Joint Effort: Collaborative Guideline Poised to Confront PsA Challenges

The 2018 American College of Rheumatology/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis has made a splash for a number of reasons: This is the first ACR-associated document on the disease, the result of a collaboration between the two heavyweight organizations associated with the PsA specialty. Moreover, in an unlikely course, patients themselves were also included in the voting panel.

Yet, perhaps the most striking aspect of this document is that it is evidence-based in a disease state that is hallmarked by a lack of evidence, particularly with regard to TNF inhibitors and biologic therapies. With so few studies available, the authors had to do their due diligence to emerge with the consensus that they did. The result is a set of recommendations that lays the foundation for guidance in using the next generation of PsA therapies, and beyond.

Jasvinder Singh, MD, MPH, who was head of the panel that created the guideline, underscored the importance of the evidence-based nature of the recommendations. “These guidelines tackle important clinical questions regardless of whether there is top-quality evidence or zero evidence available,” he said. “If the panel felt it was important, we formulated a question for it.”

The process of developing the guideline began with ACR and NPF experts evaluating patient, intervention, comparison intervention, and outcome (PICO) questions. A panel of 10 patients met in April 2017 to discuss patient considerations, and decided that treatment burden, onset of action, side effects and effectiveness, among others, were their primary considerations.

“The second thing to highlight is the transparency of the process,” Singh, professor of medicine at the University of Alabama at Birmingham, said in an interview with Healio Rheumatology. “The tables you see are the same tables the voting panel saw. If a question has zero evidence supporting it, the table tells you there is zero evidence supporting it. Nothing is an enigma or hidden from the public.”

To that point, of 80 treatment recommendations established in the new guideline, 94% are conditional, compared with just 6% that were strong. The authors meticulously outlined the methodology, taking steps to show that everything was “clear and open,” according to Singh.

The final voting panel included two patients, 11 rheumatologists, a rheumatology physician assistant, a dermatologist, and a dermatologist/rheumatologist. Recommendations that reached a consensus of 70% or greater were ultimately adopted. The experts then made strong recommendations for questions that had good evidence to back them, and conditional recommendations for questions with less rigorous evidence available. They defined strong recommendations as those that may safely be adopted by more than half of potential patients.

Different Methods

For Dafna D. Gladman MD, deputy director of the Centre for Prognosis Studies in the Rheumatic Diseases at Toronto Western Hospital, and director of the Psoriatic Arthritis Program at University Health Network, an important aspect of the methodology was the difference between this document and those from EULAR or the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). “The ACR review was based on the GRADE system, while EULAR guidelines were based on the Oxford system,” she said.

Ali A. Duarte-Garcia, MD, a fellow in the division of rheumatology and instructor in medicine at the Mayo Clinic College of Medicine and Science, explained that the GRADE approach prizes the risk-benefit ratio of any given intervention, along with quality of evidence, and patient values and preferences. “GRADE follows a standardized and rigorous process to assess evidence and create recommendations in a transparent way,” he said. “By using GRADE the ACR/NPF guideline ensures high methodological quality.”

Conversely, the GRAPPA guideline used a “hybrid method,” according to Gladman. “As a result, both GRAPPA and EULAR recommend traditional disease-modifying antirheumatic drugs as first-line medication, with EULAR specifying methotrexate as the drug of choice, while GRAPPA allows any of methotrexate, leflunomide or sulfasalazine as first-line,” she said.

Use of the GRADE methodology highlights the third key feature of the current guideline, according to M. Elaine Husni, MD, MPH, vice chair of the department of rheumatic and immunologic diseases and director of the Arthritis Center at the Cleveland Clinic: patient involvement. “We have become increasingly aware that patient-reported outcomes are very important to the disease process, in diagnosis as well as in treatment progression and disease activity,” she said. “We are gaining more evidence that patient-reported outcomes can be helpful in treating the patient as a whole.”

If there is another point in the methodology Singh believes is critical, it is the treat-to-target strategy. “This is recommended in all people with PsA at any time,” he said. “We are looking to reach low disease activity or disease remission This can impact not only quality of life and functioning today, but also social positioning, including activity at home, at work as well as prevention of long-term disability or deformity.”

