AJTCCM VOL. 30 NO. 3 2024 83
EDITORIAL
In a single-centre 11-year retrospective analysis, Seedat etal.[1] report their
experience using rituximab (RTX) as salvage treatment in 19patients
with progressive connective tissue disease-associated interstitial lung
disease (CTD-ILD), followed up for 24 months. estudy population
comprised 9 patients with rheumatoid arthritis (RA), 4with systemic
sclerosis (SSc), 3 with systemic lupus erythematosus (SLE), 1 with
anti-synthetase syndrome, 1 with dermatomyositis and 1 with mixed
connective tissue disease (MCTD). e majority (79%) had nonspecic
interstitial pneumonia (NSIP), while the remainder had usual interstitial
pneumonia (UIP). None of the patients received antibrotic therapy.
e impact of RTX was assessed on follow-up with pulmonary function
tests, high-resolution computed tomography of the chest (HRCT) and
World Health Organization (WHO) functional class. Notwithstanding
the limitations of a small retrospective study, it is noteworthy that over
the 2-year period, forced vital capacity (FVC) stabilised (mean decrease
from baseline 100 mL), the majority of the patients (82%; n=14/17)
showed no radiological progression, and overall there was no decline
in WHO functional class. No signicant adverse drug eects were
observed.
RTX is a humanised mouse chimeric monoclonal antibody directed
against CD20, a transmembrane protein expressed on B cells[2] rst
approved for the treatment of B-cell non-Hodgkin’s lymphoma in
1997. CD20 is expressed by normal pre-B and mature B lymphocytes,
but not stem cells or plasma cells.[3] The resulting depletion of
Bcells following administration of RTX lasts ~2 - 6 months before
gradual recovery to normal levels at 9 - 12 months.[2,4] Not only does
this drug aect B cells and humoral immunity, but it also aects
cellular immunity by depleting CD4+ T cells.[5] B cells are central
to the pathogenesis of autoimmune diseases. Interestingly, it has
recently been shown in vitro that B-cell-broblast crosstalk probably
plays a role in the pathogenesis of idiopathic pulmonary brosis by
upregulating brotic proteins.[6,7]
In a review of 29 studies (22 retrospective, 4 prospective, 3randomised
controlled) involving 827 patients with CTD-ILD, Wang and Li[8] found
that in the observational studies, there was a decline in FVC percent
predicted and diusing capacity for carbon monoxide (DLCO) percent
predicted following administration of RTX. However, in the randomised
controlled trials, while FVC percent predicted declined, there was no
impact on DLCO percent predicted. e radiographic ILD pattern was
documented in only 242 patients, of whom 58.7% had an NSIP pattern.
RTX was associated with an increase in adverse events (29.7%), all-
cause mortality (11.6%) and infections (20.9%).
In a comprehensive overview of RTX in CTD-ILD, Vacchi etal.[9]
conclude that RTX has been shown to stabilise or improve ILD in RA,
idiopathic inammatory myositis (IIM) and SSc. However, for ILD
in Sjögren’s syndrome, SLE and antineutrophil cytoplasmic antibody-
associated vasculitis, the evidence is tenuous.
ere have been two recent randomised controlled trials involving
RTX in CTD-ILD. In RECITAL,[10] a multicentre UK prospective
randomised double-blind phase 2b study, 97 patients with ILD
associated with SSc, IIM or MCTD were randomised to receive either
RTX or cyclophosphamide. A real-world pragmatic selection of study
participants was employed. Extrapolating from guidelines for SSc-ILD,
the investigators selected patients with severe or progressive ILD for
whom cyclophosphamide would have been the next conventional
therapeutic option. Both drugs improved lung function (gain of
99mL and 97 mL for FVC in the cyclophosphamide and RTX arms,
respectively) and quality of life scores at 24 weeks. RTX was not superior
to cyclophosphamide, but was associated with fewer adverse events and
less corticosteroid exposure.
e second trial, EVER-ILD,[11] a phase III trial, compared RTX plus
mycophenolate mofetil (MMF) with MMF plus placebo in 122 patients
with CTD-ILD (SSc, IIM, Sjögren’s syndrome, RA, MCTD), ILD with
autoimmune features, and idiopathic interstitial pneumonia. Only
patients with an NSIP pattern who had demonstrated no response, or
relapsed following corticosteroids and/or immunosuppressive drugs,
were included. This study showed superiority of RTX plus MMF
over MMF alone, indicated by improvement in FVC at 6 months
(~3.6percent predicted and 100 mL) and longer progression-free
survival (crude hazard ratio 0.47). ere was no dierence in 6-minute
walk distance, DLCO, dyspnoea, cough or brosis on HRCT. However,
the combination therapy group experienced more infections.
