Making Strides in Rheumatoid Arthritis

The 2015 American College of Rheumatology guideline on the treatment of rheumatoid arthritis may not signify a revolution in the treatment of the disease, but the guideline portends what many experts in clinical rheumatology see as brighter future for patients. Much of the excitement surrounds advances in pharmacotherapy.

While methotrexate-containing regimens remain the mainstay and little has changed with regard to tumor necrosis factor (TNF) inhibitors between 2012 and 2015, the entry of biosimilars into the FDA approval arena may represent a sea change in clinical approaches to rheumatoid arthritis (RA).

Eric L. Matteson, MD, a rheumatologist at Mayo Clinic in Rochester, Minn., expressed some of this optimism in an interview with Healio Rheumatology.

“For the past 65-plus years, we have not only been focused on pain management, but reduction of inflammation which is related to the systemic effects and joint damage of RA,” he said. “We are now more than ever focused on reducing the damage to joints caused by disease and reducing the burden of disease on patients so they live longer, better and require less joint replacement. We are more focused on understanding the pathobiology of the disease and using our understanding of it to better treat it, and especially focused on early intervention to prevent disease-related comorbidities.”

For James R. O’Dell, MD, Bruce Professor and vice chair of Internal Medicine and chief of the Division of Rheumatology at the University of Nebraska Medical Center, this means a close examination of specific treatment options.

“The biggest fundamental shift in thinking is that we should treat every patient to a target of low disease activity,” he said. “So we have to think about what combination is going to get us there. It might be methotrexate alone, or it might be methotrexate plus a TNF inhibitor, hydroxychloroquine or it might be an IL-6 inhibitor. We have options.”

Intervention Strategies

The American College of Rheumatology (ACR) guideline focuses on the approved therapies and provides clinicians with comprehensive guidance on a broad range of clinical scenarios and potential roadblocks with the drugs that may be used on-label. The main thrust of the document provides recommendations for patients with early disease, those with established disease and those with potentially high-risk comorbidities.

The guideline authors recommend a treat-to-target strategy for early RA patients, regardless of disease activity level. The target is to induce low disease activity or remission as determined by the clinician and the patient. If risk tolerance or comorbidities demand it, then another target may be chosen.

It is strongly recommended that patients naïve to disease-modifying antirheumatic drugs (DMARDs) with early symptomatic disease and low disease activity should be treated with DMARD monotherapy as opposed to double or triple therapy. In naïve patients with moderate or high activity, DMARD monotherapy is conditionally recommended over double or triple therapy, according to the guideline. In addition, methotrexate is the primary initial therapy for most patients with early, active RA.

A combination of DMARDs or a TNF inhibitor or non-TNF biologic with or without methotrexate, in no particular order, is recommended by the authors for DMARD-experienced patients with moderate or high disease activity. Biologic therapy in conjunction with methotrexate, as opposed to methotrexate alone, is re-commended for this population.

In the guideline, the authors recommend low-dose glucocorticoids — defined as less than or equal to 10 mg/day of prednisone equivalent — for patients with moderate or high disease activity, despite prior treatment with any combination of DMARD or biologic therapies. Patients in need of a bridge until the efficacy of DMARD therapy is determined also may be treated with low-dose glucocorticoids. However, the dose should be low and the duration of this bridge therapy should be brief, according to the recommendations.

Similarly, low-dose, short-term glucocorticoids — defined as less than 3 months of treatment — are recommended by the authors for patients with an RA flare-up.

Established Disease

A treat-to-target strategy, with the aim of low disease activity or remission, also is recommended for established RA patients regardless of the level of disease activity, according to the guideline. The authors recommend DMARD monotherapy for patients with low disease activity who are naïve to these therapies. For naïve patients with moderate or high activity, DMARD monotherapy also is preferred over a TNF inhibitor, according to the guideline. The authors recommend methotrexate for most patients with established disease.

Experienced, established patients with moderate or high activity should be treated with combination DMARDs along with either a TNF inhibitor, a non-TNF biologic or tofacitinib citrate (Xeljanz, Pfizer), according to the guideline. The choices may be administered with or without methotrexate, and no particular order of preference is recommended, as outlined in the guideline. The authors also recommend biologic therapy plus methotrexate over biologic monotherapy in this patient population.

