A comprehensive guide to rheumatoid arthritis drugs.
Rheumatoid arthritis (RA) is an autoimmune disorder, which means the body’s immune system mistakenly attacks healthy tissues. RA causes inflammation in the lining of the joints of the hands, wrists, elbows, spine, jaw, ankles, feet and knees. Over time, the inflammation destroys cartilage and bone, which causes joints to become stiff, painful, red and swollen. RA can also damage tissues in the heart, lungs, eyes, nerves and skin. Rheumatoid arthritis usually affects joints symmetrically: If one joint is affected, the same joint on the opposite side of the body is likely also affected.
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Medications and Side Effects
The goal of RA treatment is to relieve pain and reduce or stop inflammation, swelling, and damage to joints and organs. Medical treatment usually begins with disease-modifying antirheumatic drugs (DMARDs), which are meant to slow the disease and prevent joint deformity. Along with DMARDs nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids are often prescribed to help reduce inflammation, swelling and pain.
For people who don’t respond well enough to DMARDs, second-line treatment with biological response modifiers (biologics) may be used. All of these treatments come with side effects that can be very serious.
As with most autoimmune disorders, there is no one-size-fits-all treatment for rheumatoid arthritis. The course of treatment depends on the type and severity of symptoms. However, treatment typically involves a combination of medications. Faster-acting NSAIDs and steroids are often given along with slower-acting, but longer-lasting DMARDs.
DMARDs – Traditional and Biologic
DMARDs are designed to slow or stop the inflammatory process that damages joints and internal organs in people with RA. The drugs are taken weekly either orally or via self-injection and typically start working within eight weeks. There are two main types of DMARDs: traditional DMARDs and biologics.
Traditional DMARDs commonly prescribed include methotrexate (Rheumatrex, Trexall), leflunomide (Arava), hydroxychloroquine (Plaquenil) and sulfasalazine (Azulfidine). Methotrexate is the most commonly prescribed DMARD for people newly diagnosed with the disease. It’s been found to be the most effective with the fewest side effects.
Hydroxychloroquine may be a treatment for COVD-19, for more information see Chloroquine, Hydroxychloroquine and Z-Pak. It has serious side effects such as permanent eye damage, cardiac effects like cardiomyopathy with a risk for heart failure and heart rhythm abnormalities, severe hypoglycemia, and muscle atrophy. It can also cause suicidal behavior. Other serious effects have been reported since this medication was approved as well, including disorders of the blood, heart, ear, eye, immune system, metabolism, and skin.
Janus kinase (JAK) inhibitors are another type of traditional DMARD approved by the FDA for use in people with RA who have had an inadequate response or intolerance to methotrexate. JAK inhibitors are pills that can be used alone or in combination with methotrexate or other nonbiologic DMARD. Currently available JAK inhibitors include tofacitinib (Xeljanz), baricitinib (Olumiant) and upadacitinib (Rinvoq), with others under development.
Xeljanz warning: The FDA is warning of an increased risk of blood clots and deaths in rheumatoid arthritis (RA) patients who take a higher-than-approved dose of the JAK inhibitor Xeljanz. Because of that Xeljanz now carries a boxed warning from the FDA.
The agency said that results from a post-market safety trial found that RA patients taking Xeljanz 10 mg twice daily had an increased risk of blood clots in the lungs and death compared to patients taking a 5 mg twice-daily dose. Xeljanz’s prescribing information for RA says the dose should be 5 mg twice daily. The FDA says patients on Xeljanz should seek medical attention immediately if they have signs or symptoms of a blood clot: sudden shortness of breath or difficulty breathing; chest pain or back pain; coughing up blood; excessive sweating; clammy or bluish-colored skin.
Dementia prevention: Some research has shown that DMARDs may help prevent dementia. Analysts from NIHR (National Institute for Health Research) Southampton Biomedical Research Centre identified 3,876 patients who took DMARDs and compared them with 1,938 patients who did not. After thoroughly examining the data, researchers discovered that those who took DMARDs, particularly methotrexate, had half the risk of developing different forms of dementia, such as Alzheimer’s, compared to those who didn’t take the drugs.
