Abstract Introduction With advances in CFTR modulator therapy and multidisciplinary care, adults with cystic fibrosis (CF) are living longer and increasingly developing non-CF-related comorbidities. Autoimmune interstitial lung disease (ILD), however, remains exceptionally rare and can be easily overlooked due to overlapping respiratory symptoms and imaging findings. We describe a case of diffuse cutaneous systemic sclerosis (SSc) associated ILD in a patient with long-standing CF, emphasizing the need for diagnostic vigilance when CF patients present with unexplained respiratory decompensation. Case A 67-year-old man with well-controlled cystic fibrosis (genotype W1282X/D1152H), maintained on elexacaftor/tezacaftor/ivacaftor (Trikafta), presented with progressive cough and dyspnea. He was initially treated for a presumed acute CF pulmonary exacerbation with intravenous tobramycin and Ceftazidime/avibactam without improvement. Given the lack of clinical response, his CFTR modulator therapy was subsequently switched to vanzacaftor/tezacaftor/deutivacaftor, yet his respiratory status continued to deteriorate with worsening exertional dyspnea and hypoxia. Repeat CT chest demonstrated progressive lower-lobe reticular changes and ground-glass opacities suggestive of nonspecific interstitial pneumonia with early fibrosis. Physical examination revealed skin tightening and Raynaud’s phenomenon. Serologic evaluation showed ANA 1:640 (speckled pattern), elevated Scl-70 antibody, and positive rheumatoid factor, prompting rheumatology referral and a diagnosis of systemic sclerosis-associated ILD. Right heart catheterization confirmed WHO Group 3 pulmonary hypertension. He did not tolerate mycophenolate or inhaled treprostinil and was subsequently initiated on tocilizumab. He declined antifibrotic therapy and lung transplantation, opting for a palliative approach. Discussion To our knowledge, this represents the first reported case of systemic sclerosis-associated ILD developing in a patient with CF. The coexistence of these two fibrosing lung diseases poses significant diagnostic and therapeutic challenges, as both can produce overlapping radiographic patterns and progressive functional decline. Management is further complicated by the need to balance immunosuppression against infection risk in a population already prone to recurrent airway colonization. While no evidence currently links CFTR modulators or chronic CF-related inflammation to the pathogenesis of systemic sclerosis, this case underscores a clinically meaningful intersection that expands the spectrum of pulmonary complications seen in the aging CF population Conclusion This case underscores the importance of maintaining a broad differential when evaluating respiratory decline in patients with cystic fibrosis, as non-CF etiologies may closely mimic pulmonary exacerbations. Early recognition of atypical comorbidities and engagement of a multidisciplinary care team are essential to ensure accurate diagnosis, guide complex management decisions, and optimize outcomes in the growing adult CF population. This abstract is funded by: None
Eid et al. (Fri,) studied this question.