RA Guidelines Shift Focus to a More Patient-Centered Healthcare System

In November 2015, the American College of Rheumatology (ACR) released its new 2015 guidelines for treatment of rheumatoid arthritis (RA).¹ Since the last guidelines were released in 2012, the first oral biologic disease-modifying antirheumatic drug (DMARD) therapy has been approved, and clinical evidence has been expanding.^1-3

RA impacts 1% to 2 % of the American population. Although the exact triggers the development of RA is still unknown, many suggest that genetics, previous history of infection, and even smoking may contribute to the susceptibility of the autoimmune disease. RA is commonly associated with inflammation in small joints (eg, fingers, toes, wrists, and ankles). Initially, the synovium—or lining of the joint—becomes inflamed, and more pro-inflammatory cytokines are produced and migrate to the inflamed joint. The inflammation ultimately results in bone and joint deformation and destruction. Like many autoimmune diseases, RA is a systemic disease. It also contributes to Sjögren syndrome (chronic dry eye and dry mouth), fluid build-up in the cardiac pleura, anemia, and osteopenia.⁴

The 2015 ACR guidelines reflect advances in research, and the shift toward a more patient-centered healthcare system.¹ Improvements included in the new guidelines are an improved evidence-based method for guiding recommendations, implementation of the patient-centered treat-to-target approach, updating vaccination and tuberculosis (TB) recommendations to incorporate tofacitinib (Xeljanz/Xeljanz XR; Pfizer Inc) into the guidelines, and more specific recommendations for high-risk patients with RA and comorbidities.

Strengthening Recommendations and Personalizing Treatment Options

To provide more evidence-based recommendations, the authors of the new guidelines use the Grade of Recommendations Assessment, Development and Evaluation methodology in structuring its recommendations.1 This methodology allows for more transparency in how a recommendation is made, and grades the recommendations on a scale of high, moderate, low, or very low quality of evidence.²

Treat-to-target is an international initiative that rheumatologists are supporting for the treatment of RA.³ The approach helps guide monitoring, and promotes patient−rheumatologist collaborations to reach goals and treat RA appropriately early on. The primary targeted end points are remission for those with early RA, and low disease activity in patients with established RA if remission cannot be achieved. The novelty of this approach is that the end points are not dependent on lab values so much as they are on patient function as measured by 5 validated instruments listed in the guidelines.⁶

The approach also keeps recommendations open to the rheumatologist, by avoiding naming specific agents for a particular use. This allows the guidelines to be valid wherever patients with RA are treated. This is especially true in the treatment of established RA—patients with moderate or high disease activity can choose between a variety of classes and agents, without a particular preference for which is used first.

Inclusion of Tofacitinib Use Recommendations

When the 2012 ACR RA guidelines were published, tofacitinib just missed the chance to be included in them. Having gained US Food and Drug Administration approval in 2012, tofacitinib is the first oral biologic DMARD in RA therapy. Tofacitinib targets the JAK signaling pathway that leads to the production of more proinflammatory cytokines. Although tofacitinib is technically a non-tumor necrosis factor (TNF) biologic DMARD, its unique mechanism of action and route of administration has led to it being listed apart from the non-TNF biologic DMARD category in the guidelines. The 3 major areas that tofacitinib has been added to in the guideline are: treatment of moderate or high disease activity in patients with established RA, TB screening, and vaccination recommendations.

Originally, treatment recommendations for established RA did not include tofacitinib. Instead, the 2012 guidelines recommended initial use of non-biologic DMARD monotherapy, and then, in moderate or high disease activity, dual DMARD therapy. If patients were still experiencing moderate or high disease activity, they were recommended to try adding or switching agents in a tiered approach, first with another DMARD, then anti-TNF biologics, followed by non-TNF biologics. In the 2015 guidelines, the ACR recommends that patients with moderate or high disease activity instead try dual DMARD therapy, add an anti-TNF or non-TNF biologic, or try tofacitinib, rather than continuing with DMARD monotherapy. The new guidelines keep the therapeutic options open for patients with established RA who have moderate or high disease activity, having found evidence that suggests that any of these therapies can lead to remission or low disease activity.

Biologic DMARDs, including tofacitinib, have immunosuppressive properties, which is why many of these agents have black box warnings for increased risk of infection. Because of this, patients should be screened for TB before starting these agents, and while receiving them if they are at an increased risk for acquiring TB. For this same reason, these patients should avoid receiving live attenuated vaccines, like the herpes zoster vaccine live (Zostavax; Merck & Co, Inc).

Stronger Recommendations for Special Populations

Four high-risk comorbidities exist that impact a patient’s therapeutic options, these are: hepatitis B or C, history of malignancy, and congestive heart failure, and a history of serious infection.¹ Since publication of the 2012 ACR RA guidelines, treatment options for hepatitis have advanced considerably, and have been reflected in the new, 2015 guidelines. The new guidelines recommend that patients with hepatitis B or C should start anti-viral therapy before initiating RA therapy. In patients with hep C who are not receiving antiviral therapy; the guidelines conditionally recommend they initiate DMARD therapy over anti-TNF agents.

Patients with treated or untreated skin cancers should avoid biologic DMARD agents and tofacitinib, because they carry risks for infection and cancer; therefore non-biologic DMARD therapy is recommended in this population. Patients with a history of lymphoma should avoid anti-TNF agents; therapies such as rituximab (Rituxan; Biogen Inc. and Genentech USA, Inc), combination non-biologic DMARDs, abatacept (Orencia; Bristol-Myers Squibb Company), or tocilizumab (Actemra; Genentech, Inc) have evidence suggesting their efficacy and improved safety profiles compared with anti-TNF agents.

Similar to what was published in the 2012 guidelines, patients with congestive heart failure (ejection fraction ≤50%) should avoid anti-TNF agents, because some studies have associated them with worsening symptoms of the condition.⁴ The 2015 ACR guidelines add that combination non-biologic DMARDs, non-TNF agents, and tofacitinib are acceptable treatment alternatives for this patient population.⁷

Patients with a history of serious infections should also avoid anti-TNF agents, and instead use combination DMARD therapy or abatacept. The 2015 guidelines find that available evidence suggests that the use of combination DMARD and abatacept therapies may result in a lower risk for hospitalized infections.

Shifting Focus with the New Guidelines

The 2015 ACR guidelines have addressed the new evidence behind many of the current and new therapies, and shifted the focus of its recommendations to a more patient-centered healthcare system. Understanding these changes is important for pharmacists because they play a critical role in educating patients about their medications and any associated adverse events; this becomes especially important in the RA population, where many of their medications are associated with serious adverse events. Pharmacists can also assist in the selection and administration of immunizations to special populations, improving patient immunization adherence. Overall, pharmacists can improve patient outcomes through their drug knowledge and accessibility.

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References

1. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2016;68:1-26.
2. The GRADE working group. Welcome to the GRADE working group. www.gradeworkinggroup.org. Accessed June 1, 2016.
3. AbbVie, Inc. Setting targets. Reaching goals. Improving lives. www.t2t-ra.com. Accessed June 1, 2016.
4. 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;64:625-639.
5. The GRADE working group. Welcome to the GRADE working group. www.gradeworkinggroup.org.
6. AbbVie, Inc. Setting targets. Reaching goals. Improving lives. www.t2t-ra.com. Accessed June 1, 2016.
7. Singh JA, Saag KG, Bridges SL Jr, et al. Appendix 5: executive summary. http://www.rheumatology.org/Portals/0/Files/ACR%20RA%20GL%20Supplementary%20Appendix%205%20Exec%20Summary.pdf. Accessed on June 1, 2016.