Biologic Response Modifiers or Biologics
Biologics are DMARDs that are prescribed for people with moderate to severe rheumatoid arthritis who don’t respond to other DMARDs like methotrexate. Biologics, which have been in use since 1998, are genetically engineered proteins derived from human genes. They copy the effects of substances naturally made by the body’s immune system. Biologics are given as weekly self-injections or via monthly 2- to 3-hour intravenous infusions at a doctor’s office or infusion center. It can take up to 3 months for biologics to start working. (See MedShadow’s What Are Biologics?) Biologics include abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), rituximab (Rituxan), sarilumab (Kevzara) and tocilizumab (Actemra).
RA Remission
Experts believe that there is a “window of opportunity” for potential remission in RA patients if they are diagnosed and treated early and aggressively. Researchers are studying the treatment of early RA with a combination of DMARDs. The hope is that RA will go into remission while patients take the drug combo, and remain in remission after the drugs are stopped.
In the 2014 AVERT study (Assessing Very Early Rheumatoid arthritis Treatment), RA patients who’d had symptoms for fewer than two years were given either methotrexate alone, abatacept alone, or a combination of the two drugs. After 12 months the treatments were stopped. About 61% of patients receiving the drug combo had achieved remission, compared to about 45% of those on methotrexate alone, and 42.5% of those on abatacept alone. In those who took the drug combo, 14.8% were still in remission six months after stopping the drugs compared to 7.8% of those who only took methotrexate and 12.4% of those who took abatacept alone.
Researchers report that although patients in the abatacept plus methotrexate group were more likely to have a better outcome, at around eight months post-treatment very few patients were still in remission. In a 2019 follow-up study, those whose RA flared at least three months after treatment ended were re-treated with the drug combination. After six months of re-treatment, two-thirds of the patients had regained remission while three-quarters achieved a low disease state, which shows improvement in RA disease activity.
Side effects of DMARDs
DMARDs carry the risk of relatively mild side effects, such as nausea, vomiting, diarrhea or rash, to life-threatening infections. Side effects can include an increased risk of fatal infections from viruses, bacteria or fungi, including tuberculosis and upper respiratory problems like pneumonia and bronchitis; injection site reactions; nerve disorders; heart problems; inflammation of the optic nerve; liver damage; bone marrow suppression; and multiple sclerosis. In addition, biologics increase the risk of reactivation of herpes zoster or hepatitis B or C infections. Contact your doctor immediately if you experience any signs of infection including chills, fever, sore throat or painful urination.
Liver damage: One of the life-threatening side effects of DMARDs is liver damage. For example, methotrexate can lead to death due to liver damage, especially if it’s taken over a long period, and in people at high risk of liver damage, such as those who drink large amounts of alcohol or who have had previous liver disease. But liver toxicity can occur without any previous signs of toxicity. When methotrexate — or any DMARD — is prescribed for rheumatoid arthritis the doctor must monitor liver, kidney and other organ function very carefully throughout treatment.
If this isn’t done, the result can be disastrous. For example, Stefanos Vavalidis, 69, died in January 2016 after taking methotrexate to treat psoriasis, a skin condition resulting in itchy, scratchy skin patches. A medical inquiry found that Vavalidis’ death was “most probably associated with toxicity” from methotrexate. His physician has admitted he didn’t properly monitor his patient’s condition by failing to order complete blood tests for Vavalidis.
Folic acid: Ask your doctor about taking folic acid supplements to help protect against some of methotrexate’s side effects. Research has shown that folic acid may improve or reduce the risk of gastrointestinal and some other side effects in people with RA who take methotrexate.
Cost: While corticosteroids and NSAIDs are reasonably priced, the costs of DMARDs and biologics are steep. Prices vary by region of the country and brand vs. generic, and there are no generics for some of these drugs and region of the country. But Humira or Enbrel, for example, can cost over $8,000 about $2,700 a month for anyone without insurance and who doesn’t qualify for a price reduction program.
