Autor : Silvia Quadrelli1, 3, Diana Dubinsky1, 4, Sabrina Alvarez2
1 Fundación Sanatorio Güemes – Buenos Aires
2 Hospital Central de Mendoza
3 Hospital Británico de Buenos Aires
4 Hospital de Clínicas - Buenos Aires
Correspondencia : Silvia Quadrelli Mailing address: Gallo 1527, 6th foor. CABA (CP 1425) Telephone number: 48211117 E- mail: silvia.quadrelli@gmail.com
Abstract
Except for SSc, there are no controlled clinical trial data available to guide decision making in CVD-ILD. To date, only two powered, randomized controlled trials of treatment have been conducted in scleroderma patients; with both of these assessing the benefit of cyclophosphamide compared with placebo for the treatment of scleroderma-related interstitial lung. Currently accepted initial treatments in CVD-ILD include corticosteroids, azathioprine and mycophenolate mofetil for mild disease, while cyclophosphamide has been used in severe or rapidly progressive disease. However, an optimal general approach or specific criteria for the selection of each different treatment modality, is not completely defined. During the last decade, rituximab (RTX), has been used in the treatment of a interstitial lung disease associated to connective tissue diseases (ILD-CTD) . A recent study including 50 cases of severe and refractory ILD showed that RTX therapy resulted in an an improvement of 8.9% of the FVC. Several small retrospective studies have shown at least partial benefit of RTX in refractory PM/DM, including antisynthetase syndrome (ASS) . RTX may have a role in specific subsets of CVD-ILD. Further studies are needed, but there is enough evidence to consider RTX as a suitable and safe option for the treatment of severe, relapsing or refractory patients. Several other biologic agents are now being studied in CVD, including tocilizumab that has shown a possible therapeutic benefit in patients with CVD-ILD.
Key words: Interstitial lung disease; Autoimmune disease; Immunosuppression; Biological agents; Rituximab
The collagen vascular diseases (CVDs) are a
heterogeneous group of autoimmune disorders
withmultiple manifestations. Many of these disorders have a frequent pulmonary involvement,
especially interstitial lung disease (ILD). It may
estimated that no less than 15% of patients presenting for evaluation of ILD have an underlying
completely defined CVD1.
The frequency and histologic type of ILD vary
with the nature of the underlying CVD. The most
commonly ILD CVD-associated include rheumatoid
arthritis(RA), Progressive Systemic Sclerosis(SSc),
Dermatomyositis/Polymyositis(DM/PM), antisynthetasesyndrome(AS), mixed connective
tissue disease (MCTD) and less frequently Sjögren
syndrome (SS)2.
Some epidemiological studies show a pulmonary
involvement in 40-90% of patients with Systemic
Sclerosis (SSc) and 30-70% of patients with polymyositis/dermatomyositis, but no doubt, ILD is
most commonly observed in SSc and myositis
patients. In those patients, the finding of ILD is as
high as 90-100% of autopsy studies and the development of clinical interstitial pneumonia is common
although many times often subclinical. Around
40-75% show an impaired pulmonary function and 55-85% of patients have interstitial abnormalities
on high-resolution computed tomography (HRCT)
of the thorax3, 4.
The more common patterns of ILD encountered in patients with CVD include usual interstitial pneumonia (UIP),nonspecific interstitial
pneumonia(NSIP)organizing pneumonia(OP),
lymphoid interstitial pneumonia (LIP), and acute
interstitial pneumonia(AIP)5.
Given the high prevalence of subclinical ILD in
CTDs, it is important to determine the degree of
respiratory impairment in all patients with CTD-ILD. The decision to treat CTD-ILD is often based
on whether the patient sows clinical impact of the
ILD; whether the ILD is progressive by symptoms,
pulmonary function, and/or imaging; and not less
important, if therapy is required for the extrathoracic features of the disease6.
When considering the general approach to the
management of CTD-ILD, the concept commonly
applied in systemic vasculitis considering a phase
of induction followed by maintenance therapy, is
the most common approach. Induction therapy
usually includes high dosing of corticosteroids
(CSs) with the addition of a short-term use of a
more potent (and potentially more toxic) agent
such as cyclophosphamide (CYC) followed by a
maintenance regimen with a less toxic agent (such
as AZA or MMF) and CS tapering. It must be reminded that because of the often-poor prognosis
associated the stabilization of the disease is considered a successful outcome, and the cost-benefit
of the different therapeutic approaches must be
discussed in this setting not only into the multidisciplinary team (MDT) but mainly with patients.
