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1. Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study

Author

Herrick, A, Peytrignet, S, Lunt, M, Pan, X, Hesselstrand, R, Mouthon, L, Silman, A, Dinsdale, G, Brown, E, Czirják, L, Distler, J, Distler, O, Fligelstone, K, Gregory, W, Ochiel, R, Vonk, M, Ancuţa, C, Ong, V, Farge, D, Hudson, M, Matucci-Cerinic, M, Balbir-Gurman, A, Midtvedt, Ø, Jobanputra, P, Jordan, A, Stevens, W, Moinzadeh, P, Hall, F, Agard, C, Anderson, M, Diot, E, Madhok, R, Akil, M, Buch, M, Chung, L, Damjanov, N, Gunawardena, H, Lanyon, P, Ahmad, Y, Chakravarty, K, Jacobsen, S, Macgregor, A, McHugh, N, Müller-Ladner, U, Riemekasten, G, Becker, M, Roddy, J, Carreira, P, Fauchais, A, Hachulla, E, Hamilton, J, İnanç, M, McLaren, J, Van Laar, J, Pathare, S, Proudman, S, Rudin, A, Sahhar, J, Coppere, B, Serratrice, C, Sheeran, T, Veale, D, Grange, C, Trad, G, and Denton, C

Subjects
Adult, Male, Skin/pathology, systemic sclerosis, autoantibodies, Severity of Illness Index, Scleroderma, Diffuse/diagnosis, outcomes research, Predictive Value of Tests, Skin Tests/statistics & numerical data, Humans, Prospective Studies, Skin, Skin Tests, RNA Polymerase III, Clinical and Epidemiological Research, Early Diagnosis, Logistic Models, ROC Curve, RNA Polymerase III/analysis, Area Under Curve, Scleroderma, Diffuse, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Disease Progression, Female, Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study
Abstract

ObjectivesOur aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). MethodsThe modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. ‘Progressors’ were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). Results66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. ConclusionsTwo prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. Trial registration numberNCT02339441.

Published
2018
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2. Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS)

Author

Herrick, A, Pan, X, Peytrignet, S, Lunt, M, Hesselstrand, R, Mouthon, L, Silman, A, Brown, E, Czirják, L, Distler, J, Distler, O, Fligelstone, K, Gregory, W, Ochiel, R, Vonk, M, Ancuţa, C, Ong, V, Farge, D, Hudson, M, Matucci-Cerinic, M, Balbir-Gurman, A, Midtvedt, Ø, Jordan, A, Jobanputra, P, Stevens, W, Moinzadeh, P, Hall, F, Agard, C, Anderson, M, Diot, E, Madhok, R, Akil, M, Buch, M, Chung, L, Damjanov, N, Gunawardena, H, Lanyon, P, Ahmad, Y, Chakravarty, K, Jacobsen, S, Macgregor, A, McHugh, N, Müller-Ladner, U, Riemekasten, G, Becker, M, Roddy, J, Carreira, P, Fauchais, A, Hachulla, E, Hamilton, J, İnanç, M, McLaren, J, Van Laar, J, Pathare, S, Proudman, S, Rudin, A, Sahhar, J, Coppere, B, Serratrice, C, Sheeran, T, Veale, D, Grange, C, Trad, G, and Denton, C

Subjects
Adult, Male, Methotrexate/therapeutic use, RNA Polymerase III/immunology, Antibodies, Antinuclear/immunology, Systemic Sclerosis, Severity of Illness Index, Cohort Studies, Early Medical Intervention, Journal Article, Humans, Prospective Studies, Cyclophosphamide, Autoantibodies, Nuclear Proteins, RNA Polymerase III, Mycophenolic Acid/therapeutic use, Clinical and Epidemiological Research, Middle Aged, Mycophenolic Acid, Scleroderma, Diffuse/drug therapy, Treatment, Europe, Survival Rate, Methotrexate, Treatment Outcome, DNA Topoisomerases, Type I, Cyclophosphamide/therapeutic use, Antibodies, Antinuclear, Scleroderma, Diffuse, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Immunosuppressive Agents/therapeutic use, Nuclear Proteins/immunology, Female, Autoantibodies/immunology, Immunosuppressive Agents
Abstract

