This document discusses treatment of connective tissue disease-associated interstitial lung disease (CTD-ILD). It outlines different CTDs that can be related to ILD including systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIM), rheumatoid arthritis (RA), and others. It discusses management of SSc-ILD, RA-ILD, and IIM-ILD. Common treatments mentioned include glucocorticoids, cyclophosphamide, mycophenolate mofetil, azathioprine, rituximab, and others. Several clinical trials evaluating treatments for CTD-ILD are also summarized. Supportive therapy and lung transplantation are discussed as important components of CTD

1. Treatment of CTD-ILD
Ritasman Baisya
25/9/2020

2. Points of discussion
• Different CTDs related to ILD
• SSc-ILD management
• RA-ILD management
• IIM –ILD management
• ILD in other CTDs
• IPAF management

3. CTDs related with ILD
• Scleroderma (SSc)
• IIM – DM , ASS
• RA
• MCTD
• Sjogren syndrome (SS)
• SLE
• Interstitial pneumonia with autoimmune
features (IPAF)

4. Types of ILD in CTD

6. Types of lung involvement in CTDs
Marigliano B, Soriano A, Margiotta D, Vadacca M, Afeltra A. Lung involvement in connective tissue
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Sep;12(11):1076-84.

7. The Korean Journal of Internal Medicine Vol. 32, No. 4, July 2017

8. Treatment
• Impact of immunosuppressive therapy on CTD-ILDs are observed
• Additional research is required to determine the optimal treatment
strategies for each distinct form of CTD-ILD
• The rate of disease progression & the extent of lung injury are the
two main factors on management decision
• Supportive therapy is always indicated

10. SSC –ILD
• SSc-ILD is among the best-researched subtypes of CTD-ILD…..
• Currently one of the leading causes of death in SSc patients…..
• Presence of anti-topoisomerase I (SCL-70) , nucleolar pattern on ANA (anti-SCL-
70, anti-PM-SCL, anti-Th/To, anti-U3NRP) predict lung involvement
• Goh et al established that “extensive” ILD involving >20% of total lung volume on
HRCT, with concomitant FVC of <70% used as a cutoff when HRCT is
indeterminate……

11. Cappelli S, Bellando Randone S, Camiciottoli G, De Paulis A, Guiducci S, Matucci-Cerinic M. Interstitial lung
disease in systemic sclerosis: where do we stand? Eur Respir Rev. 2015;24:411–419

13. Treatment of SSc-ILD – when to treat ?
• SSc patients with respiratory symptoms…
• Recent disease onset (as the majority of ILD progression occurs 2–5 years after
non-Raynaud’s symptom onset) ….
• low FVC% and/or DLCO ….
• >20% lung involvement on HRCT ……

14. Glucocorticoid
• Monotherapy with corticosteroids is generally not effective.
• May be used in combination with other immunosuppressive treatments
• Chronic use of corticosteroids at a medium-high dose (>15 mg/day ) has been
associated with a higher risk of developing a scleroderma renal crisis (SRC),
particularly in patients with early diffuse disease

15. Cyclophosphamide – induction agent
Oral or IV cyclophosphamide for 6–12 months followed by MMF or
azathioprine should be used as first-line treatment for severe or
progressive disease, or disease unresponsive to mycophenolate

17. SLS1 trial
• 158 patients were randomized to either oral CYC at least 2 mg/kg/day or placebo
for 12 month
• The primary endpoint - change in forced vital capacity (FVC).
• The study cohort was composed of SSc patients with evidence of active ILD by
bronchoalveolar lavage or via thoracic HRCT , ‘early disease’ (first non-Raynaud’s
symptom within 7 years), an FVC between 45 and 85% and at least moderate
exertional dyspnea on the Mahler Dyspnea Index.
• The FVC difference at 12 months was 2.53% of predicted (P < 0.03) in favor of the
CYC group.
• The difference remained significant at 18 months from study onset but was lost
by 24 months

