Diagnosing rheumatoid arthritis (RA) early in the disease process is ideal, because treatments are more likely to be effective and less damage will occur. Guidelines from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) state that using newer biologic medications, in addition to more aggressive dosing of traditional medications, is the optimal way to achieve results.1,2 This combination tends to control disease activity and joint inflammation, decrease erosions and damage to joints, improve the quality of life for people with RA and decrease such co-morbidities as cardiovascular disease that can be associated with sustained inflammation.
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Nonetheless, treatment decisions can be complex because many factors come into play. Rheumatologists should make treatment decisions along with their patients, because patients are more likely to comply with treatment if they are involved in the decision-making process.
“Discussions should include the risks of RA, the risks of therapeutic choices and the anticipated benefits and side effects,” says Susan M. Goodman, MD, rheumatologist and associate director of the Inflammatory Arthritis Center of Excellence at the Hospital for Special Surgery (HSS) in New York.
When determining the best treatment protocol, Vivian Bykerk, MD, rheumatologist and director of the Inflammatory Arthritis Center of Excellence at HSS, considers disease characteristics to estimate a person’s prognosis. Factors include how long the patient has had the disease, how widespread the signs and symptoms are, laboratory results, imaging results and whether damage has already occurred. Poor prognostic signs in patients with RA include extensive joint involvement, positive rheumatoid factor and cyclic citrullinated peptide antibodies, increased inflammatory markers and joint erosions at initial diagnosis.
Dr. Bykerk also wants to know whether the patient has already taken medication for their symptoms, as well as their treatment goals and insurance coverage. “I’ll explore the patient’s values, their concerns about the disease and what they have read about in terms of its treatment and risk tolerance,” Dr. Bykerk continues. “Finally, we develop clear goals for treatment.”
Starting & Evaluating Treatment
The ACR and EULAR guidelines call for prescribing a disease-modifying anti-rheumatic drug (DMARD) upon diagnosing a patient with RA. In most patients with moderate to severe, active RA, methotrexate is the initial treatment of choice. In fact, most insurance companies require a patient to have had an inadequate response to methotrexate before starting a biologic, says Monica Piecyk, MD, rheumatologist at New England Baptist Hospital in Boston.
When a contraindication to methotrexate’s use exists, such as an anticipated pregnancy or a history of liver disease, another synthetic DMARD, such as leflunomide (Arava), or tumor necrosis factor (TNF) inhibitors may be options, Dr. Goodman says.
For patients with low disease activity, hydroxychloroquine or sulfasalazine may be effective. Because DMARDs can take months to become fully effective, Dr. Piecyk suggests prescribing non-steroidal anti-inflammatory drugs (NSAIDs) or short-term prednisone to patients who are unable to perform certain daily activities, because this may provide more immediate relief of pain and stiffness.
Corticosteroids are a short-term temporary treatment to bridge between therapies or calm flares until therapies indicated for long-term use take effect. Side effects are often concerning to patients and include weight gain, inability to sleep, onset of diabetes or worsened glucose control. Determine a patient’s response to therapy and make adjustments in dose, route of administration or drug over the first one to three months of treatment, Dr. Goodman advises. This requires frequent follow-up evaluations.
“I am more likely to add a second DMARD or a biologic more quickly in patients with poor prognostic signs after three months of prescribing methotrexate,” Dr. Piecyk says.
Also, keep in mind recognized prognostic predictors for poorer outcomes exist, such as smoking and anti-citrullinated protein antibody positivity.
A Closer Look at DMARDs
Methotrexate reduces daily symptoms of RA and lowers the risk for long-term joint damage by modulating the immune system. An optimal dose is 20–25 mg per week. Remission is achievable using methotrexate monotherapy in early RA 30–40% of the time.3
Patients with an inadequate response to oral methotrexate (or adverse gastrointestinal side effects) may benefit from subcutaneous methotrexate.4 Subcutaneous administration results in a higher relative bioavailability than does oral administration of methotrexate.5 “A higher relative bioavailability equals a higher effective dose of the medication for the patient, which may better control symptoms and RA progression compared with a lower dose,” Dr. Piecyk explains.
Patients are often reluctant to give a self-injection, however. “I tell patients that the needle is small, that gastrointestinal side effects should not occur and that if this medication is effective they may not require additional medication,” Dr. Piecyk says.
When pointing out methotrexate’s potential for side effects, such as hair loss and feeling unwell, Dr. Bykerk tells patients that more than 85% of patients have few, if any, difficulties with it. If problems occur, they can always try another medication. Therefore, she believes it’s worth trying because the benefits clearly outweigh the risks. She will usually reassess a patient starting on methotrexate after 8–12 weeks.