Objectives: The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. Methods: This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or ‘no immunosuppressant’. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. Results: Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: −4.0 (−5.2 to −2.7) units for methotrexate, −4.1 (−5.3 to −2.9) for MMF, −3.3 (−4.9 to −1.7) for cyclophosphamide and −2.2 (−4.0 to −0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months. Conclusions: These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed. Trial Registration Number: NCT02339441.

Published
2017
Full Text
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3. Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study

Author

Herrick, A.L., Peytrignet, S., Lunt, M., Pan, X., Hesselstrand, R., Mouthon, L., Silman, A.J., Dinsdale, G., Brown, E., Czirjak, L., Distler, J.H., Distler, O., Fligelstone, K., Gregory, W.J., Ochiel, R., Vonk, M.C., Ancuta, C., Ong, V.H., Farge, D., Hudson, M., Matucci-Cerinic, M., Balbir-Gurman, A., Midtvedt, O., Jobanputra, P., Jordan, A.C., Stevens, W.B.C., Moinzadeh, P., Hall, F.C., Agard, C., Anderson, M.E., Diot, E., Madhok, R., Akil, M., Buch, M.H., Chung, L., Damjanov, N.S., Gunawardena, H., Lanyon, P., Ahmad, Y., Chakravarty, K., Jacobsen, S., MacGregor, A.J., McHugh, N., Muller-Ladner, U., Riemekasten, G., Becker, M., Roddy, J., Carreira, P.E., Fauchais, A.L., Hachulla, E., Hamilton, J., Inanc, M., McLaren, J.S., Laar, J.M. van, Pathare, S., Proudman, S.M., Rudin, A., Sahhar, J., Coppere, B., Serratrice, C., Sheeran, T., Veale, D.J., Grange, C., Trad, G.S., Denton, C.P., Herrick, A.L., Peytrignet, S., Lunt, M., Pan, X., Hesselstrand, R., Mouthon, L., Silman, A.J., Dinsdale, G., Brown, E., Czirjak, L., Distler, J.H., Distler, O., Fligelstone, K., Gregory, W.J., Ochiel, R., Vonk, M.C., Ancuta, C., Ong, V.H., Farge, D., Hudson, M., Matucci-Cerinic, M., Balbir-Gurman, A., Midtvedt, O., Jobanputra, P., Jordan, A.C., Stevens, W.B.C., Moinzadeh, P., Hall, F.C., Agard, C., Anderson, M.E., Diot, E., Madhok, R., Akil, M., Buch, M.H., Chung, L., Damjanov, N.S., Gunawardena, H., Lanyon, P., Ahmad, Y., Chakravarty, K., Jacobsen, S., MacGregor, A.J., McHugh, N., Muller-Ladner, U., Riemekasten, G., Becker, M., Roddy, J., Carreira, P.E., Fauchais, A.L., Hachulla, E., Hamilton, J., Inanc, M., McLaren, J.S., Laar, J.M. van, Pathare, S., Proudman, S.M., Rudin, A., Sahhar, J., Coppere, B., Serratrice, C., Sheeran, T., Veale, D.J., Grange, C., Trad, G.S., and Denton, C.P.

Abstract

Contains fulltext : 191335.pdf (publisher's version ) (Open Access), OBJECTIVES: Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). METHODS: The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (+/-3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). RESULTS: 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. CONCLUSIONS: Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. TRIAL REGISTRATION NUMBER: NCT02339441.

Published
2018

4. Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study.