Since not all patients with CTD-ILD respond to RTX, it would be
useful to predict which patients are likely to benet. An innovative
prospective phase II study[12] utilised immuno-positron emission
tomography (PET)/CT with RTX radiolabelled with 89Zr to determine
levels of CD20 cells in the lung. In 21 patients with progressive
ILD non-responsive to corticosteroids and either azathioprine or
cyclophosphamide, those who had a clinical response to RTX also had
higher lung uptake of 89Zr-rituximab at baseline, suggesting that this
technique may be a predictive biomarker for selection of patients likely
to respond to RTX.
Biological drugs are not innocuous. Adverse eects to RTX include
fever, chills and ushing, which usually occur within the rst 2 hours
of infusion of the drug. Other side-eects include nausea, vomiting,
hypotension, angio-oedema, bronchospasm and chest pain. Infectious
complications are reportedly not very frequent or severe. However,
the administration of RTX in patients with autoimmune disease was
associated with an increased risk of severe COVID-19 pneumonia
during the pandemic.[13] Both RECITAL and EVER-ILD were
conducted prior to COVID-19 . Haematological derangements include
late-onset neutropenia (3 - 4 weeks after infusion),[14,15] transient
thrombocytopenia[4] and hypogammaglobulinaemia. e latter may last
up to 2 years following exposure and rarely necessitates administration
of intravenous immunoglobulin.[15] Athni and Barmettler[15] emphasise
the importance of monitoring immunoglobulin levels, a practice
frequently neglected by prescribing practitioners.
RTX-induced lung injury is a rare complication that had not been
reported prior to approval of the drug.[3,16-18] e pathogenesis is possibly
related to complement activation and the release of inflammatory
cytokines such as tumour necrosis factor alpha, interleukin 8 and
interferon gamma. In a systematic review of 45patients receiving RTX,[3]
e promise of rituximab in connective tissue disease-associated
interstitial lung disease
84 AJTCCM VOL. 30 NO. 3 2024
EDITORIAL
the most common histological nding was organising pneumonia with
or without associated NSIP or UIP. Intra-alveolar haemorrhage[19] and
a host of other pathological ndings have also been described.[20] e
onset of pulmonary toxicity may be hyperacute (within hours), delayed
(days 8 - 21) or late (1-3 months).[3] In general, withholding RTX
and administration of corticosteroids results in recovery, although
deaths have been reported.[3,21] It is noteworthy that almost all cases
of RTX-induced lung injury have been documented in association
with lymphoma and other haematological malignancies. ere are no
convincing reports of RTX-induced lung injury superimposed upon
pre-existing ILD for which RTX had been administered, although some
authors speculate that some cases may be subclinical or erroneously
attributed to progression of severe ILD.[22,23] This discrepancy may
perhaps be related to the dierent dosage and therapeutic regimens used
in autoimmune diseases as opposed to haematological malignancies.
Other rare adverse effects[24] include reactivation of hepatitis B,
progressive multifocal leucoencephalopathy and toxic epidermal
necrolysis. Administration of live vaccines is contraindicated within
4weeks of, or during, RTX treatment. Other vaccines should be given at
least 4 weeks before a dose of RTX is administered. Safety in pregnancy
and lactation is unknown.
Analysis of the eect of RTX in CTD-ILD is confounded by several
factors. RTX is oen used as a ‘last resort’ when more conventional
therapies have failed; ILD patterns, severity and evolution dier within
the same CTD disease; reports generally involve small retrospective case
series; patients oen receive other concomitant immunomodulating
drugs; and the multisystem nature of many CTDs may complicate the
interpretation of data.
Biological drugs such as RTX hold promise for the management
of CTD-ILD and represent progress in personalised medicine. A
signicant limiting factor, however, is their prohibitive cost. Accessibility
to biological agents remains limited in South Africa, not only in the state
sector but even in the private sector.[25] Fortunately, a biosimilar of RTX
has been registered, a welcome cost-reducing advantage for patients and
clinicians.
Further prospective studies of RTX are warranted in the eld of CTD-
ILD. e ndings of RECITAL and EVER-ILD are likely to prompt
trials utilising this drug earlier in the therapeutic algorithm, and in
combination with other already established therapies.
M L Wong, MB BCh, FCP (SA), FCCP, FRCP (Lond)
Division of Pulmonology, Department of Medicine, Chris Hani Baragwanath
Academic Hospital and School of Clinical Medicine, Faculty of Health Sciences,
University of the Witwatersrand, Johannesburg, South Africa
michelle.wong1@wits.ac.za
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