‘Tsunami of effort’ brings biologics to the forefront in giant cell arteritis, PMR
Reducing glucocorticoid use in the treatment of giant cell arteritis and polymyalgia rheumatica — due to the steroid’s host of related toxicities and adverse effects — has long been a goal for rheumatologists.
Now, recent FDA approvals and, critically, a steady pipeline of biologics may finally help rheumatologists turn that wish into reality.
“When we talk about GCA and PMR, we have to acknowledge that steroids have worked really well,” Leonard H. Calabrese, DO, professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and RJ Fasenmyer chair of clinical immunology at the Cleveland Clinic, told Healio Rheumatology. “But there has been a tsunami of effort to use biologic therapies to bring glucocorticoid doses down across all of our diseases. This is particularly important in GCA and PMR.”
Since the 2023 FDA approval of the interleukin (IL)-6 inhibitor sarilumab (Kevzara, Sanofi Regeneron) for PMR, several medications have been barreling toward approval along the GCA/PMR pipeline. Another IL-6 inhibitor, tocilizumab (Actemra, Genentech) is approved in GCA and moving through trials in PMR. IL-17 inhibitors like secukinumab (Cosentyx, Novartis) and Janus kinase (JAK) inhibitors such as upadacitinib (Rinvoq, Abbvie) are also being evaluated in both conditions.
Looking deeper into the pipeline, studies investigating the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) moderator abatacept (Orencia, Bristol Myers Squibb), IL-12/23 inhibition, and B-cell depletion with rituximab (Rituxan, Biogen and Genentech) have all been investigated, albeit with varying results.
“This is all very exciting news for our patients and for us as rheumatologists,” Tanaz Kermani, MD, founder and director of the multidisciplinary vasculitis program at the University of California Los Angeles, said in an interview. “For decades, we have relied on glucocorticoids as the mainstay to treat these conditions. Both conditions are relapsing despite treatment with glucocorticoids, often resulting in increased doses and prolonged exposure.”
According to Calabrese, who is also chief medical editor for Healio Rheumatology, this patient population is “particularly vulnerable” due to advanced age and the frequent presence of comorbid conditions.
“GCA is the most common form of vasculitis,” he said. “PMR is the second most common inflammatory rheumatic disease. Getting regimens that are steroid-sparing or -substituting that we can use to treat with less morbidity, and equal or better effectiveness, is really important. That is the impetus for this research.”
As experts learn more about how different medication classes perform in GCA and PMR, there are two critical questions that should be considered as research moves forward.
One pertains to how these diseases are classified.
“We have discussed the concept of a unified diagnosis under the term GCA-PMR spectrum disease (GPSD),” Bhaskar Dasgupta, MD, head of rheumatology and clinical director of research and audit at Southend University Hospital, in the United Kingdom, said in an interview. “There are major similarities between the two diseases. They are both driven by IL-6 and seem to be driven by IL-17, as well. We should be lumping them together.”
The other consideration is whether biologics will ultimately be used as first line therapy and replace glucocorticoids altogether.
“In GCA, we have a very good understanding of the pathophysiology of the disease and, as a result, we are now evaluating efficacy of medications that target different pathways,” Kermani said. “Although glucocorticoid-sparing is an important goal, we also need to understand if these biologic therapies impact other important outcomes like vascular damage, for example, and aneurysm formation in GCA. It is also important to ensure these medications improve the quality of life of our patients.”
A closer look at the research landscape, along with an examination of disease classification and stratification, may provide insight for rheumatologists tasked with managing these complex conditions.
‘Room for Improvement’ With IL-6
The key data set that led to the approval of sarilumab for PMR came in the form of the SAPHYR trial, conducted by Spiera and colleagues, who presented findings throughout 2022 and eventually published their conclusions in the New England Journal of Medicine in October 2023. In that trial, researchers analyzed 118 patients with relapsing disease during glucocorticoid taper. Primary endpoint results at 52 weeks showed sustained remission in 28% of 60 patients in the sarilumab group, compared with 10% of 58 patients in the placebo group, for a difference of 18 percentage points (P = .02).
Moreover, patients in the sarilumab group received a cumulative glucocorticoid dose of 777 mg over 52 weeks, compared with 2,044 mg for patients in the placebo arm (P < .001).
“Sarilumab takes away the CRP and tamped down the inflammatory response,” Dasgupta, who was a researcher on the paper, told Healio Rheumatology.
Moreover, there were benefits to sarilumab beyond quantifiable clinical effectiveness.
“What was particularly satisfying was that we noted that patients in the sarilumab group showed improvement in patient-reported outcomes as assessed by the EQ-5D and SF-36,” Dasgupta said. “Both physical and mental PRO scores improved.”