Author

Midtvedt O., Veale D.J., Grange C., Trad G.-S., Denton C.P., Herrick A.L., Peytrignet S., Lunt M., Pan X., Hesselstrand R., Mouthon L., Silman A.J., DInsdale G., Brown E., Czirjak L., DIstler J.H.W., DIstler O., Fligelstone K., Gregory W.J., Ochiel R., Vonk M.C., Ancu C., Ong V.H., Farge D., Hudson M., Matucci-Cerinic M., Balbir-Gurman A., Jobanputra P., Jordan A.C., Stevens W., Moinzadeh P., Hall F.C., Agard C., Anderson M.E., DIot E., Madhok R., Akil M., Buch M.H., Chung L., Damjanov N.S., Gunawardena H., Lanyon P., Ahmad Y., Chakravarty K., Jacobsen S., MacGregor A.J., McHugh N., Muller-Ladner U., Riemekasten G., Becker M., Roddy J., Carreira P.E., Fauchais A.L., Hachulla E., Hamilton J., Inanc M., McLaren J.S., Van Laar J.M., Pathare S., Proudman S.M., Rudin A., Sahhar J., Coppere B., Serratrice C., Sheeran T., Midtvedt O., Veale D.J., Grange C., Trad G.-S., Denton C.P., Herrick A.L., Peytrignet S., Lunt M., Pan X., Hesselstrand R., Mouthon L., Silman A.J., DInsdale G., Brown E., Czirjak L., DIstler J.H.W., DIstler O., Fligelstone K., Gregory W.J., Ochiel R., Vonk M.C., Ancu C., Ong V.H., Farge D., Hudson M., Matucci-Cerinic M., Balbir-Gurman A., Jobanputra P., Jordan A.C., Stevens W., Moinzadeh P., Hall F.C., Agard C., Anderson M.E., DIot E., Madhok R., Akil M., Buch M.H., Chung L., Damjanov N.S., Gunawardena H., Lanyon P., Ahmad Y., Chakravarty K., Jacobsen S., MacGregor A.J., McHugh N., Muller-Ladner U., Riemekasten G., Becker M., Roddy J., Carreira P.E., Fauchais A.L., Hachulla E., Hamilton J., Inanc M., McLaren J.S., Van Laar J.M., Pathare S., Proudman S.M., Rudin A., Sahhar J., Coppere B., Serratrice C., and Sheeran T.

Abstract

Objectives Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). Methods The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (+/-3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). Results 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. Conclusions Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. Trial registration number NCT02339441.Copyright © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Published
2018

5. Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study.

Author

Herrick, AL, Peytrignet, S, Lunt, M, Pan, X, Hesselstrand, R, Mouthon, L, Silman, AJ, Dinsdale, G, Brown, E, Czirják, L, Distler, JHW, Distler, O, Fligelstone, K, Gregory, WJ, Ochiel, R, Vonk, MC, Ancuţa, C, Ong, VH, Farge, D, Hudson, M, Matucci-Cerinic, M, Balbir-Gurman, A, Midtvedt, Ø, Jobanputra, P, Jordan, AC, Stevens, W, Moinzadeh, P, Hall, FC, Agard, C, Anderson, ME, Diot, E, Madhok, R, Akil, M, Buch, MH, Chung, L, Damjanov, NS, Gunawardena, H, Lanyon, P, Ahmad, Y, Chakravarty, K, Jacobsen, S, MacGregor, AJ, McHugh, N, Müller-Ladner, U, Riemekasten, G, Becker, M, Roddy, J, Carreira, PE, Fauchais, AL, Hachulla, E, Hamilton, J, İnanç, M, McLaren, JS, van Laar, JM, Pathare, S, Proudman, SM, Rudin, A, Sahhar, J, Coppere, B, Serratrice, C, Sheeran, T, Veale, DJ, Grange, C, Trad, G-S, Denton, CP, Herrick, AL, Peytrignet, S, Lunt, M, Pan, X, Hesselstrand, R, Mouthon, L, Silman, AJ, Dinsdale, G, Brown, E, Czirják, L, Distler, JHW, Distler, O, Fligelstone, K, Gregory, WJ, Ochiel, R, Vonk, MC, Ancuţa, C, Ong, VH, Farge, D, Hudson, M, Matucci-Cerinic, M, Balbir-Gurman, A, Midtvedt, Ø, Jobanputra, P, Jordan, AC, Stevens, W, Moinzadeh, P, Hall, FC, Agard, C, Anderson, ME, Diot, E, Madhok, R, Akil, M, Buch, MH, Chung, L, Damjanov, NS, Gunawardena, H, Lanyon, P, Ahmad, Y, Chakravarty, K, Jacobsen, S, MacGregor, AJ, McHugh, N, Müller-Ladner, U, Riemekasten, G, Becker, M, Roddy, J, Carreira, PE, Fauchais, AL, Hachulla, E, Hamilton, J, İnanç, M, McLaren, JS, van Laar, JM, Pathare, S, Proudman, SM, Rudin, A, Sahhar, J, Coppere, B, Serratrice, C, Sheeran, T, Veale, DJ, Grange, C, Trad, G-S, and Denton, CP

