Table 5.

Important treatment trials in CTD‐ILD

Study	Study design	Intervention	Outcome
Systemic sclerosis
Scleroderma Lung Study I 68	Prospective RCT n = 158 Duration: 12 months	Oral CYC (up to 2 mg/kg daily) vs placebo	Mean absolute improvement in FVC at 12 months of 2.53%, favouring CYC, greater frequency of AE in the CYC arm
FAST study 69	Prospective RCT n = 45 Duration: 12 months	IV CYC (600 mg/m2, monthly for six doses) + low‐dose prednisolone (20 mg alternate days) followed by AZA (2.5 mg/kg/day; max 200 mg) vs placebo	Trend to improvement FVC (4.19%; P = 0.08) in the active treatment arm, although statistically non‐significant
BUILD 2 (Bosentan) 70	Prospective RCT n = 163 Duration: 12 months	Bosentan 125 mg bd vs placebo	Negative primary end point with no difference in 6MWD between the groups No increase in SAE in the active treatment group
Scleroderma Lung Study II 71	Prospective RCT n = 142 Duration: 24 months	MMF 1.5 g bd vs oral CYC (up to 2.0 mg/kg/day) for 12 months followed by placebo for 12 months	Significant improvement in FVC from baseline in both arms (2.2% and 2.9%: MMF vs CYC), with no difference in FVC change between the groups Greater frequency of AE in the CYC group
LOTUSS (pirfenidone) 72	Randomized, open label n = 63 Duration: 16 weeks	Comparison of two pirfenidone up‐titration regimens: 2‐week titration vs 4‐week titration, to a maintenance dose of 801 mg tds	‘Acceptable’ tolerability profile, although a longer up‐titration may be associated with better tolerability
Pomalidomide (CC‐4047) 73	Prospective RCT n = 23 Duration: 12 months	Pomalidomide 1 mg/day vs placebo	Negative co‐primary end points with no difference in FVC, mRSS or GI symptoms at 52 weeks Enrolment discontinued early due to difficult recruitment
faSScinate 74	Prospective RCT n = 87 Duration: 48 weeks	Tocilizumab 162 mg subcutaneous weekly vs placebo	Negative secondary end point with no change in FVC or DLCO from baseline to 48 weeks
SENSCIS (nintedanib) 75	Prospective RCT n = 576 Duration: 12 months	Nintedanib 150 mg bd vs placebo	Positive primary end point with reduced annual rate of change in FVC in subjects receiving nintedanib compared to placebo (−52.4 mL vs −93.3 mL per year; P = 0.04)
Rituximab 76	Open‐label, comparative study n = 51 Duration: 4 years (range: 1–7 years)	Rituximab (n = 33) vs conventional immunosuppression (MMF, AZA or MTX) (n = 18)	At 2 years, improvement in FVC compared to baseline in rituximab group, with no change in FVC in conventional immunosuppression group
SCOT study 77	Randomized, open‐label n = 75 Duration: 54 months	Myeloablative stem cell transplantation (n = 36) vs IV CYC (n = 39)	Positive composite primary end point (incorporating death, event‐free survival, FVC and mRSS) favouring stem cell transplantation
ASTIS study 78	Randomized, open‐label n = 156 Duration: 5.8 years	Autologous stem cell transplantation (n = 79) vs IV CYC (n = 77)	Positive primary end point (death or persistent major organ failure) favouring stem cell transplantation Increased stem cell treatment‐associated mortality in the first 12 months
ASSIST study 79	Randomized, open‐label n = 19 Duration: 12 months	Non‐myeloablative stem cell transplantation (n = 10) vs IV CYC (n = 9)	Positive primary end point (improvement in mRSS or FVC) favouring stem cell transplantation
RA
Song et al. 80	Retrospective review n = 84 Median f/u: 33 months	All had RA with UIP. Forty‐one percent received glucocorticoids ± immunosuppression due to poor baseline lung function or progressive RA with UIP	Fifty percent of treated group improved or had stable lung function
Fischer et al. 81	Retrospective review n = 18 Median f/u: 2.5 years	MMF (1–1.5 g bd)	Trend to improvement in FVC following MMF commencement, with reduction in prednisolone requirement
IIM
Schnabel et al. 82	Prospective open label n = 20 Median f/u 35 months	Rapidly progressive IIM‐ILD (n = 10): IV CYC IIM‐ILD but less rapidly progressive (n = 10)	Stabilization in IIM‐ILD following IV CYC
Kameda et al. 83	Prospective open label n = 27	Rapidly progressive IIM‐ILD (n = 10): IV CYC (10–30 mg/kg every 3–4 weeks), prednisolone (>0.5 mg/kg/day) and cyclosporine A (2–4 mg/kg/day)	Fifty percent mortality rate at 3 months
Huapaya JA et al. 148	Retrospective review n = 110 f/u: 24–60 months	AZA (n = 66) MMF (n = 44)	Improved FVC% and DLCO% predicted in AZA group Improved FVC% predicted in MMF group Lower prednisolone dose in both groups More frequent AE in AZA group

6MWD, 6‐min walk distance; AE, adverse event; ASSIST, American Scleroderma Stem Cell versus Immune Suppression Trial; ASTIS, Autologous Stem cell transplantation; AZA, azathioprine; bd, twice daily; CTD‐ILD, connective tissue disease‐associated ILD; CYC, cyclophosphamide; DL_CO, diffusing capacity for carbon monoxide; f/u, follow‐up; FVC, forced vital capacity; GI, gastrointestinal; IIM, idiopathic inflammatory myopathy; IIM‐ILD, IIM‐associated ILD; ILD, interstitial lung disease; IV, intravenous; MMF, mycophenolate mofetil; mRSS, modified Rodnan skin score; MTX, methotrexate; n, number; RA, rheumatoid arthritis; RCT, randomized controlled trial; SAE, serious AE; SCOT, Scleroderma: Cyclophosphamide or Transplantation trial; SENSCIS, Safety and Efficacy of Nintedanib in Systemic Sclerosis; tds, three times daily; UIP, usual interstitial pneumonia.