Since the implementation of the Biologics Price Competition and Innovation Act of 2009, created to encourage the development and reduce the cost of biologics to consumers, a number of “biosimilars” have been developed and FDA approved for use in place of expensive brand-name drugs. Biosimilar drugs are very similar to biologics–though not exactly generic versions–and are considered interchangeable with them. To date, biosimilars for RA have been approved for infliximab, adalimumab, rituximab and etanercept. However, the only biosimilar for RA marketed in the United States so far is infliximab-dyyb (Inflectra). The delay in availability is mainly due to litigation between the brand name and biosimilar manufacturers, but issues with insurance and physicians’ prescribing habits also come into play.
In 2018 the FDA developed the Biosimilars Action Plan to further streamline the process and address the issue of drug manufacturers’ interfering with the release of biosimilars to the market. The hope is that these efforts will lead to better availability of these cost-saving medications.
Anti-Inflammatory Medications
Anti-inflammatories, including corticosteroids (also called steroids) and NSAIDs, ease inflammation, swelling and pain.
Corticosteroid medications
Corticosteroids such as prednisone are usually temporarily given to treat acute symptoms. They reduce inflammation and pain, as well as slow joint damage, but they carry the risk of serious side effects.
Side effects can include elevated pressure in the eyes (glaucoma), fluid retention and swelling, increased appetite and weight gain with fat deposits in the abdomen, face or back of the neck, or psychological effects such as mood swings, confusion, delirium or memory problems.
Long-term side effects: Taken over the long term, side effects may include bone loss, cataracts, high blood pressure, elevated blood fats and blood sugar levels, diabetes, skin bruising, fatigue and muscle weakness.
People who take corticosteroids even for a relatively short period of time are more likely to break a bone, have a blood clot or develop sepsis compared to those who don’t take the medication, according to results of a study published in the BMJ.
“We see a clear signal of higher rates of these three serious events within 30 days of filling a prescription,” lead study author Akbar Waljee, MD, of the University of Michigan School of Medicine, said in a statement. “We need to understand that steroids do have a real risk and that we may use them more than we really need to.” Waljee also advised that doctors prescribe and patients use the lowest amount of corticosteroid possible. “If there are alternatives to steroids, we should be using those when possible,” he added. For more on this study read MedShadow News.
Using corticosteroids for the long term may increase the risk of adverse events compared to occasional use, according to a study published in the journal Current Medical Research and Opinion. For more information on this study read MedShadow News.
Staph blood infections: Corticosteroids may also make patients more susceptible to life-threatening infections such as staph blood infections. In a study published in Mayo Clinic Proceedings, Danish researchers examined the medical records of 30,000 patients. People who were given systemic glucocorticoids were 2.5 times more likely than those who didn’t take the drug to have a staph bacteria-associated blood infection outside of a hospital.
The risk of infection rose the higher the dose. Patients on a 90-day corticosteroid cumulative dose up to 150 mg had a 2.4 times higher risk than non-users. But the risk for those taking more than 1,000 mg of the drug over the same time period was 6.3 times greater. See MedShadow’s Corticosteroids
It’s important to follow your doctor’s instructions for discontinuing corticosteroid treatment when the time comes. The body’s production of natural corticosteroids cuts back while you’re taking steroid medications, so stopping them abruptly may leave you without enough, causing fatigue, lightheadedness and body aches. Your doctor will give you a schedule for reducing the dose a little at a time until your body makes enough on its own.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) for Rheumatoid arthritis
NSAIDs ease pain and reduce inflammation. These include over-the-counter drugs like ibuprofen (Advil and Motrin IB) and naproxen sodium (Aleve). Stronger NSAIDs may be prescribed and they include meloxicam (Mobic), etodolac (Lodine), nabumetone (Relafen) and sulindac (Clinoril), celecoxib (Celebrex), diclofenac (Voltaren, Cataflam) and ketoprofen.
