Taking ‘shots on goal’: The continuing fight to bring precision medicine to rheumatology
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Patients across health care specialties have in recent years come to expect some form of individually tailored care — or precision medicine — as part of their disease management.
That is, unless that specialty is rheumatology, which has made some progress toward individualized precision medicine, but is not quite there yet, according to experts.
Source: S. Louis Bridges, MD, PhD
“We have a lot of work to do in order to bring the scientific knowledge that we have to bear on predicting the response of individual patients to individual drugs,” S. Louis Bridges, MD, PhD, physician-in-chief and chair of the department of medicine, as well as chief of the division of rheumatology, at the Hospital for Special Surgery, in New York, told Healio Rheumatology.
By far, the disease that most represents the high-water mark for the adoption of precision medicine in rheumatology at the moment is rheumatoid arthritis. In this space, rheumatologists have established biomarkers such as rheumatoid factor (RF) or cyclic citrullinated peptide (CCP) antibodies, and adopted treat-to-target goals like minimal or low disease activity.
However, even here, the full potential of precision medicine remains unrealized.
“Rheumatoid arthritis is an exceptionally complex disease with many environmental and genetic influences, as well as many factors which are poorly understood,” Bridges said. “I am optimistic, however, that we will soon be able to be more systematic in our approach to choosing medicines than we are today.”
The story is similar for conditions like systemic lupus erythematosus, according to Mary K. Crow, MD, physician-in-chief emerita and senior scientist at the Hospital for Special Surgery Research Institute.
“There is definitely more work and research that is needed in lupus,” she told Healio Rheumatology. “Particularly in SLE, there is rarely one well-defined immune abnormality that accounts for the disease, so it is unlikely that each patient will have a simple answer when it comes to selection of the right therapeutic agent.”
In psoriatic arthritis, the key step toward precision medicine has been the development of minimal disease activity (MDA) as an “effective tool” for treat-to-target paradigms, Philip J. Mease, MD, of Swedish Medical Center and the University of Washington, in Seattle, said in an interview.
“Taking a lesson from RA; we have accepted the concept that by treating to a target, we will have better outcomes in the long run,” Mease said. “Achievement of MDA is associated with a number of positive outcomes for many patients.”
However, unlike in RA, a reliable set of biomarkers to guide therapeutic decision-making remains elusive in PsA.
The same is true among spondyloarthropathies, according to Mease.
“We also do not have a specific target to treat toward in axial spondyloarthritis,” he added.
For example, although axial SpA carries a gene marker that has been associated with the condition — a polymorphism in HLA-B27 — its utility is imperfect.
“It is not as reliable as rheumatoid factor or CCP antibodies in RA,” Mease said.
The good news is that a new generation of rheumatologists have picked up the torch from the previous one — those who carried the specialty from the time of gold injections into the biologic era — to bring precision medicine into everyday practice.
Biomarkers in RA ‘Rapidly Developing’
“The field of biomarkers for predicting RA risk and response to antirheumatic treatments is rapidly developing,” Elena Myasoedova, MD, PhD, director of the Inflammatory Arthritis Subspecialty Group, and vice chair of rheumatology research, at the Mayo Clinic, in Rochester, Minnesota, told Healio Rheumatology.
A growing body of research validates this claim.
In a paper published in Arthritis Research & Therapy, Myasoedova and colleagues, used a machine learning approach to develop a prediction model for response to therapy in disease-modifying antirheumatic drug-naïve patients with RA. Eligible studies were those investigating methotrexate vs. placebo. The aim was to determine predictors of methotrexate response. The results demonstrated that baseline DAS28-ESR, the presence of anti-citrullinated protein antibodies (ACPA), and Health Assessment Questionnaire (HAQ) score were top predictors of a good response to methotrexate.
In addition, among patients with a DAS28-ESR greater than 3.2 at 12 weeks, an improvement of at least one point in DAS28-ESR from baseline predicted achieving a DAS28-ESR of 3.2 or less at 24 weeks. According to Myasoedova, these data can be used in clinical decision-making and discussions regarding the likelihood of achieving low disease activity at 24 weeks in patients who have not achieved low disease activity at 12 weeks.
“ACPA positivity was one of the top predictors of response to methotrexate in our recent study applying machine learning methods to individual patients’ data from randomized controlled trials,” she said. “From other studies, we know that response to rituximab (Rituxan, Genentech) and abatacept (Orencia, Bristol Myers Squibb) is enriched in RA patients who are seropositive, particularly if ACPA positive.”
The importance of CCP antibodies and RF in RA cannot be understated, according to Daniel G. Arkfeld, MD, DDS, a rheumatologist with Keck Medicine at the University of Southern California, in Los Angeles.
“Dual positivity — meaning seropositivity for both CCP and RF — impacts which biologics we will use in that patient,” he said. “T- or B-cell therapies are most effective for patients with dual positivity.”
