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1. Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis.

Author

Kowdley, K. V., Bowlus, C. L., Levy, C., Akarca, U. S., Alvares-da-Silva, M. R., Andreone, P., Arrese, M., Corpechot, C., Francque, S. M., Heneghan, M. A., Invernizzi, P., Jones, D., Kruger, F. C., Lawitz, E., Mayo, M. J., Shiffman, M. L., Swain, M. G., Valera, J. M., Vargas, V., and Vierling, J. M.

Subjects
*CHOLANGITIS, *HEPATIC fibrosis, *PEROXISOME proliferator-activated receptors, *ALKALINE phosphatase, *BILE ducts, *URSODEOXYCHOLIC acid
Abstract

BACKGROUND Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown. METHODS In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). RESULTS A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P=0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (-1.93 vs. -1.15; difference, -0.78; 95% CI, -1.99 to 0.42; P=0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting. CONCLUSIONS Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.) [ABSTRACT FROM AUTHOR]

Published
2024
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2. A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis.

Author

Hirschfield, G. M., Bowlus, C. L., Mayo, M. J., Kremer, A. E., Vierling, J. M., Kowdley, K. V., Levy, C., Villamil, A., de Guevara Cetina, A. L. Ladrón, Janczewska, E., Zigmond, E., Jeong, S.-H., Yilmaz, Y., Kallis, Y., Corpechot, C., Buggisch, P., Invernizzi, P., Londoño Hurtado, M. C., Bergheanu, S., and Yang, K.

Subjects
*CLINICAL trials, *CHOLANGITIS, *PEROXISOME proliferator-activated receptors, *ALKALINE phosphatase, *URSODEOXYCHOLIC acid
Abstract

BACKGROUND Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator-activated receptor delta agonist, has potential benefits. METHODS In this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus). RESULTS Of the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, -3.2 vs. -1.7; least-squares mean difference, -1.5; 95% CI, -2.5 to -0.5, P=0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively. CONCLUSIONS In this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733. opens in new tab; EudraCT number, 2020-004348-27.) [ABSTRACT FROM AUTHOR]

Published
2024
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3. Decreased CD57 expression of natural killer cells enhanced cytotoxicity in patients with primary sclerosing cholangitis

Author

Liu, B, Yang, G, Sun, Y, Tomiyama, T, Zhang, W, Leung, P, He, X, Dhaliwal, S, Invernizzi, P, Gershwin, M, Bowlus, C, Liu B., Yang G. -X., Sun Y., Tomiyama T., Zhang W., Leung P. S. C., He X. -S., Dhaliwal S., Invernizzi P., Gershwin M. E., Bowlus C. L., Liu, B, Yang, G, Sun, Y, Tomiyama, T, Zhang, W, Leung, P, He, X, Dhaliwal, S, Invernizzi, P, Gershwin, M, Bowlus, C, Liu B., Yang G. -X., Sun Y., Tomiyama T., Zhang W., Leung P. S. C., He X. -S., Dhaliwal S., Invernizzi P., Gershwin M. E., and Bowlus C. L.

Abstract

Background/aims: Primary sclerosing cholangitis (PSC) is a chronic inflammatory biliary disease for which the immunopathological basis remains an enigma. Natural killer (NK) cells are key components of innate immunity and seemingly play diversified roles in different autoimmune disorders (AIDs). The aim of this study was to determine the role of NK cells in the pathogenesis of PSC. Methods: The frequency and phenotype of circulating NK cells in a large cohort of patients with PSC and healthy controls (HCs) were systematically examined. In addition, the functional capacity of NK cells including cytotoxicity and cytokine production was studied. Results: The frequency of CD3−CD56dimCD16+ (defined as CD56dim) NK cells in PSC patients was significantly lower in comparison to HCs. CD56dim NK cells from PSC displayed a more immature phenotype including high expression of the natural killing receptor NKp46 and downregulation of the highly differentiated NK cell marker CD57. Interestingly, the reduction of CD57 expression of NK cells was associated with the disease severity of PSC. In addition, PSC CD56dim NK cells exhibited increased CD107a degranulation and cytolytic activity toward target cells compared with HCs. Further analysis demonstrated that CD57−CD56dim NK cells from PSC had elevated expression of NKp46, NKp30, IL-2 receptor, and KLRG1 and higher cytotoxic capacity as compared to CD57+CD56dim NK cells. Conclusions: Our data demonstrate that the differentiation of PSC NK cells is dysregulated with enhanced cytotoxic activity. This change is likely to be functionally involved in pathogenesis and disease progression, deducing the potential of NK-directed immunotherapy for PSC.

