Is B a Key to Autoimmune Therapy?: B Cell–targeted Therapies in Autoimmune Disease

Unfortunately, there are no screening methods to identify patients at risk for development of PML. A third case of PML was recently reported in an RA patient receiving rituximab, notably without prior anti-TNF treatment or risk factors for PML development, such as malignancy or heavy immunosuppression. Although the frequency of PML in RA patients receiving rituximab is rare (3 in 100,000 patients), a recent press release from Genentech notes that the information to date suggests that patients with RA who receive rituximab have an increased risk of PML. Current U.S. Food and Drug Administration recommendations are that rituximab only be used in later-stage RA patients who have inadequately responded to anti-TNF therapy, which has been our practice to date. Given that primary and secondary immune responses may be compromised even a year after therapy, it is also recommended that immunizations be given one month prior to starting rituximab, and the yearly influenza vaccine given as late as possible after the last dose.¹² This would include vaccination for the novel H1N1 virus, but avoidance of live vaccines, similar to the practice for other immunocompromised populations. I also routinely monitor serum immunoglobulin levels (yearly) given the occurrence, albeit rare, of hypogammaglobulinemia and the fact that replacement intravenous immunoglobulin can be considered in the setting of severe hypogammaglobulinemia (serum IgG<200-300 mg/dl) (see Table 3, above).

Another question that frequently arises is whether it is necessary to monitor B-cell counts. In large series of RA patients, there was no clear temporal relationship between peripheral B-cell return and loss of response, making such a recommendation difficult to substantiate. On the other hand, the detection of residual B cells using high sensitivity flow and the return of B cells increases the risk of relapse. In SLE, where incomplete B-cell depletion is more common, I routinely assess for depletion (one to two months after therapy) and reconstitution (at least at disease flare or if repeat treatment is being considered). Is long-term depletion of B cells necessary to maintain clinical benefit? In RA, transient B-cell depletion can ameliorate disease for a prolonged period, but typically not indefinitely. Repeated courses of B-cell depletion can prevent disease relapse.¹⁰ However, the optimal timing of repeated B-cell depletion remains unclear. Given the heterogeneity in treatment responses, my approach is to tailor the treatment to the patient and consider repeat B-cell depletion when disease begins to relapse. Biomarkers to assess the need for re-treatment and even to stratify patients into those likely to respond to B-cell depletion in the first place are sorely needed. Recent reports do suggest that seropositive RA patients tend to have better responses to B-cell depletion.