86 AJTCCM VOL. 30 NO. 3 2024

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Background. Connective tissue disease-associated interstitial lung disease (CTD-ILD) that progresses despite rst-line immunosuppressive

therapy is a clinical challenge. Rituximab (RTX) is a chimeric monoclonal antibody targeted to CD20+ B cells, resulting in B-cell depletion,

and has been used as a salvage therapeutic modality in severe disease.

Objectives. To investigate the therapeutic eects and safety of RTX in patients with severe CTD-ILD.

Methods. A retrospective observational analysis of patients with severe CTD-ILD treated with salvage RTX therapy and various combinations

of immunomodulatory therapy at Wits Donald Gordon Medical Centre, Johannesburg, South Africa, between January 2010 and December

2020 was performed. A total of 19 patients with progressive CTD-ILD, sucient data, and 24-month follow-up were analysed. e eects

of adding salvage RTX to standard drug therapy were investigated with serial pulmonary function testing, high-resolution computed

tomography (HRCT) of the chest, and World Health Organization functional class (FC) assessment.

Results. At 24-month follow-up from baseline, there was no signicant deterioration in forced vital capacity (0.01 L; 95% CI –0.13 - 0.14)

(p=0.91) aer commencing RTX salvage therapy. Serial HRCT of the chest showed radiological disease stability or improvement in 13 of the

19 patients (68%). FC assessment showed no signicant deterioration compared with baseline (p=0.083). No serious adverse drug reactions

or deaths were recorded.

Conclusion. Salvage RTX therapy, in combination with various immunomodulatory treatments, resulted in disease stability in the majority

of patients with severe CTD-ILD over a 24-month period.

Keywords. Connective tissue disease, interstitial lung disease, drug therapeutics.

Afr J oracic Crit Care Med 2024;30(3):e1431. https://doi.org/10.7196/AJTCCM.2024.v30i3.1431

Connective tissue disease-associated interstitial lung disease

(CTD-ILD) is a complex and heterogeneous clinical entity, associated

with significant morbidity and mortality.[1] Anti-inflammatory

and immunomodulatory therapy has remained the cornerstone of

treatment and highlights the immunological dysfunction critical to

the underlying pathophysiology of the disease. Rituximab (RTX) is a

chimeric monoclonal antibody targeted to CD20+ B cells, resulting in

B-cell depletion.[2] On-label use of RTX in connective tissue disease

(CTD) not responding to rst-line disease-modifying antirheumatic

drugs is currently limited to rheumatoid arthritis (RA), granulomatosis

with polyangiitis, and microscopic polyangiitis.[3,4] However, RTX has

been utilised as salvage therapy in refractory or severe CTD-ILD and

has been shown to improve outcomes in observational studies.[5]

Severe CTD-ILD may manifest with progressive disease despite

maximal conventional first-line therapy, such as corticosteroids

and other immunosuppressives, and is associated with increased

morbidity and mortality. Pulmonary antibrotic drugs, the use and

ecacy of which were originally studied in idiopathic pulmonary

Rituximab therapy in severe connective tissue disease-

associated interstitial lung disease: A retrospective single-centre

observationalstudy

U F Seedat,1 MB BCh, FCP (SA), MMed (Int Med) ; B Christian,1 MB BCh, FCP (SA);

P E Bosho,2 MB ChB, FC Rad (SA) Diag; P Gaylard,3 MSc (Statistics), PhD;

G K Schleicher,1 MB BCh, DTM&H, MMed (Int Med), FCP (SA), Cert Pulm (SA), FCCP

1 Wits Donald Gordon Medical Centre, University of the Witwatersrand, Johannesburg, South Africa

2 DGMC Radiology, Wits Donald Gordon Medical Centre, University of the Witwatersrand, Johannesburg, South Africa

3 Data Management and Statistical Analysis, Johannesburg, South Africa

Corresponding author: U F Seedat (ubaidseedat@gmail.com)

Study synopsis

What the study adds. Connective tissue disease-associated interstitial lung disease (CTD-ILD) is a challenging clinical entity. Rituximab

(RTX), a chimeric monoclonal antibody targeted to CD20+ B cells, resulting in B-cell depletion, has been suggested as a potential therapeutic

modality in refractory or severe disease. A single-centre experience of RTX salvage therapy in progressive CTD-ILD is presented.