“The ACR periodically reviews and updates their guidelines to reflect the availability of new treatment options and available clinical data,” S. Louis Bridges Jr., MD, PhD, Anna Lois Waters-endowed professor in the Division of Clinical Immunology and Rheumatology, and director of the Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham (UAB), director of the UAB Comprehensive Arthritis, Musculoskeletal, Bone and Autoimmunity Center, and one of the authors of the ACR guideline, told Healio Rheumatology. “For example, tofacitinib was not approved by the FDA for the treatment of RA when the 2012 guideline was developed, so it could not be included. This had changed when the literature review for the 2015 guideline was conducted.”

The guideline also provided more detailed recommendations for TNF inhibitor that may be administered with or without methotrexate. TNF inhibitors plus one or two DMARDs are recommended for patients with moderate or high disease activity who are not being treated with a DMARD. If disease activity remains high even after treatment with a single TNF inhibitor, then a non-TNF biologic is conditionally recommended in the guideline.

In cases in which disease activity remains high despite intervention with a non-TNF biologic therapy, a conditional recommendation is offered for use of another non-TNF biologic therapy, according to the guideline. For patients with moderate or high activity who have failed therapy on more than one non-TNF biologic therapies and are naïve to TNF inhibitors, a TNF inhibitor is conditionally recommended.

The authors provide a conditional recommendation for another non-TNF biologic therapy for patients with moderate or high disease activity, despite previous intervention with at least one TNF inhibitor and at least one non-TNF biologic therapy. For patients who decline non-TNF biologic therapy due to lack of efficacy or adverse events, tofacitinib is conditionally recommended by the authors.

Patients with moderate or high disease activity, even after multiple TNF inhibitors have been used, may be treated with non-TNF biologic therapy followed by tofacitinib when a non-TNF biologic therapy is not available as an option, as defined by the guideline. The authors noted this recommendation is conditional.

The authors wrote that low-dose glucocorticoids are conditionally recommended if disease activity remains moderate or high, despite use of the aforementioned DMARDs or biologic therapies. Short-term, low-dose glucocorticoids also are conditionally recommended for patients with established disease who experience a flare-up while being treated with any of the above therapies, according to the guideline.

It is suggested in the guideline that patients with established disease who demonstrate low disease activity but are not in remission, continued DMARDs, TNF inhibitor, non-TNF biologic or tofacitinib activity is strongly recommended, as opposed to discontinuation of medical therapy. Tapered DMARD, TNF inhibitor, non-TNF biologic or tofacitinib therapy is conditionally recommended for patients with established disease who are currently in remission. A strong recommendation also is offered for not discontinuing therapies in patients with established disease who are in remission, as defined by the guideline.

High-risk Comorbidities

The authors also provided recommendations for patients with high-risk comorbidities. DMARD therapy, a non-TNF biologic or tofacitinib is preferred over a TNF inhibitor in patients with moderate or high disease activity who have New York Heart Association class III or IV congestive heart failure. If heart failure occurs during TNF inhibitor therapy, DMARDs, non-TNF biologics or tofacitinib is conditionally recommended as opposed to another TNF inhibitor, as outlined by the guideline.

The authors wrote patients with active hepatitis B infection who have established disease and moderate or high RA activity who are currently or were previously being treated with effective antiviral therapy should not be treated any differently than patients without hepatitis B. The same recommendation is offered for patients with hepatitis C.

Patients with RA who have natural immunity due to a history of hepatitis B also should be treated the same as patients without this disease, according to the recommendations. However, the authors recommended clinicians monitor the viral load of these patients. Untreated patients with hepatitis B should be treated with antiviral therapy before being treated with immunosuppressive therapy.

The authors wrote that DMARD therapy is preferred over a TNF inhibitor for patients who are do not require hepatitis C treatment or who are not being treated with antivirals for that disease. However, in light of recent advances in hepatitis C therapy, the authors encouraged rheumatologists to work with hepatologists and gastroenterologists to manage this condition. DMARDs are also preferred over biologics or tofacitinib in patients with established RA and moderate or high activity who have a history of treated or untreated melanoma or non-melanoma skin cancer, according to the recommendations.

