Open Journal of Rheumatology and Autoimmune Diseases, 2012, 2, 53-58
http://dx.doi.org/10.4236/ojra.2012.23011 Published Online August 2012 (http://www.SciRP.org/journal/ojra)
53
Open-Label, Pilot Study of the Safety and Clinical Effects
of Rituximab in Patients with Rheumatoid
Arthritis-Associated Interstitial Pneumonia
Eric L. Matteson1,2, Tim Bongartz1, Jay H. Ryu3 , Cynthia S. Crowson2, Thomas E. Hartman4,
Paul F. Dellaripa5
1Division of Rheumatology, Rochester, USA; 2Department of Health Sciences Research, Rochester, USA; 3Division of Pulmonary
and Critical Care Medicine, Rochester, USA; 4Department of Radiology, Mayo Clinic College of Medicine, Rochester, USA;
5Division of Rheumatology, Brigham and Womens Hospital, Boston, USA.
Received May 24th, 2012; revised June 28th, 2012; accepted July 9th, 2012
ABSTRACT
Object ive: To investigate the clinical effect of rituximab (RTX) in the management of progressive rheumatoid arthritis
related interstitial lung disease (RA-ILD). Methods: A total of 10 patients with progressive RA-ILD were enrolled into
this 48-week, open-label treatment study. Treatment was with RTX at 1000 mg at day 1, day 15, and again at weeks 24
and 26, with concomitant methotrexate therapy. Results: The study included 4 men and 6 women. Of 7 evaluable pa-
tients at week 48, the diffusing capacity to carbon monoxide had worsened by at least 15% in 1 patient, and was stable
in 4 patients, and increased by >15% of baseline value in 2 patients. The forced vital capacity declined by at least 10%
in 1 patient, was stable in 4 patients, and increased by at least 10% in 2 patients. High resolution computed tomography
of the chest showed improvement in 1 patient, and was unchanged in 5. Three patients were withdrawn, one who had an
infusion reaction at week 0, one at week 5 who was hospitalized for congestive heart failure at week 5 and who later
died at week 32 of complications following a traumatic hip fracture, and one died at week 6 of possible pneumonia.
Conclusions: In this pilot study of 10 patients with RA-ILD treated with RTX, measures of lung disease remained sta-
ble in the majority of study completers. Further research is needed to clarify whether this treatment has a role in man-
agement of RA-ILD.
Keywords: Rheumatoid Arthritis; Interstitial Pneumonitis; Rituximab
1. Introduction
Pulmonary involvement is common in patients with rheu-
matoid arthritis (RA), and clinically overt interstitial lung
disease (ILD) is prevalent in about 8% of patients with
early RA and 19% of patients with a longer disease dura-
tion [1-3]. The 10 year incidence rate of symptomatic
pulmonary fibrosis has been described as high as 6% in
patients with RA [2,3]. The presence of ILD in RA has a
significant adverse impact on mortality [2,4].
To date, no clinical trial has assessed the efficacy of
any therapy in RA-ILD. Therapeutic strategies are en-
tirely based on therapeutic recommendations in idio-
pathic interstitial pneumonias (IIP) [5-7]. In view of
some histologic differences between IIPs and their coun-
terparts in RA, there might be important features which
could impact on treatment efficacy and prognosis [3]. At
the same time, assumptions about effectiveness of diease
modifying drugs (DMARDs) on pulmonary disease de-
rived from their impact on joint disease should be treated
with caution.
The pathogenesis of RA-ILD is unknown. Other dis-
ease related features and smoking are risk factors, and a
number of immunologic, cellular and humoral abnor-
malities have been described in RA-ILD [2,8-10]. For-
mation of B-cell follicles and germinal centers and the
presence of circulating antibodies to lung proteins have
been detected in IIP [8]. There may be a significant in-
crease in B-cell numbers in RA-ILD compared to normal
lung tissue and IIPs, and there are dense B-cell follicles
in the two most common histologic subtypes of RA-ILD,
nonspecific interstitial pneumonia (NSIP) and usual in-
terstitial pneumonia (UIP) [9].