The treat-to-target strategy is critical to delay irreversible joint damage, according to Husni, who is a member of the Healio Rheumatology Peer Perspective Board. “This has really been highlighted in rheumatoid arthritis, but there have been fewer studies using this management strategy in PsA,” she said. “It is an important concept.”

Strong, Yet Still Conditional, Recommendations

The guideline covers the gamut of PsA interventions, from oral, small molecule medications such as DMARDs; to TNF inhibitors, IL-12, IL-23, and IL-17 inhibitors; to abatacept (Orencia, Bristol-Myers Squibb) and tofacitinib (Xeljanz, Pfizer); but also nonpharmacotherapeutic approaches such as smoking cessation, weight loss and exercise, along with interventions to treat symptoms, such as NSAIDs, glucocorticoids and local glucocorticoid injections.

One recommendation pertains to adults with active disease and concomitant active inflammatory bowel disease despite treatment with a small molecule. For this group, a switch to a TNF inhibitor monoclonal antibody biologic over a TNF inhibitor soluble receptor biologic such as etanercept (Enbrel, Amgen) is strongly recommended. The evidence is of moderate quality, demonstrating that TNF inhibitor monoclonal antibody biologics are effective in IBD, but indirect evidence shows a TNF inhibitor biologic soluble receptor biologic is not effective for the treatment of IBD.

“If a patient has active PsA and also IBD, we would prefer a monoclonal antibody over a soluble receptor TNF; we might as well use something that kills two birds with one stone,” Husni said. “These guidelines have incorporated how important comorbidities may tweak treatment choices.”

“One of the key features of the guideline is the recommendation, based on efficacy and safety data, to use a TNF inhibitor prior to methotrexate in the systemic pharmacologic treatment paradigm,” Philip J. Mease, MD, clinical professor at the Swedish Medical Center/Providence St. Joseph Health and the University of Washington School of Medicine, said in an interview. “This is different from the ACR rheumatoid arthritis treatment guidelines and the EULAR PsA treatment recommendations, wherein methotrexate use is recommended before TNF inhibitor.”

Another strong recommendation from the ACR/NPF guideline is to switch to a TNF monoclonal antibody biologic over an IL-17 biologic, which carries a moderate level of evidence demonstrating the superiority of TNF inhibition for IBD. Similarly, a switch to an IL-12/23 biologic is recommended over a switch to IL-17 because of its superiority in IBD. For small molecule- and biologic-naive adults with active disease and frequent serious infections, initiation with a small molecule is preferred over TNF inhibition. The recommendation is strong, with moderate evidence, largely based on the black box warning of serious infection risk with TNF inhibitor biologics.

Generally speaking, some of the factors that may be taken into consideration when deciding on a particular therapy for a particular patient include disease severity, comorbidities, economic factors and patient preference. “In the GRAPPA treatment recommendations for peripheral arthritis, for example, TNF inhibitors and methotrexate are on a similar footing to be chosen as first systemic agent; for enthesitis and spondylitis, TNF inhibitors and other biologics are advised but not methotrexate,” Mease said.

Considering the nonpharmacologic treatments, in adult patients with active PsA, smoking cessation is strongly recommended over no smoking cessation. “Smoking status is not only a risk factor for more severe disease, but also a risk factor for failure of medications,” Singh explained.

The authors offered conditional recommendations for low-impact exercise — such as tai chi, yoga or swimming — over high-impact exercise. Physical therapy, occupational therapy, weight loss in the case of patients who are overweight or obese, massage therapy and acupuncture also received conditional recommendations.

“We wanted to be as clear as possible, which is why we don’t just recommend exercise, but specify what kind of exercise patients should engage in,” Singh said.

Other nonpharmacologic recommendations indicate that patients should initiate biologic treatment and then receive inactivated vaccines, as opposed to delaying treatment until after inactivated vaccines have been administered. Delaying the initiation of a biologic if the patient requires a live, attenuated vaccine is also recommended.

“These are often overlooked management options that can make good changes for patients,” Husni said.

