High-resolution ultrasound confirms reduced synovial hyperplasia
following rituximab treatment in rheumatoid arthritis
Hans-Rudolf Ziswiler1, Daniel Aeberli1, Peter M. Villiger1and Burkhard Mo ¨ ller1
Objective. To assess the response of RA patients to rituximab (RTX) treatment using a sensitive imaging technique for synovitis.
Methods. Twenty-three RA patients were treated with two 1000-mg infusions of the B-cell depleting antibody, RTX, in an observational
protocol. Clinical response was assessed by the European League Against Rheumatism (EULAR) response criteria. High-resolution
grey-scale and colour-coded power Doppler (PD) ultrasonography was performed at baseline and 6 months after RTX. The second to
fifth MCP and PIP joints were bilaterally examined with joints in a neutral 0 position from a palmar view and scored from 0 to 3.
Results. Median disease activity score (DAS28) improved from 5.03 to 3.56 (P¼0.001), which corresponded to a EULAR moderate
response in 11 of 23 patients and a EULAR good response in another 6 patients. Improved control of disease activity by RTX was also
indicated by tapering of median daily corticosteroid doses from 10 to 5mg, without flare ups. Mean grey-scale scores correlated with the
swollen joint count at baseline (r¼0.484, P¼0.022) and month 6 (r¼0.519, P¼0.011). Mean grey-scale scores improved upon RTX from
a 0.90 median (range 0.13–1.87) to 0.75 (range 0.19–1.50, P¼0.023). Frequency of PD positive joints was low (6.1%) at baseline and did
not significantly change following RTX treatment.
Conclusions. High-resolution grey-scale ultrasonography (US) examination confirmed reduced synovial hyperplasia, but the applied PD
method displayed no significant changes. Therefore, only grey-scale US is recommended in follow-up examinations after RTX treatment.
KEY WORDS: Arthritis, B cell, Depletion, Doppler, Grey scale, Hyperplasia, Rheumatoid, Rituximab, Synovitis, Vascularity.
Rituximab (RTX) is a chimeric monoclonal antibody directed
against the CD20 antigen expressed on pre-B and mature
B cells. RTX belongs to the new ‘beyond anti-TNF’ biologics.
Clinical efficacy of RTX for the treatment of active RA has
been documented in randomized controlled trials for patients
with inappropriate response to conventional DMARDs, such as
low-dose MTX, as well as TNF blocking agents [1–3]. B cells
provide multiple important functions by antigen presentation,
co-stimulation of T cells and antibody production related to
their derivates, the plasma cells [4, 5]; yet, the predominant
mode of action of RTX in autoimmunity is still unclear.
Recent radiographic data proved for the first time that
RTX ameliorates structural damage in RA in terms of erosions
and joint space narrowing . Macroscopic changes in synovitis
upon anti-TNF treatment could be accurately graded by MRI and
high-resolution ultrasonography (US). The data obtained by these
methods correlated with subsequent disease progression in
conventional X-rays [7–12]. To date, no studies have addressed
the short-term effect of RTX treatment on the morphological level
of synovitis with either one of these modern imaging techniques.
In this study, we monitored synovial morphology in therapeutic
B-cell depletion with US and compared the results with estab-
lished clinical parameters for response.
Patients and methods
Twenty-three patients diagnosed with RA according to the
ACR classification criteria  were treated with two infusions
of 1000mg chimeric anti-CD20 antibody RTX (Roche Pharma,
Reinach, Switzerland) 14 days apart from each other in an
observational protocol. All patients had previously failed to
respond to at least one conventional DMARD. In addition,
all but three patients also failed to respond to at least one TNF
blocking agent, in agreement with the Swiss licence for RTX
in RA. Clinical disease activity was assessed by swollen joint
count (SJC), tender joint count (TJC), ESR, serum CRP and
disease activity composite score DAS28  at baseline and
6 months after treatment with RTX. The European League
Against Rheumatism (EULAR) response criteria were calculated
prednisolone (80mg intravenously, Pfizer Zurich, Switzerland),
5mg levocetirizin-dihydrochloride (UCB-Pharma AG, Bulle,
Switzerland) and 1000mg acetaminophen tablets (Bristol-Myers
Squibb, Baar, Switzerland) were concomitantly given with RTX
infusions. Subcutaneous low-dose MTX was used in 21 of
23 patients; it was kept stable for at least 6 weeks, in maximal
tolerated doses up to 25mg/week, before RTX infusions
and during the observational phase. TNF blocking agents were
discontinued at least one treatment interval before B-cell
depletion. Orally administered corticosteroids were continued in
a stable dose and then carefully tapered, according to improved
disease activity. Local corticosteroid injections into the joints of
interest were prohibited. The patient cohort is described in
more detail in Table 1. Written informed consent was obtained
according to the Declaration of Helsinki from all participants.
The study was approved by the cantonal ethics committee of Bern.
with RTX. Methyl-
Grey-scale (synonymous for brightness or B mode), as well as
colour-coded power Doppler (PD) US were performed on the
first day of RTX infusion and again 6 months later with an
Esaote MyLab 70 x-vision (Esaote S.p.a., Genova, Italy) supply
using the 4-cm linear-array transducer 6–18MHz (L4 35). MCP
and PIP joints of digits 2–5 on both hands were examined
according to the method of Scheel et al.  from a palmar
view, with joints in neutral 0 or in maximal extended position.
The colour box in PD was adjusted to the region of interest.
The pulse repetition frequency was set to 750 MHz, with wall
filter and persistence at the lowest possible level; colour priority
included all colours. The colour gain was adapted according to
published recommendations . Grey-scale and PD images with
Immunology and Allergology, Bern, Switzerland.
Bern UniversityHospital, Clinics forRheumatology,Clinical
Submitted 21 October 2008; revised version accepted 23 April 2009.
Correspondence to: Burkhard Mo ¨ller, Inselspital, Bern University Hospital,
Clinics for Rheumatology, Clinical Immunology and Allergology, Freiburgstrasse,
3010 Bern, Switzerland. E-mail: firstname.lastname@example.org
Advance Access publication 2 June 2009
? The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: email@example.com
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