In the JournalsPerspective

Lupus heterogeneity tops list of global barriers to advancing care

Karen H. Costenbader

Disease heterogeneity and the lack of a clear disease definition are among the top barriers to advancing lupus care, according to survey data published in Lupus Science & Medicine.

“Research into the basic mechanisms of autoimmunity, and drug development and trials, are paying off in diseases as such as rheumatoid arthritis and psoriasis, with many new and effective medications coming on the market — and there is a sense that our time must be coming in lupus,” Karen H. Costenbader, MD, director of the Lupus Program at Brigham and Women’s Hospital, told Healio Rheumatology. “On the other hand, there is frustration that we are not there yet and growing recognition that there are still many barriers to having real breakthroughs for lupus care and improvement of outcomes.”

To identify barriers to drug development, and develop strategies to address those barriers, the Lupus Foundation of America, in collaboration with the Tufts University School of Medicine Center for the Study of Drug Development, founded the ALPHA Project. As part of its multiphase effort, 13 lupus experts, representing industry, academia and patients from the United States, Australia, Germany, South Korea and the United Kingdom, formed a Global Advisory Committee to guide the project.

Members of the committee conducted 17 in-depth expert interviews to characterize important barriers. The members then analyzed interview transcripts and used the information to develop a 23-question survey, which was distributed to an international group of 366 recipients, including clinicians, researchers, scientists and industry representatives. A total of 127 recipients from 20 countries responded to the survey.

 
Disease heterogeneity and the lack of a clear disease definition are among the top barriers to advancing lupus care, according to survey data.
Source: Adobe

According to survey results, the primary barriers to advancements in lupus care are disease heterogeneity and the lack of a clear disease definition, which subsequently impeded the development of clinically meaningful drug treatments, effective clinical care and patient access.

“Respondents also started to tackle the question of the definition of the lupus spectrum of related diseases, identifying 30 autoimmune conditions that may be lupus-related based on overlapping features, shared autoantibodies and pathophysiology,” Constenbader said in an interview.

Survey data also highlighted four subsequent barriers to improving outcomes in lupus, including: lack of diagnostic, predictive and prognostic biomarkers; flawed clinical trial designs; lack of access to clinicians familiar with lupus combined with limited awareness among nonexperts; lack of treatment adherence due to the patient socioeconomic status.

“Lupus is unique, with its own very complex biology and challenges that are different from those in other diseases and these need to be identified, understood, broken down and surmounted to get us where we should be — really improving diagnosis, treatment, quality of life, access to medications and treatments and survival for people with lupus,” Costenbader said. “With global alignment, we now can work to create a path forward to develop solutions.” – by Jason Laday

Disclosure: Costenbader reports consulting honoraria from AstraZeneca. Please see the full study for additional authors’ disclosures.

Karen H. Costenbader

Disease heterogeneity and the lack of a clear disease definition are among the top barriers to advancing lupus care, according to survey data published in Lupus Science & Medicine.

“Research into the basic mechanisms of autoimmunity, and drug development and trials, are paying off in diseases as such as rheumatoid arthritis and psoriasis, with many new and effective medications coming on the market — and there is a sense that our time must be coming in lupus,” Karen H. Costenbader, MD, director of the Lupus Program at Brigham and Women’s Hospital, told Healio Rheumatology. “On the other hand, there is frustration that we are not there yet and growing recognition that there are still many barriers to having real breakthroughs for lupus care and improvement of outcomes.”

To identify barriers to drug development, and develop strategies to address those barriers, the Lupus Foundation of America, in collaboration with the Tufts University School of Medicine Center for the Study of Drug Development, founded the ALPHA Project. As part of its multiphase effort, 13 lupus experts, representing industry, academia and patients from the United States, Australia, Germany, South Korea and the United Kingdom, formed a Global Advisory Committee to guide the project.

Members of the committee conducted 17 in-depth expert interviews to characterize important barriers. The members then analyzed interview transcripts and used the information to develop a 23-question survey, which was distributed to an international group of 366 recipients, including clinicians, researchers, scientists and industry representatives. A total of 127 recipients from 20 countries responded to the survey.