18. FVC % predicted in patients who received CYC or placebo
for 1 year followed by an additional year of monitoring in
SLS I

19. FAST trial
• The Fibrosing Alveolitis in Scleroderma Trial (FAST) randomized 45 patients to
active treatment (n = 22) with intravenous CYC 600 mg/m2 monthly for the first
6 months followed by AZA 2.5 mg/kg/day as maintenance therapy with
background oral prednisolone 20 mg on alternate days, compared with placebo
(n = 23).
• δFVC was more favorable in FAST than in SLS1 ( + 4.2 versus + 2.5% respectively)
• Smaller number of patients in FAST (n = 45) compared with SLS (n = 158)
• Adverse events were few, without any bone marrow toxicity and fewer cases of
hematuria

20. MMF in CTD-ILD
• The largest study of MMF use for CTD-ILD included a heterogeneous cohort
composed of 125 CTD-ILD patients ( 44 SSc-ILD, 32 PM/DM-ILD, 18 RA-ILD).
• Most were treated with MMF 3 g /day over a 3-year period
Observations –
• MMF was well tolerated, had a low rate of discontinuation, and was associated
with lower corticosteroid doses
• FVC% and/or DLCO% - Balance & stabilization in UIP and improvement in non
UIP

21. J Rheumatol. 2013 May ; 40(5): 640–646

22. SLS 2 study
• 142 patients were randomly assigned to either MMF (n=69) or CYC (n=73).
• The adjusted % predicted FVC improved from baseline to 24 months by 2·19 in MMF
group (95% CI 0·53–3·84) and 2·88 in CYC group (1·19–4·58)
• The course of the % FVC did not differ significantly between the two treatment
groups based on the prespecified primary analysis using a joint model (p=0·24)
• MMF was better tolerated and associated with less toxicity
• Hypothesis of greater efficacy of MMF than CYC at 24 months was not confirmed

24. Effect of MMF for 2 years vs CYC for 1 year followed by
placebo for 1 year on FVC % predicted in SLS II

25. Azathioprine
• AZA is commonly used to treat CTD-ILD as maintenance therapy
• Other than as used in FAST, the data for AZA are limited to small and
retrospective series
• Numerous other case series or small retrospective reports
demonstrating variable degrees of efficacy of AZA in CTD-ILD

26. Rituximab
• Several lines of evidence indicate a potential role of B cells in the
pathogenesis of scleroderma.
• RTX may improve lung function in patients with SSc- disease
modifying role in ILD
• In terms of biological treatment, interesting results on the use of
rituximab (RTX) have been published

28. Diosmosis et al study , 2010 –
• 8 SSc patients were randomized to receive two cycles of RTX at baseline and 24
weeks & six patients (control group) received standard treatment alone….
• A significant increase of FVC in the RTX group compared with baseline (mean ± SD-
68.13 ± 19.69 vs 75.63 ± 19.73, at baseline vs 1-year, respectively, P = 0.0018).
• The median percentage of improvement of FVC in the RTX group was 10.25%,
whereas that of deterioration in the controls was 5.04% (p = 0.002).
• The median percentage of improvement of DLCO in the RTX group was 19.46%,
whereas that of deterioration in the control group was 7.5% (p = 0.023).

29. EUSTAR analysis , 2014
• In 2014, a case-control analysis was carried out by the EUSTAR group
• 63 patients treated with RTX were matched with control patients from the
EUSTAR database not treated with RTX
• In patients with SSC-ILD , RTX prevented significantly the further decline of FVC
compared with matched controls ( N=9 ; 0.4 ± 4.4% vs −7.7 ± 3.6% ; p=0.02).
• No significant difference in change of DLCO

32. RECITAL trial of RTX in CTD-ILD
• IV RTX (1 g , 2 doses 15 days apart ) vs iv CYC in SSC-ILD , IIM (including ASS ) or
MCTD-ILD
• 116 patients randomised 1:1 to each of the two treatment arms and followed for
a total of 48 weeks from first dose
• The primary endpoint for the study will be change in forced vital capacity (FVC) at
24 weeks
• This is the first RCT to study the efficacy of rituximab as first-line treatment in
CTD- ILD.

