Background

Psoriatic arthritis is a chronic inflammatory condition that can occur in the general population, but most commonly arises in patients with the skin disease psoriasis. It causes swelling and pain in joints throughout the body and is seen in adults and children. Both the adult and pediatric forms are heterogeneous, presenting with diverse clinical manifestations of varying severity, including peripheral arthritis—arthritis of the large joints of the arms and legs—axial and sacroiliac arthritis, which affect joints in the spine, hips, and shoulders; bone involvement; and various forms of inflammation. Damage to structures outside the joint such as the joint capsule and entheses—sites where ligaments or tendons insert into the bones—is a distinguishing feature of psoriatic arthritis, not commonly seen in other forms of arthritis.

To advance basic, translational and clinical psoriatic arthritis research, the NIAMS held a roundtable on gaps and emerging opportunities. The meeting brought together researchers and a lay representative to discuss ways to improve understanding of the unique pathophysiology of psoriatic arthritis in adults and children, especially in early or subclinical phases. The group also explored new ways to identify therapeutic targets. Participants considered the potential of new imaging technologies (e.g., 3D MRI, ultrasound, optical) to enhance understanding of disease processes and facilitate diagnosis and treatment. Finally, attendees exchanged ideas about approaches to engage patients in research, attract new investigators into the field, and promote collaborations between rheumatologists and dermatologists conducting basic, translational and clinical research in psoriatic arthritis.

The meeting focused on the following questions:

• What are the opportunities to better understand the cellular and molecular pathogenesis of psoriatic arthritis, including the role of genetic, epigenetic, and microbiome factors?
• What can we learn from understanding the differences and similarities between psoriatic arthritis and diseases such as psoriasis, rheumatoid arthritis, and other enthesitis-related spondyloarthropathies?
• What translational studies and approaches will be most effective at identifying new drug targets for psoriatic arthritis?
• What studies will improve our ability to personalize psoriatic arthritis/psoriasis treatments?
• How can we develop improved biomarkers and imaging for psoriatic arthritis/psoriasis patients (e.g., to facilitate diagnosis, treatment stratification, assessment of early response)?
• What strategies are available to examine mechanisms underlying the relationship of metabolic and cardiovascular comorbidities to psoriatic arthritis/psoriasis?
• How can we engage patients in clinical research and trials?
• What are the best strategies for recruitment and retention of new investigators in the field of psoriatic arthritis/psoriasis research?
• How can rheumatologists and dermatologists collaborate to accelerate basic, translational, and clinical research/trials in psoriatic arthritis/psoriasis and to improve patient care?

These questions and written responses collected by the participants from their research communities in advance of the meeting served as the basis for the discussion. Although not all responses submitted in advance were discussed at the roundtable, NIAMS leadership and the appropriate program staff read each comment. The NIAMS greatly appreciates the community’s input.

Understanding the Pathogenesis of Psoriatic Arthritis

Genetics, Epigenetics and Environment

Participants agreed that the pathogenesis of psoriatic arthritis, including the role of genetic, epigenetic, and environmental factors, is not well understood. Scientists have identified a few new genes that are uniquely associated with the condition, and studies of those genes are expected to shed light on disease mechanisms. To date, few genetic studies have been conducted in children with psoriatic arthritis, but such investigations could provide unique insights into genetic susceptibility. Genomic research has revealed that most of the genetic variants associated with psoriatic arthritis are located in non-coding regions. Exploration of non-coding genetic changes may uncover epigenetic mechanisms—modifications of the genome that can affect gene activity without altering the underlying DNA sequence—in psoriatic arthritis. Exploration of the effects of environmental factors on the disease are in the early stages. For example, researchers are interested in the role of the human microbiome—the combined genetic material of the microorganisms in the human body— in psoriatic arthritis, and findings from some studies have revealed an imbalance in the gut microbiome of patients with psoriatic arthritis compared to those without the disease. Additional research could shed light on how microbes in the gut and skin affect psoriatic disease.

Differences and similarities between psoriatic arthritis and related conditions

Scientists hope that comparing the molecular mechanisms that underlie psoriatic arthritis to those operating in related conditions, particularly psoriasis, will reveal pathogenic mechanisms that are unique to psoriatic arthritis, and those that are shared with other diseases. Information about disease-specific pathways may help to reduce time to diagnosis, as well as rates of misdiagnosis, and help to identify new therapeutic targets. Identification of shared pathways may suggest drugs that could be repurposed to treat psoriatic arthritis.