For patients with a previously treated lymphoproliferative disorder who have established RA and moderate or high activity, the authors strongly recommend rituximab (Rituxan, Genentech) over a TNF inhibitor. DMARD therapy, abatacept (Orencia, BMS) or tocilizumab (Actemra, Genentech) are conditionally recommended over a TNF inhibitor, according to the authors.

Patients with a history of solid organ cancer who have moderate or high RA activity should be treated the same as patients who have no history of solid organ cancer. DMARD therapy or abatacept are preferred over a TNF inhibitor in patients with established RA and moderate or high activity who have previous serious infections.

In the guideline, patients aged 50 years old or older with early or established RA may receive the herpes zoster vaccine prior to biologic or tofacitinib therapy. This is a conditional recommendation. However, another conditional recommendation is that early or established RA patients who are currently receiving biologics should not be given a live attenuated vaccine. If vaccinated, it is strongly recommended that these patients receive killed or inactivated vaccines.

“There is also a lot of interest in the use of drugs in comorbid conditions such as heart failure, infections, etc., and the use of vaccines, so we felt it was important to address those topics,” Bridges said.

O’Dell discussed the way the recommendations were considered.

“Wherever possible, the guideline goes out of its way to weigh all the available evidence,” he said. “Unfortunately, there are many situations where we simply don’t have the evidence. In that situation, when you are trying to write a guideline, we either said we couldn’t comment on that or we were forced to come to a consensus. The guideline well outlines where those situations are. It tells you how strong the evidence is to support the recommendation. We tried to separate out opinion from fact. I wouldn’t want someone coming away from the guideline thinking they are all about consensus.”

Key Changes

In general terms, the current guideline is more far reaching than the 2012 version, according to Jeffrey R. Curtis, MD, MS, MPH, William J. Koopman-endowed professor in Rheumatology and Immunology, director of the UAB Arthritis Clinical Intervention Program, co-director of the UAB Center for Education and Research on Therapeutics of Musculoskeletal Disorders and co-director of the UAB Pharmacoepidemiology and pharmcoeconomics Unit at the University of Alabama at Birmingham.

“The use of first-line biologics is a change worth highlighting,” he said. “In the past, TNFs had been preferred. Now the biologics are on equal footing. That is a departure from the previous iteration.”

He noted the authors now are more agnostic about which first-line biologic is preferable, and that TNF inhibitors were first line for historical reasons but not necessarily because they are intrinsically better.

“Also, in early RA, the Janus kinase inhibitor tofacitinib is not as much on equal footing with the biologics,” he said. “The 2015 ACR guideline has laid out parameters surrounding its use.”

Another change is that the herpes zoster vaccine is recommended for patients aged 50 years and older as opposed to 60 years and older.

“A more aggressive vaccination schedule is recommended,” Curtis said.

Patients with RA who have a history of cancer have long been a “conundrum,” according to Curtis.

“There was some discomfort about what we may use safely in such patients,” he said. “It was suggested, for example, that if you used a biologic in a woman with breast cancer, she was at increased risk for recurrence if she subsequently was treated with a biologic for RA. However, based on new published data and now incorporated into the 2015 update, that is probably not the case.”

Bridges highlighted the information on tapering and discontinuing medications in asymptomatic patients or those in remission as a key difference between the 2012 and 2015 iterations. However, for O’Dell, the differences between the two are not so great.

“There is emphasis that more combination therapies are effective,” he said. “The critical thing isn’t what meds you use, but how to target the patient in terms of low disease activity or remission.”

The recommendation for bridge therapy is an important change, as is the use of tofacitinib and the earlier use of steroids to deal with flare-ups, according to Allan Gibofsky, MD, JD, FACP, FCLM, professor of Medicine and Public Health at Weill Cornell Medical College. “Also, the older criteria ask for predictors of poor prognosis, but these do not,” he said. “However, there is a more of an attempt to allow more detailed or custom therapy overall.”