It is important to note that IL-6 inhibition is not approved for every patient with PMR, according to Sebastian E. Sattui, MD, MS, director of the Vasculitis Center at the University of Pittsburgh Medical Center, and assistant professor of medicine in the division of rheumatology and clinical immunology at the University of Pittsburgh.
“It is currently only approved for patients with refractory or relapsing PMR,” he said.
This underscores a crucial gap in PMR management and research, according to Kenneth J. Warrington, MD, director of the vasculitis clinic, consultant in the division of rheumatology, and John F. Finn MN Arthritis Foundation professor of medicine at the Mayo Clinic College of Medicine and Science.
“We still need much more data for patients with newly diagnosed PMR,” he said.
Meanwhile, although comorbidities associated with glucocorticoids are always top of mind for rheumatologists, Sattui stressed that sarilumab is also not without its complications.
“Rheumatologists are very familiar on the potential risks of IL-6 inhibition — including cytopenias and increased risk for gastrointestinal perforation,” he said. “Benefits are more specific to the condition being treated, which in this case is the evidence of disease control, improvement in quality of life, and glucocorticoid-sparing effect.”
Warrington said he is encouraged by the efficacy demonstrated in the sarilumab trials, but he called on researchers to ask deeper questions.
“The rate of patients in sustained remission is certainly higher than seen in placebo, but it is still relatively low,” he said. “There is room for improvement and work to be done.”
That work will also include deeper investigation of IL-6 inhibition in GCA. According to Dasgupta, further efforts to classify GCA and PMR on the same spectrum will lead to more studies and, consequently, benefits for patients with both conditions.
“Circulating IL-6 has all sorts of neurological consequences,” he said. “If you inhibit IL-6, you may expect improvement in mental quality of life.”
As these studies continue, experts are keeping an eye on IL-17 and its role as a therapeutic target in GCA/PMR, as well.
‘Really Exciting’ Data in IL-17
“Since GCA and PMR are thought to be part of a spectrum of disease, there are studies suggesting that there is increased Th17 in the peripheral blood and synovial fluid of patients with PMR,” Kermani said. “Therefore, there is a rationale to study IL-17 inhibition in both PMR and GCA.”
In a 2023 paper published in The Lancet Rheumatology, Venhoff and colleagues conducted a phase 2, proof-of-concept study that assessed the use of secukinumab with a steroid taper in GCA. The analysis included 27 patients treated with the IL-17 inhibitor secukinumab and 25 patients who received placebo. Results showed that 70% of patients in the treatment arm, and 20% of those in the placebo arm, achieved sustained remission through week 28.
“Not only did we see a nice separation between the treatment arm and the placebo arm in this study, but there are also reassuring data on the safety of this class of drugs,” Warrington said. “The number one thing we look for is infection rates, which seemed to be acceptable in this secukinumab trial.”
Perhaps the most important implication of the IL-17 data pertains to the commonality between the two conditions, according to Dasgupta.
“We tend to talk about GCA and PMR separately, but there are many, many patients who have both,” he said. “In fact, many patients who go into remission in one condition will relapse with the other.”
It is for this reason that the emerging data on IL-17 inhibitors is “really exciting,” Dasgupta added.
“If we can show that secukinumab works in PMR as well as GCA, it will be major evidence of a commonality between these two conditions,” he said.
Additionally, if the move to combine GCA and PMR into a spectrum of diseases is successful, the commonality could expand the therapeutic armamentarium by allowing physicians to use agents like IL-17 inhibitors in both conditions.
“It will give us yet another potential molecule for patients with relapsing disease and severe disease,” Dasgupta said.
However, more research is needed to get to that point, according to Kermani.
“In PMR, we are only recently understanding the pathophysiology and the inflammatory pathways,” she said. “IL-17 inhibition with secukinumab was efficacious in a phase 2 study in GCA. Phase 3 studies evaluating this biologic in GCA and PMR are planned.”
That research should emerge around the same time as data investigating JAK inhibition in patients on the GCA/PMR continuum.
‘Great Interest’ in JAK Inhibition
In the SELECT-GCA trial, which was presented as a late-breaking abstract at the EULAR 2024 Congress in Vienna, Blockmans and colleagues compared the efficacy and safety of the JAK inhibitor upadacitinib with placebo in combination with a glucocorticoid taper regimen, in a cohort of 428 patients with GCA. Primary endpoint results showed that upadacitinib bested placebo in terms of sustained remission at week 52 — 46% vs. 29% (P = .0019).
