Clinical Trial Data Provides Insight into Muscle Biology, Myositis, Myopathies

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WASHINGTON, D.C.—Ongoing investigation into the disease mechanisms of inflammatory myopathies is generating needed information for the development of potential future therapeutic targets, and current data from clinical trials have shed light on myopathy concerns in different cohorts of patients. These issues were all discussed in a session titled Muscle Biology, Myositis, and Myopathies I during the 2016 ACR/ARHP Annual Meeting.

Learning in the Lab

Joseph LaConti, MD, PhD, Rheumatology Fellow, Jackson Memorial Hospital, University of Miami, opened the session describing ongoing research on the disease mechanisms underlying anti-synthetase syndrome—a syndrome encompassing a clinical spectrum of diseases including myositis, interstitial lung disease, Raynaud’s phenomenon, symmetric non-erosive arthritis, mechanic’s hand and fever.

Building on previous research that showed a correlation between disease activity and reactivity of serum anti-Jo-1 antibodies (antibodies that target histidyl-tRNA synthetase [HRS]) to the full-length recombinant HRS, Dr. LaConti described current research conducted to refine this correlation through a more detailed examination of antibody binding to subfragments of the HRS protein in order to discover new antibody epitopes associated with defined clinical manifestations.

According to Dr. LaConti, the study revealed a more precise epitope for Jo-1 antibody. Specifically, the study found an increased binding of the Jo-1 antibody to portions of the N terminus of the protein in patients with inflammatory myopathy and Jo-1 antibodies.

In addition, the study found that patients with either joint swelling or Raynaud’s disease had a higher binding affinity of Jo-1 antibodies for these more precise epitopes compared to patients who did not.

“The current study suggests that more specific epitope recognition patterns may be linked to particular clinical features of the anti-synthetase syndrome, providing the rationale for future longitudinal studies relevant to disease prognosis,” said Dr. LaConti.

Inflammatory Myopathies

Further research on the disease mechanisms behind idiopathic inflammatory myopathies was described by Ana Barrera, MD, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico, who presented data from a study looking at the role of pathogenic cytokines in disease development.

Building on previous data showing a high prevalence of anti-Ro52/TRIM21 antibodies in patients with myositis, Dr. Barrera and colleagues assessed whether there is a differential production of cytokines associated with Ro52/TRIM 21 levels in patients with recent onset idiopathic inflammatory myopathies.

The study found that Ro52/TRIM 21 levels were decreased in different cellular subsets of patients with idiopathic inflammatory myopathies, said Dr. Barrera, adding that this decrease is associated with defective ubiquitination and proinflammatory cytokine synthesis. However, the study found no correlation between Ro52/TRIM 21 levels and anti-Ro52/TRIM21 autoantibodies.

The main message for rheumatologists: “TRIM 21 is not only an autoantigen in inflammatory myopathies, but its actions as a ubiquitin ligase are involved in the pathophysiology of these disease,” Dr. Barrera said, adding that further research on the function of Ro52/TRIM 21 will have “profound implications for understanding its role in idiopathic inflammatory myopathies.”

Anti-Synthetase Syndrome

In a third presentation on ongoing research on the disease mechanisms behind anti-synthetase syndrome, Baptiste Hervier, MD, INSERM & UPMC, Paris, France, presented findings of a study that looked at the effect of two known natural cytotoxicity receptor-3 (NKp30) ligands, B7-H6 and BAT3, on disease development. Previous work showed that NK cells and the NKp30 pathway are involved in patients with active anti-synthetase syndrome, suggesting their contribution to pathogenesis of this syndrome.

The study found that the BAT3 ligand correlates with disease activity and event-free survival, which suggests, according to Dr. Hervier, that BAT3 and its receptor NKp30 may be involved in the pathogenesis of anti-synthetase syndrome.

The importance of this finding? “This innate immune pathway could further stimulate the innate immune system, promoting autoimmunity,” he said. “When confirmed, such involvement could allow for the development of new therapeutic agents for anti-synthetase syndrome.”

Clinical Questions Addressed

Whether or not the concomitant use of a statin with colchicine to treat patients with gout is associated with a risk of developing myopathy was assessed in a study by Korean investigators. The study included 674 patients with gout, 486 of whom received colchicine alone and 188 who received colchicine with a statin.

Presenting the findings of the study, Oh Chan Kwon, MD, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea, highlighted that the study found that statins can be added safely to colchcine for the treatment of gout. The study found no difference in the myopathy rate between patients who received colchicine alone or with the addition of a statin (1.4% vs 2.7%, P=0.330).

When looking at other factors that may increase the risk of developing myopathy, however, a multivariate analysis found that patients with chronic kidney disease and liver cirrhosis were associated with an increased risk. In addition, colchicine dose increment and CYP 3A4 inhibitor use were also independent risk factors for developing myopathy.

Based on these findings, Dr. Kwon emphasized that “colchicine dose increment and coadministration of CYP 3A4 inhibitors should be avoided if possible.”

‘Trim21 is not only an autoantigen in inflammatory myopathies, but its actions as a ubiquitin ligase are involved in the pathophysiology of these disease.’ —Dr. Barrera

Another clinical question addressed in a study presented by Christina Boros, MBBS, PhD, FRACP, senior lecturer, University of Adelaide Discipline of Paediatrics, was that of long-term patient-reported outcomes in adolescents and young adults diagnosed with idiopathic inflammatory myositis (IIM) in childhood.

To answer this question, 205 patients enrolled in the Juvenile Dermatomyositis Cohort and biomarker study (JDCBS: UK and Ireland) with an IIM who were aged 16 years or older were sent questionnaires for completion. Patients were asked about current disease features and damage, medication use and side effects, as well as education and employment opportunities. In addition, cross sectional and longitudinal data in the JDCBS were used to find outcome predictors.

A total of 84 of the 205 patients (41%) responded to the survey. Of these respondents, the average age was 21.5 years, average disease duration was 11.8 years, and age at onset of disease was 9.2 years.

The survey found that 49 (50%) of respondents reported current myositis and 54 (65%) reported that they still needed to take immunosuppressive medication. Persistent muscle disease affected quality of life outcomes in this cohort

Other findings included career compromise reported by 14 of 50 (28%). Among 47 patients aged 18 to 24, 21 (44.7%) were employed. Overall, the study found that patients in the study were twice as likely to be unemployed as people in similar age groups in the United Kingdom general population (odds ratio of 0.456, 95% CI, 0.24–0.84; P=0.001).

According to Dr. Boros, these findings highlight a need to find “better ways of following up on these patients as disease appears to be ‘longer-lived’ than many physicians realize. However, the possibility exists that patients with ongoing active disease were more likely to respond to the questionnaires.”

“Too many patients are ‘lost’ to medical follow-up so we do not have an accurate idea of long-term medical or social problems,” she said.

Mary Beth Nierengarten is a writer, editor and journalist with over 25 years of medical communications experience.