These observations provide a rationale for a potential
efficacy of B-cell ablative therapies in RA-ILD. The use
of a monoclonal antibody directed against CD20, a B-cell
surface marker, has already proven effectiveness in the
treatment of RA joint disease, but the effect on lung dis-

Open-Label, Pilot Study of the Safety and Clinical Effects of Rituximab in Patients with Rheumatoid
Arthritis-Associated Interstitial Pneumonia
54
ease has not been evaluated [11]. This study was per-
formed to gain a preliminary assessment of the safety and
clinical effect of rituximab, an established therapy for
RA, in patients with moderate to severe clinically overt
and progressive RA-ILD.
2. Methods
2.1. Patients
The study population consisted of 4 male and 6 female
outpatients with RA associated UIP or NSIP, ages 43 to
80 years. All patients met the revised 1987 American
College of Rheumatology classification criteria for RA [12].
The study was approved by the Institutional Review Boards
of the Mayo Clinic and the Brigham and Women’s Hospital,
and registered with Clinicaltrials gov. as NCT00578565.
Diagnosis of progressive RA-ILD of UIP or NSIP
subtype was based on the following criteria: 1) Clinical
symptoms consistent with ILD with onset between 3
months and 36 months prior to screening; 2) Progressive
ILD as demonstrated by any one of the following within
the past year: >10% decrease in forced vital capacity
(FVC), increasing infiltrates on chest radiograph or high
resolution computed tomography (HRCT), or worsening
dyspnea at rest or on exertion; 3) Diagnosis of UIP or
NSIP by either surgical lung biopsy or HRCT showing
definite or probable UIP or NSIP; 4) Abnormal pulmo-
nary function results (reduced FVC or decreased diffus-
ing capacity to carbon monoxide (DLco) or impaired gas
exchange at rest or with exercise and 5) Insidious onset
of otherwise unexplained dyspnea or exertion and bi-
basilar, inspiratory crackles on auscultation. Only pa-
tients with an FVC > 50% of predicted value at screening
and DLco > 30% of predicted value at screening were
enrolled. No patient had lung biopsy.
Patients were excluded who had clinical features sug-
gesting infection, neoplasm, sarcoidosis, ILD other than
UIP or NSIP, other collagen vascular disease, or expo-
sure to known fibrogenic drugs or environmental factors.
Other exclusions included FEV1/FVC ratio <0.6 at
screening (pre or post-bronchodilator), residual volume >
120% predicted at screening, history of unstable or dete-
riorating cardiac or neurologic disease, abnormal neu-
rologic examination, history of tuberculosis or test posi-
tive for human immunodeficiency virus or hepatitis B or
C, pregnancy or lactation, creatinine > 1.5x upper limit
of normal, and IgG and IgM levels below lower limit of
normal. Treatment exclusions included previous expo-
sure to cyclophosphamide, cyclosporine, interferon gam-
ma or beta, anti-tumor necrosis factor therapy, anti-IL1
therapy or with endothelin receptor blockers within the
last 8 weeks. Patients who had previously received ri-
tuximab or experimental therapy for RA were also ex-
cluded. No change of DMARD treatment within the last
3 months prior to trial enrollment was allowed.
2.2. Treatment
Rituximab 1000 mg was administered by intravenous
(i.v.) infusion on days 1 and 15 with repeat dosing at
weeks 24 and 26. All subjects received 100 mg of i.v.
methylprednisolone as premedication. Continuation of
DMARD treatment and oral prednisone established at
least 3 months prior to inclusion at a stable dose was al-
lowed. The use of systemic corticosteroid therapy was
permitted up to a dose of 15 mg/day during the study.
Administration of higher doses of corticosteroids at the
discretion of the patient’s primary physician was permit-
ted for a period not to exceed two weeks in the event of a
rapid clinical deterioration in clinical status.
2.3. Clinical Assessments
Measures of pulmonary efficacy and function including
the FVC, DLco and St. George’s respiratory questionnaire
were obtained at screening and at weeks 12, 24 and 48
[13]. HRCT was performed at screening and weeks 24 and
48. The HRCTs were independently assessed by a radi-
ologist expert in pulmonary radiology for ILD related
changes using a standard scoring system for ground glass
attenuation, reticulation, honeycombing, decreased atte-
nuation, centrilobular nodules, other nodules, emphysema
and consolidation on a 0 to 4 scale: 0 = no involvement, 1
= 1% - 25% involvement, 2 = 26% - 50% involvement, 3
= 51% - 75% involvement, 4 = 76% - 100% involvement
[8]. Health-related quality of life and function were as-
sessed with patient questionnaires, including the Medical
Outcomes Study Short Form 36 item instrument (SF-36),
the Health Assessment Questionnaire (HAQ), Clinical
Disease Activity Index (CDAI) and the 28 joint disease
activity score (DAS28).
