthritis & Rheumatism study published in 2013 found that just 7% of rheumatologists practiced in rural areas and nearly 19 million Americans live in a region where there are no rheumatologists within 50 miles.
Getting patients relief quickly is essential both to improving their quality of life and preventing joint erosion and other long-term damage, said Daniel Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School in Boston.
“My belief, and this is just personal, is that primary care doctors should get comfortable with starting therapy, with starting initial methotrexate monotherapy, and to reassess the patient to see if their swollen joint count has significantly improved,” along with checking bloodwork and other measures, he said.
Tackling the target
The guidelines, which were developed based on an analysis of clinical evidence using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology, provide similar prescribing guidance for all newly diagnosed patients, said Salahuddin Kazi, MD, FACP, professor of medicine in the division of rheumatic diseases at the University of Texas Southwestern Medical Center in Dallas. “Every patient, regardless of whether they have a good prognosis or a poor prognosis, should all start on 1 drug, and this drug should be 1 of the nonbiologic drugs,” he said.
That 1-drug approach is recommended in the guidelines regardless of whether the patient has been struggling with symptoms for fewer than 6 months—considered early rheumatoid arthritis—or significantly longer, which is considered established disease, said Dr. Kazi. Additional drugs can always be added as needed, he said.
But the goal is to “tame the immune system” rather than overly suppressing it, Dr. Kazi said. “Overly suppressing the autoimmune process can result in infections and cancer,” he said. “So it makes sense to take a measured approach rather than a blast-it-out-of-the-sky approach.”
A notable percentage of patients can achieve relief with methotrexate, added Dr. Kazi, citing an influential 2005 study published in Arthritis & Rheumatism. The analysis, which compared 4 different drug regimens for 1 year, including a single drug and various combinations, found that greater than 40% of patients achieved a sustained adequate suppression of disease activity on methotrexate alone.
To assess patients' disease activity over time, 5 different tools are listed in the guidelines, including CDAI (Clinical Disease Activity Index) and DAS28 (Disease Activity Score 28). In treating to target, these tools provide clinical scores to help doctors objectively quantify patients' varying perceptions of how they are faring from visit to visit, said Bernard Rubin, DO, MPH, FACP, division head of rheumatology at Henry Ford Hospital in Detroit.
“This is the conundrum in rheumatology,” Dr. Rubin said. “You are trying to take subjective patient complaints and turn them into objective measurements so that you can then somehow assess whether or not whatever you are doing is working or not.”
At Henry Ford, the preferred tool is the CDAI, as it incorporates an evaluation of disease activity along with a swollen joint count, Dr. Rubin said. But it doesn't include results of bloodwork, which are frequently not obtained until after the patient's visit and thus are not available during the office discussion, he said.
The target should be decided upon from the start of treatment with the patient's own goals in mind, whether that's returning to work or walking the dog, Dr. Solomon said. As drugs are added, if needed, those goals should be revisited. Even if remission hasn't been achieved, Dr. Solomon said, “You might not change treatment because the patient has decided that they're doing well enough. They're doing everything that they want to do.”
When to refer?
For both new and established rheumatoid arthritis patients, the guidelines recommend various alternative drug possibilities, including biologics, if moderate or high disease activity is experienced after taking a single disease-modifying anti-rheumatic drug (DMARD). The guideline authors note that the drugs are listed as options without any hierarchal preference.
To drive that point home, Dr. Kazi pointed out that a line in italics specifies that “arbitrary switching” based on insurer policy is not recommended. “They really did not want an insurance company forcing a patient who is stable to be switched to another drug just because it was cheaper,” he said.
Primary care doctors have previously shown some reluctance regarding DMARDs. In a survey of 267 physicians, 81% reported that they had prescribed 1 or more of the drugs, most commonly methotrexate, according to a 2011 study in Arthritis Research & Therapy. But slightly fewer than half of the DMARD prescribers, 46%, said they had started a patient on a DMARD along with continuing drugs prescribed by other doctors.