“If I see a good response, I may recommend staying the course or adding additional DMARDs. However, if the response is minor and the burden of disease is high, I will recommend a self-injectable biologic therapy. This requires a lengthier discussion [because] patients are not only concerned about administering injections and understanding how to minimize infectious risk, but also [in] gaining a sense of the financial cost.”
Dr. Piecyk says self-injectable forms of biologics are becoming more popular as an alternative to intravenous infusions. Abatacept and tocilizumab are two biologics that were previously available only as intravenous infusions. “Many patients prefer fewer trips to the doctor’s office,” she says.
Follow-on Biologic Response Modifiers
Follow-on biologics are generic biologics, and are made to be similar to existing biologics. However, unlike generic forms of synthetic DMARDs, these are complex biologic compounds, and they require biotechnological manufacturing using living tissue.
The U.S. Food and Drug Administration (FDA) recognizes two categories of follow-on biologics: biosimilars, which have the same mechanism of action but no clinically significant differences in safety or efficacy as the original biologic (also called a reference product), and interchangeables, which must meet the biosimilar standard and are expected to produce the same result in any given patient. In some states, pharmacists can substitute interchangeables without the prescribers’ knowledge.
Although no biosimilars are currently approved for rheumatology use in the U.S., an infliximab biosimilar called Remsima has been used in Europe to treat RA. The drug’s manufacturer, Celltrion Healthcare, is applying for FDA approval in the U.S.
‘I’ll explore the patient’s values, their concerns about the disease & what they have read about in terms of its treatment & risk tolerance. Finally, we develop clear goals for treatment.’ —Dr. Vivian Bykerk
The introduction of follow-on biologics and the approval of the first biosimilar in the U.S., Sandoz’s filgrastim-sndz (Zarxio) for Amgen’s reference product, filgrastim (Neupogen), is used by hematologists. “Approval of biosimilars will add complexity to rheumatology practice when RA drugs are approved in the United States,” Dr. Goodman says. “The advantage of follow-on biologics is that they cost less than current biologics and will, therefore, be more available to RA patients.”
Because biologics are large, complex molecules manufactured using cell lines in a precisely controlled environment, concern exists that small changes could result in an immune response to the drug with loss of efficacy. This concern will have to be addressed in large, long-term clinical trials, Dr. Goodman says.
A recent, randomized controlled trial comparing the Celltrion biosimilar to infliximab demonstrated equivalent efficacy, comparable adverse events and a comparable development of anti-drug antibodies, but was only continued for 30 weeks.6 A similar 24-week study comparing an etanercept biosimilar to reference etanercept also demonstrated comparable efficacy, immunogenicity and safety.7
“Neither study addresses the question of immunogenicity in patients who switch from the reference drug, which could occur without the prescribing physician’s knowledge in the case of interchangeables,” Dr. Goodman points out. The protections and requirements for physician and patient notification for interchangeables vary by state.
Be Wary of Increased Heart Attack Risk with NSAIDs
Rheumatologists should be aware that the FDA strengthened its warning regarding the effects of NSAIDs on the cardiovascular system in July 2015.8 In particular, after the first few weeks of therapy they carry an increased risk of heart attack. The risk is also increased with higher doses of NSAIDs, as well as for individuals without underlying cardiac disease—although the risk is greatest in those with underlying cardiac disease. The FDA recommends that patients and practitioners be on alert for heart-related side effects.
‘Approval of biosimilars will add complexity to rheumatology practice when RA drugs are approved in the United States.’ —Dr. Susan M. Goodman
“For patients with preexisting cardiac disease and those who smoke, risk–benefit discussions should reflect the heightened awareness of the cardiovascular risk of NSAIDs,” Dr. Goodman says. “For many patients, the benefits [with] regard to maintained function and quality of life outweigh the risk, and decisions can be made on an individual basis when adequate relief of symptoms is not achieved by acetaminophen alone.”
When treating a patient newly diagnosed with RA, look first to organizations’ standard protocols. Then, evaluate the individual patient, discussing their specific needs and goals. Follow-up evaluations are necessary to determine optimum treatment.
Karen Appold is a medical writer in Pennsylvania.
Beyond Drugs: Easing RA Symptoms with Exercise, Diet
In addition to medications, joint therapies, exercises and tailored diets can benefit certain patients with rheumatoid arthritis (RA). John Indalecio, OTR/L, CHT, MS, occupational therapist and staff hand therapist at the Hospital for Special Surgery (HSS) in New York, recommends several strategies for relieving joint pain, including joint protection, energy conservation and adaptive techniques and tools to ensure maximal functional independence.
“Because of the systemic nature of the disease and consequential destruction of the synovium and soft tissue, it’s important to protect joints from stress, such as challenging or pushing through pain,” Mr. Indalecio says.
Patients can integrate energy conservation techniques into daily living activities by spacing out strenuous tasks, taking frequent rest breaks—including naps—and using good ergonomic and body-sparing positioning.