2.4. Biomarkers
CD19 counts were measured at baseline and 12, 24, 36,
and 48 weeks.
2.5. Analytic Approach
The primary endpoint of the study was the safety of ri-
tuximab therapy in RA-ILD as assessed through patient
history, physical exams and laboratory parameters at 48
weeks. Secondary endpoints were assessment of progres-
sion-free survival at 48 weeks. Based on consensus rec-
ommendations, progression was defined as: decrease of
baseline FVC ≥ 10% (and at least ≥200-ml change), 15%
decrease in single-breath DLco or death from progressive
lung [7]. Other outcome parameters included radiographic

Open-Label, Pilot Study of the Safety and Clinical Effects of Rituximab in Patients with Rheumatoid
Arthritis-Associated Interstitial Pneumonia
55
progression over 48 weeks on HRCT, the St. George res-
piratory questionnaire, quality of life measures Medical
Outcomes Study SF-36, HAQ, DAS28 and CDAI.
3. Results
The study included 4 men and 6 women with mean age
64.7 years (range 43 to 80) who had RA (mean duration
13.8 years; range 0.4 to 44) and ILD (mean duration 3.2
years; range 0.0 to 7.5). Rheumatoid factor and/or anti
CCP antibody was present in 7/10 patients (pts). UIP was
present in 4 patients, and NSIP in 6. Medications at en-
rollment included prednisone (8 pts), methotrexate (4
pts), and sulfasalazine (1 pt).
Function and activity measures over the course of the
study are contained in Table 1. Baseline pulmonary
function included mean FVC 68% (min: 47%, max:
89%), mean DLco 47.6% (min: 28%, max: 73%), mean
FEV1/FVC ratio 86.5 (min: 68.8, max: 101), mean St.
George’s score 54.7 (min: 4.0, max 92.5; 0 = best, and
100 = worst), Mean SF-36 physical component score was
23.2 (min: 11.4, max: 43.5), and the mean mental com-
ponent score was 47.8 (min: 32.4, max: 57.3).
Changes in the function and activity measures are
contained in Table 1. By week 48, the DLco had wors-
ened by at least 15% (at least ≥3 ml/min/mm Hg) in 1
patient, was stable in 4 patients, and increased by >15%
of baseline in 2 patients. The FVC declined by at least
10% (and at least ≥200 ml) in 1 patient, was stable in 4
patients, and increased by at least 10% in 2 patients.
There was no clinically meaningful change in the St.
George’s respiratory score. Serial HRCT examinations
revealed improvement in 1 patient, and worsening in
another patient, with no changes noted on HRCT for the
other 5 patients assessed at week 48 (Table 2).
Among the 7 patients who reached week 48, 4 had
NSIP and 3 had UIP. Of the 3 UIP patents, 1 improved by
FVC and DLco and the other 2 remained stable by DLco,
FVC and HRCT. Of the 4 NSIP patients, 1 worsened
Table 1. Function and activity measures in patients with rheumatoid arthritis related intersitial pneumonia treated with ri-
tuximab.
