We read with interest the report by Pierer et al, in which they described an association between latent cytomegalovirus (CMV) infection and joint destruction in rheumatoid arthritis (RA) (1). This report links two lines of investigation in RA. First, frequencies of CD4+CD28null T cells in peripheral blood correlate with disease severity, more specifically with the presence and severity of extraarticular complications (2, 3). Second, high frequencies of CD4+CD28null T cells are associated with anti-CMV seropositivity (4–7). Together, these observations suggest that patients with extraarticular complications are more likely to be positive for anti-CMV IgG.
We reasoned that any association of CMV serology with extraarticular complications would be detected most readily by comparing patients with severe complications to patients without complications, as the former reportedly have the most pronounced expansion of CD4+CD28null T cells (2). We had access to sera from a large set of patients with rheumatoid vasculitis (n = 26) and Felty's syndrome (n = 14), both rare and extremely severe complications of RA. Control patients (n = 97) had a similarly long disease duration, but did not have extraarticular complications. In each group, serum samples were obtained on average at least a decade after the initial diagnosis of RA.
This cohort of patients was recruited from the inpatient and outpatient clinics at Leiden University Medical Center (LUMC) between 1985 and 1995. Patients with uncomplicated RA were from a prospective study cohort of female RA patients (8); their mean age was 49 years (range 32–64 years), and the mean disease duration was 12 years (range 8–19 years). Patients with rheumatoid vasculitis had symptoms indicative of vasculitis, including neuropathy and skin lesions; results of tissue biopsies confirmed the diagnoses. In that group, 16 patients (62%) were female, the mean age was 62 years (range 48–84 years), and the mean RA disease duration was 13 years (range 2–26 years). Patients with Felty's syndrome had RA, splenomegaly, and spontaneous, sustained neutropenia (<2.0 × 109 cells/liter) that could not be attributed to other diseases or to drug therapy (9). In the Felty's syndrome group, 57% were female, the mean age was 63 years (range 38–81 years), and the mean duration of RA was 19 years (range 4–37 years). The Medical Ethics Committee of LUMC approved the protocols, and informed consent was obtained from study participants. The procedures followed were in accordance with the Helsinki Declaration of 1975, as revised in 1983.
Anti-CMV IgG titers in patients with rheumatoid vasculitis or Felty's syndrome did not differ significantly from anti-CMV IgG titers in patients with uncomplicated RA (Figure 1A). Similarly, CMV serostatus also did not differ significantly among the 3 groups (Figure 1A). Irrespective of CMV serostatus, ∼70% of patients in all 3 groups were parvovirus B19 seropositive (Figure 1B). CMV seronegativity was therefore not associated with a general inability to make IgG antibodies in any of the groups. In summary, neither the presence nor the amount of anti-CMV IgG antibodies was associated with severe extraarticular complications in these patients.
The multiple logistic regression analysis performed by Pierer and colleagues revealed that “the strongest predictive factor for severe joint destruction was disease duration … If disease duration was not entered into the analysis, however, anti-CMV positivity and age at onset of disease exerted significant effects.” It is therefore conceivable that this association between CMV status and joint destruction was confounded by disease duration.
In conclusion, the association between CMV serostatus and articular destruction observed by Pierer et al does not appear to extend to severe extraarticular disease, despite the greater expansion of the CMV-related CD4+CD28null T cell subset in severe extraarticular disease.