Implications of the ndings. is small study suggests a possible role for RTX therapy in severe or refractory CTD-ILD.

AJTCCM VOL. 30 NO. 3 2024 87

ORIGINAL RESEARCH: ARTICLES

brosis,[6] are reserved for patients with established and progressive

pulmonary brosis.[7,8] Lung transplantation remains an option in a

minority of patients. However, advanced multisystem disease, lack of

organ availability, and a paucity of local transplant centres severely

limit this therapeutic option. Data on specic predictors of prognosis

and mortality in progressive CTD-ILD are limited.[9]

e use of RTX in CTD-ILD has evolved over the past decade.[5,10-

12] Its use, albeit limited by small studies and o-label use, has shown

potential as a feasible treatment option in slowing disease progression.

Although conventional immunosuppressive drugs have remained the

cornerstone of care in CTD-ILD, certain subgroups may require novel

drugs as salvage therapy.

is retrospective case series analyses 19 patients with refractory

CTD-ILD over a 24-month period aer the rst dose of RTX. All

patients were treated at Wits Donald Gordon Medical Centre

(WDGMC), Johannesburg, South Africa, between January 2010

and December 2020. e response to RTX was measured by serial

pulmonary function testing (PFT), high-resolution computed

tomography (HRCT) of the chest, and World Health Organization

(WHO) functional class (FC) assessment.[13]

Methods

We performed a retrospective review of a patient database managed

at a multidisciplinary clinic at WDGMC comprising pulmonologists,

rheumatologists and radiologists. Among 50 patients treated with

RTX between January 2010 and December 2020, 19 patients with

progressive CTD-ILD, 24-month follow-up and complete data were

identied. Allthe patients were aged ≥18 years, had a diagnosis of

CTD-ILD made by a multidisciplinary team (MDT) consensus based

on standardised criteria (European Alliance of Associations for

Rheumatology (EULAR)/American College of Rheumatology (ACR)

[14]), and had received at least one dose of RTX.

PFTs included the forced vital capacity (FVC) and diusion capacity

for carbon monoxide (DLCO). Data were collected at baseline prior to

RTX therapy, and at regular intervals up to 24 months from initiation

of RTX therapy.

e chest HRCT ndings were standardised based on radiological

criteria of CTD-ILD and MDT consensus. e radiological interstitial

lung disease (ILD) subtypes were described prior to RTX therapy

and at 6 - 12-monthly intervals up to 24 months. A qualitative visual

descriptive assessment was performed based on an MDT discussion,

and the terms ‘stabilisation’, ‘improvement’ or ‘progression’ of ILD

based on HRCT ndings were used. Baseline HRCT images were

compared with follow-up images side by side, noting identical

anatomical slices. Stabilisation of disease was dened as no change

in the severity of brosis and/or ground-glass opacities compared

with baseline HRCT. Progression of disease was dened as increasing

fibrosis and/or worsening ground-glass opacities compared with

baseline HRCT. Semi-quantitative and quantitative scoring systems

were not utilised.[15]

A subjective patient functional assessment was performed based on

the World Health Organization FC assessment (I - IV).[13] Values were

recorded at baseline and then at 12 and 24 months, FC I indicating

no limitation of ordinary physical activity, FC II slight limitation or

breathlessness on ordinary physical activity, FC III marked limitation

on ordinary physical activity, and FC IV discomfort or breathlessness

at rest.

Statistical analysis included the extent of the change in PFT outcome

from baseline to 24-month follow-up by repeated measures one-way

analysis of variance (ANOVA). e change in FC from baseline to

24-month follow-up was determined by the Stuart-Maxwell test for

paired categorical data. HRCT ndings of the chest could not be

analysed statistically owing to limited data points. Data analysis was

carried out using SAS version 9.4 for Windows (SAS Institute, USA).