Measure Baseline
N = 10
Week 12
N = 7
Week 12 change
from baseline
Week 24
N = 7
Week 24 change
from baseline
Week 48
N = 7
Week 48 change
from baseline
FVC, % 68 (47, 89) 80.5 (67, 100) 6.5%
(0%, 15%) 76.3 (51, 104)1.5% (–11%, 20%) 75.3 (50, 102) 2.4% (–12%, 17%)
DLco, % 47.6 (28, 73) 52.4 (35, 70) –0.5%
(–18%, 13%) 53.2 (33, 63) 15.3% (–7%, 54%) 52.0 (30, 75) 11.6% (–22%, 47%)
FEV1/FVC 86.5 (68.8, 101)88.4 (79.1, 109) 2.4%
(–5%, 8%) 91.5 (75.9, 115)3.4% (–4%, 14%) 88.1 (77, 109) 0% (–10%, 8%)
St. George’s
score 54.7 (4.0, 92.5) 50.6 (2.3, 85.5) 4.9% (–43%, 62%) 49.5 (5.0, 81.9)14.4% (–17%, 107%)51.5 (23.3, 68.5) 81.1% (–33%, 478%)
SF-36 physical
component score 23.2 (11.4, 43.5)26.7 (13.4, 42.7) 8.1% (–33%, 48%) 23.9 (17.5, 40.6)21.0% (–1%, 54%) 28.0 (19.6, 34.4) 37.0% (–31%, 116%)
SF-36 mental
component score 47.8 (32.4, 57.3)56.9 (47.7, 62.6) 7.3% (–2%, 20%) 50.0 (43.1, 64.3)–4.3% (–21%, 13%) 54.5 (39.0, 65.1) 9.9% (–10%, 62%)
DAS28 ESR 5.5 (2.2, 7.3) - - 4.6 (3.2, 6.8) –21.3%
(–42%, 9%) 3.3 (2.5, 4.4) –31.8% (–62%, 24%)
CDAI 32.5 (2.9, 54.7) –9.3, N = 1 –66%, N = 1 18.5 (2.1, 59.4)–12.4%
(–80%, 121%)10.4 (2.5, 24.6) –38.5% (–92%, 59%)
HAQ 1.2 (0.25, 2.375)0.8 (0.125, 1.625) 50.7%
(–67%, 200%)1.0 (0.375, 1.5)49.1% (–21%, 250%)1.0 (0.25, 1.5) 85.9% (–80%, 300%)
Values in table are means (minimum, maximum); N = Number, FVC = Forced vital capacity; DLco = Diffusing capacity of carbon monoxide; SF-36 = Medical
Outcomes Study Short Form 36; DAS = Disease activity score; ESR = Erythrocyte sedimentation rate; CDAI = Clinical disease activity index; HAQ = Health
assessment questionnaire.

Open-Label, Pilot Study of the Safety and Clinical Effects of Rituximab in Patients with Rheumatoid
Arthritis-Associated Interstitial Pneumonia
56
Table 2. Finding on high resolution computed tomography of the lungs.
Prior to base-
line (N = 8)
Baseline
(N = 10)
Week 24
(N = 7)
Week 48
(N = 7)
Nodular opacities 4 3 1 1
Size ≤ 5 mm 3 1 1 1
6 - 10 mm 0 1 0 0
>10 mm 1 1 0 0
Extent < 10% 3 2 0 0
10% - 40% 1 0 0 0
>40% 0 1 1 1
Irregular linear opacities 7 9 7 7
Extent < 10% 4 4 2 2
10% - 40% 3 5 5 5
>40% 0 0 0 0
Interlobular septa thickening 0 1 1 0
Ground glass infiltrates 5 9 7 6
Extent away from fibrosis 0%1 5 4 4
<10% 2 2 2 1
10% - 40% 2 2 1 1
>40% 0 0 0 0
Extent in areas of fibrosis 0% 0 3 2 1
<10% 4 3 3 3
10% - 40% 1 3 2 2
>40% 0 0 0 0
Consolidation 0 1 2 1
Emphysema 2 3 2 3
Extent < 10% 2 2 1 2
10% - 40% 0 1 1 1
>40% 0 0 0 0
Honeycombing 2 5 3 3
Extent < 10% 2 5 3 3
10% - 40% 0 0 0 0
>40% 0 0 0 0
Table 3. Individual patient pulmonary data at week 48 for 10 patients with rheumatoid arthritis related interstitial pneumo-
nia disease treated with rituximab.
Parameter Pt 1 NSIP Pt 2 NSIP Pt 3 UIP Pt 4 UIPPt 5 UIPPt 6 NSIPPt 7 NSIPPt 8 NSIP Pt 9 NSIP Pt 10 UIP
DLco S WD S S D D S W I I
FVC S WD S S D D I S W I
HRCT S WD S S D D S I W S
I = Improved; S = Stable; W = Worsened; D = Death, and WD = Withdrew from study. For DLco, worsening was defined as decrease of at least
15% and improvement was defined as increase of at least 15%. For FVC, worsening was defined as decrease of at least 10% and improvement was
defined as increase of at least 10%. Pt = Patient; FVC = Forced vital capacity; DLco = Diffusing capacity of carbon monoxide; NSIP = Nonspe-
cific interstitial pneumonitis; UIP = Usual interstitial pneumonitis.

Open-Label, Pilot Study of the Safety and Clinical Effects of Rituximab in Patients with Rheumatoid
Arthritis-Associated Interstitial Pneumonia
57
by FVC and HRCT but improved by DLco and another
worsened by DLco, 1 improved by FVC and 1 remained
stable by DLco, FVC and HRCT (Table 3).