33. RECITAL data
(A) FVC (% predicted) at baseline and
follow-up in the systemic sclerosis
(SSc) patients with lung fibrosis
treated with rituximab (RTX)
versus matched-control SSc
patients;
(B) Absolute change of FVC (%
predicted)

34. Autologous stem cell transplantation
• ASTIS trial-To compare efficacy and safety of HSCT vs 12 successive monthly
intravenous pulses of CYC
• 156 patients with early diffuse cutaneous systemic sclerosis were recruited
• HSCT showed a significant improvement of both FVC and TLC while no significant
differences in terms of DLCO were observed.
• Mean changes in FVC (6.3% vs −2.8% predicted, [95% CI, −14.7 to −2.5];p= .004), TLC (5.1%
vs −1.3% predicted; [95%CI, −11.9 to −0.9];P = .02)
• HSCT was associated with increased treatment-related mortality in the first year after
treatment, but it conferred a significant long-term event-free survival benefit and may
improve lung function

35. Anti-fibrotic agent
• In SSc, no antifibrotic drug has shown a real efficacy in prevention and treatment
of fibrosis.
• The tyrosine kinase inhibitor, imatinib mesilate, blocks the pro-fibrotic c-Abl
kinase, an important downstream signalling molecule of TGF-β
• In a proof-of-concept, double-blind RCT - imatinib was interrupted after 6 months
due to poor tolerability
• Considering the lack of clear evidence of efficacy and the quite common side-
effects, imatinib is rarely used in clinical practice.

36. Pirfenidone
• In phase II LOTUSS study, a 16-week open-label trial of pirfenidone in patients with SSc-
ILD, the adverse event profile of pirfenidone was acceptable , not affected by
concomitant use of MMF
• The effects of pirfenidone vs placebo in patients with SSc-ILD who are receiving MMF are
being investigated in SLS III
• The RELIEF trial, which investigated the efficacy and safety of pirfenidone vs placebo
given on top of anti-inflammatory therapy, in patients with progressive ILD of various
etiologies was terminated early due to slow recruitment and is yet to report results.

37. Nintedanib
• Nintedanib, a tyrosine kinase inhibitor , has antifibrotic and anti-inflammatory
effects in preclinical models of SSC- ILD.
• A randomized, double-blind, placebo-controlled trial to investigate the efficacy
and safety of nintedanib in SSC-ILD recently published ( SENSCIS® trial )
• In the primary end-point analysis, the adjusted annual rate of change in FVC was
−52.4 ml / year in nintedanib vs −93.3 ml/ year in placebo group
• The USA-FDA approved nintedanib in SSc-ILD

39. SENSCIS® trial

40. Lung transplantation
• Life-saving option for SSc-ILD patients who are not responsive to
medical therapy.
• Not always possible due to the involvement of other organs.
• The short- and intermediate-term survival of SSc-ILD are similar to
those seen in IPF

41. Tocilizumab
• Phase II faSScinate trial with progressive SSc (N = 87), exploratory analyses
suggested that tocilizumab may be associated with clinically relevant improvements
in lung function….
• Phase III focuSSced trial SSc ( 200 )- in exploratory analyses, the mean change from
baseline in FVC at week 48 was − 0.4% predicted in tocilizumab versus − 4.6%
predicted in placebo , proportion of patients with a decline in FVC of > 10% at
week 48 was 5.4% with tocilizumab and 16.5% with placebo

42. Supportive therapy
• Every lung treatment strategy must include supportive care
• Best supportive and palliative care approaches always play a central role
• Treatment of gastroesophageal reflux
• Pulmonary rehabilitation
• Low doses of opiates when dyspnoea is immovable
• Oxygen therapy when mild to severe hypoxia occurs at rest and during exercise
• Annual influenza and regular pneumococcal vaccination are recommended to reduce
the risk of pulmonary infection.