A 5% signicance level was used.

Ethical considerations

Ethics approval was granted by the University of the Witwatersrand

Human Research Ethics Committee (ref. no. M220104).

Results

Nineteen patients, with a median age of 54 years (range 22 - 77),

were included during the period January 2010 - December 2020. e

Table1. Baseline demographics (N=19)

Characteristic n (%)*

Age (baseline) (years)

Median (IQR) 54 (40 - 60)

Range 22 - 77

Gender

Female 14 (74)

Male 5 (26)

CTD prole

RA 9 (47)

SSc 4 (21)

SLE 3 (16)

ASS 1 (5)

DM 1 (5)

Mixed CTD 1 (5)

Antibody prole, n

ANA titre 1:80 1 (centromere 1)

ANA titre 1:160 4 (centromere 1, homogeneous 1,

speckled 2)

ANA titre 1:320 2 (centromere 1, speckled 1)

ANA titre 1:640 3 (homogeneous 1, nucleolar 2)

ANA titre 1:1 280 1 (speckled 1)

ANA titre 1:2 560 3 (nucleolar 1, speckled 2)

RF 11

Anti-CCP 4

Anti-centromere 2

Anti-Ro-SSA 2

Anti-SCL-70 2

Anti-JO-1 1

IQR = interquartile range; CTD = connective tissue disease; RA = rheumatoid arthritis;

SSc = systemic sclerosis; SLE = systemic lupus erythematosus; ASS = anti-synthetase syndrome;

DM = dermatomyositis; ANA = antinuclear antibody; RF = rheumatoid factor;

anti-CCP = anti-cyclic citrullinated peptide; anti-ro-SSA = anti-Sjögren’s-syndrome-related

antigen A; anti-SCL-70 = anti-topoisomerase I antibody; anti-JO-1 = anti-histidyl tRNA

synthetase.

*Except where otherwise indicated.

88 AJTCCM VOL. 30 NO. 3 2024

ORIGINAL RESEARCH: ARTICLES

patients’ CTD diagnosis and ILD pattern were

determined by an MDT consensus based on

standardised international criteria (EULAR/

ACR). Baseline demographics and disease

prole were recorded (Table1).

Pre-rituximab therapy

Immunosuppressive therapy administered

prior to and concurrent with RTX was

recorded and compared (Fig.1). All patients

received corticosteroids, as well as initial

induction therapy with cyclophosphamide,

mycophenolate mofetil, or both. Various

immunosuppressive drug combinations were

used according to the patients’ underlying CTD.

Decision to treat with rituximab

e addition of RTX was based on clinical,

radiological and biochemical factors

indicating disease progression despite rst-

line induction immunosuppressive therapy.

These factors included clinical disease

progression as well as objective measures

such as PFT indices and HRCT findings.

Despite a paucity of pre-RTX data owing to

patients being referred from other centres,

the baseline indices of the cohort were

comparable to those observed in other

studies.[10,11] The MDT decision to initiate

RTX therapy also took into account limited

published evidence at the time regarding the

use of RTX, its availability and safety prole,

the need for additional therapeutic modalities,

and the risks of long-term corticosteroid and

cyclophosphamide exposure.

Drug administration

RTX administration was in accordance with

the registered product information for RA. A

dose of 1000 mg is given intravenously and

then repeated aer 2 weeks.[4,16] is dosing

protocol was repeated at 6-monthly intervals.

e degree of B-cell depletion was monitored

using a high-sensitivity flow cytometry

technique. Over the 24-month period, 16 of

the 19 patients (84%) received all scheduled

doses (eight doses totalling 8 g), 1 patient

received six doses (total of 6 g), and 2 patients

received four doses (total of 4 g).

Post-rituximab treatment course

Pulmonary function testing

Serial spirometry ndings were analysed for

all 19 patients. At the 6-month follow-up from

baseline (Table2), the mean change in FVC

was not signicantly dierent from baseline

values (p=0.41). At the 24-month follow-up

from baseline (Table2), the mean change

in FVC was again not signicantly dierent

from baseline values (p=0.91). Owing to

incomplete data, DLCO values could not be

analysed statistically. e available PFT data

were plotted throughout the RTX therapy

study period (Figs 2 and 3).