Published
2022

4. Greater Transplant-Free Survival in Patients Receiving Obeticholic Acid for Primary Biliary Cholangitis in a Clinical Trial Setting Compared to Real-World External Controls

Author

Murillo Perez, C, Fisher, H, Hiu, S, Kareithi, D, Adekunle, F, Mayne, T, Malecha, E, Ness, E, van der Meer, A, Lammers, W, Trivedi, P, Battezzati, P, Nevens, F, Kowdley, K, Bruns, T, Cazzagon, N, Floreani, A, Mason, A, Pares, A, Londono, M, Invernizzi, P, Carbone, M, Lleo, A, Mayo, M, Dalekos, G, Gatselis, N, Thorburn, D, Verhelst, X, Gulamhusein, A, Janssen, H, Smith, R, Flack, S, Mulcahy, V, Trauner, M, Bowlus, C, Lindor, K, Corpechot, C, Jones, D, Mells, G, Hirschfield, G, Wason, J, Hansen, B, Sturgess, R, Healey, C, Gunasekera, A, Kallis, Y, Wright, G, Mathialahan, T, Evans, R, Gasem, J, Ramanaden, D, Ward, E, Bhalme, M, Southern, P, Maggs, J, Yousif, M, Srivastava, B, Foxton, M, Collins, C, Prasad, Y, Porras-Perez, F, Yapp, T, Patel, M, Ede, R, Carte, M, Koss, K, Sattianayagam, P, Grimley, C, Tidbury, J, Mansour, D, Beckley, M, Hollywood, C, Ramag, J, Gordon, H, Ridpath, J, Grover, B, Abouda, G, Rees, I, Narain, M, Salam, I, Banim, P, Das, D, Matthews, H, Mohammed, F, Jones, R, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Hutchinson, J, Gupta, P, Shah, A, Saha, S, Pollock, K, Barclay, S, Mcdonald, N, Rushbrook, S, Przemioslo, R, Millar, A, Mitchell, S, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Cramp, M, Aspinal, R, Booth, J, Williams, E, Hussaini, H, Christie, J, Chaudhry, T, Mann, S, Ala, A, Maltby, J, Corbett, C, Singhal, S, Hoeroldt, B, Butterworth, J, Douglas, A, Sinha, R, Panter, S, Shearman, J, Bray, G, Roberts, M, Forton, D, Taylor, N, Jafar, W, Cowan, M, Ch'Ng, C, Rahman, M, Wesley, E, Jain, S, Mandal, A, Wright, M, Gordon, F, Unitt, E, Austin, A, Palegwala, A, Vemala, V, Higham, A, Fraser, J, Li, A, Ramakrishnan, S, King, A, Whalley, S, Gee, I, Keld, R, Fellows, H, Gotto, J, Millson, C, Murillo Perez C. F., Fisher H., Hiu S., Kareithi D., Adekunle F., Mayne T., Malecha E., Ness E., van der Meer A. J., Lammers W. J., Trivedi P. J., Battezzati P. M., Nevens F., Kowdley K. V., Bruns T., Cazzagon N., Floreani A., Mason A. L., Pares A., Londono M. -C., Invernizzi P., Carbone M., Lleo A., Mayo M. J., Dalekos G. N., Gatselis N. K., Thorburn D., Verhelst X., Gulamhusein A., Janssen H. L. A., Smith R., Flack S., Mulcahy V., Trauner M., Bowlus C. L., Lindor K. D., Corpechot C., Jones D., Mells G., Hirschfield G. M., Wason J., Hansen B. E., Sturgess R., Healey C., Gunasekera A., Kallis Y., Wright G., Mathialahan T., Evans R., Gasem J., Ramanaden D., Ward E., Bhalme M., Southern P., Maggs J., Yousif M., Srivastava B., Foxton M., Collins C., Prasad Y., Porras-Perez F., Yapp T., Patel M., Ede R., Carte M., Koss K., Sattianayagam P., Grimley C., Tidbury J., Mansour D., Beckley M., Hollywood C., Ramag J., Gordon H., Ridpath J., Grover B., Abouda G., Rees I., Narain M., Salam I., Banim P., Das D., Matthews H., Mohammed F., Jones R., Sen S., Bird G., Prince M., Prasad G., Kitchen P., Hutchinson J., Gupta P., Shah A., Saha S., Pollock K., Barclay S., McDonald N., Rushbrook S., Przemioslo R., Millar A., Mitchell S., Davis A., Naqvi A., Lee T., Ryder S., Collier J., Cramp M., Aspinal R., Booth J., Williams E., Hussaini H., Christie J., Chaudhry T., Mann S., Ala A., Maltby J., Corbett C., Singhal S., Hoeroldt B., Butterworth J., Douglas A., Sinha R., Panter S., Shearman J., Bray G., Roberts M., Forton D., Taylor N., Jafar W., Cowan M., Ch'ng C. L., Rahman M., Wesley E., Jain S., Mandal A., Wright M., Trivedi P., Gordon F., Unitt E., Austin A., Palegwala A., Vemala V., Higham A., Fraser J., Li A., Ramakrishnan S., King A., Whalley S., Gee I., Keld R., Fellows H., Gotto J., Millson C., Murillo Perez, C, Fisher, H, Hiu, S, Kareithi, D, Adekunle, F, Mayne, T, Malecha, E, Ness, E, van der Meer, A, Lammers, W, Trivedi, P, Battezzati, P, Nevens, F, Kowdley, K, Bruns, T, Cazzagon, N, Floreani, A, Mason, A, Pares, A, Londono, M, Invernizzi, P, Carbone, M, Lleo, A, Mayo, M, Dalekos, G, Gatselis, N, Thorburn, D, Verhelst, X, Gulamhusein, A, Janssen, H, Smith, R, Flack, S, Mulcahy, V, Trauner, M, Bowlus, C, Lindor, K, Corpechot, C, Jones, D, Mells, G, Hirschfield, G, Wason, J, Hansen, B, Sturgess, R, Healey, C, Gunasekera, A, Kallis, Y, Wright, G, Mathialahan, T, Evans, R, Gasem, J, Ramanaden, D, Ward, E, Bhalme, M, Southern, P, Maggs, J, Yousif, M, Srivastava, B, Foxton, M, Collins, C, Prasad, Y, Porras-Perez, F, Yapp, T, Patel, M, Ede, R, Carte, M, Koss, K, Sattianayagam, P, Grimley, C, Tidbury, J, Mansour, D, Beckley, M, Hollywood, C, Ramag, J, Gordon, H, Ridpath, J, Grover, B, Abouda, G, Rees, I, Narain, M, Salam, I, Banim, P, Das, D, Matthews, H, Mohammed, F, Jones, R, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Hutchinson, J, Gupta, P, Shah, A, Saha, S, Pollock, K, Barclay, S, Mcdonald, N, Rushbrook, S, Przemioslo, R, Millar, A, Mitchell, S, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Cramp, M, Aspinal, R, Booth, J, Williams, E, Hussaini, H, Christie, J, Chaudhry, T, Mann, S, Ala, A, Maltby, J, Corbett, C, Singhal, S, Hoeroldt, B, Butterworth, J, Douglas, A, Sinha, R, Panter, S, Shearman, J, Bray, G, Roberts, M, Forton, D, Taylor, N, Jafar, W, Cowan, M, Ch'Ng, C, Rahman, M, Wesley, E, Jain, S, Mandal, A, Wright, M, Gordon, F, Unitt, E, Austin, A, Palegwala, A, Vemala, V, Higham, A, Fraser, J, Li, A, Ramakrishnan, S, King, A, Whalley, S, Gee, I, Keld, R, Fellows, H, Gotto, J, Millson, C, Murillo Perez C. F., Fisher H., Hiu S., Kareithi D., Adekunle F., Mayne T., Malecha E., Ness E., van der Meer A. J., Lammers W. J., Trivedi P. J., Battezzati P. M., Nevens F., Kowdley K. V., Bruns T., Cazzagon N., Floreani A., Mason A. L., Pares A., Londono M. -C., Invernizzi P., Carbone M., Lleo A., Mayo M. J., Dalekos G. N., Gatselis N. K., Thorburn D., Verhelst X., Gulamhusein A., Janssen H. L. A., Smith R., Flack S., Mulcahy V., Trauner M., Bowlus C. L., Lindor K. D., Corpechot C., Jones D., Mells G., Hirschfield G. M., Wason J., Hansen B. E., Sturgess R., Healey C., Gunasekera A., Kallis Y., Wright G., Mathialahan T., Evans R., Gasem J., Ramanaden D., Ward E., Bhalme M., Southern P., Maggs J., Yousif M., Srivastava B., Foxton M., Collins C., Prasad Y., Porras-Perez F., Yapp T., Patel M., Ede R., Carte M., Koss K., Sattianayagam P., Grimley C., Tidbury J., Mansour D., Beckley M., Hollywood C., Ramag J., Gordon H., Ridpath J., Grover B., Abouda G., Rees I., Narain M., Salam I., Banim P., Das D., Matthews H., Mohammed F., Jones R., Sen S., Bird G., Prince M., Prasad G., Kitchen P., Hutchinson J., Gupta P., Shah A., Saha S., Pollock K., Barclay S., McDonald N., Rushbrook S., Przemioslo R., Millar A., Mitchell S., Davis A., Naqvi A., Lee T., Ryder S., Collier J., Cramp M., Aspinal R., Booth J., Williams E., Hussaini H., Christie J., Chaudhry T., Mann S., Ala A., Maltby J., Corbett C., Singhal S., Hoeroldt B., Butterworth J., Douglas A., Sinha R., Panter S., Shearman J., Bray G., Roberts M., Forton D., Taylor N., Jafar W., Cowan M., Ch'ng C. L., Rahman M., Wesley E., Jain S., Mandal A., Wright M., Trivedi P., Gordon F., Unitt E., Austin A., Palegwala A., Vemala V., Higham A., Fraser J., Li A., Ramakrishnan S., King A., Whalley S., Gee I., Keld R., Fellows H., Gotto J., and Millson C.