However, Arkfeld stressed that choosing therapies is not the only way biomarker information can be used for precision medicine.
“If you are CCP-positive, you should not smoke, because smoking can trigger CCP proteins,” he said. “I also encourage patients to take care of their teeth, because gingivitis can also trigger these proteins.”
Arkfeld acknowledged that all these considerations can be overwhelming both for individual rheumatologists trying to manage a patient and for the research community at large. With that in mind, the other point to take from the Myasoedova study pertains to the potential impact of technology in precision medicine.
“Using AI and machine learning, we will be able to do a lot more research like this very quickly,” Arkfeld said. “The data are there — you just have to find the needle in the haystack. AI and machine learning will help us find it.”
‘Evolving and Becoming More Specific’
Understanding RA pathogenesis as a function of available therapies is another way to individualize treatments, according to Arkfeld.
“T- and B-cell therapies are upstream,” he said. “When you go downstream, you get TNF, [interleukin (IL)-6] and IL-1. This is where precision medicine would take us if we could fully study it.”
For example, Arkfeld suggested that for patients with swollen joints, aiming at downstream targets like TNF and IL-6 may prove beneficial.
“If CRP is elevated, an IL-6 inhibitor may be most effective,” he said.
However, there is considerable work to be done to fully elucidate these potential correlations.
“We are definitely evolving and becoming more specific over time, but, at least in the joints, all the therapies still seem to work about the same,” Arkfeld said. “As researchers gain understanding of subsets of CCP antibodies, we will be able to use specific therapies that will target those specific subsets more effectively.”
Another area ripe for RA precision medicine research is in the synovium, according to Bridges.
“There is quite a bit of heterogeneity in the composition of immune cells in synovial tissue of patients with RA,” he said. “Synovial tissue as a guide to predict therapeutic response is beginning to be studied quite extensively, particularly in Europe. There is some evidence to suggest that this approach might be useful, but we are still quite a long way off from being able to definitively predict the best medication for RA based on the synovial tissue infiltrates.”
That said, Myasoedova stated she views synovial tissue as a “very promising” pathway to precision medicine in RA.
“Synovial tissue is key to discovering and understanding RA disease pathotypes, extending beyond seropositivity, and diving into cellular and molecular signatures in association with patterns of disease progression and response to treatments,” she said.
In a paper published in Nature Medicine, Rivellese and colleagues identified a synovial B-cell molecular signature as a marker differentiating response to rituximab, compared with tocilizumab (Actemra, Genentech), in patients with RA who had an inadequate response to TNF inhibitors.
“This highlights the evolution in clinical trial design in rheumatology to a stratified, biopsy-driven approach,” Myasoedova said. “Standardizing this approach, as well as evaluating its reproducibility, feasibility and role in routine clinical practice, in conjunction with other biomarkers, requires further study.”
As researchers continue to push forward and answer these questions in RA, experts in other diseases — like lupus — are taking cues and advancing their own knowledge base.
Lupus Biomarkers: IL-16 Just One Part of the Equation
Although Crow acknowledged that “progress is being made” toward the goal of defining biomarkers in lupus, she outlined some of the specific challenges in the disease.
“We are seeing progress particularly based on the analysis of transcriptome data, which can identify the dominant molecular pathways activated in an individual patient,” Crow said. “However, ‘biomarker’ is a very general term that covers a lot of ground. Some of the most promising studies of candidate biomarkers involve some proteins found in the urine of patients with lupus nephritis, such as IL-16.”
In a paper published in Lupus Science & Medicine, Hayry and colleagues investigated IL-16 as a potential biomarker for lupus nephritis.
The results demonstrated that detectable IL-16 in urine can differentiate patients with biopsy-confirmed proliferative lupus nephritis from those who have less severe lupus nephritis subtypes or non-renal SLE. The researchers added that IL-16 in plasma and the kidney tissue, along with the urine, may represent a therapeutic target for this patient population.
Implicating IL-16 is just one part of the equation, according to Crow.
“Identifying the relevant immune mechanisms is not sufficient to improve outcomes,” she said. “New therapies are needed, and many are currently in development.”
Also in development are emerging data on cytokines in lupus, according to Crow.
“Some cytokines are elevated in many patients with SLE — for example, interferon-alpha — but the levels do not always associate with higher disease activity, so measurement of that cytokine has not been generally incorporated into clinical practice,” she said.
For Crow, the most promising data are those surrounding the molecular pathways that are activated in patients with SLE.
“Those pathways may best be evaluated by studies of blood transcriptomes,” she said. “Analysis of data obtained by RNA sequencing can provide important clues to the relative roles of B-cell differentiation vs. monocyte/macrophage activation, for example, information that may ultimately be helpful in guiding selection of therapeutic agents.”
