A new study found patients with early rheumatoid arthritis (RA) have increased membrane and soluble CD64 (sCD64), as well as impaired function of the FcR for IgG (FcɣR). Not only are all of these factors associated with joint disease activity, but also anti-rheumatic treatments improve symptoms and reduce levels of CD64.
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Peter Matt, MD, a rheumatologist at Uppsala University in Uppsala, Sweden, and colleagues published their analysis of sera from patients with RA online Sept. 25 in PLOS ONE. Their results suggest that sCD64 may be an important objective biomarker for RA. “We emphasize the role of CD64 in the early phase of autoantibody positive RA where up-regulation of membrane-bound and soluble CD64 appears to be pathognomonic,” write the authors in their discussion.
The investigators found patients with early RA had an increase in the number of CD64-expressing monocytes, as well as an increase in CD64 expression per monocyte when compared with healthy controls. Additionally, the increase of CD64 expression of monocytes correlated with patient-reported morning stiffness and pain. When they examined monocytes from patients with early RA, they also found changes in monocyte FcR expression relative to controls. The investigators also noticed a higher IgG load on the RA monocytes than on healthy control monocytes. From these observations, they concluded that the monocytes from patients with RA were in a state of constant FcɣR occupancy.
“We believe the observed FcγR occupancy in the RA monocytes contributes to the decrease in the TNFα production. This effect is probably due to a negative impact on the intracellular signaling pathways downstream of the FcγR, as otherwise stimulated monocytic TNFα production was similar in patients and controls,” they explain. The impaired FcɣR function was further reflected in changes in immune complex binding and decreased immune complex-stimulated TNFα secretion.
The investigators then examined if the FcɣR function was associated with the patients’ disease activity and found that, indeed, it was. When patients were treated with anti-rheumatic therapies, after three to four months of treatment, the investigators found clinical improvements correlated with changes in expression of CD64 and CD89. In contrast, the number of CD14-expressing monocytes remained stable during the treatment period.
The researchers next used the EULAR response criteria to group the patients who received therapy into good responders and non-responders. Although the mean concentration of IgG anti-cyclic citrullinated peptide antibodies (ACPAs) was lower in the good responders than in the non-responders, they found no significant change in the mean ACPA levels in either group following treatment. In contrast, membrane CD64 decreased in patients with a good response to treatment, but not in non-responders. The investigators then confirmed that the changes in monocyte FcR expression in both good and non-responders reflected changes in markers of disease activity. Moreover, following treatment, they found good responders had monocytes that were in the inactivated state.
The investigators then evaluated soluble forms of CD89, CD64 and CD16A to identify which of these receptors might have an active role in treatment response. They found elevated sCD64 was specific for RA and was not found in a reference group of patients with active psoriatic arthritis.
“With this study, we want to draw the attention to CD64 as an important player in early autoantibody positive RA,” write the authors in the discussion. “In our analyses, no other membrane-bound FcγRs were found significantly modified, and sCD64 was elevated only in RA plasma. The early naive RA monocytes were characterized by up-regulation of CD64 and membrane bound IgG.”
Lara C. Pullen, PhD, is a medical writer based in the Chicago area.
- Matt P, Lindqvist U, Kleinau S. Elevated membrane and soluble CD64: A novel marker reflecting altered FcγR function and disease in early rheumatoid arthritis that can be regulated by anti-rheumatic treatment. PLoS One. 2015 Sep 25;10(9):e0137474. doi: 10.1371/journal.pone.0137474. eCollection 2015.