Table 2. Overview of Immunomodulatory treatment options approved In Germany for Interstitial lung disease In autoimmune diseases.

Active substance	Administration	Reference, study type, number of pats, (n)	Disease	Approval	Primary endpoint	Outcomes	Adverse drug reactions
Immunmodulatory
Cyclophosphamide	oral	(e7) RCT, n = 158, 2006	SSc	Treatment of life-threatening autoimmune diseases	Change in FVC (% pred.) after 12 months	–primary endpoint: significantly small decline in FVC (−1.0 ±0.92%) as compared with the placebo group (−2.6 ±0.9%) –secondary endpoint - change in TLC: cyclophosphamide group (−0.3 ± 1.82%) vs. placebo group (−2.8 ± 1.2%)	–Significantly more cases of leukopenia and neutropenia on oral cyclophosphamide. –No significant difference between the groups with respect to SAEs.
	IV	(e44) Clinical observational study with RCT control group, n = 302, 2020	SSc			Change in FVC, DLCO and mRSS	–FVC: cyclophosphamide IV (−0.6 ±13.3%) vs. oral (+0.1 ±8.4%) –DLCO: cyclophosphamide IV (−4.3 ±13.0%) vs. oral (−3.9 ±13.5%) –mRSS: cyclophosphamide IV (−1.9±5.9 %) vs. oral (−3.0±.5.8%) –he comparison revealed no significant difference in lung function for SSc-ILD, but there were signs of less toxicity.	–Oral cyclophosphamide produced significantly more cases of leukopenia, hemorrhagic cystitis, and alopecia by the end of treatment. –For SAEs, the group receiving IV cyclophosphamide showed significantly more events (p = 0.025); however, this finding was no longer reproducible after adjustment for covariates.
Rituximab	IV	(21) RCT, n = 197, 2010	ANCA-vascu litis	ANCA-vasculitis as induction and maintenance therapy	Glucocorticoid-free remission after 6 months	–primary endpoint: rituximab (64%) vs. cyclophosphamide (53%) –rituximab was not inferior with respect to ANCA-associated vasculitis..	–No significant difference between the groups –More pats, on cyclophosphamide experienced > 1 SAE than on rituximab: n = 32 (33 %) vs. n = 22 (22 %) (p = 0.01)
Antifibrotic
Nintedanib	oral	(14) RCT (Phase 3), n = 663, 2019 and 2020 (15)	Progressive ILD	Treatment of chronic progressive ILD (of various etiologies)	Annual rate of decline in FVC, assessed after 52 weeks	–primary endpoint: significantly lower decrease in FVC on nintedanib (−80.8± 15.1 mL) vs. placebo group (−187.8±14.8 mL) –subanalysis for autoimmune ILD: 104.0 mL (95% confidence interval: [21.1; 186.9 mL])	–Most common side effects: diarrhea and nausea (at times requiring permanent dose reduction or drug discontinuation) –No group difference for SAE or fatal adverse side effects
		(26) RCT (Phase 3), n = 576, 2019	SSc	Primary treatment of SSc-ILD	Annual rate of decline of FVC, assessed after 52 weeks	–primary endpoint: significantly lower decrease in FVC on nintedanib (−52.4 ± 13.8) vs. placebo group (−93.3± 13.5)	–Most common side effects: diarrhea and nausea –No group difference for SAE or fatal adverse side effects.

ANCA, anti-neutrophil cytoplasmatic antibodies; DLCO, diffusing capacity for carbon monoxide; FVC, forced vital capacity; ILD, interstitial lung disease; IV intravenous; mRSS, modified Rodnan skin score; pats., patients; pred., predicted; RCT, randomized controlled trial; SAE, serious adverse event; SSc, systemic sclerosis; TLC, total lung capacity