Moreover, upadacitinib improved over placebo in nine out of 11 secondary endpoints, including complete remission between weeks 12 and 52 (37% vs 16%, P < .0001). The researchers observed no new safety signals for upadacitinib.
“The data for upadacitinib is very exciting,” Dasgupta said. “SELECT-GCA was a particularly useful trial because the studies that have been done in the past with JAK inhibitors have caused some worry that these medications will be less safe in patients older than 70 years, because of cardiovascular events or risk for cancer. This study did not pick up any new safety signals in that sense.”
Although Sattui also acknowledged the risks in the JAK-inhibitor class, he argued that these concerns should not prevent ongoing research.
“Given that both of these medications are currently being used for the treatment of other conditions, side effect profiles are well known by rheumatologists,” Sattui said.
Based on SELECT-GCA, as well as other trials of JAK inhibitors and preclinical models, Warrington stated he believes JAK inhibition has a bright future in this disease.
“We may see approval of this class of drugs for GCA,” he said.
However, Warrington is slightly less optimistic regarding JAK inhibitors in PMR, at least based on current data.
“The studies in PMR are smaller and still in earlier phases,” he said.
In a 2023 paper published in PLoS Medicine, Ma and colleagues compared the efficacy and safety of tofacitinib with placebo in patients with newly diagnosed PMR. Although the two groups were comparable in terms of efficacy at 12 and 24 weeks, reductions in PMR-AS <10, PMR-AS, CRP and ESR were observed, with no serious adverse events reported. The researchers additionally noted that JAK signaling was involved in the pathogenesis of PMR.
According to Kermani, this finding that JAK signaling is involved in the PMR disease process may be cause for optimism.
“JAK inhibitors may target both Th1 and Th17 arms of the inflammatory process,” she said. “There is a great interest in evaluating JAK inhibition in PMR and large vessel vasculitides, including GCA.”
JAK inhibitors are not the only medications that are familiar to rheumatologists being evaluated in GCA/PMR. As other mechanisms of action move through the pipeline, clinicians may soon have a variety of options to manage these patients.
Further Exploration ‘Not Clear’
“Abatacept is of interest in GCA, given a phase 2 study that showed possible efficacy,” Kermani said. “A phase 3 trial is currently underway.”
Meanwhile, and despite this research program, the picture remains unclear for abatacept in PMR. In a 2023 paper published in The Lancet Rheumatology, Saraux and colleagues conducted a proof-of-concept, randomized, placebo-controlled, parallel-group trial in 34 patients with PMR. Although half of the patients in the active therapy arm achieved the primary endpoint of low disease activity without glucocorticoids, the researchers offered an ambivalent conclusion, writing that the findings are “not strong enough” to justify larger studies of abatacept in early PMR.
“Based on the current status of the studies of these biologic agents, it seems abatacept for GCA might possibly emerge as an option in the near future,” Sattui said. “However, further plans for exploration of abatacept in PMR are not clear.”
Regarding other agents, given the attention B-cell depletion has received with the advent of chimeric antigen receptor T-cell therapy across the rheumatology field, there is some hope that rituximab may have a place in GCA/PMR management.
However, further research is necessary, according to Sattui.
“A small proof-of-concept trial showed that rituximab was effective for the treatment of patients with PMR,” he said. “However, there is limited data to support any efficacy for the treatment of patients with GCA. With the emergence of other biologic agents for the treatment of PMR, the role of rituximab or further studies remains unclear.”
Research may help clarify the picture, according to Kermani.
“Rituximab is of interest in PMR, with preliminary studies showing promise, although the role of B cells in PMR is poorly understood,” she said.
Looking deeper into the pipeline, Sattui highlighted studies of the GM-CSF-R inhibitor mavrilimumab (Kiniksa), and the IL-23 inhibitor guselkumab (Tremfya, Janssen). However, both Sattui and Kermani noted that results for IL-23 inhibition has been mixed.
“IL-12/23 inhibition was studied in GCA, but with conflicting results, and a recent phase 2 study of an IL-23 inhibitor in GCA did not meet its endpoints,” Kermani said.
As experts attempt to find a signal in the noise of these data, rheumatologists are left to continue working with these patients as best they can. Understanding the similarities and differences between the two conditions may help minimize diagnostic delays and relieve patients of their steroid regimens sooner.
The ‘Art of Medicine’
According to Calabrese, there is still a strong element of the “art of medicine” present when evaluating patients for GCA or PMR. He noted that both diagnoses are complicated by myriad mimics among older individuals, particularly in PMR where there is no high efficiency diagnostic test and no substitute for performing a careful history assessment and physical examination.