High-resolution computed tomography of the

chest

Interstitial lung disease patterns of the

19-patient cohort were described by

radiological criteria as per the ocial European

Respiratory Society/American Thoracic

Society research statement.[17] Open lung

biopsy was not performed owing to the high

surgical risk in patients with progressive ILD.

Baseline HRCT patterns were reported in all

patients: 15 patients (79%) had a radiological

pattern consistent with nonspecic interstitial

pneumonia (NSIP), and 4 (21%) a pattern

consistent with usual interstitial pneumonia

(UIP). During RTX therapy, serial HRCT scans

of the chest were performed in all 19 patients

and radiological changes were documented.

Owing to missing data and the small sample

size, statistical analysis was not feasible. e

radiological changes of ILD were described

as improvement, stability or progression of

disease by a single radiologist with experience

in CTD-ILD (Fig.4).[15]

Functional class assessment

Serial FC changes using the WHO

classication were assessed in all 19 patients.

FC did not dier signicantly from baseline

to 24 months (p=0.083) (Fig.5).

Patients, %

Drug

Prior to RTX treatment Concurrent with RTX

20 40 60 80 100

Corticosteroid

Chloroquine

Cyclophosphamide

Azathioprine

Methotrexate

Salazopyrin

Mycophenolate mofetil

Leunomide

Fig.1. Drug therapy prior to and concurrent with RTX. (RTX = rituximab.)

Table2. Disease parameters, baseline and at 6- and 12-month follow-up

PFT index

Baseline, median (IQR);

range

6-month follow-up,

mean change (95% CI)

24-month follow-up,

mean change (95% CI)

FVC (L) 2.2 (1.4 - 2.8); 0.52 - 3.6 0.09 (–0.14 - 0.32) 0.01 (–0.13 - 0.14)

PFT = pulmonary function test; IQR = interquartile range; CI = condence interval; FVC = forced vital capacity.

AJTCCM VOL. 30 NO. 3 2024 89

ORIGINAL RESEARCH: ARTICLES

Adverse events

No significant or life-threatening adverse

events related to drug therapy were recorded.

ere were no patient deaths during the study

period.

Discussion

ILD remains a common and important

manifestation of CTDs and is associated with

signicant morbidity and mortality.[2] Early

identification of CTD-ILD has pertinent

clinical implications regarding therapeutic

modalities. e presence of ILD in CTD is an

independent factor associated with decreased

survival, with 5-year mortality rates exceeding

10% (10 - 39%).[18-20] Parameters utilised

to assess the response to therapy include

PFT, HRCT of the chest, FC and clinical

symptoms. The primary goal of treatment

in this clinical scenario is to halt disease

progression, preserve pulmonary function,

and prevent associated complications and

mortality. Current rst-line therapies consist

of corticosteroids and immunomodulatory

drugs such as azathioprine, mycophenolate

mofetil and cyclophosphamide.[19] The

underlying dysregulated immune response

to host tissue highlights how modulation

of autoimmunity remains key to disease

control.[20] RTX, a chimeric monoclonal

antibody targeted to CD20+ B cells, results

in B-cell depletion,[3] causing a decrease

in humoral-mediated autoimmunity and

associated tissue damage.[21]

We report our experience of RTX use in

CTD-ILD in a patient cohort at WDGMC,

adding to the limited data available on its use

in our geographical setting. Data emerging

during the preceding decade have highlighted

RTX as a potential drug choice in severe or

refractory CTD-ILD. A retrospective analysis

by Keir etal.[5] in 2012 concluded that 7 out

of their 8-patient cohort showed a favourable

response to RTX. More recent evidence from

Atienza-Mateo etal.[11] concluded that RTX

constitutes a promising therapeutic option to

preserve lung function in patients with CTD-

ILD, regardless of their underlying pattern

of CTD or radiological prole. e Recital

trial published in 2023 compared RTX with

cyclophosphamide as induction therapy in

patients with CTD-ILD and demonstrated

non-superiority of RTX, although RTX was

associated with fewer adverse events.[12]

