BSR & BHPR Guidelines on the use of Rituximab in Rheumatoid ...

<strong>BSR</strong> & <strong>BHPR</strong> <strong>Guidelines</strong> on the use of
Rituximab in Rheumatoid Arthritis
(DRAFT GUIDELINES)
Chair of Guideline Working Group: Dr Chris Deighton
March 2010
Consultation period closes: Friday 7 th May at 12:00pm
Please send all feedback to pwhitelaw@rheumatology.org.uk

Clinical Affairs Committee
& Standards, Audit and <strong>Guidelines</strong> Working Group
Marwan Bukhari 1 , Rikki Abernethy 2, Chris Deighton 3 , Tina Ding 3 , Kimme Hyrich 4 , Mark Lunt 4 ,
Raashid Luqmani 5 , Patrick Kiely 6 , , Ailsa Bosworth 7 , Jo Ledingham 8 , Andrew Ostor 9 , Kate
Gadsby 1 , Frank McKenna 10 , Diana Finney 11 , Josh Dixey 12
1. Rheumatology Department, Royal Lancaster Infirmary, Lancaster
2. Rheumatology Department, St Helens Hospital, St Helens
3. Rheumatology Department, Derbyshire Royal Infirmary, Derby
4. ARC Epidemiology Unit, University of Manchester
5. Rheumatology Department, Nuffield Orthopaedic Centre, Oxford
6. Rheumatology Department, St George’s Healthcare, London
7. National Rheumatoid Arthritis Society, Maidenhead
8. Rheumatology Unit, Queen Alexandra Hospital, Portsmouth
9. Rheumatology Department, Addenbrooke’s Hospital, Cambridge
10. Trafford General Hospital, Manchester
11. Rheumatology Unit, Worthing and Southlands NHS Trust
12. Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry

Introduction and Objectives
1.1 Why do we need Rheumatoid Arthritis Rituximab <strong>Guidelines</strong>?
The Standards, audit and guidelines working group (SAGWAG) have recently updated the
guidelines on eligibility for anti-TNF drugs in rheumatoid arthritis (RA) [1] and have updated
the anti-TNF safety and efficacy guidelines [2]. NICE technology appraisal guidance [3] for
use of Rituximab in Rheumatoid Arthritis and a consensus statement from EULAR [4] were
published in 2007. Therefore, it is appropriate to undertake a review of the currently
available data. The group does not wish to duplicate the guidance in those documents, but
wishes to review the more recent evidence and supplement what is already known.
1.2 Objective of guidelines
To update the information provided in NICE guidance [3] , and EULAR consensus statement
on use of Rituximab in patient with rheumatoid arthritis published in January 2007 [4].
1.3 Target audience
The primary target audience for this guideline is rheumatologists, rheumatology specialist
registrars and rheumatology nurse specialist/practitioners involved in the management of
patients with Rheumatoid Arthritis. The information may also be of value to other secondary
care and primary care physicians whose patients may be receiving this treatment for
Rheumatoid Arthritis.
1.4 The areas the guideline does not cover
This guideline does not cover the use of rituximab in treatment of other rheumatological
conditions apart from Rheumatoid Arthritis
1.5 Stakeholder involvement
Patients have not been involved in the production of these guidelines but the guidelines
have been reviewed by members of NRAS
1.6 Conflict of interest statement
RA holds departmental sponsorship from Roche, Wyeth, Abbott and Schering Plough for
academic meetings. Personal sponsorship from Wyeth, Abbott and UCB to attend
international educational meetings, is involved with commercial trial recruitment in RA from
Roche and has previously sat on an advisory board for Roche
MB has attended meetings organised by Schering Plough, has been sponsored to attend
international meetings by Pfizer, Merck ,Roche, Wyeth and Abbott, and has accepted
honoraria for educational meetings from Merck, Wyeth, Abbott, Roche, UCB celltech and
Pfizer. He has also departmental sponsorship for software from Wyeth, Abbott and Roche.
Other contributors conflict of interest statement are at the end of this manuscript.