Matteson put the changes into broader perspective. “First, it is important to have the patient diagnosed properly,” he said. “Second, it is important to initiate therapy with DMARDs promptly.”

Evidence and Implications

Gibofsky expressed some concern about the strong recommendations compared with the conditional recommendations. “When one goes through the document, many strong recommendations are based on lower levels of evidence as compared with consensus opinion,” he said. “The consensus opinion defines strength of recommendation. Sometimes, strong recommendations are based on low to very low levels of evidence.”

To this point, Bridges said the guideline team followed a new method called GRADE, or Grading of Recommendations Assessment, Development and Evaluation.

“This methodology is more transparent, includes specific patient groups and interventions, as well as competing treatment alternatives and outcomes,” he said. “It also rates both the quality of the available evidence and the strength of the recommendations.”

He added the guideline offers recommendations on common clinical scenarios that may arise when using pharmacologic treatments.

“We hope that physicians will use the guideline to discuss evidence-based treatment options with their patients when developing their treatment plan,” he said. “The new recommendation for tofacitinib, for example, may provide clinicians with information they didn’t have before when determining what might work for their patient. However, the ACR continues to stress that ACR recommendations are not intended to dictate payment or insurance decisions, and they shouldn’t be used to limit or deny access to treatments. Guidelines are intended to provide guidance for particular patterns of practice and not to dictate the care of a particular patient.”

O’Dell put the issues of strength of recommendation and insurance coverage into practical terms.

“The old guidelines didn’t allow for financial or economic implications to be a consideration,” he said. “But now, the feeling is that if these two things are relatively similar in terms of outcomes, it behooves all of us to use the ones that are most economical. Still, the guiding principal is to get the patient to low disease activity.”

Biosimilar Drugs

In early February, the FDA Arthritis Advisory Committee voted positively to recommend approval for Celltrion’s CT-P13 biosimilar to infliximab (Remicade, Janssen Biotech). In a 21-to-3 vote, the committee recommended CT-P13 should receive licensure as a biosimilar product for the indications for which the originator infliximab is currently licensed in the United States and also be eligible for licensure for treatment of RA, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, adult and pediatric Crohn’s disease and adult ulcerative colitis.

Following the meeting, the ACR called for continued study of biosimilars and detailed labeling information for these products. The group also reiterated its position on distinct naming guidelines and urged caution related to extrapolation of these products. Angus Worthing, MD, FACP, FACR, member of the ACR Government Affairs Committee, testified on behalf of the ACR at the advisory committee hearing.

“As more biologic drugs are used to treat rheumatic diseases, rheumatologists are increasingly concerned about their high costs and patients being able to afford them, so the ACR strongly believes that safe and effective treatment alternatives should be made available to patients at the lowest possible cost,” Worthing said in an ACR press release.

Clinical Impact Studies

Findings from studies presented at the 2014 ACR Annual Meeting show the drugs can have clinical impact. Cohen and colleagues investigated ABP 501 (Amgen), a biosimilar candidate to adalimumab (Humira, AbbVie), in a randomized, double-blind, active-controlled, equivalence study in patients with moderate to severe RA who responded inadequately to methotrexate. The study included 264 patients in the study drug group and 262 patients treated with adalimumab. Risk ratio of ACR20 at 24 weeks served as the primary endpoint.

Results indicated 74.6% of patients in the ABP 501 arm and 72.4% of those in the adalimumab arm reached the primary endpoint. Other findings demonstrated encouraging rates of ACR50 response criteria for the study drug (49.2% for ABP 501 and 52% for adalimumab) and ACR70 criteria (26% for ABP 501 and 22.9% for adalimumab). Safety outcomes also were similar. The researchers concluded that clinical equivalence between the two drugs was demonstrated.

