Advertisement

Impact of highly effective CFTR modulator therapy on digital clubbing in patients with cystic fibrosis

      Highlights

      • Through the measurement of plaster finger casts statistically significant (p = 0.05) reversibility of digital clubbing in patients with cystic fibrosis after lung transplantation is further corroborated.
      • Measurements using the finger casts of cystic fibrosis treated with highly effective modulator therapy demonstrated statistically significant (p = 0.005) reversibility of digital clubbing in cystic fibrosis patients with corresponding, susceptible mutations.
      • The findings here suggest a previously unreported effect of HEMT. It may be anticipated that a wide variety of secondary or downstream effects, such as digital clubbing, alterations in bowel flora, or glucose metabolism, will additionally become apparent.

      Abstract

      Background

      The association of certain disease processes with digital clubbing is well documented. Digital clubbing is often reversible after successful treatment of the underlying pathology, for example, after lung transplantation in patients with cystic fibrosis (CF). We examined the effect of highly effective Cystic Fibrosis Transmembrane Regulator (CFTR) modulators, defined for the purposes of this study as ivacaftor or the combination of ivacaftor, tezacaftor, and elexacaftor (ETI), on digital clubbing.

      Materials and Methods

      Clubbing index was measured on plaster of Paris casts of right index fingers obtained from 15 patients with cystic fibrosis, before and after initiation of CFTR modulator therapy. Similar measurements were made on casts for 9 cystic fibrosis patients who underwent lung transplantation. Measurements were made on the most recent casts available before treatment and the first cast available at least 3 months after initiation of treatment. The Wilcoxon signed-rank text was used to detect any significant difference in the pre- and post-treatment casts for each individual.

      Results

      A significant decrease in the clubbing index was found after both lung transplantation and treatment with highly effective CFTR modulator therapy.

