RA Treatment Response Influenced by HLA-DRB1 Haplotype

Janis C. Kelly

April 28, 2015

An analysis of rheumatoid arthritis (RA) genetics raises the possibility that HLA-DRB1 haplotype analysis might become useful in RA clinical decision-making. The data suggest that some HLA-DRB1 haplotype variants associated with RA susceptibility were also associated with worse radiographic damage and mortality, but also better response to TNF inhibitor treatment.

"It was generally assumed that genetic factors predisposing to RA susceptibility are likely to be different to those predisposing to RA severity and treatment response. We show that this is not the case for HLA-DRB1. Many other genetic susceptibility markers could be predictors of RA outcome as well," lead author Sebastien Viatte, MD, PhD, told Medscape Medical News.

In the April 28 issue of JAMA, Dr Viatte from the Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, United Kingdom, and colleagues report that patients with valine at position 11 of HLA-DRB1 were at particular risk for worse outcomes. Interestingly, this change is outside the "shared epitope" region at positions 70 through 74. Taken together, the amino acids at positions 11, 71, and 74 within HLA-DRB1 define 16 haplotypes that appear to predict both RA susceptibility and response to tumor necrosis factor (TNF) inhibitor drugs.

Multiple Cohorts Studied

The researchers asked whether specific HLA-DRB1 haplotypes associated with RA susceptibility are also associated with severity (as measured by radiological imaging), death, and response to TNF inhibitor drugs. They used data from the Norfolk Arthritis Register (NOAR; 1691 patients and 2811 radiographs) as a discovery cohort and data from the Early Rheumatoid Arthritis Study (421 patients and 3758 radiographs) as an independent replication cohort for radiography studies. They used additional data from the NOAR cohort (2432 patients) for mortality studies and from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort (1846 patients enrolled at initiation of TNF inhibitor) for studies of treatment response. All patients were from the United Kingdom, and all were white.

The researchers found that patients with RA who had valine at position 11 of HLA-DRB1 were 75% more likely to have radiologically apparent joint damage than those with other haplotypes ([odds ratio], 1.75 [95% (confidence interval [CI]), 1.52-2.01], P = 8.7E-15). By year 5, 74% of those who were homozygous for this haplotype had joint erosions of the hands and feet compared with 61% of those who were heterozygous and 48% of those who did not carry this gene change.

The effect of valine at position 11 of HLA-DRB1 was independent of the shared epitope, whereas serine at position 11 was associated with decreased radiographic progression. "Valine at this position represents what we believe is the strongest single genetic association with radiographic damage identified to date," the authors write.

All-cause mortality was also higher in those with valine at position 11, with a hazard ratio of 1.16 (95 CI, 1.03 - 1.31; P = .01). Mortality rates for carriers of the VKA haplotype (valine at position 11, lysine at position 71, alanine at position 74) was numerically higher than for noncarriers but did not reach statistical significance (2.5% vs 1.9% per year; HR, 1.15 [95% CI, 0.99 - 1.33]; P = .08).

Although 120 different haplotypes were theoretically possible, given the possible amino acids at the three positions 11, 71, and 74, only 16 haplotypes were actually found in the NOAR patients.

RA disease severity correlated with the hierarchy in the 16-haplotype model. The authors comment, "The classification of 16 haplotypes appears to supersede the previous shared epitope model, which classified patients with RA into 2 groups of patients positive for the shared epitope or negative for it."

The VKA haplotype was also associated with a good European League Against Rheumatism (EULAR) response. Response to TNF inhibitors was about 23% greater for patients with the VKA haplotype, and every copy of the VKA haplotype increased the likelihood of moving from the EULAR categories of no response to moderate response or from moderate response to good response.

"One unexpected finding was the association with treatment response," Dr Viatte said. "Genetic markers of high disease severity seem to predict a better (and not worse) response to anti-TNF treatment. This could indicate that anti-TNF drugs target specifically a disease pathway in which HLA-DRB1 plays an important role." EULAR moderate or good response to TNF inhibitor therapy was 86% in homozygote carriers of valine at position 11 in HLA-DR1, 81% in heterozygote carriers, and 78% in noncarriers (odds ratio, 1.14; 95% CI, 1.01-1.30; P = 0.04).

