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6 Articles in this Series
Introduction
Antibody Biomarker Predicts Abatacept Efficacy
Early Infection May Lead to Ankylosing Spondylitis
Gene Testing May Predict RA Treatment Response
JIA Patients at Higher Risk for Type 1 Diabetes
Nanotechnology Could Improve Rheumatoid Arthritis Treatments
Women With Lupus at Risk for Cervical Cancer

Gene Testing May Predict RA Treatment Response

Interview with James Oliver

Doctors can choose from a variety of drugs to treat rheumatoid arthritis (RA). But figuring out which drug will work best for a patient can be difficult—patients may have to switch from one therapy to another to see whether their symptoms improve.

New insights into genetic backgrounds of rheumatoid arthritis patients may help guide treatment decisions.

A laundry list of tumor necrosis factor inhibitors (TNFi) are entering the drug market, and while TNFi agents are helping treat patients unresponsive to conventional options like methotrexate, some 30% of patients are not improving with these drugs, either.1-3 Even for those who do improve, developing resistance or adverse reactions to TNFi drugs can also be problems.4

Like cancer, RA is a progressive disease, one in which genetics have influence, and now, researchers are taking a cue from cancer treatment approaches. They are trying to understand why TNFi agents fail for some patients and work for others, and the answer may lay in a very specific genetic marker—HS1,2A—a polymorphism associated with several autoimmune chronic inflammatory conditions.

A recent study assessed hundreds of patients with RA to see how the HS1,2A enhancer polymorphism affected disease activity and response to TNFi therapy. The study looked at specific genotypes of HS1,2A and found a particular allele associated with increased disease activity and reduced likelihood of achieving disease remission after 3 months of TNFi therapy.5

A Common Thread in Failed RA Therapy

Three-hundred and twenty-nine patients took part in the research, all of which were in the earliest phases of their rheumatoid arthritis (ERA). They were evaluated at every visit, measured according to ACR/EULAR criteria to assess for clinical improvements.6

The patients were genotyped for the HS1,2A enhancer polymorphism,7 split into 2 groups – allele*2 being of interest because it has a binding site for NF-κB, a protein complex known to transactivate responsive genes associated with the inflammatory phenotype.8 Twenty-eight percent of the patients had allele*2 and 10.9% had allele*1, figures comparable to past research.9

Not only did patients with the allele*2 show more active disease at baseline, they also were less likely to get a good EULAR-response and disease remission after 3 months of therapy, compared to their respective counterparts:

  • Good-EULAR response: 35.9% vs 56.4%, OR (95% CIs): 0.43 (0.24 – 0.78)
  • EULAR-remission: 14.1% vs 34.6%, OR (95% CIs): 0.31 (0.14 – 0.67)

Six months into therapy, these patients were also more likely to require TNF-blockers added to their regimen (26.1% vs 12.2%, p = 0.01).

Researchers also wanted to assess whether the HS1,2A polymorphism could be related to a different NF-kB pathway activation on B cells. Using Ingenuity Pathway Analysis (IPA) software, the researchers were able to investigate the biological networks related to the polymorphism based on the 2 distinct genotypes.

They found specific genes functionally related to the polymorphism – or “focus genes” – which appeared to map to 3 networks related to cell death and survival, immunological disease, and cell-to-cell signaling and interaction, the authors reported.

“Moreover, the 2/2 genotype was linked to the top canonical pathway ‘NF-kB signaling’ with TNF-alpha, CD40 and CD40 ligand as top upstream regulators,” the authors reported. Such findings further explain the potential significance of the HS1,2A polymorphism in assessing and even predicting a patient’s disease severity and response to intervention.

Incorporating more precision-based strategies into the RA treatment setting is not a far-fetched idea, according to researchers, especially given the fact gene expression biomarkers already have been used to great success in guiding optimized treatment strategies in the cancer field.

Developing a Blood-Based Biomarker

Other research also presented at this year’s EULAR meeting suggests blood-based genetic testing could be useful tool for analyzing treatment response to pharmacological treatment, specifically TNFi’s.

In another study presented at this year’s EULAR meeting, researchers analyzed 44 blood samples taken from RA patients being treated with adalimumab (Humira; AbbVie Inc.) – 31 showing positive response to the drug and 12 not showing response.10

Gene level paired-analysis indicated significant changes for patients who responded well to adalimumab, where a downregulation of 1776 transcripts and upregulation of 943 transcripts occurred after 3 months of treatment. Non-responders to the drug, however, showed no noticeable differences in gene expression from baseline to 3 months.

“What was most promising, is that many of the most significant changes in gene expression over time in good responders are already known to be involved in rheumatoid arthritis,” James Oliver, of the Arthritis Research UK, Center for Genetics and Genomics, Center for Musculoskeletal Research, University of Manchester, UK, told Practical Pain Management.

These findings will require validation in a large independent cohort of patients on adalimumab therapy, and since the changes were apparent at 3 months, the biomarkers would not be used as predictive markers before treatment, Mr. Oliver explained.

“Nevertheless, they could certainly aid early detection of non-responder patients at 3 months and support timely switching to an alternative treatment,” something that could help reduce the risk of disability and promote more responsible pharmacological spending, said Mr. Oliver.

Further pathway analysis of the genes revealed “both differentially expressed and differentially spliced genetic variants in (good-responding patients) were heavily enriched for relevant processes including antigen processing and presentation, ribosome biogenesis and T- and B-cell receptor signaling.” The genes most upregulated were oftentimes encoders for immunoglobulin and MHC II components, perhaps a signal of immune cells migrating from the synovium into the blood, the researchers concluded.

Studies reported on in this article were presented as part of this year’s meeting of the European League Against Rheumatism (EULAR). The authors of the studies declared no conflicts of interest.

References

  1. Lipsky PE, Heijde DM van der, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000;343:1594-1602.
  2. Weinblatt ME, Kremer JM, Bankhurst AD, at al. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999;340:253–259.
  3. Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: The ARMADA trial. Arthritis Rheum. 2003;48:35–45.
  4. Finckh A, Simard JF, Gabay C, et al. Evidence for differential acquired drug resistance to anti-TNF agents in rheumatoid arthritis. Ann Rheum Dis. 2008;67:746–752.
  5. Sante GD, Tolusso B, Fedele AL, et al.  HS1,2A enhancer polymorphism in rheumatoid arthritis determines high disease activity, high nf-kb activity in B cells and leads to a differential response to therapy. Presented at: Annual Meeting of the European League Against Rheumatism (EULAR); June 8-11, 2016; London, England.
  6. Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum. 2011;63(3):573-86.
  7. Giambra V, Fruscalzo A, Giufre M, et al. Evolution of human IgH3'EC duplicated structures: Both enhancers HS1,2 are polymorphic with variation of transcription factor's consensus sites. Gene. 2005;346:105-114.
  8. Simmonds RE, Foxwell BM. Signaling, inflammation and arthritis: NF-kappaB and its relevance to arthritis and inflammation. Rheumatology (Oxford). 2008;47(5):584-590.
  9. Tolusso B, Frezza D, Mattioli C, et al. Allele *2 of the HS1,2A enhancer of the Ig regulatory region associates with rheumatoid arthritis. Ann Rheum Dis. 2009;68(3):416-419.
  10. Oliver J, Plant D, Orozco G, et al.  Whole transcriptome investigation of response to anti-TNF treatment in rheumatoid arthritis. Presented at: Annual Meeting of the European League Against Rheumatism (EULAR); June 8-11, 2016; London, England.
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