B cell depletion: an effective therapy in rheumatoid arthritis
Submitting InstitutionUniversity College London
Unit of AssessmentClinical Medicine
Summary Impact TypeTechnological
Research Subject Area(s)
Medical and Health Sciences: Clinical Sciences, Immunology
Summary of the impact
Research at UCL pioneered B cell depletion to treat rheumatoid arthritis
(RA) and also stimulated the development of B-cell-directed therapies for
other autoimmune rheumatic, haematological and neurological diseases. Now
NICE approved, B cell depletion (based on rituximab) in RA is as effective
as the alternative (anti-TNFα drugs) and an option for patients unable to
gain benefit from anti-TNFα drugs. Rituximab offers drug-cost savings of
up to £5,000/annum/patient and for many is a more convenient therapy,
being given as an infusion only every five months apart, or more. B cell
depletion has also proved to have an excellent safety profile, with many
receiving repeated courses of treatment. As a consequence of UCL research,
rituximab has brought substantial benefit to patients with many autoimmune
diseases, including over 200,000 who have been treated with rituximab for
RA so far.
In the 1980s and early 1990s it was a general view that rheumatoid
arthritis (RA) was caused by T cells that attacked specific targets in
joints. The consequent release of toxic cytokines by joint macrophages was
generally agreed to be responsible for inflammation. Yet, despite more
than 20 years of research, no consistently autoreactive T cell had been
identified. Research at UCL conducted by Jonathan Edwards and Geraldine
Cambridge led to the hypothesis that B cells played an essential role in
the pathogenesis of RA .
Following anatomical and immunohistochemical studies of normal and
diseased human synovium they found that a receptor (CD16) was
constitutively expressed on macrophages in synovial lining and to a lesser
extent in other sites affected in the disease. The consequence of CD16
activation was to stimulate macrophages to generate TNFα, a powerful
pro-inflammatory cytokine known to be involved in joint inflammation. CD16
appeared to be activated by soluble complexes of particular
autoantibodies, previously described in RA patients. They suggested that
the constant supply of autoantibodies capable of forming these small
`activating' complexes was due to expansion of B cells (responsible for
autoantibody generation) in a manner that avoided usual pathways to
control their number . This led to the hypothesis that removing
B cells would reduce the inflammatory stimulus and also break the vicious
cycle of autoreactive B cell expansion.
Towards the end of the 1990s, Roche developed a drug, rituximab (which
binds the CD20 marker on all mature B cells), for the treatment of B-cell
cancers notably lymphomas. Edwards and Cambridge were quick to recognise
that since both B-cell lymphoma and RA involved uncontrolled proliferation
of B cell clones, rituximab might well be what they had been waiting for
to treat patients with RA. Proof of concept followed with the clinical
success of a small trial of the B-cell-depleting agent, rituximab, in 5
patients with intractable RA in 1998/9 by the UCL team, and confirmed by
them in a larger cohort [3, 4].
The first randomised trial started in 2002 and was published in NEJM in
2004 . The results indicated that rituximab produced results in
patients with RA that at least matched those of patients treated with TNFα
blockade. Successful treatment of patients with systemic lupus
erythematosus by the group followed . Rituximab was licensed
for the treatment of patients with RA in 2006.
References to the research
 Edwards JCW, Cambridge G. B-cell targeting in rheumatoid arthritis
and other autoimmune diseases. Nat Rev Immunol. 2006 6(5):394-403. http://dx.doi.org/10.1038/nri1838
 Leandro MJ, Edwards JC, Cambridge G. Clinical outcome in 22 patients
with rheumatoid arthritis treated with B lymphocyte depletion. Ann Rheum
Dis. 2002 Oct;61(10):883-8.
 Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A,
Emery P, Close DR, Stevens RM, Shaw T. Efficacy of B-cell-targeted therapy
with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004
 Leandro MJ, Edwards JCW, Cambridge G, Ehrenstein MR, Isenberg DA. An
open study of B lymphocyte depletion in systemic lupus erythematosus.
