Background Many patients with RA are well controlled on anti-TNF therapy, but up to 40% do not achieve or sustain an acceptable response. B cell depletion therapy based on rituximab (RTX) is then often used to try and induce clinical remission. There is no clear protocol for patients who subsequently fail to respond adequately to RTX or other biologic therapies. The possibility of combining sequential TNF inhibition therapy and B cell depletion to improve response and aim for long term remission in some patients has not yet been adequately explored.
Objectives The aim of this pilot study was to investigate the effect of reintroduction of a TNF inhibitor (using adalimumab, ADA) on the clinical response and laboratory parameters in patients who achieved adequate B cell depletion after RTX, but who only attained a partial responses.
Methods In this prospective study 8 seropositive patients with established active RA (median DAS28>3.2) were treated with RTX after previous (but then loss of) response to ADA. Clinical response to RTX is delayed sometimes for months after B cells are depleted. Here, all patients achieved adequate depletion (<1 CD19+cell/ml) but experienced only a partial response to RTX at 3-5 months (ΔDAS28>1.2 but DAS28 still above 3.2). The primary end-point was whether clinical response improved after reintroduction of ADA. Clinical data was collected pre-RTX, at ADA re-introduction (study entry), and then every 2 months. Blood samples were collected from study entry (Time 0) to the end of 12 months follow up (after ADA re-introduction), noting B cell return (CD19+ absolute numbers >5 CD19+ cell/ml), CRP and serum BAFF. In addition, we compared the effect of the sequential regime on patients who relapsed within the 12 month follow up period (DAS>2.6) with those achieving and maintaining remission for greater than 12 months (ie DAS28<2.6). Comparisons were made using Mann Whitney U tests.
Results Remission or low disease activity (DAS28<3.2) was achieved in all patients for a median of 6.5 months (range: 3 to >12) after ADA re-introduction. Two patient groups were defined on the basis of remaining on ADA and in clinical remission at the end of 12 months follow up (n=4) or not (those who flared within 3 to 11 months) (n=4). CD19 absolute numbers at repopulation were similar between patients. Those with a longer response (remission >12 months) presented with significantly higher BAFF levels at ADA reintroduction and also significantly lower SJC and TJC (p=0.05; p=0.001 respectively), although these patients had significantly higher CRP levels than those with shorter response (p=0.04).
Conclusions This pilot study suggests that remission or low disease activity might be achieved for patients with a previous loss of response to anti-TNF therapy and only partial response to RTX, when ADA was reintroduced before B cell reconstitution. In some patients this improved response was sustained for at least 12 months while other patients flared (as often seen following RTX treatment). This raises the possibility that reintroduction of ADA could not only improve response but also interfere with mechanisms of relapse/flare after RTX.
Disclosure of Interest : I. De La Torre Employee of: Dr. De la Torre is since February 2013 an European Physician working for Eli-Lilly&Co. This proyect was supported by Abbvie Co. between 2011-2012., M. Leandro: None declared, L. Valor: None declared, D. Hernández: None declared, L. Carreño: None declared, G. Cambridge: None declared
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