Except for SSc, there are no controlled clinical
trial data available to guide decision making in
CTD-ILD. Being a heterogeneous group of patients, it is hard to generate evidence based data
and, being realistic, recruitment to trials is challenging and will be difficult to have powered studies that provide such evidence in the short term.
Most available information come from registries,
case series or individual case reports. To date,
only two powered, randomized controlled trials
of treatment have been conducted in scleroderma
patients; with both of these assessing the benefit
of cyclophosphamide compared with placebo for
the treatment of scleroderma-related interstitial
lung disease (ILD)7,8. Thus, there is much that is
unknown regarding optimal treatment of other CTD-related pulmonary disease and even in scleroderma patients, the magnitude of the effect of the
studied treatments, the optimal dose and length
of therapy and the potentially different groups of
patients with different rate of responses is a nonanswered challenge.
In the absence of evidence supporting disease
modifying effects of aggressive treatment of
CTD-ILD and taking into account the potential
toxic effects of immunosuppressant treatment,
the majority of clinicians tend to base their therapeutic decisions on disease severity and the level
of functional impairment experienced by the affected patient. The underlying histological pattern, may preduct prognosis, and, only to a certain
extent, predicts response to treatment. Organizing
pneumonia and cellular NSIP can be expected to
improve or even regress with therapy, and, on the
other hand, the presence of UIP, characterized by
marked architectural destruction predicts no hope
of regression with treatment making stabilization
of disease and slowing of further decline the best
potential outcome.
Currently accepted initial treatments in CTD-ILD include corticosteroids, azathioprine and
mycophenolate mofetil for mild disease, while
cyclophosphamide has been used in severe or
rapidly progressive disease. However, an optimal
general approach or specific criteria for the selection of each different treatment modality, is not
completely defined.
Although, corticosteroids are very widely used
in the management of CTD-associated pulmonary disease, there are few evidence-based data
about their usefulness or to define their use. The
dose and route of corticosteroid administration is
guided mainly by expert opinion, and by reference
to data generated from nonpulmonary disease.
Azathioprine shows an immunosuppressant
effect through inhibition of T- and B-lymphocyte
proliferation. Although, commonly used in combination with oral corticosteroids in the treatment
of CTD-ILD, azathioprine has not been studied as
monotherapy in any prospective randomized trials. On the other hand, the information available
based on RCT is only about scleroderma. In the
study by Hoyles et al of intravenous cyclophosphamide, azathioprine (at a dose of 2.5 mg/kg/d)
was used as maintenance therapy for 6 months
following initial treatment with intravenous cy-clophosphamide7.
Cyclophospamide is the drug of choice for induction therapy in patients with severe or progressing disease. In the placebo-controlled trial of oral
cyclophosphamide in SSc-ILD, beneficial effects
at 1 year on FVC levels, dyspnea, skin thickening, and quality of life were statistically better in
the treatment group8. In a subsequent placebo-
controlled study of intravenous cyclophosphamide
(once a month for 6 months), followed by oral
azathioprine, the the magnitude of the benefit on
FVC was similar to those seen in the Taskin trial.
HOwever, because of the small size of the sample
(n = 45), those results were nor definetely significant (p = 0.08)7. Based on these two studies, it was
concluded in a EULAR statement that cyclophosphamidewas an appropriate therapy in SSc-ILD9.
It must be remarked that no treatment effect was
observed in the SLS trial in those patients with
mild disease on HRCT, but the treatment effect on
FVC was more significant when the disease was
extensive and fibrotic8.
MMF is also a quite well established option for
patients with mild disease, maintenance therapy
or contraindication for corticosteroids. MMF
has been shown to be well tolerated in systemic
sclerosis with retrospective studies suggesting
that the drug has favorable effects on systemic
manifestations of disease10, 11, 12. The scleroderma
lung study (SLS) II is currently evaluating the effect of MMF as first-line therapy compared with
cyclophosphamide in scleroderma ILD in a 2- year
randomized controlled trial (NCT00883129).
Recent advances presented as an abstract at the
CHEST meeting 2015 showed at 24 months the
improvement in %FVC was comparable in the two
treatment groups but leukopenia/thrombocytopenia were noted significantly less frequently in the
MMF arm13.
Given the scarcity of evidence-based data to
select any treatment and the only partially successful reported results, new therapies have been
explored in the last years. Initially investigated for
refractory or very severe disease, those new options
are being considered for a wider population and
even as first line therapies and not only following
the failure of the more conventional treatment.