If necessary, a therapist can fabricate a hand splint. Splints can be custom-molded or prefabricated and be worn during daily activity or at night to neutralize deformity. Night splints can include wrists, as well as fingers and thumbs, and place joints in stress-free positions. A hand therapist can also guide patients on proper exercises to maintain joint flexibility, provide strategies to manage pain and edema, and demonstrate tools and equipment to protect joints.
“It is important to actively move the joints throughout the pain-free range,” Mr. Indalecio says. “Moving a joint 10 times daily through the full arc of motion will help prevent loss of motion. But pushing hard on a painful joint may contribute to its destruction over time.”
Heating swollen joints via warm compresses, heating pads and a paraffin bath can increase range of motion and decrease morning stiffness, he continues. Although studies on wearing compression gloves at night for arthritic hands are inconclusive, Mr. Indalecio says many patients report pain relief and increased dexterity when using them. Gloves are most frequently worn at night.
Smartphone apps built for RA self-management can track symptom changes and help patients accurately inform rheumatologists of their status over time and, thus, help guide treatment. Some comprehensive and user-friendly apps include RheumaTrack RA (from axovis GmbH), MyRA (from Crescendo Bioscience Inc.) and My Pain Diary (by Damon Lynn). The first two are free, and the latter costs $4.99 to download.
Food’s Integral Role
It’s also important to advise patients to make food choices that reduce inflammation, rather than cause it, says Dana Pitman, MS, RD, CDN, registered dietician at HSS. Be aware that some drugs may increase or decrease appetite, thereby affecting nutritional status.
In addition, monitor drug and nutrient interactions, because foods can affect how the body absorbs or uses drugs, Ms. Pitman advises. The former can make a drug less effective or inhibit the excretion of drugs—potentially causing a toxic buildup.
Specifically, corticosteroids can lead to high blood sugar and increased bone loss with long-term use. To offset steroid-induced high blood sugar, patients should drink 2 L of water daily; avoid packaged sweets, desserts and sugar-sweetened beverages; eat lean protein and non-starchy vegetables and no more than two to three servings of fruit per day; and consume small amounts of healthy fats, such as olive oil, avocados and nuts.
In addition, including lots of calcium-rich foods, such as low-fat dairy, green leafy vegetables, fatty fish, almonds, white beans and homemade broths, can offset bone loss associated with chronic steroid use, Ms. Pitman continues. A calcium supplement with vitamin D may also help.
Disease-modifying anti-rheumatic drugs (DMARDs) can result in gastrointestinal-related side effects, such as nausea and vomiting, as well as folate deficiency. In such instances, try small, nutrient-dense meals or snacks every two to three hours, opting for cold or room temperature foods. Consider smoothies or blended drinks for mouth sores or a sore tongue. A supplement may be necessary to increase the amount of folate in the diet. Eating whole grains, dark leafy greens, citrus fruits and orange-colored vegetables and fruits can help.
Ultimately, a Mediterranean diet consisting of high amounts of minimally processed foods, fruits, non-starchy vegetables, low-fat dairy and fatty fish is ideal.
- Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012 May;64(5):625–639. doi:10.1002/acr.21641.
- Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2015 May 12. pii: annrheumdis-2015-207524. doi: 10.1136/annrheumdis-2015-207524. [Epub ahead of print]
- Barnabe C, Sun Y, Boire G, et al. Heterogeneous disease trajectories explain variable radiographic, function and quality of life outcomes in the Canadian early arthritis cohort (CATCH). PLoS One. 2015 Aug 24;10(8):e0135327. doi:10.1371/journal.pone.0135327.
- Schiff MH, Jaffe JS, Freundlich B. Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: Drug-exposure limitations of oral methotrexate at doses ≥15 mg may be overcome with subcutaneous administration. Ann Rheum Dis. 2014 Aug;73(8):1549–1551.
- Pichlmeier U, Heuer KU. Subcutaneous administration of methotrexate with a prefilled autoinjector pen results in a higher relative bioavailability compared with oral administration of methotrexate. Clin Exp Rheumatol. 2014 Jul–Aug;32(4):563–571.
- Choe JY, Prodanovic N, Niebrzydowski J, et al. A randomised, double-blind, phase III study comparing SB2, an infliximab biosimilar, to the infliximab reference product Remicade in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis. 2015 Aug 28. pii: annrheumdis-2015-207764. [Epub ahead of print].
- Emery P, Vencovský J, Sylwestrzak A, et al. A phase III randomised, double-blind, parallel-group study comparing SB4 with etanercept reference product in patients with active rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis. 2015 Jul 6. pii: annrheumdis-2015-207588. [Epub ahead of print].
- U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA strengthens warning that non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. 2015 July 9 (updated July 17, 2015).