Side effects from any NSAID may include tinnitus (ringing sound in ears), stomach irritation and ulcers, edema (feet swelling), liver and kidney damage, and an increased risk of blood clots, heart attack, stroke and other heart problems. (See MedShadow’s The Lowdown on NSAIDs for Pain)
Heart attack/stroke: In 2015 the FDA strengthened an existing warning for NSAIDs that the risk of heart attack or stroke can occur within weeks of taking the drugs and can increase the longer the medication is taken, as well as at higher doses.
In addition, NSAIDs can increase the risk of heart attack or stroke in patients with or without heart disease or risk factors for heart disease, the agency noted. However, patients with heart disease or risk factors for it have a greater likelihood of a cardiovascular event. Some NSAIDs likely carry a higher risk of heart attack and stroke than others, but the FDA said it is unclear at this point which ones are in the higher risk group. The cardiovascular warning does not apply to aspirin, which is an NSAID.
The FDA has stated: Ask a doctor or pharmacist before use if you are taking aspirin for heat attack or stroke, because naproxen may decrease this benefit of aspirin.
A study in the BMJ found that the risk of heart attack with NSAIDs can arise in as little as a week after starting the drugs. The researchers conducted a meta-analysis that looked at data from studies on about 447,000 people between the ages of 40 and 79. Of that number, more than 61,000 had a heart attack.
The researchers reported that in people who took them, non-aspirin NSAIDs ( ibuprofen, naproxen, diclofenac and two COX-2 inhibitors, rofecoxib and celecoxib) boosted the risk of a heart attack by between 20% and 50% compared with people who didn’t take them. And that higher risk was seen at any dose, whether taken for a week, a month or longer than a month. In addition, the risk rose with higher doses. But researchers also noted that the risk is still quite small. Overall, the risk of heart attack due to NSAIDs is on average about 1%.
People who regularly use common NSAIDs may also be at an increased risk of heart failure requiring hospitalization according to a study published in the BMJ. The results of the study are not entirely surprising given that previous research has found a correlation between NSAIDs and heart failure.
In the BMJ study, researchers in Europe analyzed the risk in 10 million NSAID users. Those people used 27 different types of NSAIDs, including COX-2 inhibitors between 2000-2010.
People that were currently using one of the drugs had a 19% higher risk of hospitalization due to heart failure compared to those that had used them in the past. The risk also appeared to be dose-dependent, meaning the more of the medication taken each time, the higher the risk.
The working group for Cardiovascular Pharmacotherapy of the European Society of Cardiology has expressed concerns similar to those of the FDA. The group published a review and position paper on non-aspirin NSAIDs. Among their key findings: The drugs should not be used in people who either have cardiovascular disease or are at high risk for it. According to the group of European medical experts, more prudent use of non-aspirin NSAIDs commonly sold over the counter is needed due to the risk of cardiovascular events associated with this drug class.
GI risk: The working group added that in patients with gastrointestinal risks, a proton pump inhibitor drug (e.g. Nexium) should be taken due to an NSAID’s potential in causing gastrointestinal bleeding. The researchers conclude that when it comes to prescribing non-aspirin NSAIDs, each case requires “a careful evaluation of the risk of cardiovascular complications and bleeding.”
Some NSAIDs not as risky: Certain NSAIDs also appeared riskier than others, such as ibuprofen, naproxen and diclofenac. The COX-2 inhibitors rofecoxib and etoricoxib also had a higher risk. Interestingly, the COX-2 inhibitor celecoxib, which is on the market in the US, was not associated with a higher risk of heart failure when taken at the standard dose.
The authors noted that because their study was observational in nature, it could not directly prove cause and effect. However, they concluded that their work “offers further evidence that the most frequently used individual traditional NSAIDs and selective COX-2 inhibitors are associated with an increased risk of hospital admission for heart failure.”
