The extent of B-cell activation and dysfunction preceding lymphoma development in HIV-positive people

Shepherd, L.; Borges, Ã.H.; Harvey, R.; Bower, M.; Grulich, A.; Silverberg, M.; Weber, J.; Ristola, M.; Viard, J.-.; Bogner, J.R.; Gargalianos-Kakolyris, P.; Mussini, C.; Mansinho, K.; Yust, I.; Paduta, D.; Jilich, D.; Smiatacz, T.; Radoi, R.; Tomazic, J.; Plomgaard, P.; Frikke-Schmidt, R.; Lundgren, J.; Mocroft, A.; Losso, M.; Kundro, M.; Schmied, B.; Karpov, I.; Vassilenko, A.; Mitsura, V.M.; Paduto, D.; Clumeck, N.; De Wit, S.; Delforge, M.; Florence, E.; Vandekerckhove, L.; Hadziosmanovic, V.; Begovac, J.; Machala, L.; Sedlacek, D.; Kronborg, G.; Benfield, T.; Gerstoft, J.; Katzenstein, T.; Møller, N.F.; Pedersen, C.; Ostergaard, L.; Wiese, L.; Nielsen, L.N.; Zilmer, K.; Jelena, S.; Nakkusosakond, S.; Kohtla-Järve, N.; Ristola, M.; Aho, I.; Girard, P.-.; Pradier, C.; Fontas, E.; Duvivier, C.; Rockstroh, J.; Schmidt, R.; Degen, O.; Stellbrink, H.J.; Stefan, C.; Fätkenheuer, G.; Chkhartishvili, N.; Gargalianos, P.; Xylomenos, G.; Armenis, K.; Sambatakou, H.; Szlávik, J.; Gottfredsson, M.; Mulcahy, F.; Turner, D.; Burke, M.; Shahar, E.; Hassoun, G.; Elinav, H.; Haouzi, M.; Elbirt, D.; Sthoeger, Z.M.; D'Arminio Monforte, A.; Esposito, R.; Mazeu, I.; Mazzotta, F.; Gabbuti, A.; Vullo, V.; Lichtner, M.; Zaccarelli, M.; Antinori, A.; Acinapura, R.; Plazzi, M.; Lazzarin, A.; Castagna, A.; Gianotti, N.; Galli, M.; Ridolfo, A.; Sacco, O.L.; Rozentale, B.; Uzdaviniene, V.; Matulionyte, R.; Staub, T.; Hemmer, R.; Reiss, P.; Ormaasen, V.; Maeland, A.; Bruun, J.; Knysz, B.; Gasiorowski, J.; Inglot, M.; Horban, A.; Bakowska, E.; Flisiak, R.; Grzeszczuk, A.; Parczewski, M.; Maciejewska, K.; Aksak-Was, B.; Beniowski, M.; Mularska, E.; Gensing, M.; Jablonowska, E.; Malolepsza, E.; Wojcik, K.; Mozer-Lisewska, I.; Caldeira, L.; Maltez, F.; Oprea, C.; Victor, B.; Panteleev, A.; Panteleev, O.; Yakovlev, A.; Trofimora, T.; Khromova, I.; Kuzovatova, E.; Borodulina, E.; Vdoushkina, E.; Jevtovic, D.; Gatell, J.M.; Miró, J.M.; Moreno, S.; Rodriguez, J.M.; Clotet, B.; Jou, A.; Paredes, R.; Tural, C.; Puig, J.; Bravo, I.; Domingo, P.; Gutierrez, M.; Mateo, G.; Sambeat, M.A.; Laporte, J.M.; Falconer, K.; Thalme, A.; Sonnerborg, A.; Blaxhult, A.; Flamholc, L.; Scherrer, A.; Weber, R.; Cavassini, M.; Calmy, A.; Furrer, H.; Battegay, M.; Schmid, P.; Kuznetsova, A.; Kyselyova, G.; Sluzhynska, M.; Gazzard, B.; Johnson, A.M.; Simons, E.; Edwards, S.; Phillips, A.; Johnson, M.A.; Mocroft, A.; Orkin, C.; Scullard, G.; Clarke, A.; Leen, C.; Gatell, J.; Gazzard, B.; Horban, A.; Karpov, I.; Losso, M.; d'Arminio Monforte, A.; Pedersen, C.; Reiss, P.; Rockstroh, J.; Rockstroh, J.; Kirk, O.; Kirk, O.; Peters, L.; Matthews, C.; Fischer, A.H.; Bojesen, A.; Raben, D.; Kristensen, D.; Grønborg Laut, K.; Larsen, J.F.; Podlekareva, D.; Cozzi-Lepri, A.; Schultze, A.; Amele, S.