Psoriatic arthritis and psoriasis share genomic signatures, and genome-wide association studies have uncovered substantial overlap in susceptibility genes for the two conditions. However, even when the same gene is implicated in the two conditions, the specific genetic variants, or SNPs, within the gene might differ. Consequently, it is possible that the effects on gene expression and function are different in the two conditions. A number of drugs currently used to treat psoriasis have also been tested for psoriatic arthritis, and results show that those therapies are more effective in treating psoriasis than psoriatic arthritis. Most patients with psoriasis show sustained response to TNF inhibitors, while only about half of psoriatic arthritis patients show such a response. New drugs that target the cytokines IL-23 and IL-17 have led to dramatic clearing of psoriatic skin lesions, but appear to be less effective in mitigating psoriatic arthritis. Researchers are interested in understanding how the mechanisms involved in response to these therapies differ in psoriatic arthritis and psoriasis.

Advancing Translational Research

Research Resources

Only a few mouse models of psoriatic arthritis have been created. They reproduce some features of the disease, but they do not fully reflect psoriatic arthritis as described in humans. Recently developed technologies for gene editing (e.g., CRISPR) provide new opportunities to generate mouse models that may more closely approximate the psoriatic arthritis susceptibility mutations found in humans. Such models would be useful for studies of pathogenesis, as well as for translational research to assess potential therapies.

Identifying the molecular pathways that underlie the pathogenesis of psoriatic arthritis is particularly challenging because the disease can affect many parts of the body (e.g., skin, bone marrow, gut, entheses, and joints) and multiple cell types (e.g., immune cells, osteoclasts, synovial fibroblasts, and skin cells). Therefore, research using patient samples (e.g., synovial tissue, synovial fluid, peripheral blood, skin) represents an important opportunity for advancing translational research. The NIH, along with several partners, is currently pursuing a novel strategy for translational research in lupus and rheumatoid arthritis through the Accelerating Medicines Partnership (AMP) that could serve as a model for research in psoriatic arthritis. As part of the AMP, new technologies for studying single cells such as RNA-seq, single cell RNA-seq, and ATAC-seq are being developed that might also prove useful for the study of psoriatic disease. While collecting blood samples is straightforward, obtaining synovial fluid can be more difficult. Recently, through the AMP, researchers in the United States have begun performing synovial biopsies to obtain tissue to study rheumatoid arthritis, and this approach could be applied to studies of psoriatic arthritis. Another possible source of tissue is synovectomy, a procedure to remove synovial tissue, but accessing samples would require close coordination with surgeons who perform the procedure.

Psoriatic Arthritis as a Model for Understanding Preclinical Autoimmunity

About 25 percent of individuals with psoriasis will go on to develop psoriatic arthritis. Therefore, psoriasis represents a major risk factor for psoriatic arthritis. Following cohorts of psoriasis patients could allow identification of genetic and environmental risk factors that predispose to psoriatic arthritis and enable researchers to identify biomarkers for early detection. For example, some small studies suggest that many psoriasis patients without clinical arthritis show subclinical signs of joint inflammation. By identifying risk factors and biomarkers of disease progression, clinical scientists and physicians may eventually be able to intervene early with extant or emerging therapies to delay or prevent psoriatic arthritis. Cohort studies may also help to improve understanding of the mechanisms involved in the transition from preclinical to clinical disease, and provide samples and data to test hypotheses regarding how the condition arises.

Fostering Clinical Research and New Therapies

Personalized Treatments for Psoriatic Arthritis

Psoriatic arthritis patients vary with regards to the number and type of joints affected, the timing of disease onset, and response to therapy. The disease can be classified into different clinical subtypes (e.g. skin psoriasis, poor nail formation, inflammation of an entire digit, no rheumatic factor, and radiographic evidence of new bone formation near a joint). Moreover, it is possible that psoriatic arthritis represents not one disease, but rather several distinct but related conditions that require different treatment and management. Studies of cells and tissues in psoriatic arthritis may enable treatment that is based on molecular, rather than clinical, phenotypes.