Guideline Limits

Singh was careful to acknowledge the limitations of the guideline, and provided insight on the process. “When you keep adding PICO question after PICO question, a document like this can become too big very quickly,” he said. “We tried to be comprehensive but realize we are unable to cover every scenario of pharmacological and nonpharmacological management.”

With that in mind, Singh acknowledged some of the other limitations of the document. For example, there are limited options for patients unable to receive a biologic; the document does not cover PsA in pregnancy; there was little consideration of cost-effectiveness, since high-quality data on cost-effectiveness are lacking; and little consideration of comorbidities such as fibromyalgia, hepatitis, depression and anxiety, malignancy and cardiovascular disease.

“The ACR/NPF guideline states that it gave lower consideration to the cost of the therapy compared to the quality of evidence for benefit,” Duarte-Garcia told Healio Rheumatology. “The ACR/NPF guideline also provided several examples where the initial use of a DMARD could be considered instead of a biologic, such as mild disease.”

For Duarte-Garcia, all clinicians must understand the differences between guideline documents available for reference. “The ACR/NPF psoriatic arthritis guideline is the first published with a focus in North American patients and health system,” he said. “The prior EULAR and GRAPPA guidelines covered treatments both for dermatologic and musculoskeletal manifestations of the disease or had a European focus.”

Overall, though, clinicians such as Duarte-Garcia are happy to have a document to reference for complicated patient cases. “Research has shown that in the context of low certainty of evidence, clinicians prefer to have recommendations that assist in decision-making,” he continued. “With the rapid expansion of treatments that target psoriatic arthritis and the lack of head-to-head comparisons among the drugs, the ACR/NPF PsA guideline provides a summary and recommendation about how to approach treatment decisions.”

That said, Husni stressed that the guideline is not a “complete recipe or a cookbook,” but, rather, an opportunity to provide reasons for the choice of therapy when discussing options with a patient. “It is sometimes difficult to prioritize which medication to use first,” she said. “A guideline like this makes it helpful to select an appropriate therapy for a particular patient.”

Collaborative Process

Discussing the collaboration between ACR and NPF experts, along with patients, Singh noted that if the voting panel failed to reach the 70% level of agreement during an initial vote, there was more discussion, followed by another vote. The authors also provided a written explanation for all conditional recommendations.

Thinking of the big picture, Gladman suggested there were two reasons for the collaboration. “One, it allowed dermatologists from the NPF to participate in the ACR process,” she said. “Second, it allowed the ACR the luxury of not having to deal with the guideline for the psoriasis aspect of psoriatic arthritis, as NPF together with the American Academy of Dermatology were working on guidelines for psoriasis. It also meant that the dermatologists did not have to worry about guidelines for arthritis.”

Both Mease and Singh described the collaboration between the two participating organizations as “natural,” with Singh stressing that the full membership bodies of both the ACR and NPF had access to and participation in the process. “We were able to combine our resources,” Singh said. “And it was important for us that we were not developing these guidelines in isolation. By doing it this way, we wanted to make sure the communities of clinicians who treat this disease are in alignment.”

“The ACR brings a wealth of experience and expertise in guideline development, as well as resources,” Mease added. “The NPF has had longstanding focus on PsA in its mission, since PsA is such a key condition in many psoriasis patients. Many of the professional members of the guidelines task force volunteer for both organizations.”

The scope of the questions that were included in the final document were largely the result of patient involvement, according to Singh. “They had a voice,” he said. “They highlighted how they thought about clinical aspects, medication and other issues.”

This process underscored patient values with regard to the whole treatment paradigm. However, Husni stressed that there is still a disconnect between what patients feel is important and what happens in clinical trials. “This disconnect falls into many levels,” she said. “Patients and researchers often feel differently about how to prioritize disease manifestations, about treatments and about prognosis. One of the most important considerations is that patients and physicians often come into the treatment process with different goals and more transparency on this will help optimize patient care.”

Husni suggested that physicians are focused on preventing disease progression and disability, whereas patients are thinking about their daily lives. “Often, patients come in and just don’t want to feel so tired,” she said.

Keeping fundamental goals in mind is useful in eliminating the disparities between physician and patient goals, according to Husni. “At the end of the day, both sides want the same thing,” she said. “We just need to make sure the agendas are aligned.”