      Conclusions

      These results add to the body of evidence demonstrating the efficacy of highly effective CFTR modulator therapy, the first agents that act directly at the dysfunctional chloride channel responsible for CF. By demonstrating that CFTR modulator therapy is capable of reversing digital clubbing, this study suggests a beneficial effect on lung pathology aside from air flow and gas transfer.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Cystic Fibrosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Vandemergel X.
        • Decaux G.
        Le point sur l'ostéoarthropathie hypertrophique et l'hippocratisme digital [Review on hypertrophic osteoarthropathy and digital clubbing].
        Rev Med Brux. 2003; 24: 88-94
        • Shneerson J.M.
        Digital clubbing and hypertrophic osteoarthropathy: the underlying mechanisms.
        Br J Dis Chest. 1981; 75: 113-131https://doi.org/10.1016/0007-0971(81)90043-7
        • Sorscher E.J.
        Cystic fibrosis.
        in: Jameson J Fauci A.S. Kasper D.L. Hauser S.L. Longo D.L. Loscalzo J Harrison's principles of internal medicine, 20e. McGraw-Hill, 2018
        • Pitts-Tucker T.J.
        • Miller M.G.
        • Littlewood J.M
        Finger clubbing in cystic fibrosis.
        Arch Dis Child. 1986; 61: 576-579https://doi.org/10.1136/adc.61.6.576
        • Behrman R.E.
        • Kliegman R.
        • Jenson H.B.
        • Nelson W.E.
        Cystic fibrosis - clinical manifestations.
        In Nelson textbook of pediatrics. 16th ed. W.B. Saunders Company, 2000: 1315-1319
        • Nakamura C.T.
        • Ng G.Y.
        • Paton J.Y.
        • Keens T.G.
        • Witmer J.C.
        • Bautista-Bolduc D.
        • Woo M.S.
        Correlation between digital clubbing and pulmonary function in cystic fibrosis.
        Pediatr Pulmonol. 2002; 33: 332-338https://doi.org/10.1002/ppul.10082
        • Lemen R.J.
        • Gates A.J.
        • Mathé A.A.
        • Waring W.W.
        • Hyman A.L.
        • Kadowitz P.D.
        Relationships among digital clubbing, disease severity, and serum prostaglandins F2alpha and E concentrations in cystic fibrosis patients.
        Am Rev Respir Dis. 1978; 117: 639-646https://doi.org/10.1164/arrd.1978.117.4.639
        • Augarten A.
        • Goldman R.
        • Laufer J.
        • Szeinberg A.
        • Efrati O.
        • Barak A.
        • Miller M.S.
        • Yahav Y.
        Reversal of digital clubbing after lung transplantation in cystic fibrosis patients: a clue to the pathogenesis of clubbing.
        Pediatr Pulmonol. 2002; 34: 378-380https://doi.org/10.1002/ppul.10193
        • Lopes-Pacheco M.
        CFTR Modulators: The changing face of cystic fibrosis in the era of precision medicine.
        Front Pharmacol. 2020; 10: 1662https://doi.org/10.3389/fphar.2019.01662
        • Ramsey B.W.
        • Davies J.
        • McElvaney N.G.
        • Tullis E.
        • Bell S.C.
        • Dřevínek P.
        • Griese M.
        • McKone E.F.
        • Wainwright C.E.
        • Konstan M.W.
        • Moss R.
        • Ratjen F.
        • Sermet-Gaudelus I.
        • Rowe S.M.
        • Dong Q.
        • Rodriguez S.
        • Yen K.
        • Ordoñez C.
        • JS Elborn
        • VX08-770-102 Study Group
        A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.
        N Engl J Med. 2011; 365: 1663-1672https://doi.org/10.1056/NEJMoa1105185
        • Wainwright C.E.
        • Elborn J.S.
        • Ramsey B.W.
        • Marigowda G.
        • Huang X.
        • Cipolli M.
        • Colombo C.
        • Davies J.C.
        • De Boeck K.
        • Flume P.A.
        • Konstan M.W.
        • McColley S.A.
        • McCoy K.
        • McKone E.F.
        • Munck A.
        • Ratjen F.
        • Rowe S.M.
        • Waltz D.
        • Boyle M.P.
        • TRAFFIC Study Group; TRANSPORT Study Group
        Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR.
        N Engl J Med. 2015; 373: 220-231https://doi.org/10.1056/NEJMoa1409547
        • Taylor-Cousar J.L.
        • Munck A.
        • McKone E.F.
        • van der Ent C.K.
        • Moeller A.
        • Simard C.
        • Wang L.T.
        • Ingenito E.P.
        • McKee C.
        • Lu Y.
        • Lekstrom-Himes J.
        • Elborn J.S.
        Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del.
        N Engl J Med. 2017; 377: 2013-2023https://doi.org/10.1056/NEJMoa1709846
        • Heijerman H.G.M.
        • McKone E.F.
        • Downey D.G.
        • Van Braeckel E.
        • Rowe S.M.
        • Tullis E.
        • Mall M.A.
        • Welter J.J.
        • Ramsey B.W.
        • McKee C.M.
        • Marigowda G.
        • Moskowitz S.M.
        • Waltz D.
        • Sosnay P.R.
        • Simard C.
        • Ahluwalia N.
        • Xuan F.
        • Zhang Y.
        • Taylor-Cousar J.L.
        • McCoy K.S.
        • VX17-445-103 Trial Group
        Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial.
        Lancet. 2019; 394: 1940-1948https://doi.org/10.1016/S0140-6736(19)32597-8
        • Burgel P.R.
        • Durieu I.
        • Chiron R.
        • Ramel S.
        • Danner-Boucher I.
        • Prevotat A.
        • Grenet D.
        • Marguet C.
        • Reynaud-Gaubert M.
        • Macey J.
        • Mely L.
        • Fanton A.
        • Quetant S.
        • Lemonnier L.
        • Paillasseur J.L.
        • Da Silva J.
        • Martin C.
        French cystic fibrosis reference network study group. rapid improvement after starting elexacaftor-tezacaftor-ivacaftor in patients with cystic fibrosis and advanced pulmonary disease.
        Am J Respir Crit Care Med. 2021; 204: 64-73https://doi.org/10.1164/rccm.202011-4153OC
        • Waring W.W.
        • Wilkinson R.W.
        • Wiebe R.A.
        • Faul B.C.
        • Hilman B.C.
        Quantitation of digital clubbing children. Measurements of casts of the index finger.
        Am Rev Respir Dis. 1971; 104: 166-174https://doi.org/10.1164/arrd.1971.104.2.166
        • Lin Lawrence I-Kuei.
        A concordance correlation coefficient to evaluate reproducibility.
        Biometrics. 1989; 45: 255-268https://doi.org/10.2307/2532051
        • Rutherford J.D.
        Digital clubbing.
        Circulation. 2013; 127: 1997-1999https://doi.org/10.1161/circulationaha.112.000163
        • Kronemann N.
        • Bouloumié A.
        • Bassus S.
        • Kirchmaier C.M.
        • Busse R.
        • Schini-Kerth V.B.
        Aggregating human platelets stimulate expression of vascular endothelial growth factor in cultured vascular smooth muscle cells through a synergistic effect of transforming growth factor-β 1 and platelet-derived growth factor AB.
        Circulation. 1999; 100: 855-860https://doi.org/10.1161/01.cir.96.11.3888
        • Atkinson S.
        • Fox S.B.
        Vascular endothelial growth factor (VEGF)-A and platelet-derived growth factor (PDGF) play a central role in the pathogenesis of digital clubbing.
        J Pathol. 2004; 203: 721-728https://doi.org/10.1002/path.1565