Abstract

Background & Aims: The Primary Biliary Cholangitis (PBC) Obeticholic Acid (OCA) International Study of Efficacy (POISE) randomized, double-blind, placebo-controlled trial demonstrated that OCA reduced biomarkers associated with adverse clinical outcomes (ie, alkaline phosphatase, bilirubin, aspartate aminotransferase, and alanine aminotransferase) in patients with PBC. The objective of this study was to evaluate time to first occurrence of liver transplantation or death in patients with OCA in the POISE trial and open-label extension vs comparable non-OCA–treated external controls. Methods: Propensity scores were generated for external control patients meeting POISE eligibility criteria from 2 registry studies (Global PBC and UK-PBC) using an index date selected randomly between the first and last date (inclusive) on which eligibility criteria were met. Cox proportional hazards models weighted by inverse probability of treatment assessed time to death or liver transplantation. Additional analyses (Global PBC only) added hepatic decompensation to the composite end point and assessed efficacy in patients with or without cirrhosis. Results: During the 6-year follow-up, there were 5 deaths or liver transplantations in 209 subjects in the POISE cohort (2.4%), 135 of 1381 patients in the Global PBC control (10.0%), and 281 of 2135 patients in the UK-PBC control (13.2%). The hazard ratios (HRs) for the primary outcome were 0.29 (95% CI, 0.10–0.83) for POISE vs Global PBC and 0.30 (95% CI, 0.12–0.75) for POISE vs UK-PBC. In the Global PBC study, HR was 0.20 (95% CI, 0.03–1.22) for patients with cirrhosis and 0.31 (95% CI, 0.09–1.04) for those without cirrhosis; HR was 0.42 (95% CI, 0.21–0.85) including hepatic decompensation. Conclusions: Patients treated with OCA in a trial setting had significantly greater transplant-free survival than comparable external control patients.