doi:10.1111/hiv.12546

Objectives: B-cell dysfunction and activation are thought to contribute to lymphoma development in HIV-positive people; however, the mechanisms are not well understood. We investigated levels of several markers of B-cell dysfunction [free light chain (FLC)-κ, FLC-λ, immunoglobulin G (IgG), IgA, IgM and IgD] prior to lymphoma diagnosis in HIV-positive people. Methods: A nested matched case–control study was carried out within the EuroSIDA cohort, including 73 HIV-positive people with lymphoma and 143 HIV-positive lymphoma-free controls. Markers of B-cell dysfunction were measured in prospectively stored serial plasma samples collected before the diagnosis of lymphoma (or selection date in controls). Marker levels ≤ 2 and > 2 years prior to diagnosis were investigated. Results: Two-fold higher levels of FLC-κ [odds ratio (OR) 1.84; 95% confidence interval (CI) 1.19, 2.84], FLC-λ (OR 2.15; 95% CI 1.34, 3.46), IgG (OR 3.05; 95% CI 1.41, 6.59) and IgM (OR 1.46; 95% CI 1.01, 2.11) were associated with increased risk of lymphoma > 2 years prior to diagnosis, but not ≤ 2 years prior. Despite significant associations > 2 years prior to diagnosis, the predictive accuracy of each marker was poor, with FLC-λ emerging as the strongest candidate with a c-statistic of 0.67 (95% CI 0.58, 0.76). Conclusions: FLC-κ, FLC-λ and IgG levels were higher > 2 years before lymphoma diagnosis, suggesting that B-cell dysfunction occurs many years prior to lymphoma development. However, the predictive value of each marker was low and they are unlikely candidates for risk assessment for targeted intervention.

The extent of B-cell activation and dysfunction preceding lymphoma development in HIV-positive people / L. Shepherd, Ã.H. Borges, R. Harvey, M. Bower, A. Grulich, M. Silverberg, J. Weber, M. Ristola, J.-. Viard, J.R. Bogner, P. Gargalianos-Kakolyris, C. Mussini, K. Mansinho, I. Yust, D. Paduta, D. Jilich, T. Smiatacz, R. Radoi, J. Tomazic, P. Plomgaard, R. Frikke-Schmidt, J. Lundgren, A. Mocroft, M. Losso, M. Kundro, B. Schmied, I. Karpov, A. Vassilenko, V.M. Mitsura, D. Paduto, N. Clumeck, S. De Wit, M. Delforge, E. Florence, L. Vandekerckhove, V. Hadziosmanovic, J. Begovac, L. Machala, D. Sedlacek, G. Kronborg, T. Benfield, J. Gerstoft, T. Katzenstein, N.F. Møller, C. Pedersen, L. Ostergaard, L. Wiese, L.N. Nielsen, K. Zilmer, S. Jelena, S. Nakkusosakond, N. Kohtla-Järve, M. Ristola, I. Aho, P.-. Girard, C. Pradier, E. Fontas, C. Duvivier, J. Rockstroh, R. Schmidt, O. Degen, H.J. Stellbrink, C. Stefan, G. Fätkenheuer, N. Chkhartishvili, P. Gargalianos, G. Xylomenos, K. Armenis, H. Sambatakou, J. Szlávik, M. Gottfredsson, F. Mulcahy, D. Turner, M. Burke, E. Shahar, G. Hassoun, H. Elinav, M. Haouzi, D. Elbirt, Z.M. Sthoeger, A. D'Arminio Monforte, R. Esposito, I. Mazeu, F. Mazzotta, A. Gabbuti, V. Vullo, M. Lichtner, M. Zaccarelli, A. Antinori, R. Acinapura, M. Plazzi, A. Lazzarin, A. Castagna, N. Gianotti, M. Galli, A. Ridolfo, O.L. Sacco, B. Rozentale, V. Uzdaviniene, R. Matulionyte, T. Staub, R. Hemmer, P. Reiss, V. Ormaasen, A. Maeland, J. Bruun, B. Knysz, J. Gasiorowski, M. Inglot, A. Horban, E. Bakowska, R. Flisiak, A. Grzeszczuk, M. Parczewski, K. Maciejewska, B. Aksak-Was, M. Beniowski, E. Mularska, M. Gensing, E. Jablonowska, E. Malolepsza, K. Wojcik, I. Mozer-Lisewska, L. Caldeira, F. Maltez, C. Oprea, B. Victor, A. Panteleev, O. Panteleev, A. Yakovlev, T. Trofimora, I. Khromova, E. Kuzovatova, E. Borodulina, E. Vdoushkina, D. Jevtovic, J.M. Gatell, J.M. Miró, S. Moreno, J.M. Rodriguez, B. Clotet, A. Jou, R. Paredes, C. Tural, J. Puig, I. Bravo, P. Domingo, M. Gutierrez, G. Mateo, M.A. Sambeat, J.M. Laporte, K. Falconer, A. Thalme, A. Sonnerborg, A. Blaxhult, L. Flamholc, A. Scherrer, R. Weber, M. Cavassini, A. Calmy, H. Furrer, M. Battegay, P. Schmid, A. Kuznetsova, G. Kyselyova, M. Sluzhynska, B. Gazzard, A.M. Johnson, E. Simons, S. Edwards, A. Phillips, M.A. Johnson, A. Mocroft, C. Orkin, G. Scullard, A. Clarke, C. Leen, J. Gatell, B. Gazzard, A. Horban, I. Karpov, M. Losso, A. d'Arminio Monforte, C. Pedersen, P. Reiss, J. Rockstroh, J. Rockstroh, O. Kirk, O. Kirk, L. Peters, C. Matthews, A.H. Fischer, A. Bojesen, D. Raben, D. Kristensen, K. Grønborg Laut, J.F. Larsen, D. Podlekareva, A. Cozzi-Lepri, A. Schultze, S. Amele. - In: HIV MEDICINE. - ISSN 1464-2662. - 19:2(2018 Feb), pp. 90-101.

