Immunophenotyping to establish RA risk
Another finding of interest is an increase in the synovial tissue CD38 plasmablasts as detected by RNA sequencing in seropositive arthralgia subjects.
“Their pattern looks more like early RA or established RA,” he noted.
Similarly, the proportion of B cells is already increased in the seropositive arthralgia subjects, compared with healthy subjects, and is similar to that seen in established seropositive and seronegative RA patients.
After looking at “a whole range of immunophenotypes,” Dr. Veale and his colleagues found that several other genes (not just for CD38) are expressed at increased levels in the arthralgia patients.
“The pattern that we’re seeing is that the seropositive arthralgia patients look more like the early rheumatoid and the established rheumatoid patients when we actually analyze their gene signatures using immunophenotyping,” he said.
The patients in this study were all referred by general practitioners, but another study – the PRAIRI study – recruited seropositive arthralgia patients from the community and randomized them to receive a single rituximab infusion or placebo (Ann Rheum Dis. 2019;78:179-85).
“What they showed is that patients who received one dose of rituximab actually developed rheumatoid arthritis at a slower rate and at a later time than the patients who received placebo,” he said.
At 1-year follow-up, there was no difference in the rate of development of RA between the groups; rituximab had merely delayed the onset of RA, he said.
“They do discuss in this paper what the effect would be if you continued treatment in these patients: Would we actually prevent the onset of rheumatoid arthritis in a significant cohort of patients?” he said. “But we don’t know that.”
Could immune checkpoint inhibition reveal RA risk?
Recent findings from work with immune checkpoint therapy in the hematology/oncology arena, however, raise other interesting possibilities with respect to early treatment and prevention of RA.
A number of case reports have documented the development of autoimmune diseases in patients with cancer who have undergone treatment with checkpoint inhibitors.
“Essentially what happens in cancer is that the activated T cells upregulate immune checkpoint molecules. ... and what these molecules do is they make the T cells essentially resistant to attacking the tumor cells,” he explained, noting that the molecules include programmed death 1 (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4).
Checkpoint inhibitors bind to these molecules and “free up these activated T cells to attack the tumor cells” both through cytokines (interferon release) and direct cell cytotoxicity, he said.
This is relevant for rheumatology patients, because the PD-1 checkpoint molecule is overexpressed in pathogenic T cells in RA and systemic lupus erythematosus.
A closer look at his own RA patients showed that those who were ACPA positive had higher levels of soluble PD-1 than did the ACPA-negative RA patients – a finding that has been replicated in two other cohorts, he noted.
“So we wanted to look at our seropositive arthralgia subjects and see if there is something in their gene signatures on immunophenotyping which actually would give us a clue in terms of this checkpoint inhibitor pathway,” he said. “What we found is that the anti–PD-1 signature is increased in our arthralgia patients, and again, the pattern of expression is more similar to early rheumatoid arthritis and established rheumatoid arthritis, and is significantly different from both healthy controls and patients with osteoarthritis.”
PD-1 expression was also found to be increased on CD4- and CD8-positive T cells taken from the synovial tissues in these patients, he said.
Immunostaining of the T cells showed, interestingly, that the ligand for PD-1 is “almost absent,” he noted.
“So there’s an overexpression of PD-1, but there’s a downregulation of the ligand for PD-1, so that means that the PD-1 pathway is not active in these patients because the PD-1 ... has no ligand to actually bind on to.”
This suggests that “something else may happen that will upregulate the ligand – maybe a second hit,” thereby allowing PD-1 to bind and become active, he said.
“I realize what I’ve been talking about is fairly controversial, but I think it may be possible soon to predict a diagnosis of rheumatoid arthritis before clinical arthritis develops, but not in everybody,” he said, noting that current diagnostic tools are often unreliable.
For example, CRP levels in most of his study subjects remained normal even after converting to meet RA criteria, he explained.
However, “the checkpoint inhibitor story is absolutely fascinating,” he said.
“It’s unmasked an RA phenotype in patients who are receiving these drugs, and we have identified that the PD-1 pathway is altered in the synovial tissue, not just in patients with established rheumatoid arthritis, but also in subjects before they have developed arthritis and they have circulating autoantibodies,” he said.
The CD38 plasmablasts found to be present in the synovial tissue before RA presents clinically may also represent a therapeutic target, he added.
Dr. Veale disclosed financial relationships (research grants, consulting fees, speaker’s bureau, and “other” relationships) with AbbVie, Pfizer, UCB, Roche, and Janssen.