Combined biologic therapy with belimumab and rituximab in a patient with primary Sjogren syndrome


DOI: https://dx.doi.org/10.18565/therapy.2019.8.140-150

Benevolenskaya S.S., Korolkova A.A., Myachikova V.U., Kuvardin E.S., Zotkina K.E., Khadzhidis A.K., Grigorieva I.N., Bekhtereva I.A., Krivolapov U.A., Lila A.M., Maslyanskiy A.L.

1) V.A. Almazov National research medical Centre of the Ministry of Healthcare of Russia, Saint-Petersburg; 2) North-western State medical University named after I.I. Mechnikov of the Ministry of Healthcare of Russia, Saint-Petersburg; 3) V.A. Nasonova research institute of rheumatology of the Russian Academy of Sciences, Moscow; 4) St. Petersburg State pediatric medical University of the Ministry of Healthcare of Russia, Saint-Petersburg
Case report of patient with primary Sjogren syndrome (pSS), who got combined biologic therapy with belimumab and rituximab, is presented. The therapy was administred because of severe uncontrolled sicca syndrome, risk of Mucosa-associated lymphoid tissue lymphoma (MALT-lymphoma) development. Evaluation of unstimulated whole salivary flow, Shirmer’s test, ESSDAI (Sjogren’s Syndrome Disease Activity Index) аnd ESSPRI (Sjogren’s Syndrome Patient Reported Index) was done at 5 and 10 months after therapy started. Histopathological study of minor salivary gland was performed initially and after 5 months of treatment. As a result, there were a decrease in sicca syndrome and fatigue, normalization of acute phase reactants, partial reduction of antinuclear and rheumatoid factors, reduction of gammaglobulinemia. Histopathological study of minor salivary gland, what was done after 5 mounth of treatment, showed reduced density of lymphocytic infiltration and amounts of B cells. Thе obtained data shows the possibility of using rituximab – belimumab combination in certain clinical situations, but it should be further confirmed in randomized clinical trial.
Keywords: Sjogren syndrome, rituximab, belimumab, BAFF, B lymphocytes, plasma cells
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Literature


  1. Del Papa N., Vitali C. Management of primary Sjоgren’s syndrome: recent developments and new classification criteria. Ther Adv Musculoskelet Dis. 2018 Feb; 10(2): 39–54.

  2. Fragkioudaki S., Mavragani C.P., Moutsopoulos H.M. Predicting the risk for lymphoma development in Sjogren syndrome: an easy tool for clinical use. Medicine (Baltimore) 2016 Jun; 95(25): e3766.

  3. Titsinides S., Nikitakis N., Piperi E., Sklavounou A. MALT lymphoma of minor salivary glands in a Sjogren’s syndrome patient: a case report and review of literature. J Oral Maxillofac Res. 2017 Jan–Mar; 8(1): e5.

  4. Friedman J.A., Miller E.B., Huszar M. A simple technique for minor salivary gland biopsy appropriate for use by rheumatologists in an outpatient setting. Clin Rheumatol. 2002 Aug; 21(4): 349–50.

  5. Caporali R., Bonacci E., Epis O., Bobbio-Pallavicini F., Morbini P., Montecucco C. Safety and usefulness of minor salivary gland biopsy: retrospective analysis of 502 procedures performed at a single center. Arthritis Rheum. 2008 May 15; 59(5): 714–20.

  6. Shiboski C.H., Shiboski S.C., Seror R., Criswell L.A., Labetoulle M., Lietman T.M., Rasmussen A., Scofield H., Vitali C., Bowman S.J., Mariette X. International Sjogren’s Syndrome Criteria Working Group. 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjogren’s syndrome: a consensus and data-driven methodology involving three international patient cohorts. Ann Rheum Dis. 2017; 76: 9–16.

  7. Larsson A., Bredberg A., Henriksson G., Manthorpe R., Sallmyr A. Immunohistochemistry of the B-Cell Component in lower lip salivary glands of Sjogren’s syndrome and healthy subjects. Scandinavian Journal of Immunology. 2005 Jan; 61(1): 98–107.

  8. Dinescu S.C., ForTofoiu M.C., Bumbea A.M., Ciurea P.L., Busuioc C.J., Musetescu A.E. Histopathological and immunohistochemical profile in primary Sjogren’s syndrome. Rom J Morphol Embryol. 2017; 58(2): 409–17.

  9. Ramos-Casals M., Brito-Zeron P., Bombardieri S., Bootsma H., De Vita S., Dorner T., Fisher B.A., Gottenberg J.E., Hernandez-Molina G., Kocher A., Kostov B., Kruize A.A., Mandl T., Ng W.F., Retamozo S., Seror R., Shoenfeld Y., Siso-Almirall A., Tzioufas A.G., Vitali C., Bowman S., Mariette X. EULAR-Sjogren Syndrome Task Force Group. EULAR recommendations for the management of Sjogren’s syndrome with topical and systemic therapies. Ann Rheum Dis. 2019; 0: 1–16.

  10. Nocturne G., Cornec D., Seror R., Mariette X. Use of biologics in Sjogren’s syndrome. Rheum Dis Clin North Am. 2016 Aug; 42(3): 407–17.

  11. Letaief H., Lukas C., Barnetche T., Gaujoux-Viala C., Combe B., Morel J. Efficacy and safety of biological DMARDs modulating B cells in primary Sjogren’s syndrome: systematic review and meta-analysis. Joint Bone Spine. 2018 Jan; 85(1): 15–22.

  12. Carubbi F., Cipriani P., Marrelli A., Benedetto P., Ruscitti P., Berardicurti O., Pantano I., Liakouli V., Alvaro S., Alunno A., Manzo A., Ciccia F., Gerli R., Triolo G., Giacomelli R. Efficacy and safety of rituximab treatment in early primary Sjоgren’s syndrome: a prospective, multi-center, follow-up study. Arthritis Res Ther. 2013 Oct 30; 15(5): R172.

  13. Delli K., Haacke E.A., Kroese F.G., Pollard R.P., Ihrler S., van der Vegt B., Vissink A., Bootsma H., Spijkervet F.K. Towards personalised treatment in primary Sjogren’s syndrome: baseline parotid histopathology predicts responsiveness to rituximab treatment. Ann Rheum Dis. 2016 Nov; 75(11): 1933–38.

  14. Devauchelle-Pensec V., Mariette X., Jousse-Joulin S., Berthelot J.M., Perdriger A., Puechal X., Le Guern V., Sibilia J., Gottenberg J.E., Chiche L., Hachulla E., Hatron P.Y., Goeb V., Hayem G., