Response to "Safety of biologic and nonbiologic disease-modifying antirheumatic drug therapy in veterans with rheumatoid arthritis and hepatitis B virus infection: a retrospective cohort study" Florenzo Iannone, School of Medicine, University of Bari 13 July 2015 Author list Giuseppe Lopalco1, Michele Barone2, Luca Cantarini3, Florenzo Iannone1 Author details 1Rheumatology Unit, Interdisciplinary Department of Medicine, University of Bari, Italy 2Gastroenterology Unit, Department of Emergency and Organ Transplantation, University of Bari, Italy 3Rheumatology Unit, Department Research Center of Systemic Autoimmune and Autoinflammatory Disease, Italy Abbreviations DMARDs: disease-modifying antirheumatic drugs. Key words Rituximab, anti-TNF, Rheumatic disease Comment In the recent years, there has been increasing concern about the safety of biologic drugs in rheumatic patients with comorbid hepatitis B virus (HBV) infection, both in terms of hepatotoxicity and HBV reactivation . We have read with great interest the recent article published by Burton et al on this journal . The authors provided evidence that, among US veterans affected with rheumatoid arthritis (RA) and laboratory evidence of prior HBV infection, hepatotoxicity was low, without difference between biologic and non-biologic DMARDs. They studied 566 patients with near-normal serum alanine aminotransferase (ALT) levels (<1.5 times the upper limit of normal for clinical laboratory monitoring, or 66 IU/ml) at the beginning of treatment. The exposure of interest was the initiation of a new DMARD, thus each patient could contribute with more treatment episodes. The outcome of interest was hepatotoxicity, defined as an increase in ALT levels >100 IU/ml in 1 year follow-up period. Hepatotoxicity was detected in 26 (2.7%) out of 959 treatment episodes and was comparable in patients on biologic (2.6%) and conventional (2.8%) DMARDs. The authors concluded that in their RA cohort the occurrence of HBV related hepatotoxicity was infrequent, regardless of the treatment. The selection criteria adopted in this study did not distinguish patients with previous HBV infection (HBcAb and HBsAb positive) from carriers (HBsAg or HBeAg or HBV-DNA positive). Nevertheless, these findings reinforce our recently published data on the impact of biologic drugs on patients affected with rheumatic diseases and prior resolved HBV infection . The design of our study was a bit different as we focused on the possible reactivation of HBV occult infection, and as second endpoint we evaluated hepatotoxicity. The latter was considered mild if ALT levels were >1x upper limits and severe when ALT levels were >2 upper limits. We included 1218 Caucasian patients with RA, Psoriatic arthritis, Ankylosing spondylitis, and undifferentiated Spondyloarthritis, undergoing treatment with different biologic drugs, mainly TNF blocking agents, because their active disease notwithstanding the therapy with conventional DMARDs across the years 2001 to 2012. We found 179 patients with previous resolved HBV infection (anti-HBc-positive, HBsAg-negative), of whom 146 were on TNF inhibitors, 14 on rituximab, and 19 on other biologics, whereas 959 patients without HBV infection were considered as the control group. During a mean follow-up time ranging from 19.5 to 57 months, no HBV reactivation was seen. With regard to hepatotoxicity, a mild elevation of ALT levels was significantly higher in in patients with HBV infection (17/179) than in controls (42/959) (p<0.01), but when the severe ALT increase was considered no significant difference (3/179 and 9/959) was found. In spite of some difference in methodology, either studies [2,3] have clearly shown that the use of biologic and non-biologic DMARDs in rheumatic patients with previous resolved HBV infection is safe and severe hepatotoxicity rarely occurs. Nevertheless, a careful monitoring of these patients is needed. References 1. Calabrese LH, Zein NN, Vassilopoulos D. Hepatitis B virus (HBV) reactivation with immunosuppressive therapy in rheumatic diseases: assessment and preventive strategies. Ann Rheum Dis. 2006;65:983–9. 2. Burton MJ, Curtis JR, Yang S, Chen L, Singh JA, Mikuls TR, Winthrop KL, Baddley JW. Safety of biologic and nonbiologic disease-modifying antirheumatic drug therapy in veterans with rheumatoid arthritis and hepatitis B virus infection: a retrospective cohort study. Arthritis Res Ther. 2015;17:136. doi: 10.1186/s13075-015-0628-z. 3. Barone M, Notarnicola A, Lopalco G, Viggiani MT, Sebastiani F, Covelli M, Iannone F, Avolio AW, Di Leo A, Cantarini L, Lapadula G. Safety of long-term biologic therapy in rheumatologic patients with a previously resolved hepatitis B viral infection. Hepatology. 2015;22. doi: 10.1002/hep.27716. Competing interests The authors declare that they have no competing interests.