43. Recent drug trials
Agent Type of molecule Trial name (ClinicalTrial.gov
identifier)
Population; sample size Lung function endpoint/s Estimated primary
completion date
a
Lanifibranor Peroxisome proliferator-
activated receptor agonist
FASST (NCT02503644) Patients with dcSSc; n = 132 Changes from baseline in
FVC % predicted and DLco %
predicted at weeks 24 and
48 (secondary endpoints)
October 2017
Anabasum / lenabasum RESOLVE-1 (NCT03398837) Patients with dcSSc; n = 354 Change from baseline in
FVC at week 53 (secondary
endpoint)
March 2020
Riociguat Guanylate cyclase
stimulator
RISE-SSc (NCT02283762) Patients with dcSSc; n = 121 Change from baseline in
FVC % predicted at week 52
(secondary endpoint)
October 2018 (actual
Tocilizumab Interleukin-6 receptor
antagonist
focuSSced (NCT02453256) Patients with SSc and mRSS
of 10–35; n = 212
Change from baseline in
FVC at week 48 (secondary
endpoint)
January 2018 (actual
Abatacept Elective T-cell costimulation
modulator
ASSET (NCT02161406) Patients with dcSSc; n = 88 Change from baseline in
FVC % predicted at week 52
(secondary endpoint)
September 2018
Nintedanib Tyrosine kinase inhibitor SENSCIS (NCT02597933) Patients with SSc-
ILD; n = 580
Annual rate of decline in
FVC (mL/year) over
52 weeks (primary
endpoint)
October 2018

44. Ifetroban Antagonist of
thromboxane A2 /
prostaglandin
endoperoxide
receptor
NCT02682511 Patients with
dcSSc (n = 14)
or SSc-PAH
(n = 20)
Changes from baseline in FVC and
DLco at weeks 12, 26, 52
(secondary endpoints)
December 2019
Pirfenidone Pyridone analogue SLS III (NCT03221257) Patients with
SSc-ILD on
background
MMF; n = 150
Changes from baseline at month
18 in:
• FVC % predicted (primary
endpoint)
• DLco % predicted
• Mahler Modified Transitional
Dyspnoea Index
• Total lung capacity (HRCT)
April 2021
Rituximab CD20-directed
cytolytic antibody
RECITAL (NCT01862926
)
Patients with
CTD-
ILD; n = 116
Changes from baseline in FVC at
week 24 (primary endpoint) and
week 48 (secondary endpoint)
November 2019
Agent Type of molecule Trial name Population Lung function endpoint/s Estimated
primary
completion date
a

45. PFT is enough for predicting treatment response

46. Cappelli S, Bellando Randone S, Camiciottoli G, De Paulis A, Guiducci S, Matucci-Cerinic M. Interstitial lung
disease in systemic sclerosis: where do we stand? Eur Respir Rev. 2015;24:411–419

47. RA -ILD
• No universally accepted guidelines regarding RA-ILD screening or treatment
initiation
• First line therapy is prednisone at high doses, for prolonged duration.
• Extensive RA-ILD - has recently been found to apply to RA-ILD by Dawson et al
• In a cohort of 40 patients with RA-ILD, addition of DMARDS to tapering doses of
prednisone was associated with improvement in baseline FVC.
• The DMARDS used by treating physicians in this study included methotrexate,
leflunomide and azathioprine

48. Therapy in RA-ILD
• MMF has been shown to stabilize RA-ILD at doses of 1–2 mg / day in patients with
limited diseases, although it does not always appear to be effective in
ameliorating the articular manifestations of the disease ….
• The safety and efficacy of Rituximab are currently under investigation for patients
with RA-ILD …..
• An open label pilot study with RA-ILD patients showed that FVC remained stable
in most patients treated with rituximab in combination with MTX at week 48 …..

