Tackling treatment refractory disease a top priority in rheumatology: experts

Unmet needs for new therapies and trial designs, particularly for patients with treatment-refractory disease, remain a top priority in rheumatology, international experts agree.

Coming together at the 21st annual Advances in Targeted Therapies (ATT) meeting, more than 100 leading scientists and clinical researchers identified and prioritised unmet research needs in rheumatology, focusing on rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpA), systemic lupus erythematosus (SLE) and other systemic autoimmune rheumatic diseases.

They highlighted several overarching themes: the need to innovate clinical trial design with emphasis on studying patients with refractory disease, the development of trials that take into account disease endotypes and patients with overlapping inflammatory diseases, and the need to better understand the prevalence and incidence of inflammatory diseases in developing regions of the world.

In a report of the findings published in the Annals of the Rheumatic Diseases, the authors led by Dr Kevin Winthrop from the Oregon Health Sciences University, US, said there was broad agreement that management of patients with RA who are refractory to available treatments is arguably the greatest unmet need in RA.

They suggested there is a need to better define treatment refractory states both phenotypically and molecularly, and that the definitions of molecular subgroups could eventually lead to a personalised approach to treatment.

They also flagged the need to focus on refractory patients in both the study of novel targeted therapies and in the study of existing therapies in novel combinations or sequences.

“Importantly, patients who have received multiple biologics/small molecules should not be excluded from clinical trials since they have the greatest unmet need.

“Novel targeted therapies should be studied in refractory patients, as should novel combinations or sequences of existing therapies, similar to the way oncologists use checkpoint inhibitors,” the authors wrote.

Similarly for PsA the experts said a ‘major unmet need’ is management of the therapy refractory patients who have ‘tried everything’.

They noted that patients with PsA are often included in trials only if they have been naïve to previous conventional synthetic Disease Modifying anti-Rheumatic Drugs (csDMARDs) or biologic DMARDs (bDMARDs).

“More attention needs to be paid to patients who are more ‘difficult-to-treat’ across all conditions, as well as those who have multiple complications or co-morbidities or those who have failed other csDMARDs or bDMARDs.”

More emphasis on disease subtypes

Stressing that there has not been sufficient emphasis on trial designs that concentrate on well-defined disease subtypes, the authors said:

“Many diseases have multiple subtypes (eg axial and peripheral PsA or limited/diffuse systemic sclerosis with multiple serological subtypes) and trial designs which mix those subtypes could obscure the success of treatments in specific subgroups. Likewise, trial designs which are able to dissect (or include) overlapping diseases are also needed.”

With regard to PsA, the authors noted the homogeneity imposed by clinical trial design may exclude important patient subgroups.

“For example, the great majority of patients have polyarticular involvement (entry criteria: ³3-5 inflamed joints) with few studies examining oligoarticular disease (<5 inflamed joints); thus, the common oligoarticular PsA represents an unmet need in PsA trials.”

“Phase IIIB or IV trials which specifically enrich the patient population for the domain or subtype in question are needed,” the authors said.

AxSpA, SLE and other systemic autoimmune rheumatic diseases

The experts identified a variety of unmet needs for axSpA, most importantly the need to better understand the role of the microbiome in potential disease pathogenesis and potential therapy. Also understanding disease pathology specifically with regard to why interleukin-23 (IL-23) inhibition does not improve the disease.

According to the authors, recent failures in clinical trials of SLE demonstrate weaknesses in current methodology and opportunities for improvement in multiple areas. They suggest reducing heterogeneity of clinical trial participants, developing new outcome disease activity measures, standardising serological testing and conducting organ-specific trials. Also, to consider alternative trial designs including adaptive trials and withdrawal trials.

The experts discussing other systemic autoimmune rheumatic diseases highlighted the unmet needs primarily within systemic sclerosis, and similar to the other disease areas, identified the issue of improving clinical trials of utmost importance.

“Recent and current clinical trials have failed to demonstrate efficacy for a variety of agents in the treatment of this disease, although results suggest that some disease manifestations may actually be improved by certain agents.”

They suggest improving trial design by reducing heterogeneity in disease endotypes and the use of organ-specific outcome measures.

Noting that a dearth of predictable biomarkers also makes it difficult to target drug trials to those with the greatest potential for benefit from specific therapeutic interventions, the experts highlighted the need to identify predictive biomarkers, and also suggested the inclusion of patient-reported outcome of specific manifestations (eg calcinosis) for clinical trials to allay patients’ concerns about entering trials.

Lastly, the experts agreed that more emphasis needs to be placed on understanding unmet needs in developing regions of the world, such as Africa, multiple areas in Asia and Central and South America.

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