The scenario of CVD-ILD is that of a group of potentially life-threatening diseases whose available
treatments are associated with serious adverse
effects and heterogeneous responses to treatment.
New options with better rates of response and fewer side effects are an urgent need in CVD-ILD
patients.
During the last decade, rituximab (Rtx), an
anti-CD 20+ mAb, has been used in the treatment of a several rheumatic inflammatory diseases. Rituximab, a chimeric (human/mouse)
monoclonal antibody with a high affinity for the
CD20 surface antigen expressed on pre-B and
B-lymphocytes, produces a rapid depletion of B
cells from the peripheral circulation. Rituximab
acts via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and
apoptosis to effectively deplete B cells for 6-9
months in over 80% of patients.The mechanism
of B-cell killing by rituximab is believed to depend
on its antibodydependent cell-mediated cytotoxicity. The rationale for its use in immune-mediated
diseases is based on that mechanism of action14.
It was originally approved for the treatment of
non-Hodgkin’s lymphoma and for the treatment
of ANCA-associated vasculitis and rheumatoid
arthritis. Evidence for potential benefits of RTX
in other autoimmune diseases has been published
in the last decade15. The shared immune dysfunction underlying these conditions has promoted the
research of its use in CTD-ILD.
The first report of successful treatment of
scleroderma- associated ILD with Rtx was in 2008,
in a cohort of eight patients, showing significant
improvement of FVC and diffusing capacity of
carbon monoxide (DLCO) compared to a matched
group who received standard treatment16. Keir
and colleagues17 reported 8 cases of CTD-ILD (5
IIM-ILD; median FVC, 45% of predicted; median
DLCO, 25% of predicted) with refractory ILD and
used RTX as rescue therapy. Before RTX infusion,
all patients had decline in FVC and DLCO, and after
RTX infusion, DLCO improved of 22% (P 5 .04)
and FVC 18% (P 5 .03). The same Bromptom’s
group reported later a larger experience with RTX
infusions in 50 cases of severe and refractory ILD.
Amongst those patients, 33 suffered CTD-ILD
(10 IIM, 8 SSc, 9 undifferentiated CTD), DLCO
was 24.5% of predicted, and FVC was 44.0% of
predicted. In 85% of the patients with CTD-ILD
the response was considered positive. In the 6 to
12 months previous to the treatment with RTX, a
median decline in FVC of 13.3% and in DLCO of
18.8% had been shown and in the 6 to 12 months
post-treatment with RTX therapy an improvement
of 8.9% of the FVC (P<.01) and a stabilization of the DLCO (P<.01) were noted18. In contrast to
this data, Dodds et al showed in 20 patients with
CTD-ILDs treated with rituximab no improvement
in FVC, DLCO or total lung capacity, but interestingly, those patients remained stable. A subgroup
analysis of nine patients with myositis demonstrated an improvement in FVC (P = 0.011)19. In
the study of the European Scleroderma Trial and
Research (EUSTAR) group (n = 63)20 that analysed scleroderma patients that received RTX in
routine clinical practice upon the decision of their
physicians, the effects of RTX treatment on lung
function was studied in SSc patients with FVC<70% predicted, and evidence for ILD on HRCT
(n = 9). The DLCO was significantly improved in
patients treated with RTX compared with baseline
(41.1 ± 2.8 vs 44.8 ± 2.7%; p = 0.03). In contrast
to RTX-treated patients, patients in the control
group showed a decline in FVC at follow-up. This
resulted in significant differences between RTX
treated and matched controls in change of FVC%
predicted in both the percentage (0.4 ± 4.4 vs −7.7 ± 3.6; p = 0.02) and the absolute change (0.8 ± 2.2 vs −4.8 ± 1.7; p = 0.01). Those studies suggest that in individuals with SSc-ILD for whom
cyclophosphamide is not a convenient option or
fails to induce a therapeutic response, rituximab
may be an effective alternative.
However, the most attractive use of RTX is the
treatment of inflammatory myopathies (IIM). The
pulmonary involvement in this group of patients is
particularly severe and clinical experience shows
that those are the patients who fail more frequently with the use of conventional approaches,
including cyclophosphamide and high doses of
corticosteroids.
Several small retrospective studies have shown
at least partial benefit of Rtx in refractory PM/DM,
including antisynthetase syndrome (ASS)21-23. A
small retrospective series of 11 patients with antisynthetase syndrome–ILD studied RTX as a rescue
therapy24.