In another study, Vencovsky and colleagues studied SB4 (Samsung Bioepis), a biosimilar of etanercept (Enbrel, Amgen), in a randomized, double-blind multicenter trial that included patients with moderate to severe disease despite methotrexate treatment. There were 299 patients treated with a 50-mg dose of the study drug and 297 treated with subcutaneous etanercept. All patients were treated for 52 weeks and observed for the primary outcome of ACR20. At week 52, per-protocol analysis results indicated 80.8% of those in the study drug arm and 81.5% of those receiving etanercept reached the primary endpoint. ACR50, ACR70 and safety profile results were similar between the two groups.

“There are few concerns about biosimilars with regard to efficacy and toxicity,” O’Dell said. “Once they have gone through the process of being labeled biosimilar, then we can feel good that they are similar. However, it must be noted that when we say similar we mean similar, and not identical.”

Gibofsky put a finer point on this. “Biosimilars are essentially the same drugs, designed to do the same thing as the drugs they replicate,” he said. “They do not offer any advantage in terms of control over disease than what we already have. The main advantage is that they will cost less.”

Curtis agreed. “This is not so much a scientific advance as it could be a population impact in terms of cost, accessibility, copayment, etc.,” he said. “The availability of these drugs could lead to expanded access. They could save patients and insurance companies money.”

He suggested this may be problematic for insurance companies, but that clinicians, of course, are in favor of expanded access.

“We need to reduce difficulties of the approval process,” he said. “All of these patients do not need to be on methotrexate.”

Overall costs to treat the disease may not fundamentally change even with the cheaper drugs, according to O’Dell.

“We hold a lot of hope that they will drastically decrease cost, but my concern is about third-party payers and what they will tell clinicians they have to do,” he said. “If a company tells me I have to use this over that, mostly I am okay with it. But if they tell me I have to switch a patient who is doing well from one drug to another, then I have a problem. We should not be required to switch.”

Future Guidelines

Future guidelines are likely to address biosimilars that are coming to market.

“The ACR does currently have a position paper on their usage that we felt effectively explained where we stand on the issue until more evidence becomes available,” Bridges said. “In the case of the 2015 guideline, there were other topics we could not consider due to scope and time restraints, so you will likely see even more updates in the future.”

Development is moving so fast that it is difficult for guidelines to keep pace. Biosimilars may soon be available, Curtis said.

“These may offer expanded patient access to biologics, reduced costs and perhaps even lower clinician burden to navigate the prior approval process required by many insurance companies,” he said. “However, we need to ensure the highest rigor of biosimilars in regards to safety and effectiveness and transparency regarding their use.”

In the Pipeline

Gibofsky cited the approval of tofacitinib as a reason for optimism.

“It is a smaller molecule,” he said and added that baricitinib (Eli Lilly and Company) is another drug in this class that is moving through trials and possibly toward approval.

O’Dell raised some questions about tofacitinib. “What is the niche?” he said. “Where does it fit into what we do? Should we use it after methotrexate failure or failure on biologics? We are still looking at studies and the guideline doesn’t yet give us direction.”

In another class, the immunosuppressive drug tocilizumab has been approved, and O’Dell suggested there are others in development.

“We do not yet know the timeline on these drugs,” he said. “We may have more soon.”

As for the therapies that have been around longer, there is some movement in terms of trials and approval, but how that movement will impact the clinic is up for debate.

“The new IL-6 inhibitors are struggling to differentiate from the ones we have had for the last 5 years,” Curtis said. “Whether we need second or third is a little questionable, given limited space and resources.”

A similar case can be made for TNF inhibitors.

“There are five TNF inhibitors approved, and four of them are basically monoclonal antibodies,” O’Dell said.

“When we are talking about treating RA, 85% to 90% of the time these drugs are considered to be similar to each other in terms of efficacy and toxicity.”

He noted that there are some differences in terms of small, specific populations that may be treated with each drug. “When we are treating inflammatory eye disease, for example, monoclonals work better. Some people believe certolizumab pegol (Cimzia, UCB), which is a pegylated antibody, has advantages for pregnant mothers, but it has not been proven. So we should consider these drugs similar, but not exactly the same.”

“What we are seeing primarily is increased numbers of agents in classes that already exist,” Gibofsky said.

Curtis reminded clinicians to keep an open mind.

“There are always new molecules coming down the road,” he said.