Published
2022

5. HLA haplotypes in primary sclerosing cholangitis patients of admixed and non‐European ancestry

Author

Henriksen, E. K. K., Viken, M. K., Wittig, M., Holm, K., Folseraas, T., Mucha, S., Melum, E., Hov, J. R., Lazaridis, K. N., Juran, B. D., Chazouillères, O., Färkkilä, M., Gotthardt, D. N., Invernizzi, P., Carbone, M., Hirschfield, G. M., Rushbrook, S. M., Goode, E., Ponsioen, C. Y., Weersma, R. K., Eksteen, B., Yimam, K. K., Gordon, S. C., Goldberg, D., Yu, L., Bowlus, C. L., Franke, A., Lie, B. A., and Karlsen, T. H.

Published
2017
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7. Glycomic analysis of antibody indicates distinctive glycosylation profile in patients with autoimmune cholangitis

Author

Zhou, X, Kailemia, M, Sun, Y, Shuai, Z, Yang, G, Dhaliwal, S, Cristoferi, L, Leung, P, Invernizzi, P, Bowlus, C, Lebrilla, C, Ansari, A, Ridgway, W, Zhang, W, Gershwin, M, Zhou X., Kailemia M. J., Sun Y., Shuai Z., Yang G. -X., Dhaliwal S., Cristoferi L., Leung P. S. C., Invernizzi P., Bowlus C. L., Lebrilla C. B., Ansari A. A., Ridgway W. M., Zhang W., Gershwin M. E., Zhou, X, Kailemia, M, Sun, Y, Shuai, Z, Yang, G, Dhaliwal, S, Cristoferi, L, Leung, P, Invernizzi, P, Bowlus, C, Lebrilla, C, Ansari, A, Ridgway, W, Zhang, W, Gershwin, M, Zhou X., Kailemia M. J., Sun Y., Shuai Z., Yang G. -X., Dhaliwal S., Cristoferi L., Leung P. S. C., Invernizzi P., Bowlus C. L., Lebrilla C. B., Ansari A. A., Ridgway W. M., Zhang W., and Gershwin M. E.

Abstract

Glycosylation of antibodies, particularly in the Fc domain, critically modulate the ability of antibodies to bind to FcRs, maintaining immune quiescence to achieve a finely orchestrated immune response. The removal of sialic acid and galactose residues dramatically alters the physiological function of IgGs, and alterations of Ig glycosylation have been associated with several autoimmune disorders. However, Ig glycosylation has not been extensively studied in autoimmune cholangitis. We applied triple quadruple mass spectroscopy with subsequent multiple reaction monitoring to elucidate the profile, composition and linkage of sugar residues of antibody glycans in patients with primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and healthy controls (HC). Agalactosylated, HexNAc terminated IgG1 glycoforms were enriched in both PBC and PSC. Levels of IgM glycans at site N439 and fucosylated glycans in J chain, were significantly decreased in PBC compared to PSC and HC. PSC patients had decreased bisecting glycoforms and increased biantennary glycoforms on IgA compared to PBC. Importantly, our data demonstrate the association of distinct branching and composition patterns of Ig glycoforms with disease severity and liver cirrhosis, which highlight the importance of glycan biology as a potential mechanism and/or a disease specific signal of inflammation.