Arthritis Rheum. 2002 Oct;46(10):2673-7. http://dx.doi.org/10.1002/art.10541
Details of the impact
As a result of the research described above, rituximab is now in
widespread use as a treatment for RA, with usage rising every year [a].
By the end of July 2013, Roche estimated that 228,801 patients have been
treated with rituximab for RA [b].
In March 2006, the FDA approved rituximab for use in combination with
methotrexate in adult patients with moderately to severely active RA who
have had an inadequate response to anti-TNFα therapy. Approval by the
European Medicines Agency (EMA) came in July of the same year. Towards the
end of 2006, a consensus statement and guidance document on the use of
rituximab for routine care of patients with RA was issued by the European
League Against Rheumatism (EULAR), describing the treatment as "a major
advance in the therapeutic armamentarium for patients with rheumatoid
In 2007, NICE issued guidance (updated in 2011) recommending rituximab as
Rituximab in combination with methotrexate is recommended as an option
for the treatment of adults with severe active rheumatoid arthritis who
have had an inadequate response to, or have an intolerance of, other
disease-modifying anti-rheumatic drugs (DMARDs), including at least one
tumour necrosis factor (TNF) inhibitor [d].
British Society for Rheumatology (BSR) and British Health Professionals
in Rheumatology (BHPR) issued further guidelines on the use of rituximab
in 2010 [e]. Rituximab was also recommended in guidelines issued
by the American College of Rheumatology (ACR) in 2008, updated in 2012 [f].
Benefits to patients
The use of rituximab extends treatment to those patients who cannot have
anti-TNFα drugs because of contra-indications (a history of cancer or
pre-malignant conditions and patients with history of recurrent and/or
serious infections or considered to be at a high risk of infection). Data
from a collaboration of different European registries shows that 36% of
patients received rituximab as first-line biologic [g].
Rituximab is also indicated as a second line treatment for patients where
anti-TNFα drugs failed, and this amounts to between 30 and 40% of patients
that are considered for biologic therapy. One patient, for whom three
anti-TNFα drugs had failed, described the impact of rituximab as follows:
"Blood tests showed that my levels of inflammation were the lowest
that they'd been for years. I was less tired and had more mental and
physical energy. I resumed several of my hobbies... Mabthera transformed
my life... the effects have been radical. I can truthfully say that I
haven't experienced this level of wellbeing for many years" [h].
A major advantage of rituximab is that it can be given as two infusions
two weeks apart (or four smaller weekly injections), with effects
persisting for 6-12 months thereafter. From the patient's perspective,
this is a more convenient schedule of administration than other biologics
(typically administered 12-24 times per year). Furthermore, as the UCL
team and others have demonstrated, rituximab infusions can be repeated on
an annual basis for several years. Loss of response to rituximab in
patients with RA that have previously responded well is rare, and it is
well tolerated with excellent safety profiles in RA and in patients with
many other conditions [i].
Rituximab costs £5,000 per annum less than other biologics. In the UK it
is generally the next choice before other more expensive alternatives such
as tocilizumab, abatacept or belimumab. Use in patients in this setting
has already generated considerable savings to the NHS. The economic impact
of rituximab has been greater in low and middle income countries (for
example, Brazil) where the lower cost of rituximab makes it the first-line
biologic for RA [j].
Use of rituximab in other conditions
The success of B cell depletion therapy in RA has led directly to it
being used for autoimmune rheumatic diseases (such as systemic lupus
erythematosus, ANCA associated vasculitis, Behcets syndrome, myositis,
anti-phospholipid syndrome, Sjogren's syndrome, neuromyelitis optica).
Rituximab is licensed for ANCA-associated vasculitis [k], is
approved for funding by NHS England for SLE [l], and has been
nationally commissioned for the treatment of Behcets disease [m]
and neuromyelitis optica [n].
Sources to corroborate the impact
[a] As reported by Roche (the drug's manufacturers) in their 2013 Half
[b] Email correspondence from Roche. Available on request.