Surgical Approaches

Gibofsky stressed the importance of advancement in surgical intervention.

“We are moving away from joint replacement and toward the re-establishment of joint health with other body tissue,” he said. “There is increased interest in growing cartilage in a test tube and injecting it to reestablish the joint.”

While this approach shows great promise, O’Dell voiced some reservations.

“There are exciting things going on in the lab with regard to building cartilage and building joints,” he said. “But these data are not ready for prime time just yet.”

That said, surgical joint replacement can be considered a help for clinicians in the treatment of RA.

“We need more of these types of interventions,” O’Dell said.

Moving Forward

The mainstay of RA therapy remains dealing with inflammation.

“If you can shut off inflammation, some evidence suggests the joints can repair themselves,” O’Dell said. “To some degree that is the future.”

It is important to remember that patients with RA have historically died prematurely, according to O’Dell.

“They die of heart attacks as a result of prolonged inflammation,” he said. “Now that we can treat inflammation more effectively, we are seeing less atherosclerosis, less cardiovascular disease. Some data are showing us that we may have changed the curves for mortality.”

Bridges said that as treatments continue to advance, so do the treatment goals.

“Twenty years ago, all we could do with the options available was to help our patients manage the disease as best as possible and maintain as much quality of life as they could,” he said. “Now, we have knowledge and treatment options that allow us to be more aggressive in our treatment and management of RA to where the goal is returning patients back to their pre-disease state — or as close to it as possible — and keep them there.”– by Rob Volansky

• References:
• Cohen SB, et al. Paper #2054. Presented at: American College of Rheumatology Annual Meeting. Nov. 14-19, 2014; Boston.
• Singh JA, et al. Arthritis Care & Research. 2015;doi:10.1002/acr.22783.
• Singh JA, et al. Arthritis Rheumatol. 2016;doi:10.1002/art.39480.
• Singh JA, et al. Arthritis Rheumatol: Supplementary Appendix 5. 2016;doi:10.1002/art.39480.
• Vencovsky J, et al. Paper #2055. Presented at: American College of Rheumatology Annual Meeting. Nov. 14-19, 2014; Boston.

• For more information:
• S. Louis Bridges Jr., MD, PhD, can be reached at University of Alabama at Birmingham, Shelby Building, Room 178B, 1825 University Blvd., Birmingham, AL 35294; email: lbridges@uab.edu.
• Jeffrey R. Curtis, MD, MS, MPH, can be reached at Faculty Offices Tower, Room 802, 510 20th St. South, Birmingham, AL 35294; email: jcurtis@uab.edu.
• Allan Gibofsky, MD, JD, FACP, FCLM, can be reached at 535 East 70th St., New York, NY 10021; email: gibofskya@hss.edu.
• Eric L. Matteson, MD, can be reached at 200 1st St. SW, Rochester, MN 55905; email: matteson.eric@mayo.edu.
• James R. O’Dell, MD, can be reached at 600 S 42nd St. #2603, Omaha, NE 68198; email: jrodell@unmc.edu.

Disclosures: Bridges reports no relevant financial disclosures. Curtis reports he is a consultant for and receives honoraria and research support from Roche/Genentech, UCB, Janssen, CORRONA, Amgen, Pfizer, Bristol-Myers Squibb and Crescendo AbbVie. Gibofsky reports he is a stockholder for AbbVie, Amgen, Bristol-Myers Squibb and Pfizer; is a consultant for AbbVie, Celgene, Horizon, Iroko, Pfizer and Relburn; and is a speaker for AbbVie, Amgen, Celgene and Pfizer. Matteson reports he is an investigator for Biogen-IDEC, Centocor, Genentech, Hoffman-LaRoche, Mesoblast, Pfizer and UCB; receives grant support from Centocor/Johnson & Johnson, Genentech, Mayo Foundation, Novartis, the National Institutes of Health, Pfizer and the Rheumatology Research Foundation; and is a consultant for Centocor, GSK and Novartis. O’Dell reports he is on the advisory boards for Medac, Antares, Bristol-Myers Squibb, Eli Lilly and Company, GSK and Cresendo.