Published
2020

8. Effects of Tumor Necrosis Factor Antagonists in Patients With Primary Sclerosing Cholangitis

Author

Hedin, C, Sado, G, Ndegwa, N, Lytvyak, E, Mason, A, Montano-Loza, A, Gerussi, A, Saffioti, F, Thorburn, D, Nilsson, E, Larsson, G, Moum, B, van Munster, K, Ponsioen, C, Levy, C, Nogueira, N, Bowlus, C, Gotlieb, N, Shibolet, O, Lynch, K, Chapman, R, Rupp, C, Vesterhus, M, Jorgensen, K, Rorsman, F, Schramm, C, Sabino, J, Vermeire, S, Zago, A, Cazzagon, N, Marschall, H, Ytting, H, Ben Belkacem, K, Chazouilleres, O, Almer, S, Bergquist, A, Hedin C. R. H., Sado G., Ndegwa N., Lytvyak E., Mason A., Montano-Loza A., Gerussi A., Saffioti F., Thorburn D., Nilsson E., Larsson G., Moum B. A., van Munster K. N., Ponsioen C. Y., Levy C., Nogueira N. F., Bowlus C. L., Gotlieb N., Shibolet O., Lynch K. D., Chapman R. W., Rupp C., Vesterhus M., Jorgensen K. K., Rorsman F., Schramm C., Sabino J., Vermeire S., Zago A., Cazzagon N., Marschall H. -U., Ytting H., Ben Belkacem K., Chazouilleres O., Almer S., Bergquist A., Hedin, C, Sado, G, Ndegwa, N, Lytvyak, E, Mason, A, Montano-Loza, A, Gerussi, A, Saffioti, F, Thorburn, D, Nilsson, E, Larsson, G, Moum, B, van Munster, K, Ponsioen, C, Levy, C, Nogueira, N, Bowlus, C, Gotlieb, N, Shibolet, O, Lynch, K, Chapman, R, Rupp, C, Vesterhus, M, Jorgensen, K, Rorsman, F, Schramm, C, Sabino, J, Vermeire, S, Zago, A, Cazzagon, N, Marschall, H, Ytting, H, Ben Belkacem, K, Chazouilleres, O, Almer, S, Bergquist, A, Hedin C. R. H., Sado G., Ndegwa N., Lytvyak E., Mason A., Montano-Loza A., Gerussi A., Saffioti F., Thorburn D., Nilsson E., Larsson G., Moum B. A., van Munster K. N., Ponsioen C. Y., Levy C., Nogueira N. F., Bowlus C. L., Gotlieb N., Shibolet O., Lynch K. D., Chapman R. W., Rupp C., Vesterhus M., Jorgensen K. K., Rorsman F., Schramm C., Sabino J., Vermeire S., Zago A., Cazzagon N., Marschall H. -U., Ytting H., Ben Belkacem K., Chazouilleres O., Almer S., and Bergquist A.

Abstract

Background & Aims: Few patients with primary sclerosing cholangitis (PSC) and inflammatory bowel diseases (IBDs) are exposed to tumor necrosis factor (TNF) antagonists because of the often mild symptoms of IBD. We assessed the effects of anti-TNF agents on liver function in patients with PSC and IBD, and their efficacy in treatment of IBD. Methods: We performed a retrospective analysis of 141 patients with PSC and IBD receiving treatment with anti-TNF agents (infliximab or adalimumab) at 20 sites (mostly tertiary-care centers) in Europe and North America. We collected data on the serum level of alkaline phosphatase (ALP). IBD response was defined as either endoscopic response or, if no endoscopic data were available, clinical response, as determined by the treating clinician or measurements of fecal calprotectin. Remission was defined more stringently as endoscopic mucosal healing. We used linear regression analysis to identify factors associated significantly with level of ALP during anti-TNF therapy. Results: Anti-TNF treatment produced a response of IBD in 48% of patients and remission of IBD in 23%. There was no difference in PSC symptom frequency before or after drug exposure. The most common reasons for anti-TNF discontinuation were primary nonresponse of IBD (17%) and side effects (18%). At 3 months, infliximab-treated patients had a median reduction in serum level of ALP of 4% (interquartile range, reduction of 25% to increase of 19%) compared with a median 15% reduction in ALP in adalimumab-treated patients (interquartile range, reduction of 29% to reduction of 4%; P =.035). Factors associated with lower ALP were normal ALP at baseline (P <.01), treatment with adalimumab (P =.090), and treatment in Europe (P =.083). Conclusions: In a retrospective analysis of 141 patients with PSC and IBD, anti-TNF agents were moderately effective and were not associated with exacerbation of PSC symptoms or specific side effects. Prospective studies are needed to inv

Published
2020

9. Follow-up magnetic resonance imaging/3D-magnetic resonance cholangiopancreatography in patients with primary sclerosing cholangitis: challenging for experts to interpret

Author

Zenouzi, R., Liwinski, T., Yamamura, J., Weiler-Normann, C., Sebode, M., Keller, S., Lohse, A. W., Schramm, C., Aabakken, L., Arrivé, L., Bowlus, C. L., Bungay, H., van Buuren, H. R., Cardinale, V., Carey, E. J., Chazouillères, O., Cheung, A., Culver, E. L., Dufour, J. F., Dumonceau, J. M., Eaton, J. E., Eddowes, P. J., Färkkilä, M., Floreani, A., Franceschet, I., Hohenester, S. D., Kemmerich, G., Krawczyk, M., Zimmer, V., Lenzen, H., Levy, C., Marschall, H. U., Marzioni, M., Motta, R., Muratori, L., Pereira, S. P., Poley, J. W., Rimola, J., Ringe, K. I., Rushbrook, S., Simpson, B. W., Schrumpf, E., Spina, J. C., Terziroli Beretta-Piccoli, B., Trauner, M., Tringali, A., Venkatesh, S. K., Vesterhus, M., Villamil, A., Weismüller, T. J., Ytting, H., Zenouzi, R., Liwinski, T., Yamamura, J., Weiler-Normann, C., Sebode, M., Keller, S., Lohse, A.W., Schramm, C., Aabakken, L., Arrivé, L., Bowlus, C.L., Bungay, H., van Buuren, H.R., Cardinale, V., Carey, E.J., Chazouillères, O., Cheung, A., Culver, E.L., Dufour, J.F., Dumonceau, J.M., Eaton, J.E., Eddowes, P.J., Färkkilä, M., Floreani, A., Franceschet, I., Hohenester, S.D., Kemmerich, G., Krawczyk, M., Zimmer, V., Lenzen, H., Levy, C., Marschall, H.U., Marzioni, M., Motta, R., Muratori, L., Pereira, S.P., Poley, J.W., Rimola, J., Ringe, K.I., Rushbrook, S., Simpson, B.W., Schrumpf, E., Spina, J.C., Terziroli Beretta-Piccoli, B., Trauner, M., Tringali, A., Venkatesh, S.K., Vesterhus, M., Villamil, A., Weismüller, T.J., Ytting, H., Culver, E, and Gastroenterology & Hepatology

