Extended report Figure 3 Mean change from baseline for DAS28 using CRP over time. CRP, C-reactive protein; DAS28, disease activity score based on 28 joints. to suggest that seropositive patients (RF and/or anti-CCP) have a higher likelihood of response to B-cell-depleting therapy com- pared with seronegative patients, in particular for improving signs and symptoms;18–22 however, the statistical signiﬁcance of these ﬁndings remains to be determined. Radiographic end- points were not assessed in this ofatumumab trial and data are not currently available for the persistence of response beyond 24 weeks. The safety information gathered in this study is consistent with that observed in short-term studies of rituximab in active RA.18 23 24 Although a greater proportion of patients receiving ofatumumab experienced mild to moderate infusion-related reactions on the day of ﬁrst infusion, despite steroid premedi- cation, less than 1% of ofatumumab patients experienced an infusion-related reaction on the day of second infusion. This ﬁnding may be explained by the sudden cytokine release that follows the pronounced B-cell lysis occurring after CD20 liga- tion, as previously reported in non-Hodgkin’s lymphoma patients treated with rituximab.25 The rate of serious infections in patients treated with ofatumumab was low and comparable to placebo. Although progressive multifocal leukoencephalop- athy has been reported with rituximab,26 no such cases were identiﬁed with ofatumumab in the current small study of lim- ited duration, which excluded patients who screened positive for JC virus DNA at baseline (one patient excluded). Similarly, serious opportunistic infections were reported in ocrelizumab trials, but were not observed in this study.27 28 Ofatumumab is a fully human mAb, thereby offering a low immunogenicity potential. Although all patients in the study were on methotrexate, which may suppress the development of antidrug antibodies,29 and patients only received one course of treatment over 24 weeks, no anti-ofatumumab antibodies were detectable in any of the treated patients. In contrast, 7.9% and 5.4% of RA patients who received the chimeric mAb rituximab 500 mg administered twice and 1000 mg administered twice, respectively, in a study of a similar patient population, developed human antichimeric antibodies at 24 weeks.19 Overall, 11% of patients with RA have tested positive for auto-antibodies at any 2124 time after receiving rituximab.26 There was no reported correla- tion between the development of these human antichimeric anti- bodies and safety or efﬁcacy; nevertheless, the possibility of loss or reduction of efﬁcacy, local reactions, serum sickness/immune complex-mediated disease and major allergic reactions (eg, urti- caria, bronchospasm, bronchoconstrictions) is well recognised.30 In addition to its efﬁcacy in RA demonstrated in this trial, ofatu- mumab is approved for the treatment of refractory chronic lym- phocytic leukaemia.31 The mechanism of B-cell tumour lysis is probably through the activation of both complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. Compared with rituximab, ofatumumab demonstrates increased binding of C1q and more potent complement-dependent cyto- toxicity, even in chronic lymphocytic leukaemia cells with low CD20 expression levels.32 It is unknown at this time, however, whether these mechanistic differences can translate to improved safety, tolerability, efﬁcacy, or potency over rituximab. In summary, ofatumumab is a fully human mAb binding an epitope of CD20 distinct to that recognised by rituximab. A sin- gle course of two infusions of 700 mg was efﬁcacious and safe in biological-naive, active RA patients on background metho- trexate up to 24 weeks after treatment. As expected for a fully human mAb, ofatumumab did not induce immunogenicity. Acknowledgments The authors would like to thank all participating investiga- tors and their staff who provided and cared for patients and collected data for the study: Argentina: E Lucero, O Rillo, D Siri, I Strusberg, J Velasco; Australia: S Hall, P Nash, P Youssef; Chile: M Aliste, R Jimenez, P Miranda, F Radrigan, N Stevensen; Czech Republic: L Bortlik, J Vencovsky, P Vitek; Hungary: B Rojkovich, F Szanyó, E Vereckei; Peru: E Cabello, O Castañeda; Poland: S Jeka, A Racewicz, Z Ruzga, A Sawicki; Romania: C Zainea; Russian Federation: O Ershova, O Lesnyak, E Nasonov, T Polikarpova, A Rebrov; Spain: RA Blanco, VR Valverde, MI Oyarzabal, FN Sarabia; UK: A Hammond, T Sheeran. Funding This study was sponsored and funded by Genmab and GlaxoSmithKline under a collaborative agreement. Competing interests Genmab and GlaxoSmithKline provided ﬁnancial support to the institutions that participated in this study. PCT has received research grants from Merck, UCB, AstraZeneca, GlaxoSmithKline and Roche and has been an invited speaker and advisor for Abbott, Bristol-Myers Squibb, Centocor, Roche, Schering-Plough, Wyeth (acquired by Pﬁzer in October 2009), Genmab, Ann Rheum Dis 2011;70:2119–2125. doi:10.1136/ard.2011.151522