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Combination Biologic Therapy in PsA: The beginning of a new era?

Apr 05, 2022 6:00 am

Without question, basic immunology is at the foundation of rheumatology as a discipline. Indeed, for many rheumatologists, it was the intricacies of the immune system that attracted us into the field. With each passing year, extraordinary advances in scientific methods begat tremendous gains in our understanding of the immune system. 

Based on those developments, there was an ever-increasing progress in comprehension of the immunopathophysiology of various autoimmune systemic inflammatory rheumatologic disorders. Back in the day, no matter their ultimate career goals, the majority of trainees in rheumatology rotated through basic immunology labs. In that process, we were exposed not only to the latest immunologic literature, but also to the state-of-the-art in laboratory methods, including animal models of autoimmune disease. 

A seminal event that truly transformed rheumatology was the successful introduction of targeted biologic therapies in the early 1990’s. The tremendous success observed in these initial studies, particularly with inhibitors of the key pro-inflammatory cytokine TNF, spawned not only further research into the development of additional agents with varied mechanisms of action, but also raised the goals of therapy. 

In the days when intramuscular gold injections were indeed the ‘gold standard’ of therapy, any level clinical response was considered acceptable. In the new age of TNF inhibitors, with their enhanced efficacy in several inflammatory arthritides, rheumatologists started considering more sublime targets, such as remission. In addition to development of immunomodulatory agents with varied mechanisms of action, consideration was given to alternate treatment approaches. 

With their background in immunology, many rheumatologists looked towards combination biologic therapy as a possible avenue to achieve greater clinical responses. After all, in animal models of autoimmune disease, treatment with agents possessing different mechanisms achieved some spectacular results. In myriad experimental models, combination biologic therapy achieved additive or even synergistic efficacy. Moreoever, lower than standard dosages could be utilized, offering the possibility of reduced toxicity. There was even the promise of less long-term resistance to a single mechanism of action, with potentially more longer term benefit. While all understood that induced animal models of human rheumatologic conditions were absolutely not the same as spontaneously arising human autoimmune disease, the promise of so many studies was intoxicating. 

A harsh awakening came with the data from several key studies published in the early 2000’s, both in rheumatoid arthritis (RA). Combinations of a TNF inhibitor with an IL-1 inhibitor, and a TNF inhibitor with a T-cell costimulatory inhibitor both failed. While there was no or minimal indication of any added clinical benefit, there was a definite biologic signal – more serious infections. These disappointing data cast a pall over the whole concept of combination biologic therapy for more than a decade. As one indication, product labels for most biologic agents include a specific proscription concerning use in combination. 

Excitingly, we may be entering a new era, driven by results in psoriatic arthritis (PsA) and other related diseases. In PsA, there has seemingly been a groundswell of anecdotal experience with the use of combinations of biologic therapy, particularly TNF inhibition, in conjunction with the targeted synthetic DMARD (tsDMARD) apremilast. While economically potentially challenging, most rheumatologists and dermatologists have been encouraged to try such a combination based upon expectations of safety – and the anecdotes seem to support that. Controlled studies of this combination would be of great value to practitioners. 

More definitively, there is now data on the use of 2 biologic agents in combination. At the most recent 2022 ECCO (European Crohns and Colitis Organization) meeting, data from the phase 2A VEGA study were presented. This study randomized 214 patients with moderate to severely active Ulcerative Colitis (UC) to treatment with the TNF inhibitor golimumab, the IL-23 inhibitor guselkumab, or both biologics in combination. While the data have not yet been published, suffice it to say that there is tremendous excitement generated by the data, in that there was indeed greater efficacy achieved, yet there did not appear to be concerning safety signals with the combination. Based upon these data, further studies of this combination are proceeding in UC. In addition, the AFFINITY study in PsA will assess the same combination, compared with guselkumab monotherapy, in patients with PsA. 

Finally, it would seem, the idea of combination biologic therapy may no longer be an albatross darkening the outlook for rheumatologists. It seems that the question is now not IF, but rather WHEN, and more importantly, which combinations of targeted therapies will be proven effective in PsA and in other rheumatologic diseases. 

This may be the opening of a new era in therapy!

Dr. Arthur Kavanaugh is Professor of Medicine at the University of California, San Diego School of Medicine. In addition, he is the Director of the Center for Innovative Therapy in the UCSD Division of Rheumatology, Allergy, and Immunology. Dr Kavanaugh has authored more than 500 publications. He is on the editorial board for several journals, and has served as peer reviewer for many scientific journals. Dr Kavanaugh’s main research interest is in clinical research, particularly translational aspects of rheumatology research. This has included work delineating the pathophysiology of rheumatic diseases as well as defining changes associated with novel immunomodulatory therapies. The focus of many clinical projects has been RA and psoriatic arthritis, but Dr Kavanaugh has conducted many studies in other autoimmune conditions, including SLE, ankylosing spondylitis, inflammatory bowel disease, and others. In addition, he has performed studies focusing on novel imaging methods and also clinical outcomes. 

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