Abstract

OBJECTIVES: Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). METHODS: The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). RESULTS: 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. CONCLUSIONS: Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. TRIAL REGISTRATION NUMBER: NCT02339441.

Published
2018

6. OP0123 Prediction of progressive skin thickening in early diffuse systemic sclerosis using three-monthly skin scores from the european scleroderma observational study (ESOS)

Author

Herrick, A, primary, Peytrignet, S, additional, Pan, X, additional, Hesselstrand, R, additional, Mouthon, L, additional, Brown, E, additional, Czirják, L, additional, Distler, JH, additional, Distler, O, additional, Fligelstone, K, additional, Gregory, W, additional, Ochiel, R, additional, Silman, A, additional, Vonk, M, additional, Lunt, M, additional, and Denton, C, additional

Published
2017
Full Text
View/download PDF

7. Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS)

Author

Herrick, A.L., Pan, X., Peytrignet, S., Lunt, M., Hesselstrand, R., Mouthon, L., Silman, A., Brown, E., Czirjak, L., Distler, J.H., Distler, O., Fligelstone, K., Gregory, W.J., Ochiel, R., Vonk, M.C., Ancuta, C., Ong, V.H., Farge, D., Hudson, M., Matucci-Cerinic, M., Balbir-Gurman, A., Midtvedt, O., Jordan, A.C., Jobanputra, P., Stevens, W.B.C., Moinzadeh, P., Hall, F.C., Agard, C., Anderson, M.E., Diot, E., Madhok, R., Akil, M., Buch, M.H., Chung, L., Damjanov, N., Gunawardena, H., Lanyon, P., Ahmad, Y., Chakravarty, K., Jacobsen, S., MacGregor, A.J., McHugh, N., Muller-Ladner, U., Riemekasten, G., Becker, M, Roddy, J., Carreira, P.E., Fauchais, A.L., Hachulla, E., Hamilton, J., Inanc, M., McLaren, J.S., Laar, J.M. van, Pathare, S., Proudman, S., Rudin, A., Sahhar, J., Coppere, B., Serratrice, C., Sheeran, T., Veale, D.J., Grange, C., Trad, G.S., Denton, C.P., Herrick, A.L., Pan, X., Peytrignet, S., Lunt, M., Hesselstrand, R., Mouthon, L., Silman, A., Brown, E., Czirjak, L., Distler, J.H., Distler, O., Fligelstone, K., Gregory, W.J., Ochiel, R., Vonk, M.C., Ancuta, C., Ong, V.H., Farge, D., Hudson, M., Matucci-Cerinic, M., Balbir-Gurman, A., Midtvedt, O., Jordan, A.C., Jobanputra, P., Stevens, W.B.C., Moinzadeh, P., Hall, F.C., Agard, C., Anderson, M.E., Diot, E., Madhok, R., Akil, M., Buch, M.H., Chung, L., Damjanov, N., Gunawardena, H., Lanyon, P., Ahmad, Y., Chakravarty, K., Jacobsen, S., MacGregor, A.J., McHugh, N., Muller-Ladner, U., Riemekasten, G., Becker, M, Roddy, J., Carreira, P.E., Fauchais, A.L., Hachulla, E., Hamilton, J., Inanc, M., McLaren, J.S., Laar, J.M. van, Pathare, S., Proudman, S., Rudin, A., Sahhar, J., Coppere, B., Serratrice, C., Sheeran, T., Veale, D.J., Grange, C., Trad, G.S., and Denton, C.P.

