Monday, December 12, 2011

B-Cell Depletion and other B-Cell Directed Therapies in Rheumatoid Arthritis

William Rigby and colleagues looked at patients with inadequate response to a biologic / rituximab, who then received a combination of Rituximab and another biologic DMARD. The study is open-label and combinations were heterogenuous, so results need to be treated with caution. Patients received 500 mg rituximab plus their current biologic (etanercept, adalimumab, infliximab, or abatacept) and non-biologic DMARD treatment at a stable dose. Proportion of development of serious adverse event within 24 weeks of receiving first course of rituximab has been selected as primary endpoint of the study. The safety profile was consistant with previously reported results for rituximab with methotrexate and rituximab with other nonbiologic DMARDs.
Will these results be stable over a longer period of time?

[TUE] 2196
Safety of Rituximab in Combination with Other Biologic Disease- Modifying Antirheumatic Drugs in Rheumatoid Arthritis: 48-Week Data From SUNDIAL.
William Rigby1, Philip J. Mease2, Ewa Olech3, Mark Ashby4 and Swati Tole4.
1Dartmouth Medical School, Lebanon, NH, 2Swedish Medical Center, Seattle, WA, 3Oklahoma Medical Research Foundation, Oklahoma City, OK, 4Genentech, Inc., South San Francisco, CA
Conclusion: The overall safety profile of RTX used in combination with a biologic DMARD at 48 wks was consistent with that previously reported for RTX methotrexate and RTX nonbiologic DMARDs. Despite patterns consistent with clinical benefit, conclusions regarding efficacy results cannot be drawn due to the lack of a control group and differences in baseline characteristics compared with previous studies.

Ocrelizumab didn’t show aclear advantage over rituximab and concerns about serious and opportunistic infection rates has led to the cessation of the programme for RA and SLE, though the patients were still followed (?).

[SUN] 873
The poster on Ocrelizumab had been withdrawn.

Ofatumumab is an anti-CD20 MAB, but nothing on ofatumumab at the ACR 2011. This seems strange as M. Østergaard and colleagues published a study in 2010: Arthritis Rheum 2010 Aug;62(8):2227-38. They looked at “Ofatumumab, a human anti-CD20 monoclonal antibody, for treatment of rheumatoid arthritis with an inadequate response to one or more disease-modifying antirheumatic drugs: results of a randomized, double-blind, placebo-controlled, phase I/II study.” Conclusion: “Our findings indicate that ofatumumab, administered as 2 i.v. infusions of doses up to 1,000 mg, is clinically effective in patients with active RA.”

Epratuzumab is a humanized anti-CD22 drug, which has a more immunomodulatory effect and a combination of mild B-cell depletion. Target disease might be Sjoegren's syndrome.
No posters on epratuzumab in rheumatoid arthritis at the ACR 2011.

There’s another another B-cell depleting agent under development, called veltuzumab, a human anti-CD20 MAB, but nothing has been published at the ACR 2011 meeting.

Besides B-cell depletion alternative components of the B-cell pathway may be targeted: BLyS (B-lymphocyte stimulator) and APRIL (A PRoliferation Inducing Ligand) are such candidates. Atacicept inhibits BLyS and APRIL to bind to B-cells. Atacicept is a human recombinant fusion protein. There has been a study by R.F. van Vollenhoven and colleagues: Arthritis Rheum 2011 Jul;63(7):1782-92. The phase II, randomized, placebo-controlled trial of Atacicept has ben done in patients with rheumatoid arthritis and an inadequate response to methotrexate. Conclusion: “The primary end point (ACR20-CRP response) was not met despite significant biologic effects of atacicept that were consistent with its proposed mechanism of action. Modest effects of atacicept were seen for some secondary efficacy end points. Treatment with atacicept raised no new safety concerns.”

For B-cell depletion and other B-cell directed therapies in rheumatoid arthritis it seems we have to stick to rituximab, a well established therapy.
Though there might be no other CD-20 therapy on the horizon for rheumatoid arthritis, it may be that in about two years there’ll be a similar. Rituximab is cheaper than other biologic agents in Germany. Longer intervals are possible, but I haven’t found any data on how to predict prolonging intervals between twin infusions of rituximab without loosing efficacy. Interesting will also be combinations with other bisologics. How about combining rituximab with denosumab in our osteoporotic patients?

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