Participants noted the emerging opportunity to use “big data” approaches that employ bioinformatics and computational biology to better understand risk factors for and pathways involved in disease. A few institutions have collected longitudinal data and samples from individuals with psoriatic disease, which could provide large quantities of data for such analyses. Several organizations are working to incorporate data from electronic medical records into research, although the need to ensure data privacy and security, and resolve technical issues related to data sharing, have been challenges. The American College of Rheumatology has developed the Rheumatology Informatics System for Effectiveness (RISE) Registry, which leverages electronic health records to facilitate rheumatology research. Finally, to facilitate precision medicine—the tailoring of treatments to a particular patient’s biology, environment, and lifestyle—efforts are underway to assemble large research cohorts and collect substantial amounts of data. For example, the NIH All of Us initiative seeks to enroll at least a million people to improve treatment for a variety of diseases.

Researchers have begun to incorporate information about patient preferences into clinical research through the use of patient-reported outcomes tools. Such patient-centered approaches will help to ensure that treatments address the symptoms that have the greatest impact on patients’ quality of life.

Biomarkers to Facilitate Diagnosis and Treatment

A major challenge in treating psoriatic arthritis is the difficulty of detecting patients with early or subtle disease. The search for highly sensitive imaging and biomarkers of early disease activity is of considerable interest to diagnose and, ideally, to assess treatment response in patients with psoriatic arthritis. Biomarkers that can identify early psoriatic arthritis would also allow for screening of psoriasis patients. A number of potential biomarkers for psoriatic arthritis are being investigated including soluble markers (e.g., matrix metalloproteases, C-reactive protein), cell populations (e.g., relevant T cell subsets, osteoclast precursors), and tissue resident markers in the joints (e.g., RANKL) or skin. Participants noted that biomarkers might vary between different cell types such as immune cells, osteoclasts, synovial fibroblasts, and skin cells. Thus, it may be necessary to define specific biomarkers for each cell and tissue type. Investigators also are exploring the utility of various imaging modalities (e.g., Doppler ultrasound, MRI, PET-CT) for assessing psoriatic arthritis and enabling prevention strategies. A number of candidate radiographic biomarkers (e.g., bone marrow edema) are being studied. In addition, researchers currently are searching for biomarkers that correlate with imaging changes in joints.

Concurrent Health Conditions in Individuals with Psoriatic Arthritis

Patients with psoriatic arthritis are at increased risk of a number of other health conditions, often referred to as comorbidities, such as uveitis, gastrointestinal disorders, obesity and metabolic syndrome, depression and anxiety, and cardiovascular disease (CVD). A good deal of research has focused on CVD risk in psoriasis and psoriatic arthritis patients. In psoriasis, researchers are studying CVD risk factors and biomarkers, such as cholesterol levels, inflammation, and increased blood clotting. They also are looking at the relationship between CVD and alterations in immune function and metabolism. Metabolic changes in patients with psoriasis appear to be influenced by nutrition and the microbiome, and scientists are exploring whether this also is the case in psoriatic arthritis. Other researchers are examining metabolic abnormalities, including diabetes in patients with psoriatic arthritis. Alterations in adipose (fat) tissues also have been linked to psoriatic conditions. There is an opportunity for research to understand whether these changes contribute to the other health problems commonly seen in patients with psoriasis and psoriatic arthritis.

Engaging Patients in Clinical Research and Trials

The roundtable participants emphasized the potential of social media and related technologies to provide patients with opportunities to participate in research. For example, the National Psoriasis Foundation has developed Citizen Pscientist, an online psoriatic research network that allows participants to take surveys and use data to generate hypotheses while also interacting with a community of individuals that share their condition.

Recruiting patients for clinical trials remains an important goal. One potential barrier has been the reluctance of patients to participate in studies that would require them to discontinue current medications. New clinical trial designs that allow patients to stay on therapy could increase the number of volunteers for clinical trials. The NIH, through a Recruitment Innovation Center funded under the Clinical and Translational Science Awards program, is developing new approaches to improve clinical trial recruitment. Patient advocacy organizations, such as the National Psoriasis Foundation, play a key role in connecting researchers with individuals interested in participating in clinical studies, for example by helping patients in locations that lack academic medical centers find clinical trials.