The extent of B-cell activation and dysfunction preceding lymphoma development in HIV-positive people

Shepherd, L.;Borges, Ã. H.;Harvey, R.;Bower, M.;Grulich, A.;Silverberg, M.;Weber, J.;Ristola, M.;Viard, J. -P.;Bogner, J. R.;Gargalianos-Kakolyris, P.;Mussini, C.;Mansinho, K.;Yust, I.;Paduta, D.;Jilich, D.;Smiatacz, T.;Radoi, R.;Tomazic, J.;Plomgaard, P.;Frikke-Schmidt, R.;Lundgren, J.;Mocroft, A.;Losso, M.;Kundro, M.;Schmied, B.;Karpov, I.;Vassilenko, A.;Mitsura, V. M.;Paduto, D.;Clumeck, N.;De Wit, S.;Delforge, M.;Florence, E.;Vandekerckhove, L.;Hadziosmanovic, V.;Begovac, J.;Machala, L.;Sedlacek, D.;Kronborg, G.;Benfield, T.;Gerstoft, J.;Katzenstein, T.;Møller, N. F.;Pedersen, C.;Ostergaard, L.;Wiese, L.;Nielsen, L. N.;Zilmer, K.;Jelena, S.;Nakkusosakond, S.;Kohtla-Järve, null;Ristola, M.;Aho, I.;Girard, P. -M.;Pradier, C.;Fontas, E.;Duvivier, C.;Rockstroh, J.;Schmidt, R.;Degen, O.;Stellbrink, H. J.;Stefan, C.;Fätkenheuer, G.;Chkhartishvili, N.;Gargalianos, P.;Xylomenos, G.;Armenis, K.;Sambatakou, H.;Szlávik, J.;Gottfredsson, M.;Mulcahy, F.;Turner, D.;Burke, M.;Shahar, E.;Hassoun, G.;Elinav, H.;Haouzi, M.;Elbirt, D.;Sthoeger, Z. M.;A. D'Arminio Monforte^{Membro del Collaboration Group};Esposito, R.;Mazeu, I.;Mazzotta, F.;Gabbuti, A.;Vullo, V.;Lichtner, M.;Zaccarelli, M.;Antinori, A.;Acinapura, R.;Plazzi, M.;Lazzarin, A.;Castagna, A.;Gianotti, N.;M. Galli^{Membro del Collaboration Group};Ridolfo, A.;Sacco, Osp. L;Rozentale, B.;Uzdaviniene, V.;Matulionyte, R.;Staub, T.;Hemmer, R.;Reiss, P.;Ormaasen, V.;Maeland, A.;Bruun, J.;Knysz, B.;Gasiorowski, J.;Inglot, M.;Horban, A.;Bakowska, E.;Flisiak, R.;Grzeszczuk, A.;Parczewski, M.;Maciejewska, K.;Aksak-Was, B.;Beniowski, M.;Mularska, E.;Gensing, M.;Jablonowska, E.;Malolepsza, E.;Wojcik, K.;Mozer-Lisewska, I.;Caldeira, L.;Maltez, F.;Oprea, C.;Victor, B.;Panteleev, A.;Panteleev, O.;Yakovlev, A.;Trofimora, T.;Khromova, I.;Kuzovatova, E.;Borodulina, E.;Vdoushkina, E.;Jevtovic, D.;Gatell, J. M.;Miró, J. M.;Moreno, S.;Rodriguez, J. M.;Clotet, B.;Jou, A.;Paredes, R.;Tural, C.;Puig, J.;Bravo, I.;Domingo, P.;Gutierrez, M.;Mateo, G.;Sambeat, M. A.;Laporte, J. M.;Falconer, K.;Thalme, A.;Sonnerborg, A.;Blaxhult, A.;Flamholc, L.;Scherrer, A.;Weber, R.;Cavassini, M.;Calmy, A.;Furrer, H.;Battegay, M.;Schmid, P.;Kuznetsova, A.;Kyselyova, G.;Sluzhynska, M.;Gazzard, B.;Johnson, A. M.;Simons, E.;Edwards, S.;Phillips, A.;Johnson, M. A.;Mocroft, A.;Orkin, C.;Scullard, G.;Clarke, A.;Leen, C.;Gatell, J.;Gazzard, B.;Horban, A.;Karpov, I.;Losso, M.;d'Arminio Monforte, A.;Pedersen, C.;Reiss, P.;Rockstroh, J.;Rockstroh, J.;Kirk, O.;Kirk, O.;Peters, L.;Matthews, C.;Fischer, A. H.;Bojesen, A.;Raben, D.;Kristensen, D.;Grønborg Laut, K.;Larsen, J. F.;Podlekareva, D.;Cozzi-Lepri, A.;Schultze, A.;Amele, S.

