Rheumatology Fellows Shine in Florida: Research Highlights from NYRIF

VBCR - August 2015, Volume 4, No 4 - Rheumatology Update
Chase Doyle

The North American Young Rheumatology Investigator Forum (NYRIF) was established to provide clinical and research fellows in the field of rheumatology with an informal mentoring environment to share their original work. At this year’s NYRIF, prior to the 2015 annual Congress of Clinical Rheumatology, 41 fellows presented studies that were evaluated by an international panel of rheumatologists in the presence of their peers.

For this article, Value-Based Care in Rheumatology interviewed Iain B. McInnes, MD, PhD, Professor of Medicine and Director of the Institute of Infection, Immunity and Inflammation at the University of Glasgow, Scotland. Head judge and moderator of this year’s NYRIF, McInnes was asked to single out 4 studies from an impressive field of research.

Anti-MDA5 Autoantibody Shows Significant Association with Interstitial Lung Disease and Poor Survival in Patients with Dermatomyositis

According to data presented by the winning study, autoantibodies can be used in the assessment of patients with dermatomyositis (DM) and clinically amyopathic dermatomyositis (CADM). Analysis showed a significant association between anti-MDA5 positivity and interstitial lung disease (ILD).

“Fifty percent of anti-MDA5–positive subjects had ILD versus 25.5% of MDA5-negative subjects,” reported the study’s lead author, Siamak Moghadam-Kia, MD, Department of Medicine, Division of Rheumatology and Clinical Rheumatology, Univer­sity of Pittsburgh, PA. “Anti-MDA5 was also strongly associated with rapidly progressive ILD (P <.001).”

As Moghadam-Kia explained, CADM is a subset of DM, presenting with the characteristic rashes of DM without objective muscle weakness. ILD is a major cause of morbidity and mortality in patients with DM, and was defined by fibrosis on imaging studies of patients within the cohorts.

For this study, Moghadam-Kia and colleagues identified 61 patients with CADM and 61 age- and gender- matched DM controls. The researchers then examined the cohorts for the presence of anti-MDA5 antibody, drawing associations from their natural history.

According to Moghadam-Kia, CADM was not associated with anti-MDA5 or ILD in patients with DM, and anti-MDA5 frequency was similar in CADM (13.1%) and DM (13.1%). Anti-MDA5 was, however, significantly associated with ILD and rapidly progressive ILD. Although the presence of the anti-MDA5 antibody was significantly associated with poor survival (P = .007), the presence of ILD or CADM was not predictive of survival.

“It looks like people who have this antibody may need more intensive assessment, investigation, and treatment,” said McInnes. “This study may help us to segregate those patients who are likely to do less well, but it won’t be this antibody on its own. It will probably be a combination of antibodies and other factors that, put together, will model those patients who are going to be in trouble.”

Mouse Model Offers Theory Behind Inflammation in Patients with Lupus

Using ultrasound-mediated damage to the blood–brain barrier, researchers in a mouse-based study showed early inflammatory changes in the blood vessels, suggesting a possible reason behind inflammation in people with lupus.

“Preliminary data suggest that antiphospholipid-type natural antibodies have a stronger association with vascular damage at the 30-day time point than other pathogenic-type antibodies,” reported Melissa Butts, DO, Rheumatology Department, Walter Reed National Military Medical Center, Bethesda, MD. “We are currently assessing if the antiphospholipid antibodies are co-localized with C3b and ferritin breaches at a specific location along the endothelium.”

According to Butts, researchers used multiple high-intensity–focused ultrasound exposures to induce cerebral vascular injury within the blood–brain barrier and then performed tissue staining to assess vascular integrity and injury. In longitudinal studies with multiple vascular injuries over time, a sustained neuroinflammation was evident 30 days after injury and correlated with neurocognitive deficits. Work is ongoing to delineate if there is a correlation between the increased vascular weakness at the 30-day time point and increased binding of the pathogenic antibodies.

