First Studies Show Which Genes Respond to PsA Treatment

October 29, 2014

For the first time, we know which genes are altered by treatments for psoriatic arthritis (PsA), and how. One study compares etanercept and methotrexate. Another looks at how infliximab works in PsA and rheumatoid arthritis, showing conclusively that the two conditions are different.

Rosenberg A, Fan H, Chiu YG et al. Divergent Gene Activation in Peripheral Blood and Tissues of Patients with Rheumatoid arthritis, Psoiatic Arthritis and Psoriasis following Infliximab Therapy. PLoS One (2014) doi:10.1371/journal.pone.0110657 Published online Oct. 21, 2014

Cuchacovich R, Perez-Alamino R, Zea AH, Espinoza LR. Distinct genetic profile in peripheral blood mononuclear cells of psoriatic arthritis patients treated with methotrexate and TNF-inhibitors. Clinical Rheumatology (2014) doi:10.1007/s10067-014-2807-8 Published online Oct. 24, 2014

Two unrelated studies published last week offer the first very close look at how medications used against psoriatic arthritis (PsA) act by altering gene expression, and at how these responses differ between people who have PsA or related conditions and healthy controls.

In the grand tradition of good science leading to more questions, both teams found that tumor necrosis factor inhibitors (TNFI) modulate some unanticipated molecular pathways. Of course this is tantalizing from the perspective of drug development.

In the first study above (Rosenberg et al), a team at the University of Rochester (NY) Medical Center compared gene activities in patients with PsA, psoriasis, or rheumatoid arthritis (RA), looking at genes extracted from both blood and synovial tissues. They also compared gene activation patterns measured before and after treatment with the TNFI infliximab (Remicade).

The other researchers, Cucacovich et al from the Louisiana State University Health Sciences Center in New Orleans, compared gene responses in PsA patients treated with methotrexate or the TNFI etanercept (Enbrel).

Several noteworthy revelations from the Rochester study:

1. People taking infliximab for PsA show the greatest gene activation after 10 weeks of treatment, while those treated for rheumatoid arthritis (RA) showed peak responses after 2 weeks. "This may explain why skin responses often lag behind the joint response to anti-TNF agents in PsA," the authors write.

2. Pathways triggered by infliximab in PsA are those affecting CD14+ monocytes active in the innate immune system (proliferation endothelial cells, inflammatory responses, cell migration and apoptosis).

3. While the TNFI triggers the innate immune system in PsA, it triggers CD14+ cells of the adaptive immune system (T and B cells) in RA. This confirms a previously suggested pathological distinction between the two conditions, despite their similar symptoms.

4. Gene changes in response to infliximab were far more extensive for PsA patients than for those with RA or psoriasis, and the genetic effects of the drug were distinctive for all 3 disorders (implying that drug targeting can be focused further).

Perhaps not surprisingly, pathways activated by etanercept in the Louisiana study are similar to those linked to the effects of infliximab on PsA in the other report. Both teams also found effects on the complement system and on pathways involving fibroblasts and keratinocytes.

The team in New Orleans are the first to assess the genetic effects of methotrexate in PsA. It appears to target many of the genetic regions also affected by etanercept, but the two drugs also have distinctive actions, implying a synergy of effect.

However, the Louisiana team studied only genes extracted from peripheral blood, while the Rochester researchers also assessed synovial tissue. They found that changes in genetic expression in blood don't correlate well with those in tissue.

Although the numbers of genes analyzed here is huge, patient samples were small. The Rochester results include only 12 patients with PsA (and similarly small numbers in the other groups), while the Louisiana report includes only 12 altogether: 9 PsA patients (3 each taking etanercept, methotrexate monotherapy, or no treatment) and 3 healthy controls. Also, the Rochester authors concede that their synovial tissue samples are too few to "provide a comprehensive assessment of the joint response".