Subjects
Adult, Liver Cirrhosis, Male, medicine.medical_specialty, Cirrhosis, Cholangiopancreatography, Magnetic Resonance, Cholangitis, Sclerosing, Constriction, Pathologic, Primary sclerosing cholangitis, Cholangiocarcinoma, Diagnosis, Differential, 03 medical and health sciences, Imaging, Three-Dimensional, 0302 clinical medicine, Surveys and Questionnaires, Image Interpretation, Computer-Assisted, medicine, Humans, Pharmacology (medical), In patient, Expert Testimony, Cholangiopancreatography, Endoscopic Retrograde, Magnetic resonance cholangiopancreatography, Endoscopic retrograde cholangiopancreatography, Hepatology, medicine.diagnostic_test, business.industry, Elevated total bilirubin, Gastroenterology, Reproducibility of Results, Magnetic resonance imaging, Middle Aged, medicine.disease, Bile Ducts, Intrahepatic, Bile Duct Neoplasms, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, Clinical Competence, Radiology, Bilirubin levels, business, Follow-Up Studies
Abstract

Background: In patients with primary sclerosing cholangitis follow‐up magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) is performed by many centres, particularly for the early detection of biliary malignancies and strictures. Clinically meaningful MRI‐based definitions of primary sclerosing cholangitis related complications are, however, lacking.Aim: To investigate how primary sclerosing cholangitis experts interpret follow‐up MRI/MRCP with a focus on conclusions that may impact clinical decision‐making in primary sclerosing cholangitis.Methods: Within the International Primary Sclerosing Cholangitis Study Group, an online survey on 16 real‐life primary sclerosing cholangitis cases including clinical and biochemical information as well as a T2‐weighted liver MRI/3D‐MRCP was conducted. The interpretation of images and subsequent recommendations were assessed using a multiple‐choice questionnaire. An inter‐rater reliability calculation (Fleiss′ kappa) was performed and factors potentially affecting the interpretation of magnetic resonance images were analysed using generalised linear mixed‐effect models.Results: Forty‐four members/associates of the International Primary Sclerosing Cholangitis Study Group (median experience in the care of primary sclerosing cholangitis patients: 14 years) completed the survey. The MRI interpretation significantly varied among the participants. The lowest agreement was found with respect to the indication to perform subsequent endoscopic retrograde cholangiopancreatography (ERCP; Κ = 0.12, 95%CI 0.11‐0.14). Elevated total bilirubin was the variable with the strongest effect on the rate of suspected dominant strictures, cholangiocarcinoma or ERCP recommendations. Liver cirrhosis did not prevent participants from recommending ERCP. Overall, the survey participants′ recommendations contrasted the real‐life management and outcome.Conclusions: In primary sclerosing cholangitis, the interpretation of follow‐up MRI/3D‐MRCP significantly varies even among experts and seems to be primarily affected by bilirubin levels. Generally accepted MRI‐based definitions of primary sclerosing cholangitis‐related complications are urgently needed.

Published
2018
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12. Serum microRNAs as novel biomarkers for primary sclerosing cholangitis and cholangiocarcinoma

Author

Bernuzzi, F, primary, Marabita, F, additional, Lleo, A, additional, Carbone, M, additional, Mirolo, M, additional, Marzioni, M, additional, Alpini, G, additional, Alvaro, D, additional, Boberg, K M, additional, Locati, M, additional, Torzilli, G, additional, Rimassa, L, additional, Piscaglia, F, additional, He, X-S, additional, Bowlus, C L, additional, Yang, G-X, additional, Gershwin, M E, additional, and Invernizzi, P, additional

Published
2016
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13. Advances in pharmacotherapy for primary biliary cirrhosis

Author

Mousa, H, Lleo, A, Invernizzi, P, Bowlus, C, Gershwin, M, Mousa H. S., Lleo A., Invernizzi P., Bowlus C. L., Gershwin M. E., Mousa, H, Lleo, A, Invernizzi, P, Bowlus, C, Gershwin, M, Mousa H. S., Lleo A., Invernizzi P., Bowlus C. L., and Gershwin M. E.

Abstract

Introduction: Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease mostly seen in middle-aged women characterized by progressive nonsuppurative destruction of small bile ducts resulting in intrahepatic cholestasis, parenchymal injury and ultimately end-stage liver disease. Despite major breakthroughs in our understanding of PBC, there remains only one FDA-approved agent for treatment: ursodeoxycholic acid (UDCA) to which one-third of patients are unresponsive. Areas covered: Biochemical response to treatment with UDCA is associated with excellent survival rates in PBC patients. However, there is a need for alternative treatments for nonresponders. Results from human epidemiological and genetic studies as well as preclinical studies in PBC animal models have provided a strong impetus for the development of new therapeutic agents. In this review, we discuss the recent advances in translational research in PBC focusing on promising therapeutic approaches, namely immune-based targeted therapies and agents targeting the synthesis and circulation of bile acids. Expert opinion: We are in a new era for the development of novel therapies for PBC. Data on fibrates, budesonide and obeticholic acid offer encouragement for nonresponders to UDCA.