“Elucidation of these pathophysiologic mechanisms may prove useful in guiding development of future targeted therapies for neuropsychiatric systemic lupus erythematosus,” Butts concluded.

“This could be one of the reasons why inflammation is initiated in people who have lupus,” said McInnes. “Now, that’s a long step because it’s a mouse study, but [Butts] did a beautiful job of describing the model and understood its strengths and its limitations. It’s a work in progress, but the work presented was impressive.”

Comparison of Clinical and Imaging Characteristics of Axial Psoriatic Arthritis and Axial Spondyloarthritis

In a study that could one day aid in earlier diagnosis of spondyloarthropathies, researchers used referral patterns to distinguish true inflammatory back pain from back pain caused by inflammatory arthritis in the broader population.

“In this comparative study between axial psoriatic arthritis (axPsA) patients and axial spondyloarthritis patients without psoriasis (axSpA), we found a higher prevalence of female gender, uveitis, and positive HLA-B27 in the axSpA group, similar to previous reports,” noted Abhijeet Danve, MD, research fellow at the University of Nebraska Medical Center, Omaha. “Our findings do not confirm the previous reports of more symmetry and more severe disease in ankylosing spondylitis compared to axPsA patients.”

Although axial involvement in psoriatic arthritis is common (between 40% and 70%), according to Danve, few studies compare low-grade sacroiliitis on x-ray or magnetic resonance imaging in patients with axPsA versus those with axSpA.

In a meta-analysis of 168 patients with SpA, 135 patients with axSpA were compared with 33 patients with axPsA. Among the patients with axSpA, there were fewer females (33% vs 57%), a higher prevalence of uveitis (29% vs 12%), a higher incidence of HLA-B27 (80% vs 50%), and higher scores indicating joint pain, swelling, and inflammation.

“The earlier we treat people who have true inflammation in the spine, the better their long-term outcomes are likely to be,” said McInnes. “Unfortunately, recent evidence shows there’s actually a delay in reaching diagnosis in such people. One of the efforts that we’re making as a community is to identify these people and get them into rheumatology services earlier.”

Genomic Sequencing of Patients with Gout Shows Relationship Between Genes and Dose Levels

Genomic sequencing of genes that metabolize and clear uric acid in patients with gout shows a relationship to xanthine oxidase inhibitor (XOI) dose. According to data presented at NYRIF, researchers identified single nucleotide variants (SNVs) associated with differences in the dose needed to lower uric acid levels.

“Though the sample size is modest,” noted lead author of the study, Kristen Cook, MD, Wheaton Franciscan Healthcare-All Saints, Mount Pleasant, WI, “we identified 2 SNVs that were associated with a higher dose of XOI and 2 SNVs with a smaller change in SUA [serum uric acid] level.”

As Cook explained, XOIs offer effective, long-term uric acid–lowering therapy. However, it is still unclear why some patients need higher or lower doses to achieve the same SUA level. For this study, researchers enrolled patients with gout who were on stable doses of an XOI and who were at their goal SUA level.

Of nearly 2 million base pairs mapped, 129 SNVs were identified. For the primary outcome, 2 SNVs were associated with a higher XOI dose: rs1346644 on XO (P = .031) and rs2470900 on AOX1 (P = .034). According to Cook, both of these SNVs are intronic and have an unknown impact on protein function. For the secondary outcome, 2 SNVs were associated with a smaller change in SUA: rs206801 on XO (P = .041) and rs1057251 on MOCOS (P = .047).

“The one exon allele detected, rs1057251, when present, predicts a smaller change in SUA with standard doses of XOI, which at least could start to explain why some patients need higher XOI doses to reach a goal SUA,” Cook concluded.

“Dr Cook tried to work out whether there were genetic variances in the uric acid metabolism pathway that meant that someone was more or less likely to change their uric acid level,” said McInnes. “It was a very elegant approach and an important step in trying to understand factors in the patient that affect target levels of uric acid.”

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