The strength of the 16-haplotype model in predicting both RA progression and response to TNF inhibitor treatment might have implications for clinical trial design. Dr Viatte said, "The shared epitope has been superseded by the 16-haplotype models. However, the 16-haplotype model is more complex than the simple shared epitope model. Depending on the research question, either of the two models could be used. Importantly, the effect of HLA-DRB1 position 11, outside the shared epitope, should be considered in future studies."

Dr Viatte added that the results of this study will not change clinical practice but show that patients can be stratified into 16 different risk categories at diagnosis, according to their genetic predispositions. "The clinical usefulness of such stratification in the care of patients with RA will need to be compared with current practice in a clinical trial," he said.

Cautious Support

In an accompanying editorial, David T. Felson, MD, MPH, from the Boston University School of Medicine, and Lars Klareskog, MD, PhD, from the Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden, write that the results of the study are important because they may add to the ability to predict RA outcomes and help optimize individual treatment strategies. In addition, the data add to the understanding of the molecular mechanisms underlying the disease process and strongly implicate HLA-related immune events in RA disease course and mortality, as well as onset.

However, the editorial writers caution about the methodology used to assess TNF inhibitor response. They note that adjustment for baseline variables, as was done in this analysis, may yield paradoxical findings because regression to the mean might affect the outcome measure.

Patients were required to have high Disease Activity Scores (DAS) to be included in the cohort used to judge TNF inhibitor response. "However, because measurement of this parameter is associated with noise, a spuriously high baseline DAS can regress to its mean (often lower) value at follow-up measurement and some of that apparent decrease in DAS may not reflect actual improvement in underlying disease activity, but rather variation in measurement," Dr Felson and Dr Klareskog write. "Any factors associated with high levels of disease activity at baseline (in this case the VKA haplotype that encodes the peptide-binding region of HLA) would be spuriously found to be associated with DAS response."

Dr Felson and Dr Klareskog further note that the unadjusted DAS data "suggest a very minor association between VKA haplotype and DAS response (ie, no alleles, mean decline in DAS of 2.43; 2 alleles, a mean decline in DAS of 2.58, a difference of 6%)."

Veena Taneja, PhD, an immunologist at the Mayo Clinic in Rochester, Minnesota, agreed with the editorialists: "Even if corroborative analyses suggest an association of this haplotype with response, the effect on treatment response is small and less than other major factors affecting response," she said.

Dr Taneja told Medscape Medical News that she found Dr Viatte and colleagues' data convincing, and that the findings are in line with other recently reported data on the association between valine and leucine at position and RA radiographic changes. However, she suggested, additional consideration of possible interactions between HLA-DR and HLA-DQ molecules, as a factor in disease severity, and of nongenetic factors, such as smoking, would have been helpful.

"Previous studies have associated smoking with severe disease, especially in DR4-positive patients. A correlation with smoking with the three positions 11, 71, 74 would have helped show whether interaction with smoking plays a role in severity in association with these positions. In the absence of those correlations, we are missing a piece of the puzzle," Dr Taneja said.

Haplotype analysis is now widely available, but Dr Taneja warned that the technique needs further validation before it is likely to be applicable in RA clinical treatment.

"Most importantly, we need to develop animal models to understand the interaction of HLA-DR with nongenetic factors, like smoking and the microbiome, and with other genetic factors to understand disease pathogenesis," Dr Taneja said.

The study was funded by Arthritis Research UK, by the National Institute for Health Research Manchester Musculoskeletal Biomedical Research Unit, and by the Innovative Medicines Initiative Be the Cure. Dr Viatte was supported by a research grant from the Swiss Foundation for Medical-Biological Scholarships, managed by the Swiss National Science Foundation, and financed by a donation from Novartis to the Swiss Foundation for Medical-Biological Scholarships. One coauthor reported receiving speaker's fees from AbbVie and honoraria from Pfizer. Another coauthor reported receiving personal fees from Johnson & Johnson, Pfizer, and Novartis. Another coauthor reported receiving consultancy fees and grant support from Eli-Lilly, Pfizer, and AbbVie. The other authors, the editorialists, and Dr Taneja have disclosed no relevant financial relationships.

JAMA. 2015;313:1623-1624, 1645-1656. Article abstract, Editorial extract

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