1.7 Rigour of development
Statement of scope of literature search and strategy involved.
The current NICE eligibility and response criteria were reviewed [3], and evidence was
sought to determine whether these should be modified and also whether there was evidence
available to update the EULAR consensus statement [4] particularly regarding safety issues.
This evidence was sought through a medline search using key words “rituximab” and
“rheumatoid arthritis” to identify English language articles published prior to April 2010 and
also a manual search of databases from <strong>BSR</strong>, EULAR and ACR annual meetings in 2007,
2008 and 2009.
Evidence was graded according to the strength of the literature to support each statement,
using the grading suggested by the Royal College of Physicians of London
(http://www.rcplondon.ac.uk/college/ceeu/conciseGuidelineDevelopmentNotes.pdf) and the
document was prepared in accordance with the principles outlined in the Appraisal of
<strong>Guidelines</strong> Research and Evaluation (AGREE) guidelines (www.agreecollaboration.org).
1.8 Statement of when guideline with be updated
In 3 years or earlier if significant information on use of rituximab in treatment of patients with
rheumatoid arthritis becomes available before that date.
1.9 How will these guidelines be publicised and implemented?
The full guidelines will be published on the <strong>BSR</strong> web-site, and sent to all <strong>BSR</strong> members and
Primary Care Trusts. A summary of the guidelines will be published in Rheumatology, with
web links to the full guidelines. Implementation of some parts will depend on negotiations
with NICE, whereas aspects of safety can be implemented on publication.
1.10 Cost implications
A detailed health economic analysis is beyond the scope of these guidelines. No funding has
been received to assist with the development of these guidelines,
The guidelines
The current NICE eligibility and response criteria were reviewed, and evidence was sought
to determine whether these should be modified. An update on safety aspects based on the
increasing experience of this drug was performed to advise colleagues regarding toxicity and
the safe use of the drug.
1. Eligibility and response criteria
Current NICE guidelines [3] state that rituximab should be used
a. with methotrexate
b. in patients who have had an inadequate response to or intolerance of other
DMARDs, including treatment with at least one anti-TNF therapy
c. by specialist physicians experienced in diagnosis and treatment of
rheumatoid arthritis

d. It should be continued only if patients show an improvement in disease
activity of 1.2 points or more.
e. Repeat courses should be given with methotrexate and no more than 6
monthly.
The group discussed this and raised several questions after scrutinising the current
evidence:
i. Can rituximab be given without other DMARDs, or with alternatives to
methotrexate?
ii. Can rituximab be given before anti-TNF therapy, and are there any particular
categories of RA patients who might benefit from such an approach?
iii. Should the eligibility and response criteria be modified?
iv. Should the suggested frequency of repeat infusions be modified?
i. Can rituximab be given without other DMARDs, or with alternatives to methotrexate?
Recommendation 1: If methotrexate is contra-indicated, rituximab should be used in
rheumatoid arthritis either alone, or with leflunomide.
(Level III evidence, grade of recommendation B)
The initial proof of concept trial [5] included cyclophosphamide or methotrexate as the
concomitant treatment. 161 patients were randomised. Although this was the initial open
label trial, little difference existed between those treated with methotrexate and rituximab and
those treated with cyclophosphamide and rituximab. In this trial, rituximab was also used as
monotherapy with good efficacy, but this did not achieve significance versus placebo due to
the small numbers in each group. The percentage figures for efficacy at 24 weeks are
summarised in the table below.
Strategy
% achieving
ACR20
% achieving
ACR50
% achieving
ACR70
Methotrexate 38 13 5
Rituximab alone 65 33 15
Cyclophosphamide
and rituximab
Methotrexate and
rituximab
76 41 15
73 43 23
Table 1 . Efficacy of rituximab when used with a variety of other concomitant medications in
161 patients [5]