Abstract

Contains fulltext : 174691.pdf (publisher's version ) (Open Access), OBJECTIVES: The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. METHODS: This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. RESULTS: Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: -4.0 (-5.2 to -2.7) units for methotrexate, -4.1 (-5.3 to -2.9) for MMF, -3.3 (-4.9 to -1.7) for cyclophosphamide and -2.2 (-4.0 to -0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months. CONCLUSIONS: These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed. TRIAL REGISTRATION NUMBER: NCT02339441.

Published
2017

8. Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS).

Author

Herrick, AL, Pan, X, Peytrignet, S, Lunt, M, Hesselstrand, R, Mouthon, L, Silman, A, Brown, E, Czirják, L, Distler, JHW, Distler, O, Fligelstone, K, Gregory, WJ, Ochiel, R, Vonk, M, Ancuţa, C, Ong, VH, Farge, D, Hudson, M, Matucci-Cerinic, M, Balbir-Gurman, A, Midtvedt, Ø, Jordan, AC, Jobanputra, P, Stevens, W, Moinzadeh, P, Hall, FC, Agard, C, Anderson, ME, Diot, E, Madhok, R, Akil, M, Buch, MH, Chung, L, Damjanov, N, Gunawardena, H, Lanyon, P, Ahmad, Y, Chakravarty, K, Jacobsen, S, MacGregor, AJ, McHugh, N, Müller-Ladner, U, Riemekasten, G, Becker, M, Roddy, J, Carreira, PE, Fauchais, AL, Hachulla, E, Hamilton, J, İnanç, M, McLaren, JS, van Laar, JM, Pathare, S, Proudman, S, Rudin, A, Sahhar, J, Coppere, B, Serratrice, C, Sheeran, T, Veale, DJ, Grange, C, Trad, G-S, Denton, CP, Herrick, AL, Pan, X, Peytrignet, S, Lunt, M, Hesselstrand, R, Mouthon, L, Silman, A, Brown, E, Czirják, L, Distler, JHW, Distler, O, Fligelstone, K, Gregory, WJ, Ochiel, R, Vonk, M, Ancuţa, C, Ong, VH, Farge, D, Hudson, M, Matucci-Cerinic, M, Balbir-Gurman, A, Midtvedt, Ø, Jordan, AC, Jobanputra, P, Stevens, W, Moinzadeh, P, Hall, FC, Agard, C, Anderson, ME, Diot, E, Madhok, R, Akil, M, Buch, MH, Chung, L, Damjanov, N, Gunawardena, H, Lanyon, P, Ahmad, Y, Chakravarty, K, Jacobsen, S, MacGregor, AJ, McHugh, N, Müller-Ladner, U, Riemekasten, G, Becker, M, Roddy, J, Carreira, PE, Fauchais, AL, Hachulla, E, Hamilton, J, İnanç, M, McLaren, JS, van Laar, JM, Pathare, S, Proudman, S, Rudin, A, Sahhar, J, Coppere, B, Serratrice, C, Sheeran, T, Veale, DJ, Grange, C, Trad, G-S, and Denton, CP

Abstract

OBJECTIVES: The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. METHODS: This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. RESULTS: Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: -4.0 (-5.2 to -2.7) units for methotrexate, -4.1 (-5.3 to -2.9) for MMF, -3.3 (-4.9 to -1.7) for cyclophosphamide and -2.2 (-4.0 to -0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months. CONCLUSIONS: These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed. TRIAL REGISTRATION NUMBER: NCT02339441.