Although the goal of using genetic information to guide treatments in lupus remains on the horizon, experts are diligently at work on the problem.
Wrangling Genes
According to Crow, studying the genes expressed in tissue — skin or kidney — can also be informative. However, she cautioned that those tissues are not “readily accessed” and more studies are required before the data can be applied to patient management.
In one study, published in Nature Reviews Rheumatology, Fasano and colleagues aimed to understand cellular and molecular heterogeneity in SLE.
“In particular, some genes involved in the clinical heterogeneity of SLE and some phenotype-related loci (STAT4, IRF5, PDGF genes, HAS2, ITGAM and SLC5A11) have an association with clinical features of the disease,” they wrote.
In addition, epigenetic variation — such as DNA methylation, histone modifications and microRNAs — influences gene expression and cell function, but does not modify the genome sequence, according to their findings.
“Data from both genome-wide association studies as well as information from the study of patients with a significant genetic variant in a single gene — monogenic lupus — are providing important information regarding the key mechanisms relevant to SLE pathogenesis,” Crow said. “Multiple genetic variants that are statistically associated with a diagnosis of SLE can be traced either to induction of type I interferon or response to type I interferon.”
It is important to translate this information into practical therapeutic interventions, according to Crow.
“Other genetic variants are associated with altered threshold for lymphocyte activation and may support development of autoimmunity,” she said. “Other genetic variants can impair the clearance by the immune system of immune complexes. Some genetic variants contribute to the evolution of lupus nephritis to end-stage renal disease in a number of distinct diseases, including SLE. APOL1 is a gene with variants that contribute to chronic kidney disease in SLE, diabetes, and other disorders.”
Crow additionally called on both researchers and regulators to take the next steps once the genes have been identified.
“There is the possibility that so-called genetic risk scores, including data from multiple gene variants, may prove useful in identifying those at risk for developing SLE or a more serious form of the disease,” she said.
Looking deeper into precision medicine approaches, Crow predicted that technologies like RNA sequencing and proteomic analysis will soon — as in, a matter of years — become part of regular clinical practice.
“There are studies currently active at various academic and patient care centers studying the utility of data obtained from RNA sequencing of blood samples in guiding patient management,” she said. “My guess is that such approaches will become incorporated into clinical practice in the next few years. As that kind of complex data requires very sophisticated analytic tools, it will be important to validate the utility of the guidance provided by such tools.”
As lupus researchers move to develop these tools, experts continue to wrestle with similar puzzles in PsA and axial SpA.
A PsA ‘Success Story’
According to Mease, the most critical progress toward making precision medicine a reality in PsA has involved disease activity measures.
He added that MDA — a composite measure that accounts for myriad complications of PsA, from swollen joints and enthesitis to skin, pain and HAQ score — has been accepted by both clinicians and regulatory agencies as a “good metric” for the disease.
“We routinely use it in clinical trials — it has been established as an effective tool for measuring PsA disease activity,” Mease said.
Another metric is the Disease Activity index for Psoriatic Arthritis (DAPSA) score, which, according to Mease, is comparable to MDA in terms of demonstrating disease improvement in PsA.
“The definition of these disease activity markers has been a success story in showing that there is value in trying to treat to target,” Mease said. “It is teaching clinicians and patients that there is value in tracking these metrics.”
Despite these advances, there are still “deficiencies” pertaining to biomarkers in PsA, he added.
“There is no clear antibody profile like RF or CCP, no autoantibodies that define the presence of PsA or axial SpA,” Mease said.
And although CRP and ESR have been used in the PsA setting, Mease noted the flaws with these biomarkers.
“They are often not elevated even in patients with very active disease,” he said.
Axial SpA Measures ‘Just Not as Reliable’
Although disease activity measures have been a success story in PsA, the same cannot be said for axial SpA, according to Mease, who pointed to findings published in The Annals of the Rheumatic Diseases by Molto and colleagues, who randomly assigned 160 patients to usual care or a treat-to-target strategy, and assessed them using both Axial Spondyloarthritis International Society (ASAS) and Ankylosing Spondylitis Disease Activity Score (ASDAS) criteria.
The results demonstrated that patients failed to meet the primary endpoint for ASAS disease activity but did reach thresholds based on ASDAS criteria.
“If they had used ASDAS criteria as the primary endpoint, they would have shown a statistically significant improvement for tight disease control vs. a less targeted approach,” Mease said. “But, according to the ACR guidelines, we still do not have a specific target to treat toward in axial SpA, and that is a shame.”
A further complicating factor is that many of the features measured in axial SpA, such as duration of morning stiffness or degree of “fibromyalgia-ness,” are subjective, he added.
With this in mind, it may be more useful to look at genetic markers as a pathway toward precision medicine in axial SpA. However, this, too, is flawed.
