Genetic variation may explain why biologics help some patients, but fail others

LONDON - Psoriasis patients carrying HLA-C*06:02 experience a significantly better early response to ustekinumab but are less likely to achieve high rates of response to anti-TNFs, a large dataset set has confirmed. However, the analysis also suggested that that previously unreported genetic loci may have a stronger association with biological response.

Biological therapies, which target specific components of key proinflammatory immune pathways, can be highly effective in the treatment of moderate-to-severe psoriasis, but a substantial fraction of patients experience no response or limited response to some of these drugs.  

Failure to respond carries a high cost, both economically and in terms of patient care, so the PSORT Consortium was formed in search for predictors of treatment response, and in this study PSORT researchers at King’s College London in the UK looked for genetic predictors.

The researchers used data from the British Association of Dermatologists Biologic Interventions Register (BADBIR), which includes detailed treatment records, Psoriasis Area and Severity Index (PASI) disease severity scores, and demographic and clinical measurements for more than 13,000 psoriasis patients, of which 3,320 have been genotyped.

The researchers examined associations with response to anti-tumour necrosis factor (anti-TNF) (adalimumab, etanercept and infliximab) and anti-interleukin (IL)-12/23 (ustekinumab) drugs for candidate HLA variants in patients with severe disease (baseline PASI > 10) in an initial cohort of 2467 patients. They looked at the response to ustekinumab in 223 patients and the response to anti-TNFs in 519 patients, which was “a much bigger data set than anyone has previously analysed,” said Nicholas Dand from King’s College London, presenting the findings to the Psoriasis: From Gene to Clinic International Congress, in London on Nov. 30.

The results supported findings from previous studies that HLA-C*06:02 is positively associated with early response to ustekinumab (PASI 75 and 90 at 3 months; P < 0.01) but negatively associated with excellent longer-term response to anti-TNF agents (PASI 90 and 100 at 12 months, P < 0.01). The study also validated findings from previous studies linking biological response with established psoriasis susceptibility loci, such as TRAF3IP2 in the IL17 signalling pathway (adalimumab) and the LCE3B and LCE3C genes within the epidermal differentiation complex (anti-TNFs).

However, Dr. Dand added that the study’s results also indicated the presence of previously unreported genetic loci that display stronger association with biological response.

“These findings are intriguing, but we must be a little bit wary of over interpreting them at this stage. There are extended haplotypes across the HLA region, so this could represent the same association signal as HLA-C*06:02,” he said. “With our current sample number, it would be difficult to unpick whether it is this allele HLA-C*06:02 or other HLA alleles entirely that are biologically relevant to response.”

He added: “As our unique datasets continue to accrue we expect our statistical power to allow identification of novel genetic associations to improve. We will subsequently examine in detail the interplay between genetics and patient-specific clinical and demographic factors, with the aim of predicting response and stratifying patients according to their most likely effective biologic.”

REFERENCE

Genetic variation contributes to response to biologics: initial findings of the Psoriasis Stratification to Optimise Relevant Therapy (PSORT) consortium Dand N on behalf of the PSORT consortium. FC07. Psoriasis: From Gene to Clinic International Congress, London , 30th November 2017, 13.45.  http://psoriasisg2c.com/wp-content/uploads/2017/11/Online-Psoriasis-G2C-Programme-2017.pdf (page 58)