Comment on: Rheumatoid factor positivity rather than anti-CCP positivity, a lower disability and a lower number of anti-TNF agents failed are associated with response to rituximab in rheumatoid arthritis

Comment on: Rheumatoid factor positivity rather than anti-CCP positivity, a lower disability and a lower number of anti-TNF agents failed are associated with response to rituximab in rheumatoid arthritis SIR, The recent article of Quartuccio et al. [1], ‘Rheumatoid factor positivity rather than anti-CCP positivity, a lower disability and a lower number of anti-TNF agents failed are associated with response to rituximab in rheumatoid arthritis’, draws the stated conclusion on the basis of a multivariate analysis in which RF status, but not anti-cyclic citrullinated peptide (anti-CCP) antibody status, remains significant in the model. However, this finding may be expected on the basis of multicollinearity of RF and anti-CCP. Only one of two variables that are significantly correlated will be significant in a multivariate model; this does not mean that the other variable is not significant, but rather that it is redundant. Furthermore, lower disability and a lower number of anti-TNF agents are significantly associated in a multivariate regression model analysing ACR50 responses, but not in a model for European League Against Rheumatism (EULAR) moderate-to-good responses. This observation also suggests to us that the title is somewhat misleading. The authors note that ‘RF-negative cases showed a longer disease duration . . . and included a higher number of patients who failed more than one anti-TNF agent’. Conversely, no differences were seen in clinical variables for anti-CCP-positive vs anti-CCP-negative patients. This phenomenon may explain why RF-positive patients were more likely than RF-negative patients to achieve ACR50 responses, as longer disease duration and failure of more than one anti-TNF agent are associated with poorer outcomes, and further limit the conclusion that RF, but not anti-CCP positivity, is associated with response to rituximab in RA. The proportions of ACR50 responders among RF-positive and anti-CCP-positive patients are almost identical, 75 vs 72% (Table 1) [assuming a typographical error in the sentence, ‘ACR response 50 was seen in 58/78 RF-positive/CCP-negative patients’, as the data appear to characterize RF-positive/CCP-positive patients]. To be sure, 82% of patients who are RF positive and anti-CCP negative have ACR50 response rates vs 43% of anti-CCP-positive-only subjects. However, only seven patients are anti-CCP positive/RF negative, and most anti-CCP-positive patients have response rates similar to those of RF-positive patients. The reference of Carson et al. [2], cited to support the suggestion that treatment with rituximab can have a major effect on RF-producing B-cell clones and less so on anti-CCP-producing B-cell clones, was published in 1991, before reports of anti-CCP antibodies. Any slightly differential effect of rituximab on biological markers may be explained by an overall effect on inflammation rather than only on B-cells, as larger decreases in RF than anti-CCP titres have also been described after treatment with infliximab [3, 4] or adalimumab [5]. Finally, we have substantial concern about the value of prediction of responses to any therapy in groups of patients, according to any variable, to a physician caring for an individual patient. Of course, there are situations in which the prognosis of a poor response is clinically useful—most obviously for antibiotics with no (zero) antimicrobial activity against a given pathogen. But in this study, the group with the least likelihood of a response, patients who were negative for both RF and anti-CCP, had a response rate of 21%. A 1 in 5 likelihood of a response in a patient who has failed several other biological agents would appear a reasonable treatment option. We would treat such a patient, and would be concerned that reimbursement authorities would use data from groups to potentially deny treatment to individuals who really need it and might derive benefit.