49. Drug toxicity in RA lung
• The ACR recommends avoiding methotrexate in patients with underlying ILD .
• MTX has been reported to improve ILD due to RA itself …..
• MTX pneumonitis is most frequent within the first year of treatment and the reported
incidence of this adverse reaction varies from 0.86 to 6.9%...
• Some recommend that patients with RA who are about to start methotrexate treatment
undergo a baseline chest X-ray and PFTs - Identifying patients with ILD and poor lung
reserve is the most important objective.
• The test should also serve as a reliable baseline for future comparison in the event of
suspected pneumonitis.

51. IIM-ILD
• IIM-ILD is common & associated with poorer prognosis than IIM overall
• Occurs most frequently in patients with the ASS
• AntiMDA-5, anti-PM-SCL, and anti-Ro-52 are also associated with a higher risk of
ILD with rapid progression
• IIM-ILD ranges in severity from mild subclinical disease which does not progress,
to a rapidly progressive acute interstitial pneumonitis with high short-term
mortality

52. Treatment response
• Most IIM-ILD responds well to immunosuppression ….
• Acute fulminant pneumonitis is characteristically unresponsive regardless of HRCT
pattern…
• Anti-synthetase antibodies have been associated with greater treatment responsiveness
and risk of ILD recurrence…
• Earlier disease is generally more responsive to therapy…..
• Anti MDA-5 – rapid progressive and poor response
• Other disease-related factors (respiratory muscle weakness, aspiration and related
infections, cardiac disease, iatrogenic lung injury, spontaneous pneumomediastinum, lung
cancer, etc.) can mimic ILD and to be treated

53. Steroid
• Doses of prednisone varying between 40 mg and 100 mg daily were
used over sustained periods of time
• Takada et al- intensive approach has better outcome than step-up
approach

54. CYC
• CYC used in severe or refractory myositis related ILD
• IV CYC demonstrated efficacy in refractory IIM-ILD in a single, small open label
trial - mean FVC improvement 15%
• A recent systematic review of 12 studies summarized the evidence supporting the
use of CYC in myositis related ILD
• After pooling the results, improvement of 58% (34/59) - > 10% in vital capacity,
64% (27/42) - > 10% in DLCO and 67% (35/52) had a significant improvement in
their HRCT scores

55. MMF
• 32 patients with PM/ DM- ILD - treated with MMF, with doses ranging between 2-
3 g/d with improvement in FVC at 156 weeks (9.7% +/-4.9%; p=0.04)…..
• Mira-Avendano et al described- 9 patients with PM /DM- ILD in a retrospective
review, treated with MMF - All patients had stabilization of their PFTs and a
reduction in dyspnea……

56. Azathioprine
• Very little data supports the use of AZA in myositis - ILD
• Mira-Avendano et al - retrospectively reviewed 13 patients with PM or DM- ILD
treated with AZA in combination with steroids.
• They showed a reduction in dyspnea and stabilization of PFTs after 12 months of
therapy

57. Calcineurin inhibitor- Cyclosporine (CsA)
• CsA use in the treatment of myositis - ILD was first reported in the
1980s & retrospective studies have suggested efficacy….
• Cavagna et al - retrospectively studied 17 patients with myositis
related ILD resistant to steroids…..
• They demonstrated improvement in FVC (median improved from 60%
to 75%, p <0.001 ) & DLCO (median improved from 60% to 66%,
p=0.001) after one year of treatment with CsA….

58. Tacrolimus
• Wilkes et al retrospectively reported - 13 patients with myositis -ILD
treated with tacrolimus unresponsive to steroid & at least one IS
• Majority had improvement FVC and DLCO with tapering of
prednisone dose.
• A recent systematic review ( Ge Y et al ) of 8 studies- 93.3% had
improvement in their muscle strength & most patients had
improvement or stability in their DLCO (13/16, 81%) or FVC (25/28,
89%)

59. Rituximab
• Rituximab is increasingly used in patients with myositis refractory to
other therapies ….
• A recent trial including 200 patients with refractory adult DM, juvenile
DM, and adult DM- no difference in treatment vs comparator arm ….
• Case series , small series , open label study proved its benefit