“When a patient with possible GCA initially presents, the first issue at hand is whether they represent a medical emergency, which would be suggested by the presence of visual symptoms or other signs of head and neck ischemia,” Calabrese said. “Making certain assumptions when encountering such, as in a patient referred for new onset headache and elevated acute phase reactants, can be perilous.
“One assumption is that we logically think that anyone who has experienced significant, even transient visual loss would seek medical help can lead to diagnostic error, as documented clinical experience informs us that this scenario is actually not uncommon,” he added. “All patients with suspected GCA need a careful review for ocular symptoms, for detecting their presence mandates prompt therapy as the diagnostic process accelerates.”
Patients who present with possible PMR represent another diagnostic challenge, according to Calabrese, who stressed that, in this setting, the practitioners must always address two questions.
“One is whether the diagnosis is correct, particularly with reference to conditions that must be ruled out, such as occult infection or malignancy, and the other question is whether the patient has GCA as well,” he said.
For these reasons, Calabrese argued that patients diagnosed by non-rheumatologists should complete “at least a confirmatory consultation” with a rheumatologist.
“This consultation would be for both a diagnosis and planning a course of therapy that will be maximally effective and the least toxic,” he added.
The good news is that wider recognition and explorations of these challenges ultimately may make the diagnosis more accurate and accessible in rheumatology, as well as inform other practitioners who may see such patients initially, Calabrese said.
The next consideration pertains to whether biologics can be introduced before steroids in newly diagnosed patients.
“At this time, I do not believe all patients with newly diagnosed PMR need to start with an agent like sarilumab,” Kermani said. “However, patients with difficulty tapering glucocorticoids due to relapses should definitely be offered this medication. I would also discuss it with patients where I am concerned about the potential side effects of prolonged exposure to glucocorticoids, regardless of whether they have newly diagnosed or relapsing disease.”
Moving forward, Sattui called for research and treatment paradigms that complement one another, especially in light of concerns over disease modification and vascular complications.
“GCA is a heterogeneous disease, and the emerging number of agents will allow us to better understand benefits of treatment in patients,” he said. “This is true in particular regard to our ability to prevent vascular complications or modify disease outcomes, given that there are some concerns regarding our ability to truly intervene in both using our current therapeutics. Disease phenotyping could improve the care of these patients, especially if all those treatments are not equal.”
This movement toward precision medicine could broaden the horizon for GCA/PMR management overall, according to Dasgupta.
“We are getting more ambitious with our goals,” he said. “We are able to use biologic medications safely for a longer period than we could for glucocorticoids.”
However, increased use of biologics in the GCA/PMR setting will require ongoing education of both patients and providers, according to Sattui.
“Dissemination of information to our non-specialty colleagues is crucial, particularly regarding the signs and symptoms to assess in these patients, as well as the urgency for referral, especially in patients with GCA,” he said. “In the case of PMR, recent recommendations still encourage the referral of most patients at least for an initial evaluation, but this should be emphasized in specific groups, such as those at high risk for steroid toxicity or a lack of response to standard doses of steroids. Although non-specialty providers will not be prescribing steroid-sparing agents, it is important for them to be aware of the growing therapeutic tools, and yet another benefit of access to specialty care and evaluation.”
- References:
- Blockmans D, et al. LBA0001. Presented at: EULAR 2024 Congress; June 12-15, 2024, Vienna, Austria.
- Ma X, et al. PLoS Med. 2023;doi:10.1371/journal.pmed.1004249.
- Saraux A, et al. Lancet Rheumatol. 2023;doi:10.1016/S2665-9913(23)00246-1.
- Spiera RF, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2303452.
- Venhoff N, et al. Lancet Rheumatol. 2023;doi:10.1016/S2665-9913(23)00101-7.
- For more information:
- Leonard H. Calabrese, DO, can be reached at 3500 Euclid Ave. Cleveland OH, 44195; email: calabrl@ccf.org.
- Bhaskar Dasgupta, MD, can be reached at Nether Mayne, Basildon, Essex, SS16 5NL; email: bhaskar.dasgupta@aru.ac.uk.
- Sebastian E. Sattui, MD, MS, can be reached at BST S723, 3500 Terrace St., Pittsburgh, PA 15261; email: ssattui@pitt.edu.
- Tanaz A. Kermani, MD, can be reached at 2020 Santa Monica Blvd. Suite 540, Santa Monica, CA 90404, email: tkermani@mednet.ucla.edu.
- Kenneth J. Warrington, MD, can be reached at 200 First St. SW, Rochester, MN 55905; email: warrington.kenneth@mayo.edu.
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