Published
2017

9. Zibotentan in systemic sclerosis-associated chronic kidney disease: a phase II randomised placebo-controlled trial.

Author

Stern EP, Host LV, Wanjiku I, Escott KJ, Gilmour PS, Ochiel R, Unwin R, Burns A, Ong VH, Cadiou H, O'Keeffe AG, and Denton CP

Subjects
Humans, Pyrrolidines, Single-Blind Method, Renal Insufficiency, Chronic chemically induced, Renal Insufficiency, Chronic complications, Scleroderma, Systemic chemically induced, Scleroderma, Systemic complications, Scleroderma, Systemic drug therapy
Abstract

Background: We report results from a phase II randomised placebo-controlled trial assessing zibotentan, a highly selective endothelin receptor antagonist (ERA), in chronic kidney disease (CKD) secondary to systemic sclerosis (SSc)., Methods: This trial included three sub-studies: ZEBRA 1-a randomised placebo-controlled, double-blind trial of zibotentan in SSc patients with CKD2 or CKD3 (and glomerular filtration rate (GFR) >45 ml/min) over 26 weeks; ZEBRA 2A-a 26-week placebo-controlled, single-blind trial of zibotentan in scleroderma renal crisis patients not requiring dialysis; and ZEBRA 2B-an open label pharmacokinetic study of zibotentan in patients on haemodialysis., Results: Sixteen patients were screened for ZEBRA 1. Of these, 6 patients were randomised to zibotentan and 7 to placebo. In ZEBRA 1, there were 47 non-serious adverse events (AE) during the trial. Twenty-seven occurred in the placebo group and 20 in the zibotentan group. One serious adverse event (SAE) occurred during ZEBRA1, in the placebo arm. Descriptive statistics did not suggest an effect of study drug on serum sVCAM1. Estimated GFR numerically declined in patients treated with placebo at 26 weeks and 52 weeks. In contrast, average eGFR increased in zibotentan-treated cases. The 4 patients in ZEBRA 2A experienced 8 non-serious AEs, distributed equally between placebo and zibotentan. There was one SAE each in placebo and zibotentan groups, both unrelated to study medication. ZEBRA 2B recruited 8 patients, 6 completed first dosing, and 2 completed a second dosing visit. Pharmacokinetic analysis confirmed zibotentan levels within the therapeutic range. Three patients experienced 3 non-serious AEs. One SAE occurred and was unrelated to study drug., Conclusions: Zibotentan was generally well-tolerated. ZEBRA 1 did not show any effect of zibotentan on serum sVCAM-1 but was associated with numerical improvement in eGFR at 26 weeks that was more marked at 52 weeks. ZEBRA 2B suggested a feasible dose regimen for haemodialysis patients., Trial Registration: EudraCT no: 2013-003200-39 (first posted January 28, 2014) ClinicalTrials.gov Identifier: NCT02047708 Sponsor protocol number: 13/0077., (© 2022. The Author(s).)

Published
2022
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10. Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled, proof-of-concept trial.