 
Disease heterogeneity and the lack of a clear disease definition are among the top barriers to advancing lupus care, according to survey data.
Source: Adobe

According to survey results, the primary barriers to advancements in lupus care are disease heterogeneity and the lack of a clear disease definition, which subsequently impeded the development of clinically meaningful drug treatments, effective clinical care and patient access.

“Respondents also started to tackle the question of the definition of the lupus spectrum of related diseases, identifying 30 autoimmune conditions that may be lupus-related based on overlapping features, shared autoantibodies and pathophysiology,” Constenbader said in an interview.

Survey data also highlighted four subsequent barriers to improving outcomes in lupus, including: lack of diagnostic, predictive and prognostic biomarkers; flawed clinical trial designs; lack of access to clinicians familiar with lupus combined with limited awareness among nonexperts; lack of treatment adherence due to the patient socioeconomic status.

“Lupus is unique, with its own very complex biology and challenges that are different from those in other diseases and these need to be identified, understood, broken down and surmounted to get us where we should be — really improving diagnosis, treatment, quality of life, access to medications and treatments and survival for people with lupus,” Costenbader said. “With global alignment, we now can work to create a path forward to develop solutions.” – by Jason Laday

Disclosure: Costenbader reports consulting honoraria from AstraZeneca. Please see the full study for additional authors’ disclosures.

    Perspective
    David A. McLain

    David A. McLain

    Why has it been so hard to develop new therapeutic agents in lupus? After all, lupus is the leading cause of death among chronic inflammatory diseases in young women aged 15-24 years, with higher mortality rates than diabetes mellitus or HIV. Despite these statistics, overall funding for lupus research has been on the decline, particularly through the NIH. Over the past 60 years, there has been only one new agent developed and approved by the FDA, belimumab (Benlysta, GlaxoSmithKline).

    In 2018, a review in Lupus Science & Medicine stated that three new agents for lupus had been stopped in phase 3, representing $1 billion in development costs. This survey study wanted to explore the reasons that stakeholders in all the various lupus groups – academic including basic science research, private practice, clinical research, industry, patient advocacy, patients, regulators, pediatric and adult rheumatology, dermatology and immunology – felt were holding back progress in lupus. Of the 366 survey candidates, only 127 (35%) returned the survey.

    I think their results parallel our experience in practice. Lupus is a very heterogeneous disease with patients falling into many different groups – renal lupus, cutaneous lupus, APS, CNS lupus, ‘rhupus’ syndrome and others. The survey identified obstacles to progress in lupus. Foremost was the lack of diagnostic, predictive, or prognostic biomarkers and the lack of a biomarker to predict a response to therapy in clinical trials. They also found that trials in lupus were flawed.

    The BILAG is often used in trials, and I personally find the BILAG has too many “moving parts” and requires training, a computer, and 50 minutes to complete. This is not practical for clinical practice even though Magellan Rx Management is asking for it as one measure to approve continuation of belimumab. It is sensitive to changes in the disease over time but it should be noted that sleep disorders, depression and fibromyalgia may confound the lupus disease activity when using the BILAG.

    In 2015 study published in Arthritis Research & Therapy, Mikdashi noted that “With the exception of the mucocutaneous, hematologic, and renal domains, a significant relationship of the individual BILAG component scoring with Medical Outcome Study Short Form SF20+ measured global assessment of patient well-being and health status has been demonstrated”.

    The survey respondents also felt there was a shortage of lupus professionals in the community and a lack of awareness of lupus by community physicians. They also felt the socioeconomics played a role in patients not receiving effective management. Finally, they identified a lack of treatment adherence, which is a problem in many disease states including gout and osteoporosis in rheumatology.

    There is a phase 2 planned with a meeting of the stakeholders, in which, hopefully, progress will be made in finding useful disease activity markers and indices that will lead to new therapies for this difficult, multifaceted disease.

    • David A. McLain, MD, FACP, FACR
    • Executive director, Alabama Society for the Rheumatic Diseases
      Symposium director, Congress of Clinical Rheumatology

    Disclosures: McLain reports no relevant financial disclosures.