Facilitating Recruitment and Retention of New Investigators

The group discussed the need for mentors to help attract new researchers into the field. The participants suggested that a meeting to connect early-career dermatologists and rheumatologists interested in psoriatic arthritis research with mentors would be helpful. A number of organizations have developed programs to help new investigators navigate the grant-writing process. For example, the Orthopaedic Research Society sponsors grant writing workshops for junior investigators hoping to obtain federal grants such as the NIH R01, and this model could be useful for organizations focused on psoriatic arthritis. Participants noted that a number of existing organizations support new psoriatic arthritis researchers in a variety of ways. The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) encourages participation by new investigators in its meetings and other activities. The American College of Rheumatology has launched an effort to match early stage rheumatology researchers with mentors in their field. The Pediatric Dermatology Research Alliance has also focused on mentoring and bringing early career scientists to their meetings.

Funding opportunities sponsored by the NIH or by professional and voluntary organizations play a critical role in supporting early stage researchers. Participants noted that NIH training grants help prepare individuals for research careers. In addition, the NIH’s K08 and K23 clinically oriented career development awards provide junior investigators with clinical degrees with an opportunity to apply for research funding. In the areas of psoriasis and psoriatic arthritis, the National Psoriasis Foundation provides a variety of funding opportunities for new investigators. The Rheumatology Research Foundation sponsors awards programs for early stage researchers studying rheumatic diseases.

In addition to funding research and mentoring individual researchers, it might also be useful for established investigators to develop materials that would help junior investigators learn about existing research resources and expectations for research in the field. In the past, various professional societies did this by developing white papers to propagate research standards in particular areas. These resources provided new investigators with information about established norms and standards for research in a particular disease area.

The group also noted that team science offers an excellent opportunity to attract and train new investigators. Established investigators can help by identifying missing expertise within their team and recruiting new investigators with relevant skills. Researchers could also encourage individuals from other fields with an interest in clinically oriented research to consider working on psoriatic arthritis. Bringing in researchers from other disciplines (e.g., immunology, molecular biology, epigenetics, computational biology) would result in a wider range of perspectives and approaches to addressing research questions.

Facilitating Collaboration between Disciplines to Accelerate Research and Improve Patient Care

Participants noted that because the fields of rheumatology and dermatology have substantial clinical overlap (e.g., scleroderma, cutaneous lupus, psoriatic arthritis), many collaborative efforts already exist. Some academic health centers have established combined clinics that allow individuals in these specialties to work together on basic and clinical research. In addition, in recent years, many large medical centers have developed programs for dual training in rheumatology and dermatology. Individuals with this training are actively looking for research opportunities that draw on both specialties. The advent of electronic medical records and biobanks has led to new opportunities for collaboration. In many cases, analysis of the data and samples from such sources requires the expertise of both dermatologists and rheumatologists. In addition, the group emphasized the importance of fostering greater communication with other medical specialties and disciplines where researchers are looking at pathways implicated in psoriatic arthritis. Groups such as the Federation of Clinical Immunology Societies (FOCIS) could serve as a forum to foster interdisciplinary approaches to immune-based diseases.

Participants

ADAMOPOULOS, Iannis M.Phil., D.Phil., University of California, Davis
COLBERT, Robert, M.D., Ph.D., National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health
COOPER, Kevin, M.D., Case Western Reserve University (co-chair)
GELFAND, Joel, M.D., MSCE, University of Pennsylvania
GUDJONSSON, Johann, M.D., Ph.D., University of Michigan
LIAO, Wilson, M.D., University of California, San Francisco
OLIVER, Alyce, M.D., Ph.D., Augusta University
RITCHLIN, Christopher, M.D., M.P.H., University of Rochester (co-chair)
SCHER, Jose, M.D., New York University
SEIDEN, Richard, J.D., Foley & Lardner LLP
WARD, Nicole, Ph.D., Case Western Reserve University

NIAMS

BURROWS, Stephanie, Ph.D.
CARTER, Robert H., M.D.
CAUGHMAN, Cindy, M.P.H.
CIBOTTI, Ricardo, Ph.D.
KATZ, Stephen I., M.D., Ph.D. (co-chair)
LINDE, Anita M., M.P.P.
REUSS, Reaya, M.S.
SERRATE-SZTEIN, Susana A., M.D.
WITTER, James, M.D., Ph.D.