Compared to the 8 months’pretreatment
data 6 patients had an FVC improvement of
greater than 10% and 3 had a DLCO increase of
greater than 15% during the 7 months of follow-up
after RTX infusion and the thoracic HRCT scan
showed a regression of the ground-glass opacities
in 4 patients. However, the controlled randomized
study of 195 Rtx treated patients with refractory
myositis did not show any statistical difference
between the two treatment arms for primary and secondary endpoints, but the authors found that
patients with anti-aaRS antibody had a shorter
time to improvement compared with patients
without myositis-specific antibodies25. Recently,
a retrospective analyses of 24 Rtx-treated ASS
patients with ILD was performed with a median
follow-up time of 52 months. Significant improvements, both in PFT and ILD extent in HRCT
images were observed. Thirty four of 112 ASS
patients showed ILD and received Rtx; 24 of those
34 had severe ILD. In these 24 patients, the me-
dian percentage of predicted forced vital capacity,
forced expiratory volume in 1 s (FEV1) and DLCO
increased by 24%, 22% and 17%, respectively after
the infusion of Rtx. The most pronounced effects
on lung function were observed in patients with a
longer disease (duration <12 months at the first
Rtx cycle). In this group, seven patients increased> 30% in FVC, FEV1 and DLCO during the observation period25. Twenty one percent (7/34) of the
patients died during the follow-up, most of the
deaths were related to infections. The mortality
rate for the total cohort was 32% (25 of 78) suggesting that the mortality rate was not higher in
the Rtx-treated group than in non-Rtx-treated
ASS patients.
Concerning RA-ILD, the results of 10 patients
(4 UIP, 6 NSIP, baseline FVC 68%, baseline DLCO,
48%) treated with RTX were reported initially by
Matteson27 showing that measures of lung disease
remained stable in the majority of study completers.
Later, a multicentre study in 188 patients with RA-ILD during a 25-year period (65% UIP), analysed
57 patients that were treated with a biologic agent.
No difference in all-cause or respiratory mortality
was reported in patients treated with biologics
versus other agents. However, there was a statistically significant difference in respiratory mortality
between patients treated with anti-TNF (n 5 30)
versus RTX (n 5 27) (15% vs 4%; P 5 .04) and in
all-cause mortality in 31% of patients treated with
anti-TNF versus 8% of patients treated with RTX
(P 5 .03) in the UIP subgroup28.
Over half a million people worldwide have received rituximab therapy during the last 15 years.
The drug appears to be safe and well tolerated29.
Frequently reported adverse effects include infusion reactions manifested by fever, chills, headache, nausea, bronchospasm, hypotension and
angioedema30. Most of these reactions are mild, and
take place only during the first infusion. Infectious complications are fequent, although reported in
50% of patients in the early post-treatment period,
they are usually mild, mainly upper respiratory
tract infections and less frequently herpes zoster
and influenza. More serious infections hjave been
occasionally reported. Progressive multifocal
leukoencephalopathy (PML) is the most serious
complication associated to infection or reactivation
of JC virus, but has been reported in few patients,
usually with risk factors for PML development,
mainly lymphoproliferative diseases.
A systematic literature review conducted using
PubMed, the Cochrane Library and EMBASE for
reviews, meta-analyses, clinical studies and randomized controlled trials, case studies and series,
showed that in 65 studies of RTX an association
with non-infectious pulmonary toxicity was demonstrated in 121 cases; however, only 6 of these cases
had an underlying rheumatological condition31.
Clinical trials studying RTX in ANCA-related
vasculitis have allowed to compare the rate of side
effects of cyclophosphamide and RTX. The Rituximab in ANCA-Associated Vasculitis (RAVE) trial32 randomly assigned 197 patients with newly diagnosed or relapsed AAV to intravenous rituximab
(375 mg/m2 weekly for 4 weeks) or control (oral
daily CYC, 2.0 mg/kg per day, followed by azathioprine once remission was achieved). The second
trial was the Rituximab Versus Cyclophosphamide
in ANCA-associated Vasculitis (RITUXVAS) study33,
that randomly assigned 44 patients with AAV and
renal involvement to standard therapy (intravenous
CYC, 15 mg/kg every 2 weeks for three doses, then
every 3 weeks thereafter until remission, followed
by azathioprine, 2 mg/kg per day, when in remission) or the addition of rituximab (375 mg/m2 weekly for four doses) to a CYC-containing regimen
(intravenous CYC, 15 mg/kg, with first and third
rituximab doses). In the RAVE trial, the number
of total or severe adverse events were similar in
both groups. Fourteen percent of patients in the
rituximab group and 17% of patients in the CYC
group had treatment- or disease-related events
leading to discontinuation of therapy. During
18-month follow-up of these patients, the number
or rates of total adverse events, serious adverse
events, and non-disease-related adverse events
did not significantly differ. Leukopenia was more
common in the CYC group (23% versus 5%), but
serious infections were similar in both groups (12%
with rituximab versus 11% with control).