Our cohort of patients had varied CTD

proles, with RA being the most common

diagnosis (n=9). As a whole, the patient

cohort had significantly impaired baseline

indices despite prior treatment with rst-line

therapies, with values comparable to other

studies.[10,11] All patients had received at least

four other immunosuppressive drugs prior to

the decision to start RTX. e majority of our

patients achieved disease stability of severe

CTD-ILD, which is considered a positive

response to treatment in this challenging

clinical scenario. e progressive decline in

pulmonary function stabilised, with a mean

decrease in FVC from baseline of 0.01 L (95%

CI –0.13 - 0.14) at the 24-month follow-up.

Radiological features of CTD-ILD can be

assessed qualitatively. In the present study,

we relied on visual descriptive changes of ILD

on HRCT interpreted by a single experienced

radiologist. HRCT findings were used in

combination with other clinical parameters

to assess the course of disease. At 24 months’

follow-up, 17 patients had HRCTs available

for review. Of these, 13 were interpreted as

disease stability, 3showed disease progression,

and 1 showed improvement. Most of the

benefit appeared to be in the radiological

NSIP group, with progressive disease seen in

3 of the 4 patients with radiological UIP.

Baseline

FVC (L)

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.0

6m 12m 18m 24m

Time of assessment

Fig.2. FVC changes over time (24 months). (FVC = forced vital capacity.)

Time of assessment

Baseline 6m 12m 18m 24m

DLCO (%)

Fig.3. DLCO changes over time (24 months). (DLCO = diusion capacity for carbon monoxide.)

90 AJTCCM VOL. 30 NO. 3 2024

ORIGINAL RESEARCH: ARTICLES

The WHO FC assessment (I - IV) for

eort tolerance was utilised as a subjective

measure of functional impairment. Results

were varied, with some patients reporting

symptomatic improvement while others had

progressive functional impairment. Overall,

FC did not show signicant worsening from

baseline to 24 months’ follow-up (p=0.083).

Another important aspect of our study was

the analysis of immunosuppressive drug use

prior to and concurrent with RTX treatment.

RTX therapy was associated with use of fewer

concurrent drugs, possibly mitigating other

drug-related adverse events.

Limitations of our study include the

small sample size, a single-centre cohort

of patients, limited statistically significant

ndings and subgroup analysis, the absence

of histological diagnosis, lack of a control

group, non-standardised immunosuppressive

drug therapies, and the retrospective design

of the study. Insucient pre-RTX data points

also prevented plotting of the trend of clinical

decline prior to RTX use. Despite these

limitations, our study suggests that RTX is a

promising therapeutic option in a challenging

patient population, with stabilisation of FVC

decline and functional impairment. Our data

add to the growing pool of evidence that RTX

can be considered in progressive CTD-ILD,

with an acceptable safety prole.

Conclusion

We report our experience of RTX in

severe and progressive CTD-ILD at our

centre. The addition of RTX to first-line

immunosuppressive therapy as a salvage

therapeutic modality may result in disease

stability as measured by radiological changes,

PFT and subjective measures of disease

severity. Further studies are required to

investigate the role of RTX as a therapeutic

option in the challenging clinical scenario of

severe CTD-ILD.

Declaration. e research for this study was done

in partial fullment of the requirements for UFS’s

MMed (Int Med) degree at the University of the

Witwatersrand.

Acknowledgements. We thank the WDGMC

Research Oce and its sta, DGMC Radiology,

Dr Sue Tager, and the patients under the care of

the attending physicians.

Author contributions. UFS collected and collated

data, drew up the protocol and manuscript. GKS

served as the primary supervisor and manuscript

editor. GKS and BC provided the data set. PEB

reported the HRCT scans and assisted with the

interpretation of radiological data. PG assisted

with data interpretation, statistical analyses, and

preparation of the gures.

Funding.None.

Conicts of interest.None.

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Received 23 August 2023. Accepted 14 June 2024. Published 11 October 2024.