Published
2015

17. Cloning and analysis of the promotor region of the human fibronectin gene.

Author

Dean, D C, Bowlus, C L, and Bourgeois, S

Abstract

Human fibronectin (FN) genomic clones were isolated by screening a human genomic library with a 75-base oligonucleotide. The sequence of the oligonucleotide corresponds to a region near the 5' end of the human FN cDNA clone pFH6 that contains the amino-terminal coding sequences but does not extend to the 5' end of the mRNA [Kornblihtt, A. R., Umezawa, K., Vibe-Pedersen, K. & Baralle, F. E. (1985) EMBO J. 4, 1755-1759]. The 5' end of the FN gene is found on a 3.7-kilobase-pair EcoRI fragment that contains about 2.7 kilobase pairs of flanking sequence. The first exon is 414 base pairs long, with a 5' untranslated region of 267 base pairs. As deduced on the basis of the position of the initiation codon, FN is synthesized with a 31-residue amino acid extension on the amino terminus that is not present in the mature polypeptide. This amino-terminal extension appears to contain both a signal peptide and a propeptide. The first 200 base pairs of 5'-flanking sequence is very G + C rich. Upstream of this the sequence becomes relatively A + T rich. The sequence ATATAA is found at -25 and the sequence CAAT is present at -150. The sequence GGGGCGGGGC at -102 exhibits homology to the binding site for the transcription factor SP1, and the sequence TGACGTCA at -173 exhibits homology to 5'-flanking sequences important for induction by cAMP.

Published
1987
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19. Genotype-phenotype analysis across 130 422 genetic variants identifies RSPO3 as the first genome-wide significant modifier gene in primary sclerosing cholangitis

Author

Albert Pares, Vries, E. M., Alexander, G., Alvaro, D., Bergquist, A., Beuers, U., Bjornsson, E., Boberg, K. M., Bowlus, C. L., Chapman, R. W., Chazouilleres, O., Cheung, A., Dalekos, G., Eksteen, B., Ellinghaus, D., Farkkila, M., Festen, E. A., Floreani, A., Folseraas, T., Goode, E., Gotthardt, D. N., Hirschfield, G. M., Hoek, B., Holm, K., Hohenester, S., Hov, J. R., Imhann, F., Invernizzi, P., Jiang, X., Eaton, J., Juran, B. D., Lazaridis, K. N., Leppa, V., Liu, J. Z., Lofberg, J., Manns, M. P., Marschall, H-U, Marzioni, M., Mason, A. L., Melum, E., Milkiewicz, P., Muller, T., Pares, A., Rupp, C., Rushbrook, S. M., Rust, C., Sampaziotis, F., Sandford, R. N., Schramm, C., Schreiber, S., Schrumpf, E., Silverberg, M., Srivastava, B., Sterneck, M., Teufel, A., Tittmann, L., Vallier, L., Vila, A. V., Vries, B., Weismuller, T. J., Wijmenga, C., Zachou, K., Franke, A., Anderson, C. A., Karlsen, T. H., Ponsioen, C. Y., Weersma, R. K., Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Department of Health and Life Sciences

21. An adult case of acute lymphoblastic leukaemia presenting as hepatic dysfunction.

Author

Aoki CA, Bowlus CL, and Rossaro L

Subjects
Antineoplastic Agents therapeutic use, Asparaginase therapeutic use, Bone Marrow pathology, Drug Therapy, Combination, Female, Glucocorticoids therapeutic use, Humans, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Prednisone therapeutic use, Liver Diseases etiology, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis
Abstract

Acute hepatic dysfunction is a rare and often fatal presentation of haematological malignancies. We describe an adult case of acute lymphoblastic leukaemia presenting as an acute hepatitis. Due to the elevation in the patient's transaminases and bilirubin, standard acute lymphoblastic leukaemia induction therapy could not be used. Instead the combination of prednisone and asaparaginase were used to successfully induce remission.

Published
2005
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22. Costs of hepatitis C.

Author

Leigh JP, Bowlus CL, Leistikow BN, and Schenker M

Subjects
Adult, Aged, Carcinoma, Hepatocellular economics, Carcinoma, Hepatocellular mortality, Cost-Benefit Analysis, Costs and Cost Analysis, Cross-Sectional Studies, Female, Health Expenditures statistics & numerical data, Hepatitis C, Chronic drug therapy, Hepatitis C, Chronic mortality, Humans, Interferon alpha-2, Interferon-alpha administration & dosage, Interferon-alpha economics, Liver Neoplasms economics, Liver Neoplasms mortality, Liver Transplantation economics, Male, Middle Aged, Recombinant Proteins, Ribavirin administration & dosage, Ribavirin economics, Survival Rate, United States epidemiology, Hepatitis C, Chronic economics
Abstract