“About 85% of patients with radiographic axial SpA and 70% to 75% of those with non-radiographic axial SpA have a mutation in HLA-B27,” Mease said. “But many patients with confirmed disease are negative for HLA-B27, and you also have people who are positive for this mutation who do not have axial SpA. It is just not as reliable as CCP or RF in RA.”
Putting ‘Shots on Goal’
The dream of reliable biomarkers and genetic signatures, clearly defined disease activity measures and targeted therapeutic interventions will take some time to become a reality across the spectrum of rheumatic and autoimmune diseases. However, from Mease’s perspective, the future of precision medicine in the specialty remains bright.
“When we were training and first beginning to treat patients, older rheumatologists were happy to just keep our patients alive and active with the flawed therapies we had at the time,” Mease said. “But new rheumatologists are not satisfied with 50% or 70% improvement. They are seeing what is being done in other specialties and are looking for cures.”
That said, younger rheumatologists clearly understand the challenges that remain.
“There is a lot more work to be done to advance this field from research bench to clinical practice, including studies of precision, reproducibility, generalizability, feasibility for routine clinical utility, clinical implementation, safety, and cost-effectiveness of the use of the novel biomarkers,” Myasoedova said. “Although precision medicine approaches may not be quite ready for prime time in terms of their use in routine clinical practice, I believe that precision medicine is becoming an emerging reality in RA, and the degree of precision will increase as more research is being done in this space.”
Myasoedova additionally stressed that buy-in from all corners of the health care system, including patients, is essential.
“With any existing and emerging treatment approaches, patient participation and patient preferences are the keys to the success of treatment in general and should be the cornerstone of personalized medicine,” she said.
The same is true for lupus, according to Crow, who encouraged rheumatologists to enroll their patients in relevant research studies.
“I would like to encourage participation, in particular, in clinical trials of drugs in development but also laboratory studies that investigate the underlying mechanisms of disease,” she said. “More research is the road to gaining better therapies, additional guidance on how to use those therapies, and better outcomes for patients.”
For Crow, there is no shortage of spaces that require more research in SLE precision medicine, from blood transcriptomes to autoantibodies.
“We need more individuals characterized based on their blood transcriptomes, with the resulting data related to the patient’s genome sequencing,” she said. “I also favor studying in detail the autoantibody specificities expressed in patients, as those specificities — the self-antigens that are targeted by the autoantibodies — are likely to provide important clues as to how SLE is initiated and how flares develop.”
Thinking bigger, Mease pointed toward the groundbreaking study of chimeric antigen receptor T cells in lupus as a big leap forward and a source of hope for the future of precision medicine in rheumatology.
“We now have this glimmer of hope based on work that is being done in lupus that we can achieve long-term remission, safely, in our other diseases and conditions,” he said. “I love that people are taking these shots on goal, because they are sure to get results sooner than later.”
- References:
- Coffey CM, et al. Mayo Clin Proc. 2019;doi:10.1016/j.mayocp.2019.05.023.
- Duong SQ, et al. Arthritis Res Ther. 2022; doi:10.1186/s13075-022-02851-5.
- Fasano S, et al. Nat Rev Rheumatol. 2023;doi:10.1038/s41584-023-00948-y.
- Fava A, et al. Arthritis Rheumatol. 2022;doi:10.1002/art.42023.
- Fitzgerald O, et al. Nature Reviews. 2021;doi:10.1038/s41572-021-00293- y.
- Hayry A, et al. Lupus Sci Med. 2022;doi:10.1136/lupus-2022-000744.
- Kiely PDW. Rheumatology (Oxford). 2016;doi:10.1093/rheumatology/kev356.
- Liu J, et al. Front Med (Lausanne). 2021;doi:10.3389/fmed.2021.802934.
- Molto A, et al. Ann Rheum Dis. 2021;doi:10.1136/annrheumdis-2020-219585.
- Rivellese F, et al. Nat Med. 2022;doi:10.1038/s41591-022-01789-0.
- For more information:
- Daniel G. Arkfeld, MD, DDS, can be reached at 1520 San Pablo St., Suite 1000, Los Angeles, CA, 90033; email: meg.aldrich@med.usc.edu.
- S. Louis Bridges, MD, PhD, can be reached at 535 E. 70th St., 8th Floor, New York, NY, 10021; email: bridgesl@hss.edu.
- Mary K. Crow, MD, can be reached at 515 E. 71st St., New York, NY, 10021; email: crowm@hss.edu.
- Philip J. Mease, MD, can be reached at 601 Broadway, Seattle, WA, 98122; email: pmease@philipmease.com.
- Elena Myasoedova, MD, PhD, can be reached at 201-299 2nd Ave. SW, Rochester, MN, 55902; email: myasoedova.elena@mayo.edu.
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