Recent data has suggested the possible role for leflunomide in patients intolerant of
methotrexate [6]. There is very little data available regarding the combination of rituximab
with other biologic therapies. In a small study with only 18 patients [7], patients were treated
with etanercept and rituximab with good efficacy and no apparent significant increase in side
effects with the etanercept discontinued a week before, and recommenced a week after the
infusions. However, combination of other biologics has been associated with increased
incidence of side effects, particularly infections, without increase in efficacy and therefore
this area requires further research before any recommendation can be made,
ii. Can rituximab be given before anti-TNF therapy, and are there any particular categories of
RA patients who might benefit from such an approach?
Recommendation 2: Rituximab could be given in rheumatoid arthritis before anti-TNF
treatment, particularly in patients who have an absolute or relative contra-indication
to anti-TNF therapy.
(Level Ib evidence, grade of recommendation A)
In observational data from the Swiss biologics register it was suggested that response to
rituximab is better after the failure of the first anti-TNF agent, rather than switching to a
second anti-TNF drug [8]. This supports the current NICE guidelines on the current
sequencing of biological therapy. However, are there any data to support the use of
rituximab prior to the failure of an anti-TNF agent? A dose ranging study ascertained patients
between the ages of 18 and 80 with moderate to severe active RA despite ongoing
treatment with MTX 10-25 mg per week (orally or parenterally) (acronym DANCER [9]). Two
thirds of patients had not had treatment with a prior biologic. These patients had a
numerically higher ACR20 response than those who had been on a previous anti-TNF
therapy. An observational study from Leeds supported the efficacy of rituximab after
conventional DMARD failure, and prior to exposure to anti-TNF therapy [10]. The efficacy
and safety of rituximab as first-line biologic therapy in patients with active rheumatoid
arthritis is specifically being investigated in the SERENE and MIRROR The initial data from
these studies has been presented as abstracts at ACR 2008 [11,12]. More recently the
IMAGE data (presented at EULAR 2009) has not only shown efficacy in biologic naive
patients but reduction in joint damage [13]. The response rates in this study are similar to
those seen with anti-TNF therapies suggesting that rituximab could be considered prior to
the use of anti-TNF, particularly in patients where anti-TNF therapy has an absolute or
relative contra-indication. These are shown in the table below for the active groups in all
three trials

Endpoints % pts
SERENE
MIRROR
IMAGE
N=170
N=346
N=244
ACR 20 51 197 80
ACR 50 26 124 64.8
ACR 70 10 61 46.8
EULAR
moderate/good
Clinical remission
(DAS28 28, and a CRP > 1.5mg/dl. The
Edwards et al trial stipulated that patients must be rheumatoid factor positive [5]. Other
studies have not used this as an inclusion criterion but have only had small numbers of seronegative
patients included.
Evidence suggests that patients who are sero-negative for both RF and ACPA do not
respond as well to rituximab as patients who are sero-positive for one or both however there
may be some benefit in seronegative patients . One study failed to show significant response
compared with placebo – but this study had 52% of patients achieved an ACR 20 on placebo
[9]. Another study showed significant response in both groups but less in seronegative than
seropositive patients (ACR 20 of 41% in seronegative and 54% in seropositive) [14]. A
recent pooled analysis of 670 patients has also confirmed this [15], the result of the pooled
analysis is shown in table 3 below.

Week 24 Week 48
Seropositive Seronegative Seropositive Seronegative
ACR Responses (n) 514 106 506 101
ACR20 (%) 62.3* 50.9 71. 1* 51.5
ACR50 (%) 32.7* 19.8 44.9** 22.8
ACR70 (%) 12.1 5.7 20.9* 6.9
EULAR Outcomes (n) 507 105 496 101
EULAR Response (%) 74.8* 62.9 84.3* 72.3
Mean change DAS28 -1.97** -1.50 -2.48*** -1.72
DAS28 Categories (n) 510 105 499 101
Low Disease (%) 16.9 10.5 26.5* 12.9
DAS28 Remission (%) 10.6 4.8 13.2 5.9
*p

iv. Should the suggested frequency of repeat infusions be modified?
Recommendation 5: Re-treatment with rituximab in rheumatoid arthritis should be
considered when initial treatment response of at least a moderate EULAR response
has been lost. The frequency of infusion should be no less than 24 weeks.
(Level III evidence, grade of recommendation B)
In a small study, delaying the second treatment predicted a flare of disease, and attenuated
the secondary response [20]. An open label study looking at re-treatment has shown that a
fixed re-treatment at 24 weeks and treating when a flare occurs have similar outcomes [21].
Data from Switzerland [20] suggests that the median duration of response in 83 RA patients
was 12.7 months (inter-quartile range 9.4,22.3). There was some evidence that the efficacy
of repeat infusions is cumulative. This was predicted by a good response to the first infusion.
This lasts for further infusions [21].
In trials looking at re-treatment at fixed time intervals and treatment according to either fixed
protocol based on DAS28 [21] or on fixed time intervals [22,23] , the burden of inflammation
and number of flares are reduced. In an open follow up study in patients having more than
one dose of rituximab [23] the interval between dosing was stable at 33 weeks (SD 10
weeks) in responders to the first dose. This was not different when stratified by anti-TNF
therapy and non anti-TNF therapy exposed patients. There are some data that suggest an
added benefit from six monthly infusions [24] but there no longer term studies to suggest
regular 6 monthly infusions are beneficial.
Safety aspects
Recommendation 6: Etanercept should be stopped 4 weeks before and adalimumab
and infliximab 8 weeks before commencing rituximab therapy in rheumatoid arthritis.
(Level IV evidence, grade of recommendation C)
As part of the clinical trial protocol in phase 2 and phase 3 studies etanercept was stopped 4
weeks before and adalimumab and infliximab 8 weeks before commencing rituximab
therapy. There is no recommendation mandated in the SmPC [25] for a washout period and
no information available as to whether this washout period is necessary.
Recommendation 7. Commencement of biologic therapy following treatment with
rituximab should only be done with caution.
(Level IV evidence , grade of recommendation C)