Objective: To estimate the direct and indirect costs of the hepatitis C virus (HCV) in the United States in 1997., Design: Aggregation and analysis of national data sets collected by the National Center for Health Statistics, the Health Care Financing Administration, and other government bureaus and private firms. To estimate costs, we used the human capital method, which decomposes costs into direct categories, such as medical expenses, and indirect categories, such as lost earnings and lost home production. We consider HCV that results in chronic liver disease separate from HCV that results in primary liver cancer., Results: We estimate $5.46 billion as the cost of HCV in 1997. Costs are split as follows: 33% for direct and 67% for indirect costs. Hepatitis C virus that results in chronic liver disease contributes roughly 92% of the costs, and HCV that results in primary liver cancer contributes the remaining 8%. The total estimate of $5.46 billion is conservative, because we ignore costs associated with pain and suffering and the value of care rendered by family members., Conclusions: To our knowledge, only one estimate of the annual costs of HCV in the 1990s has appeared in the literature, $0.6 billion. However, that estimate was not supported by an explanation of the methods. Our estimate, which relies on detailed methods, is nearly 10 times the original estimate. Our estimate of $5.46 billion is on a par with the cost of asthma ($5.8 billion [1994]).

Published
2001
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23. Functional and molecular responses of human intestinal Caco-2 cells to iron treatment.

Author

Tallkvist J, Bowlus CL, and Lönnerdal B

Subjects
Absorption, Biological Transport physiology, Caco-2 Cells, Carrier Proteins genetics, Gene Expression drug effects, Gene Expression physiology, HLA Antigens genetics, Hemochromatosis Protein, Histocompatibility Antigens Class I genetics, Humans, Intestinal Mucosa cytology, Intestinal Mucosa metabolism, Manganese metabolism, Membrane Proteins genetics, Zinc metabolism, Cation Transport Proteins, Enterocytes drug effects, Iron pharmacology, Iron-Binding Proteins, Ubiquitin-Conjugating Enzymes
Abstract

Background: Divalent metal transporter 1 (DMT1), HFE, and stimulator of iron transport (SFT) are transmembrane proteins that have been implicated in the regulation of iron homeostasis., Objective: The objective of this study was to investigate whether absorption and transepithelial movement of iron correlated with gene expression of DMT1, HFE, and SFT in an experimental model of human absorptive enterocytes., Design: Caco-2 cells were exposed to iron-supplemented media in either the presence or the absence of serum for 24, 72, and 168 h. At each time point, the uptake and transepithelial movement of iron were examined and gene expression of DMT1, HFE, and SFT was measured. Manganese and zinc absorption was also examined at 168 h., Results: Iron treatment in the presence or absence of serum reduced the uptake and transepithelial movement of iron by approximately 50% after 72 and 168 h. No effect was observed at 24 h. The uptake and transepithelial movement of manganese were similar to those of iron at 168 h, whereas the effects on zinc were less pronounced. In the absence of serum, iron treatment was associated with a reduction of DMT1 expression by 50% at 72 and 168 h. HFE expression was dependent on serum, but iron treatment did not alter HFE expression. SFT expression was not affected by iron., Conclusions: Iron treatment decreased cellular uptake of iron, manganese, and zinc, suggesting that these metals may utilize the same apical transporter. The transepithelial movement of iron and manganese, but not of zinc, was reduced across iron-treated Caco-2 cells, suggesting that iron and manganese are regulated by the same mechanism at the basolateral membrane. The gene expression of DMT1, HFE, and SFT did not fully correlate with the functional responses of Caco-2 cells. This may have been a result of posttranscriptional regulation of these genes or regulation of other genes involved in the uptake and transepithelial movement of iron in Caco-2 cells.

Published
2000
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24. Cloning of a novel MHC-encoded serine peptidase highly expressed by cortical epithelial cells of the thymus.

Author

Bowlus CL, Ahn J, Chu T, and Gruen JR

Subjects
Amino Acid Sequence, Animals, Antigen Presentation, Antigens, Differentiation, B-Lymphocyte metabolism, Base Sequence, Carboxypeptidases chemistry, Consensus Sequence, Cosmids, Epithelial Cells enzymology, Fluorescent Antibody Technique, Indirect, Histocompatibility Antigens Class II metabolism, Humans, In Situ Hybridization, Lysosomes enzymology, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Sequence Alignment, Sequence Homology, Amino Acid, Serine Endopeptidases isolation & purification, Thymus Gland growth & development, Genes, Major Histocompatibility Complex genetics, Serine Endopeptidases genetics, Thymus Gland enzymology
Abstract

Antigen presentation by cortical thymic epithelial cells (cTEC) during the positive selection of T cells has been shown to differ from that of other antigen-presenting cells. In the case of MHC class II presentation, cathepsin L as opposed to cathepsin S is responsible at least in part for the degradation of invariant chain. Other proteases, however, must be involved. We have identified a putative serine protease that is specifically expressed in the thymus. Encoded within the class I major histocompatibility complex (MHC) region, this gene has sequence homology with lysosomal prolylcarboxypeptidase, suggesting that it is a serine protease. We have, therefore, designated this gene thymus-specific serine protease (TSSP). In situ hybridization and immunofluorescence staining reveal that TSSP is expressed exclusively by cortical thymic epithelial cells, with the strongest staining noted around vessels and the thymic capsule. The identification of TSSP further supports the theory that MHC class II antigen processing and presentation in the thymic cortex involves a proteolytic milieu that differs from that of other antigen-presenting cells., (Copyright 1999 Academic Press.)

Published
1999
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