[c] Smolen JS, Keystone EC, Emery P, Breedveld FC, Betteridge N,
Burmester GR, Dougados M, Ferraccioli G, Jaeger U, Klareskog L, Kvien TK,
Martin-Mola E, Pavelka K; Working Group on the Rituximab Consensus
Statement. Consensus statement on the use of rituximab in patients with
rheumatoid arthritis. Ann Rheum Dis. 2007 Feb;66(2):143-50. Epub 2006 Oct
[d] NICE technology appraisal guidance 195. Adalimumab, etanercept,
infliximab, rituximab and abatacept for the treatment of rheumatoid
arthritis after the failure of a TNF inhibitor.
[e] Bukhari M, Abernethy R, Deighton C, Ding T, Hyrich K, Lunt M, Luqmani
R, Kiely P, Bosworth A, Ledingham J, Ostör A, Gadsby K, McKenna F, Finney
D, Dixey J; BSR and BHPR Standards, Guidelines and Audit Working Group.
BSR and BHPR guidelines on the use of rituximab in rheumatoid arthritis.
Rheumatology (Oxford). 2011 Dec;50(12):2311-3.
[f] Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM,
Moreland LW, O'Dell J, Winthrop KL, Beukelman T, Bridges SL Jr, Chatham
WW, Paulus HE, Suarez-Almazor M, Bombardier C, Dougados M, Khanna D, King
CM, Leong AL, Matteson EL, Schousboe JT, Moynihan E, Kolba KS, Jain A,
Volkmann ER, Agrawal H, Bae S, Mudano AS, Patkar NM, Saag KG. 2012 update
of the 2008 American College of Rheumatology recommendations for the use
of disease-modifying antirheumatic drugs and biologic agents in the
treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012
[g] Chatzidionysiou K, Lie E, Nasonov E, Lukina G, Hetland ML, Tarp U,
Gabay C, van Riel PL, Nordström DC, Gomez-Reino J, Pavelka K, Tomsic M,
Kvien TK, van Vollenhoven RF. Highest clinical effectiveness of rituximab
in autoantibody-positive patients with rheumatoid arthritis and in those
for whom no more than one previous TNF antagonist has failed: pooled data
from 10 European registries. Ann Rheum Dis. 2011 Sep;70(9):1575-80.
[h] Jean Bailey-Dering. My experience of rituximab (Mabthera) infusions.
03/12/08. Case study on website of the National Rheumatoid Arthritis
[i] Tony HP, Burmester G, Schulze-Koops H, Grunke M, Henes J, Kötter I,
Haas J, Unger L, Lovric S, Haubitz M, Fischer-Betz R, Chehab G,
Rubbert-Roth A, Specker C, Weinerth J, Holle J, Müller-Ladner U, König R,
Fiehn C, Burgwinkel P, Budde K, Sörensen H, Meurer M, Aringer M, Kieseier
B, Erfurt-Berge C, Sticherling M, Veelken R, Ziemann U, Strutz F, von
Wussow P, Meier FM, Hunzelmann N, Schmidt E, Bergner R, Schwarting A,
Eming R, Hertl M, Stadler R, Schwarz-Eywill M, Wassenberg S, Fleck M,
Metzler C, Zettl U, Westphal J, Heitmann S, Herzog AL, Wiendl H, Jakob W,
Schmidt E, Freivogel K, Dörner T; GRAID investigators. Safety and clinical
outcomes of rituximab therapy in patients with different autoimmune
diseases: experience from a national registry (GRAID). Arthritis Res Ther.
2011 May 13;13(3):R75.
[j] Data on prescribing costs in Brazil. Copy of files available on
[k] SPC for rituximab; http://www.medicines.org.uk/emc/medicine/2570#POSOLOGY
[l] Interim Clinical Commissioning Policy Statement: Rituximab for the
treatment of Systemic Lupus Erythematosus in adults. September 2013.
Reference: NHS ENGLAND A13/PS/a2. Copy available on request.
[m] National Specialised Commissioning Team. Behçet's Syndrome Service
Specification. April 2012. Copy available on request.
[n] National Specialist Commissioning Team. Neuromyelitis Optica Service
Specification. 2012-3. Copy available on request.