In the RITUXVAS trial, at 12 months, the percentage of patients experiencing severe adverse
events (42% with rituximab versus 36% with control), the incidence of severe adverse events, and
the incidence of infections (0.66 per patient-year
in the rituximab group versus 0.60 in the control
group) were similar between the two treatment
groups. At last follow-up, death rates were identical in both groups (18%). Taken together, these
data suggest that rituximab is not a more dangerous alternative to CYC as first-line therapy in AAV,
and it should be the case in CTD-ILD patients.
All the published evidence suggest that RTX
may have a role in specific subsets of CTD-ILD,
such as the antisynthetase syndrome (even as first
line therapy) and those cases in which conventional treatment with CYC is contraindicated or has
not been successful. Further studies are needed
to more precisely define its role in CTD-ILD, but
there is enough evidence to consider RTX as a suit-
able and safe option for the treatment of severe,
relapsing or refractory patients. It is important
to remark that in many patients CTD-ILD is a
life-threatening condition or result in severe morbidity and disability and that all the established
treatments have limited results or are completely
useless in a certain subgroup pf patients.
Several other biologic agents are now being
studied in CTD, especially in RA, however the role
of these in related ILD remains unclear. Tocilizumab (an anti-interleukin-6 receptor antibody),
has been reported to produce pneumonitis and
exacerbation of pre-existing ILD related to RA34.
But also several case reports have shown a possible
therapeutic benefit in patients with CTD-ILD35, 36,
37. Although there is no experience for the use of
this agent as a primary treatment in ILD, it might
be considered in the failure of better studied treatments in refractory severe disease34.
The IL1 receptor antagonist, Anakinra, has not
reported non-infective pulmonary toxicity. There
is, however, little to suggest therapeutic benefit36,
although it may have promising potential benefits
in the treatment of silicosis38.
A different category category of biologic agent,
of particular interest in the field of interstitial lung
disease, is the tyrosine kinase inhibitors. The results of the INPULSIS clinical trials showing benefit of nintedanib in Idiopathic Pulmonary Fibrosis
(IPF)39 have raised enthusiasm about the potential
benefit of nintedanib in fibrotic forms of CTD-ILD (UIP or fibrotic NSIP. However those results cannot be extrapolated to the treatment of CTD-ILD
yet and there is currently no literature to support
a possible therapeutic role. However, it is possible
that these agents may have a benefit, especially in
RA-ILD, the CTD-ILD with closer similarities to
idiopathic pulmonary fibrosis. Initial evidence of
benefitial effect in preclinical models of pulmonary
fibrosis in scleroderma40. The drug is currently
only approved for IPF treatment but clinical trials
including other “fibrotic” conditions are expected
in the next future.
Today, pharmacologic intervention with immunosuppression is the mainstay of therapy for all
forms of CTD-ILD, but should be reserved only for
those that show clinically significant and/or progressive disease. However, it is crucial to remark
that once a patient has received a diagnosis of mild
ILD in the context of a CTD, he or she must be
meticulously followed in the search of a progressing disease. That is the most common course of
the disease and taking into account that treatment
rarely reverses the disease and most of the times
only get an stabilisation, the delay of the initiation
of treatment may have considerable consequences.
The management of CTD-ILD is not yet evidence
based and there is an urgent need for controlled
trials across the spectrum of CTD-ILD. Robust
clinical trials are urgently needed to improve the
decision making in these conditions. An ongoing
clinical trial, the RECITAL study (NCT01862926),
is assessing, in a double dummy, randomized controlled trial, the efficacy of rituximab compared
with intravenous cyclophosphamide when given
as first-line therapy in progressive CTD-ILD (including scleroderma, IIM, and MCTD). Until the
publication of those results, the available evidence
permit to select RTX as the treatment of choice
following the clinical judgement of a MDT.
Conflicts of interest: The authors do not declare conflicts of interests related to the content of this publication.
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