• Rheumatoid Arthritis
• Infections
• DMARDs (biologic)

Patients with rheumatic diseases and chronic, or less frequently, resolved hepatitis B virus (HBV) infection, can develop viral reactivation during antitumor necrosis factor therapy.1–3 Treatment with chemotherapeutic regimens that includes rituximab (RTX) without prophylactic antiviral therapy, has been linked to HBV reactivation in lymphoma patients with chronic (27%–80%), or resolved (3%–25%) HBV infection.1 ,4 Since there are no data available for rheumatic patients, we studied the safety of RTX in such patients with chronic or resolved HBV infection.

Forty-one consecutive patients with various rheumatic diseases (rheumatoid arthritis/RA: n=34, other: n=7) who had received ≥1 cycle of RTX and had ≥6 months of follow-up were included in this prospective study. Patients were treated with the standard dose of RTX (1 gm intravenous at days 1 and 15, table 1). Patients were screened for HBV at baseline (HBsAg, anti-HBc, anti-HBs); those found with chronic or resolved infection were tested for HBV DNA (baseline and end of follow-up as previously described).2 HBV DNA was undetectable in all patients at baseline. Anti-HBs titres were measured in all anti-HBs+ patients (HBV vaccinated: n=4, resolved infection: n=9) at baseline and end of follow-up and alanine aminotrasferase (ALT) levels every 3 months. Statistical analysis was performed using Wilcoxon matched-pairs test (GraphPad Prism, GraphPad Software Inc, San Diego, California, USA). p Values of ≤0.05 were considered significant.

Patient characteristics are shown in table 1. Two RA patients with chronic HBV infection (♂ 68 and ♀ 58 years old) with normal ALT and undetectable HBV DNA at baseline (HBV carriers), were treated with RTX and oral antivirals (lamivudine and entecavir, respectively); during follow-up, over 50 and 36 months, respectively, HBV DNA remained undetectable and ALT was within normal limits. There was no HBV reactivation (HBsAg and HBV DNA negative) during the same period (median=13, range=6–50 months) in the 12 patients with resolved HBV infection (anti-HBc only: n=3, anti-HBc+ anti-HBs+: n=9).

The effect of RTX on the levels of protective anti-HBs in patients with history of HBV vaccination or resolved infection was studied. Although there was a slight decrease in titres this did not reach statistical significance (p=0.29, table 1) while none of the patients demonstrated a decrease below protective levels (<10 IU/l, figure 1). During follow-up, IgG levels decreased in the whole group (1087±345 to 963±324 mg/dl, p=0.002) and the subgroup of anti-HBs+ patients (p=0.14, table 1).

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Figure 1

The change in anti-HBs titres during RTX therapy in patients with resolved HBV infection (HBsAg−/anti-HBc+/anti-HBs+, n=9) and vaccinated patients (HBsAg−/anti-HBc−/anti-HBs+, n=4) is depicted. The dotted line indicates the cut-off limit (10 IU/l) for protective immunity. RTX, rituximab; HBV, hepatitis B virus.

Despite the limitations of the small number of patients and the absence of patients with positive HBV DNA at baseline, this is the first study evaluating the risk for HBV reactivation in rheumatic patients with resolved HBV infection. We did not observe any viral reactivation in such patients, and no significant change in protective anti-HBs titres during RTX treatment in contrast with recent data from lymphoma patients receiving RTX-containing chemotherapeutic regimens.5 Even though these preliminary findings are reassuring, further studies are needed in order to evaluate the exact risk of HBV reactivation in previously infected patients. In the meantime, close virological monitoring in rheumatic patients receiving RTX therapy is mandatory.1