Although not formally assessed, clinical joint disease
activity parameters including the mean DAS28 and
CDAI were improved in surviving patients by weeks 24
and 48. Mean Medical Outcomes Study Short Form 36
and Health Assessment Questionnaire scores were glob-
ally unchanged by weeks 24 and 48. As expected, CD19
counts dropped dramatically, from normal to zero or near
0 in most patients by week 24, and continued to be low at
week 48 (data not shown).
Three patients did not complete the 48 weeks study.
One patient had an infusion reaction with the first infu-
sion, and withdrew from the study. One patient was hos-
pitalized for congestive heart failure at week 5, unlikely
to be related to study drug, and later died at week 32 of
complications following a traumatic hip fracture. An-
other patient died at week 6 of possible pneumonia and
adult respiratory distress syndrome; a causative organism
was not recovered.
4. Discussion
The overall research objective of this study was to ex-
amine the course of patients with progressive RA-ILD
treated with rituximab by evaluation of safety and pro-
gression-free survival at 48 weeks following initial treat-
ment. Facing the current lack of clinical trial data in RA-
ILD, we expected also to gain important information on
the usefulness of potential study endpoints, the magni-
tude of response that can be expected in a clinical trial of
RA-ILD, and potential difficulties that can be associ-
ated with a certain trial design and the overall feasibility
of a full-scale randomized controlled trial.
In this pilot study of 10 patients with progressive
RA-ILD who were treated with conventional doses of
rituximab used in the management of RA, there were sig-
nificant adverse events including two deaths. Given the
small number of patients, the relationship of these events
to treatment vs. underlying disease is unclear. Of the 7
patients who reached week 48, only 1 could be said to
have improved, while 1 worsened and 5 were stable. Al-
though the numbers of patients in the study was small, it
could not be determined whether patients with NSIP or
UIP were more likely to respond.
As an aim of the study was to determine if use of this
therapy would result in improvement, it could be con-
cluded that there was not a signal for clinical efficacy of
this treatment for RA IP. However, 5 patients remained
stable, which may be of significance since worsening of
parameters of lung disease was a requirement for enroll-
ment into the trial. Nevertheless, it cannot be disregarded
that three patients did not complete the study, including
two patients who died. Of these noncompleters, the death
following the hip fracture was unlikely related to the
study drug, and it is uncertain whether the death at week
6 due to possible pneumonia and respiratory distress
syndrome was related to the study drug. Pulmonary tox-
icity to rituximab has been reported principally in pa-
tients receiving it for malignancy indications, with iso-
lated cases reported in rheumatoid arthritis [14,15]. In
general, the most common presentation is acute/subacute
hypoxemic organizing pneumonia starting 2 weeks after
the last infusion (often around the 4th cycle when given
weekly). Adult respiratory distress syndrome has also
been reported, usually within hours after the first infusion
[16]. In one survey of 45 patients with presumed rituxi-
mab pulmonary injury, 8 patients died [16].
Clearly, further research is needed to clarify whether
this treatment has a role in management of RA-ILD in
less advanced disease, or in specific histopathologic pat-
terns of disease. This research will necessarily include
the development of improved sets of outcomes for
evaluation of patients with RA-ILD [14].
5. Author Contributions
All authors were involved in drafting the article or re-
vising it critically for important intellectual content, and
all authors approved the final version to be published. Dr.
Matteson had full access to all of the data in the study
and takes responsibility for the integrity of the data and
the accuracy of the data analysis. Study conception and
design: Bongartz, Matteson, Ryu. Acquisition of data:
Matteson, Bongartz, Dellarippa. Analysis and interpreta-
tion of data: Matteson, Bongartz, Dellaripa, Hartman,
Ryu, Crowson.
6. Funding
Funding for this project was provided by the Mayo Clinic
Foundation, and was supported by NIH/NCRR CTSA
Grant Number UL1 RR024150. Its contents are solely
the responsibility of the authors and do not necessarily
represent the official views of the NIH. The study drug
was provided without cost by Genentech, Inc.
7. Acknowledgements
We would like to especially thank our study coordinators
Ms. Jane Jaquith and Jade Cumberbatch as well as the
staff of the Mayo Clinic Clinical and the Brigham and
Women’s Hospital Research Units for their time and
dedication in facilitating the conduct of this study.
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