61. Rituximab in IIM-ILD
• In 2009, a retrospective case series reported a significant improvement on HRCT /
PFT in 7/11 ASS - ILD, following 6 months of RTX …..
• Marie et al. – 7 anti Jo-1(+) patients with refractory ILD treated with RTX in
combination only with steroids- all improved after 1 year .
• A retrospective study of 50 patients with severe ILD treated with RTX ;33 had ILD
associated with CTD
• Within CTD-ILD cohort, patients with myositis were most likely to improve in PFTs
(FVC and DLCO) following RTX therapy.

62. • 34 - ASS & severe ILD ( FVC < 70%, DLCO <60, mechanical ventilation)
treated with RTX with follow-up for 12 months or more
• Median increase in FVC % & DLCO % was 24% and 17%, respectively.
• Seven patients with a disease duration of less than 12 months and/or
acute ILD onset, had a median improvement of more than 30% in FVC
or DLCO.

63. IVIG
• Data supporting IVIG use for the ILD component of myositis is limited …
• In a case series , 5 patients received 0.4 g/kg of IVIG for 5 consecutive days as a
rescue therapy - 3 died of respiratory failure & 2 had stabilization of their ILD
• Myositis with SSc with early-stage ILD has been treated with IVIG (2 g/kg/month)
& AZA (150 mg/day)- GGOs, septal thickenings, and lung function improved
following treatment
• IVIG can be considered in patients with refractory disease as salvage therapy or
those with contraindications to immunosuppression

64. Plasmapheresis
• The role of plasmapheresis in myositis related ILD remains unclear
• It could be considered as salvage therapy in patients with severe
respiratory failure

65. Key points in treatment of myositis ILD
• Severe or rapidly progressive ILD ,respiratory failure - more aggressive treatment - high
dose corticosteroids with CYC, rituximab, or calcineurin inhibitor …..
• Milder disease /chronic presentation- agents with an overall safer side effect (e.g.
steroids in combination with MMF or AZA )
• PFTs should be performed every 3 to 6 months, or earlier if needed.
• A fall >10% in FVC or >15% in DLCO, a marked clinical deterioration, progression to
respiratory failure, or disease progression on HRCT - disease progression and treatment
failure.
• Non-pharmacologic measures - oxygen therapy, vaccination, and smoking cessation play
an important role

67. Sjogren-ILD
• The majority of SS-ILD patients receive glucocorticoid therapy,
antimalarials or immunosuppressive treatment
• Corticosteroids administered with hydroxychloroquine, azathioprine or
CYC resulted in improved FVC and DLco in SS-ILD patients with
histologically proven nonspecific interstitial pneumonia
• there are few studies assessing the effects of rituximab on lung
function in SS-ILD

68. MCTD- ILD
• Most patients diagnosed with MCTD were extremely responsive to corticosteroid
therapy
• Conventional therapies for MCTD-ILD include a combination of corticosteroids
with steroid-sparing agents
• Corticosteroids, CYC, hydroxychloroquine, MTX and different types of
vasodilators have also been used in MCTD –ILD

69. ILD in lupus
• The prevalence of ILD is lower in SLE than in the other CTDs (3-13%)
• Treatment for SLE-ILD typically includes corticosteroids along with steroid-
sparing agents.
• The chosen treatment strategy is based on expert opinion

70. IPAF

71. Treatment in IPAF
• Data on IPAF treatment are limited to case series further research is needed for optimal
treatment strategy in the IPAF
• As IPAF is a research consensus statement and not a disease or a well-defined entity, it is
unsure whether a specific management distinct from that of IPF is needed
• No RCTs supporting immunomodulation in IPAF, and the proposed treatment strategies
are extrapolated from CTD-ILD studies
• IPAF and a non-UIP pattern may benefit from immunomodulation, however this needs
confirmation.
• Trial of antifibrotic in IPAF ongoing

73. A review on treatment of CTD-ILD

74. References
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