Author

Hobbs AJ, Moyes AJ, Baliga RS, Ghedia D, Ochiel R, Sylvestre Y, Doré CJ, Chowdhury K, Maclagan K, Quartly HL, Sofat R, Smit A, Schreiber BE, Coghlan GJ, and MacAllister RJ

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Double-Blind Method, Female, Humans, Male, Middle Aged, Young Adult, Neprilysin therapeutic use, Pulmonary Arterial Hypertension drug therapy
Abstract

Background and Purpose: Pulmonary arterial hypertension (PAH) is an incurable, incapacitating disorder resulting from increased pulmonary vascular resistance, pulmonary arterial remodelling, and right ventricular failure. In preclinical models, the combination of a PDE5 inhibitor (PDE5i) with a neprilysin inhibitor augments natriuretic peptide bioactivity, promotes cGMP signalling, and reverses the structural and haemodynamic deficits that characterize PAH. Herein, we conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of repurposing the neprilysin inhibitor, racecadotril, in PAH., Experimental Approach: Twenty-one PAH patients stable on PDE5i therapy were recruited. Acute haemodynamic and biochemical changes following a single dose of racecadotril or matching placebo were determined; this was followed by a 14-day safety and efficacy evaluation. The primary endpoint in both steps was the maximum change in circulating atrial natriuretic peptide (ANP) concentration (Δ max ), with secondary outcomes including pulmonary and systemic haemodynamics plus mechanistic biomarkers., Key Results: Acute administration of racecadotril (100 mg) resulted in a 79% increase in the plasma ANP concentration and a 106% increase in plasma cGMP levels, with a concomitant 14% fall in pulmonary vascular resistance. Racecadotril (100 mg; t.i.d.) treatment for 14 days resulted in a 19% rise in plasma ANP concentration. Neither acute nor chronic administration of racecadotril resulted in a significant drop in mean arterial BP or any serious adverse effects., Conclusions and Implications: This Phase IIa evaluation provides proof-of-principle evidence that neprilysin inhibitors may have therapeutic utility in PAH and warrants a larger scale prospective trial., (© 2019 The British Pharmacological Society.)

Published
2019
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11. Disability, fatigue, pain and their associates in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study.

Author

Peytrignet S, Denton CP, Lunt M, Hesselstrand R, Mouthon L, Silman A, Pan X, Brown E, Czirják L, Distler JHW, Distler O, Fligelstone K, Gregory WJ, Ochiel R, Vonk M, Ancuta C, Ong VH, Farge D, Hudson M, Matucci-Cerinic M, Balbir-Gurman A, Midtvedt Ø, Jordan AC, Stevens W, Moinzadeh P, Hall FC, Agard C, Anderson ME, Diot E, Madhok R, Akil M, Buch MH, Chung L, Damjanov N, Gunawardena H, Lanyon P, Ahmad Y, Chakravarty K, Jacobsen S, MacGregor AJ, McHugh N, Müller-Ladner U, Riemekasten G, Becker M, Roddy J, Carreira PE, Fauchais AL, Hachulla E, Hamilton J, Inanç M, McLaren JS, van Laar JM, Pathare S, Proudman S, Rudin A, Sahhar J, Coppere B, Serratrice C, Sheeran T, Veale DJ, Grange C, Trad GS, and Herrick AL

Subjects
Adult, Cost of Illness, Europe, Fatigue etiology, Female, Fingers, Hand Strength, Health Surveys, Humans, Male, Pain etiology, Prospective Studies, Scleroderma, Diffuse complications, Skin Ulcer etiology, Skin Ulcer physiopathology, Disability Evaluation, Fatigue physiopathology, Pain physiopathology, Scleroderma, Diffuse physiopathology, Severity of Illness Index
Abstract

Objectives: Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features., Methods: Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined., Results: The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean (s.d.) HAQ-DI 1.1 (0.83)], with 'grip' and 'activity' being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (ρ = 0.34, P < 0.0001 and ρ = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers (P = 0.004), pulmonary fibrosis (P = 0.005), cardiac (P = 0.005) and muscle involvement (P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (ρ = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (ρ = 0.40, P < 0.0001), decreasing hand function (ρ = 0.57, P < 0.0001) and increasing fatigue (ρ = -0.53, P < 0.0001)., Conclusion: The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Published
2018
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