Impact on Clinical Practice

There is some discussion as to how, and when, these guidelines will impact clinical practice. “In the United States, rheumatologists have been able to use anti-TNF agents as first-line drugs for some time, and many have done so,” Gladman said. “Therefore, it is not clear whether the guideline will change practice or just validate current practice for many rheumatologists.”

The impact on clinical practice may not be observed immediately, but ultimately will be, according to Mease. “It takes time for guideline recommendations to be transmitted to clinicians, patients and payors and for their implications to sink in,” he said. “If a clinician and/or patient is inclined to utilize a TNF inhibitor more quickly in the treatment paradigm, with the goal of achieving better disease control, function and quality of life, as well as inhibiting progressive structural damage, then this guideline may be used in the discussion between clinician and patient and between the clinician’s office and payors.”

Duarte-Garcia once again focused on non-clinical matters. “Data from claims show that in the U.S., the majority of the patients that begin treatment for PsA start with a DMARD, particularly methotrexate,” he said. “This recommendation could have profound impact in practice and cost of PsA treatment.”

“There may be pushback by payors who have traditionally required stepping through methotrexate treatment before being willing to approve the use of a TNF inhibitor, but the presence of the ACR/NPF guidelines may make appeals a bit easier,” Mease added. “Also, knowing that this is an official guideline may ease some patients’ concerns about initiating a biologic treatment.”

In the Pipeline

When a guideline like this emerges, it is only natural for experts to wonder when the next iteration will occur, and what it might contain. Mease and colleagues conducted the recent Study of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects with Psoriatic Arthritis trial (SEAM-PsA) trial, which showed that 50% of patients reached ACR20 on methotrexate monotherapy, compared with 60% of those in the etanercept arm. In addition, 23% of the patients on methotrexate achieved minimal disease activity, compared with 36% for etanercept.

“Patients, clinicians, payors and other stakeholders will have to take these findings into consideration when starting treatment in a patient with PsA,” Duarte-Garcia said.

“This result reinforces the ACR/NPF guidelines, but it was also noted that methotrexate performed very well in both musculoskeletal and skin endpoints, reinforcing its use in resource-challenged situations,” Mease said.

The authors of the recommendations worked to cover therapies that were approved within a month prior to publication, along with others that were on the approval track, according to Singh. “We knew that some of these therapies would be approved and some would not,” he said.

“In addition to secukinumab (Cosentyx, Novartis) and ixekizumab (Taltz, Lilly), both IL-17A inhibitors approved for PsA, bimekizumab (UCB), which inhibits two members of the IL-17 family, IL-17A and IL-17F, is entering phase 3 development after showing excellent response in all key domains of PsA and no new safety signals in comparison to the IL-17A profile,” Mease said.

He added that several IL-23 drugs, including guselkumab (Tremfya, Janssen), which is approved for psoriasis, risankizumab (Abbvie), and tildrakizumab (Sun Pharma), are in development. “The first two of these have demonstrated good efficacy in key clinical domains tested in phase 2 trials in PsA; results from the tildrakizumab phase 2 trial are not yet reported,” he said.

JAK inhibitors other than tofacitinib are also being tested in PsA; Mease believes they will join tofacitinib as highly effective oral agents. “The JAK inhibitors include filgotinib (Galapagos NV), baricitinib (Olumiant, Lilly), and upadacitinib (Abbvie), as well as several that are only designated by letters and numbers at this time,” he said. “There may be subtle differences in efficacy and safety of these compounds based partly on their particular JAK selectivity.”

Gladman added that TYK2 inhibitors are currently under investigation as well. “Moreover, we have multiple biosimilars to various anti-TNF agents, which will hopefully reduce the cost of these drugs,” she said.

While many of the drugs in the pipeline are in the “drawing board” stage, according to Mease, the variability in their anticipated mechanism of action bodes well for the field. “The good news about having a number of different medicines with different mechanisms of action is that we have increasing likelihood of being able to find a medicine that works well for an individual patient to achieve remission or low disease activity,” he said. “If this effect wears off, there will be multiple options to jump to.”