It's unclear if that initial prescribing hesitation has changed in the years since, said Dr. Solomon, 1 of the study's authors. But he and Dr. Kazi think primary care doctors should become more comfortable with methotrexate, as it is frequently—with critical exceptions such as in women interested in becoming pregnant—the optimal drug to start. The latest guidelines spell out the recommended monitoring, including bloodwork to check kidney and liver function, beginning every 2 to 4 weeks for the first several months and gradually increasing beyond that to every 12 weeks after 6 months.
Patients taking methotrexate must be educated about the importance of severely restricting alcohol consumption, Dr. Solomon said. To counteract some of methotrexate's potential side effects, such as hair loss and nausea, folic acid can be prescribed. “Most patients who take folic acid with their methotrexate will tolerate the drug,” he said.
In cases where a doctor remains uncomfortable using methotrexate, and a rheumatology referral is delayed, another option is to prescribe hydroxychloroquine as it doesn't involve ongoing monitoring, Dr. Kazi said. (According to the guidelines, no blood work is recommended for follow-up once baseline counts are taken.) Hydroxychloroquine is probably the least effective of the DMARDs, Dr. Kazi said, “but it's better than doing nothing.”
Short-term use of low-dose steroids also can bring some badly needed relief to patients, Dr. Rubin said. (“Low dose” is defined by the guidelines as the lowest dose that provides relief and no more than 10 mg of prednisone or equivalent per day.) DMARDs could take up to 90 days to take effect, he added, and the steroids ensure that the patient is comfortable and feeling good during that time period. However, it is important to rapidly taper steroid treatment as tolerated with the goal of discontinuation once other anti-inflammatory treatments are in full effect.
If a patient responds to the first drug prescribed, a primary care doctor can often manage his or her care moving forward, particularly in telephone consultation with a rheumatologist, Dr. Solomon said. But once a patient requires more than 1 drug to tackle inflammation, the risk of toxicities and interactions becomes greater, he said. “And most primary care doctors at that point would defer to a rheumatologist, if there is 1 available.”
Primary care cautions
But Dr. O’Dell expresses some concern about primary care physicians starting methotrexate, given its nuances and potential toxic effects, saying that he'd prefer hydroxychloroquine if a rheumatology referral is difficult to obtain. “I would be a little bit hesitant to recommend kind of carte blanche methotrexate by primary care doctors,” he said.
Dr. O’Dell does support prescribing low-dose steroids when they are vital to keeping patients' lives functioning, such as allowing them to stay on the job. But he stresses that doses should be restricted to 5 or 10 mg daily, which he said doesn't always happen. “Very commonly we see patients early on being on 20, 30, 40 milligrams, and as a bridge to getting them seen by a rheumatologist,” he said.
One drawback of steroids' effectiveness in reducing joint swelling, though, is that the drug might delay diagnosis, particularly if blood test results are inconclusive, Dr. O’Dell said. “It is absolutely a catch-22,” he said. “But nevertheless it's problematic. Because if you get to a rheumatologist and the rheumatologist can't be comfortable with the diagnosis, then you might have gotten into a situation of short-term gain but long-term problems.”
Once the patient is being treated by a rheumatologist, the primary care doctor should be a critical partner in watching for other inflammatory ripple effects of the disease, Dr. O’Dell said. The potential inflammatory effects on the cardiovascular system, he said, mean that doctors should move aggressively to treat elevated cholesterol levels or blood pressure. Doctors also can look out for the lung problems that are sometimes related to the inflammatory disease as well as monitor for infections, given the immune-suppressing drugs. It's important to check that newly diagnosed patients are up to date on all of their vaccines, Dr. O’Dell said.
But above all, push to get patients to rheumatologist pronto, Dr. O’Dell said. Even in regions of the country with a shortage, typically patients can be squeezed in if they have developed inflammation and their anti-cyclic citrullinated peptide (CCP) antibodies are positive, he noted: “That is a free pass into most rheumatologists' office very quickly.”