There is insufficient evidence to make a recommendation on use of another biologic after
rituximab although the limited evidence available has not shown any safety issues.
There is one paper on the safety of combination therapy with rituximab and etanercept for
patients with rheumatoid arthritis [7]. In this small study with only 18 patients, patients were
treated with etanercept and rituximab with good efficacy and no apparent significant increase
in side effects with the etanercept discontinued for a week before and recommenced a week
after the rituximab infusions.
Genovese et al [26] have published data on incidence of serious infection events in
Rheumatoid arthritis patients who participated in an international rituximab clinical trial
programme and subsequently entered a safety follow up study which permitted additional
biological DMARD (anti TNF – 81%, abatacept, anakinra or other experimental therapy). 185
of 2578 patients who entered safety follow up study received another biological DMARD.
Mean time interval between course of rituximab and commencing another biologic agent was
9 months (SD 6). Mean follow up after commencement of another biologic was 12 months
(SD 9). At the time of commencing another biologic agent 88.6% of patients had peripheral
B-cell depletion. There was no increase in serious infection events per 100 patient-years
following commencement of further biologic drug (5.49 events/100 patient-years) compared
with period between rituximab treatment and commencement of another biologic drug (6.99
events/100 patient years). Further data from this study was presented as an abstract at
EULAR 2009 [27]. Of the now 216 patients who had commenced further biologic agent
there was still no increase in occurrence of serious infection event (serious infections before
another biologic commenced 5.73 per 100 patient year versus 5.36 per 100 patient year
after commencing other biologic). The rates for the 178 patients who received anti-TNF
therapy after rituximab similarly showed no increase in serious infection with 5.99 per 100
patient year prior to commencement of anti-TNF versus 5.22 per100 patient year after
commencement of anti-TNF therapy.
Further data is needed before conclusive advice can be given regarding the risk of serious
infection events in patients who receive another biologic drug while B Cell depleted.
Recommendation 8: Immunoglobulin levels should be checked before commencing
rituximab in rheumatoid arthritis, as well as 4-6 months after infusions and prior to
any re-treatment. It is recommended that the possibility of increased risk of infection
in patients with low IgG

patients developing IgM

of recurring or chronic infections or with underlying conditions which may further
predispose patients to serious infection.
(Level IV evidence, grade of recommendation C)
Apart from infusion reactions, serious infections are the most common significant adverse
event following rituximab infusion. In the DANCER study [9] had rate of 4.7 per 100 patient
years in those treated with rituximab compared with the placebo rate of 3.2 per 100 patient
years. In the REFLEX study [14] the rates were 5.2 per 100 patient years in the rituximab
group and 3.7 per 100 patient years in the placebo group.
Follow up of patients from clinical trials of rituximab in an open labeled extension safety
study published in 2010 showed infections and serious infections over time remained stable
across 5 courses of treatment at 4 – 6 serious infection event/100 patient-years [28]. No data
is available beyond 5 course of treatment.
For reasons of general safety, patients with a history of recurrent significant infection, or
known active infection, or any major episode of infection requiring hospitalisation or
intravenous antibiotics within 4 weeks of screening, or oral antibiotics within 2 weeks prior to
screening, were excluded from the clinical trial programme investigating the efficacy and
safety of rituximab in rheumatoid arthritis. Experience in these patient populations is
therefore limited. A small observational study did not show any increase in infections in
patients with bronchiectasis treated with rituximab when compared with patients without
identified risk of recurrent infections treated with anti-TNF therapy [32].
A further observational study identified 161 patients with RA treated with rituximab, 30 of
whom had a previous history of serious of recurrent infection including contra-indication for
initiating (or maintaining) anti-TNF therapy was reported in 2009 [33]. Previous history of
infection included bronchopneumonia or lung abscess (11), septicaemia (2), joint prosthesis
infection (3), septic arthritis (2), tendon sheath infection (1), endocarditis (1), pyelonephritis
(2) osteitis (3) and various bacterial skin infections (7). 21 of these infections had occurred
while the patient was on anti-TNF therapy. During mean follow up of 19.9 months 6 patients
(20%) developed further infection after treatment with rituximab. Immunoglobulin levels after
treatment with rituximab were within normal range.
However, until further data is available, caution should be exercised in all patients with a
propensity to infection.
Recommendation 11: Patients who have not already had pneumococcus
immunization should ideally receive this 3 months before commencing first course of
rituximab.
(Level IIa evidence, grade of recommendation B)
Bingham et al compared the immunization responses in a group of patients with rheumatoid
arthritis following treatment with rituximab compared with a group treated only with
methotrexate [34]. Although the response to tetanus toxoid (a T cell dependent antigen)