The era of personalized therapy has also reached the PsA arena, according to Mease. “Although we are not there yet with individual profiling of a person’s autoimmune disease, recent studies are showing us the way there,” he said. “We anticipate much better pinpointing of which mechanism of action will be best for the patient in front of us.”

Another piece of the puzzle lies in identifying patients at risk for PsA. “This is true particularly since the skin manifestations of psoriasis typically precede the onset of PsA,” Mease said. “These individuals are an appropriate population to assess for this risk with biomarker profiling.”

As for a cure? Mease remains uncertain. “This is still a ways away, but again, it is possible that in the more distant future methods to achieve this goal will be discovered,” he said.

Looking ahead to that next iteration of the recommendations, Singh noted it will likely come when drugs with new mechanisms of action begin to emerge and gain approval. He stressed that the document should be flexible with regard to disease- or drug-specific components. “If a drug is launched only for axial disease, for example, then we might update that section and leave the section on peripheral disease alone,” he said. “If a drug only gets launched for IBD, we will only have to update that portion, and so on.”

Perhaps the most critical reason to keep an eye on the pipeline is because there is still a proportion of patients who fail to respond to treatments in the current armamentarium, according to Husni. “There is always a need to look at, and for new medications,” she said, adding another facet to Singh’s comment on disease states. “Many of these newer medications, like the IL-17 inhibitors, have been great at clearing the skin, but are not as effective in the joints. We are still looking for those new agents that will help achieve skin and joint clearance.”

In the end, for Singh, there is a clear roadmap to the next phase of PsA treatment, including more head-to-head trials; studies on enthesitis, axial disease and arthritis mutilans; randomized trials of non-pharmacological interventions; investigation of combination treatments and vaccinations; robust registry data for comorbidities; and further evaluation of the role of NSAIDs and glucocorticoids in managing PsA.

“Several new therapies have been approved in the last 10 years, with many more coming, but clinicians lacked any guidance on several important issues,” he said. “In short, that is why we put this document forth. We hope it benefits both clinicians and patients.” – by Rob Volansky

• References:
• Mease PJ, et al. RMD Open. 2018;doi:10.1136/rmdopen-2017-000606.
• Singh JA, et al. Arthritis Care Res. 2018;doi:10.1002/acr.23789.
• Singh JA, et al. Arthritis Rheumatol. 2018;doi:10.1002/art.40726.
• Singh JA, et al. J Psoriasis Psoriatic Arthritis. 2018;doi:10.1177/2475530318812244.

• For more information:
• Ali A. Duarte-Garcia, MD, can be reached at 200 1st St. SW, Rochester, MN 55902; email: blahnik.emily@mayo.edu.
• Dafna D. Gladman, MD, can be reached at 399 Bathurst St. 1E-410B, Toronto, Ontario, Canada M5T 2S8; email: dafna.gladman@utoronto.ca.
• M. Elaine Husni, MD, MPH, can be reached at 500 Euclid Ave. A50, Cleveland, OH 44195; email: husnie@ccf.org.
• Philip J. Mease, MD, can be reached 601 Broadway St., Suite 600, Seattle, Washington 98122; email: pmease@philipmease.com.
• Jasvinder Singh, MD, MPH, can be reached at 500 22nd St. South, Floor 2, Birmingham, AL 35233; email: jsingh@uabmc.edu.

Disclosures: Duarte-Garcia and Husni report no relevant financial disclosures. Gladman reports consulting fees, speaking fees, and/or honoraria from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer and UCB — all in amounts of less than $10,000 each. Mease reports research, consulting, and speaker associations with a number of pharmaceutical companies, including AbbVie, Amgen, Bristol Myers Squibb, Celgene, Galapagos, Genentech, Gilead, Janssen, Lilly, Novartis, Pfizer, Sun, and UCB. Singh reports consulting fees — in amounts of less than $10,000 each — from Allergan Pharmaceuticals, Bioiberica, Crealta/Horizon, Fidia Pharmaceuticals, Iroko, Medscape, Merz, Regeneron, Savient, Takeda, UBM and WebMD, as well as research support from Savient Pharmaceuticals and Takeda.