Blood Pressure: In a study in the European Heart Journal, researchers found that ibuprofen and naproxen may increase blood pressure in patients with RA or osteoarthritis compared to prescription celecoxib. Researchers also found that ibuprofen may increase the risk of cardiovascular disease in those with RA or osteoarthritis. The study showed that the average blood pressure of those given celecoxib decreased by 0.3 mmHg over 24 hours. However, ibuprofen and naproxen increased blood pressure by 3.7 and 1.6 mmHg, respectively. Researchers also found that the percentage of patients with normal blood pressure who developed high blood pressure after taking one of the pain medications was 23% for ibuprofen, 19% for naproxen and 10% for celecoxib.
Research presented at an annual meeting of the American College of Cardiology found that taking an NSAID along with misoprostol (Cytotec), used for conditions such as stomach ulcers, inducing labor, causing abortion and treating postpartum bleeding, may help to reduce the risk of cardiovascular side effects associated with NSAIDs. Researchers analyzed the medical records of over 1.6 million people in the Veterans Affairs health system database who took prescriptions of an NSAID and/or Cytotec between 2005 and 2013. A combination pill containing the NSAID diclofenac and misoprostol is currently approved to help prevent ulcers in people taking the NSAID for RA. For more information read MedShadow News.
After examining data from the Danish Cardiac Arrest Registry, researchers in Denmark came to the conclusion that common over-the-counter (OTC) NSAIDs should only be available with a prescription due to the serious cardiovascular risks associated with them. Yet, NSAIDs are sold without any restrictions, giving people the idea that they are very safe, the researchers argue in their study, published in the European Heart Journal.
The researchers found that overall, NSAIDs, except for aspirin, are associated with a 31% elevated risk of cardiac arrest. Ibuprofen – more than half of all NSAIDs used in the study – was linked to a 50% higher cardiac arrest risk. The authors caution that the maximum dose of ibuprofen per day should be 1,200 milligrams. A regular-strength OTC ibuprofen pill is 200 mg.
Naproxen was found to be the safest OTC NSAID. There was no increased cardiac arrest risk with the COX-2 inhibitor celecoxib, which is only available by prescription. Two other NSAIDs, ketoprofen and diclofenac, were associated with a 31% higher risk of heart issues.
NSAIDs compared to acetaminophen: In a study from Denmark, published in the BMJ, researchers looked at 252 studies covering more than 6.3 million Danish people. They examined the cardiovascular risks of starting diclofenac compared with starting ibuprofen, naproxen and acetaminophen. Diclofenac, ibuprofen and naproxen are all NSAIDs, acetaminophen is not. People who started diclofenac were 50% more likely to experience an adverse cardiovascular event within 30 days compared to those who didn’t take any of the drugs. Cardiovascular event risk increased by 30% in those starting diclofenac compared to naproxen, and 20% compared to those beginning on ibuprofen or acetaminophen. Diclofenac was also associated with 2.5 times greater risk of experiencing gastrointestinal bleeding compared with the other three drugs.
Kidney damage: Taking NSAIDs over a period of time can lead to kidney damage. If you take them while you are dehydrated or when your blood pressure is low you can develop sudden kidney failure or acute kidney injury. If you’re taking NSAIDs for RA it’s important to take note of the ingredients in other over-the-counter medications you may take, such as headache, fever or cold medication, so that you’re not taking more of the NSAID than you realize, putting your kidneys at further risk.
Researchers at the University of Sydney found that doctors prescribed NSAIDs for too long a period and without precautions taken against the development of side effects. The study, reported in the journal Pain, found that for men aged 70 and older, “mean duration of treatment was five years, although Australian and international guidelines suggest short-term treatment with doses taken as needed.” Just as concerning is the finding that despite guidelines to the contrary, “only 25% of NSAIDs users were prescribed a proton pump inhibitor (PPI) to prevent or manage side-effects.”
The conclusion? NSAIDs are not a great choice for long-term pain management. You may want to discuss other pain management options with your health care provider. And use lower doses of NSAIDs, less often.
Conclusion: As with most autoimmune disorders, there is no one-size-fits-all treatment for rheumatoid arthritis. The course of treatment depends on the type and severity of symptoms. However, treatment typically involves a combination of medications. Faster-acting NSAIDs and steroids are often given along with slower-acting, but longer-lasting DMARDs.