2018

Abstract

Objectives: B-cell dysfunction and activation are thought to contribute to lymphoma development in HIV-positive people; however, the mechanisms are not well understood. We investigated levels of several markers of B-cell dysfunction [free light chain (FLC)-κ, FLC-λ, immunoglobulin G (IgG), IgA, IgM and IgD] prior to lymphoma diagnosis in HIV-positive people. Methods: A nested matched case–control study was carried out within the EuroSIDA cohort, including 73 HIV-positive people with lymphoma and 143 HIV-positive lymphoma-free controls. Markers of B-cell dysfunction were measured in prospectively stored serial plasma samples collected before the diagnosis of lymphoma (or selection date in controls). Marker levels ≤ 2 and > 2 years prior to diagnosis were investigated. Results: Two-fold higher levels of FLC-κ [odds ratio (OR) 1.84; 95% confidence interval (CI) 1.19, 2.84], FLC-λ (OR 2.15; 95% CI 1.34, 3.46), IgG (OR 3.05; 95% CI 1.41, 6.59) and IgM (OR 1.46; 95% CI 1.01, 2.11) were associated with increased risk of lymphoma > 2 years prior to diagnosis, but not ≤ 2 years prior. Despite significant associations > 2 years prior to diagnosis, the predictive accuracy of each marker was poor, with FLC-λ emerging as the strongest candidate with a c-statistic of 0.67 (95% CI 0.58, 0.76). Conclusions: FLC-κ, FLC-λ and IgG levels were higher > 2 years before lymphoma diagnosis, suggesting that B-cell dysfunction occurs many years prior to lymphoma development. However, the predictive value of each marker was low and they are unlikely candidates for risk assessment for targeted intervention.

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	Parole chiave
	
				B-cell dysfunction; biomarkers; free light chains; HIV; immunoglobulins; lymphoma; Health Policy; Infectious Diseases; Pharmacology (medical)
			
	Settori scientifico-disciplinari dell'articolo (sola visualizzazione)
	
				Settore MED/17 - Malattie Infettive
Settore BIO/14 - Farmacologia
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
			
	Data di pubblicazione
	
				feb-2018
			
	Rivista in ANCE
	
				HIV MEDICINE
			
	DOI
	
				https://dx.doi.org/10.1111/hiv.12546
			
	Tipologia
	
				Article (author)
			
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				01 - Articolo su periodico

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