emained normal, the response to pneumococcal polysaccharide (T cell independent
antigen) given 28 weeks after course of rituximab was reduced in those that had received
rituximab – with a 2 fold rise in titre in response to more that 1 serotype found in 57% of
patients as compared with 82% of control patients. It is therefore recommended that patients
should have polysaccharide and primary immunization prior to treatment with rituximab.
Recommendation 12: Patients should receive influenza vaccination before rituximab
treatment and annually (prior to rituximab retreatment if possible) at a time when B
cells are likely to be returning.
(Level IIa evidence, grade of recommendation B)
There are reports of patients who have been previously treated with rituximab having a
decreased response to some influenza antigen [35,36]. Patients are considered to have an
inadequate response 87 – 150 days after treatment with rituximab [37]. Van Assen [35]
showed markedly reduced response 4 – 8 weeks after rituximab with modestly restored
response when vaccination was delayed to 6 -10 months following rituximab. Although it
might seem prudent for patients to receive annual influenza immunisation prior to rituximab
infusions, this may be impractical due to limited availability of appropriate influenza
vaccination at certain times of each year.
Recommendation 13: Patients at risk should be screened for Hepatitis B and C
infection prior to going onto rituximab. Rituximab should be used cautiously for
patients with HBV infection, but prophylactic administration of lamivudine may be
beneficial for preventing reactivation of HBV.
(Level III evidence, grade of recommendation B)
A case has been reported of successful prophylaxis against hepatitis B reactivation using
lamivudine in a patient receiving rituximab [38]. Rituximab treatment has been reported as
being effective in treating Hepatitis C associated cryoglobulinaemic vasculitis [39], but there
have also been reports of up to a quarter of these patients developing severe systemic
reaction after rituximab infusions [40].
Recommendation 14: Prompt discontinuation of rituximab and reduction or
discontinuation of other immunosuppressants should be undertaken when
Progressive Multifocal Leukoencephanopathy is suspected, and appropriate
investigations should be undertaken.
(Level IV evidence, grade of recommendation C)
Progressive Multifocal Leukoencephalopathy (PML) is a rare, progressive, demyelinating
disease of the central nervous system that usually leads to death or severe disability. PML is
caused by activation of the JC virus, a polyomavirus that resides in latent form in up to 80%
ot healthy adults. JC virus usually remains latent, typically only causing PML in
immunocompromised patients. The condition usually leads to severe disability and death.
The factors leading to activation of the latent infection are not fully understood. PML has
been reported in HIV-positive patients, immunosuppressed cancer patients, translplant

patients and patiients with autoimmune disease, including systemic lupus erythematosus
who were not receiving rituximab. However there have been reports of PML in patients
treated with rituximab for non-Hodgkins lymphoma and also a small number of cases in
patients treated for autoimmune diseases including 2 cases in patients with SLE. There have
now been 3 cases reported in patients with rheumatoid arthritis treated with ritxumab in
approximately 100,000 rheumatoid arthritis patients treated with rituximab worldwide. 2 of
these cases had confounding factors – one of oropharyngeal carinoma treated with
chemotherapy and radiotherapy [41], and one elderly patient with sustained lymphopenia
and low CD4+ cells prior to rituximab therapy. However the 3 rd case does not seem to have
any confounding issues.
Patients should be monitored regularly for new or worsening neurological symptoms and if
there is any suspicion of PML, in consultation with a neurologist, a MRI scan and CSF PCR
for JC virus DNA should be undertaken.
Summary
This guideline has reviewed the current literature on rituximab and has put
recommendations on it’s efficacy and safety and will hopefully provide a handy
reference to heath care professionals on the use of rituximab.
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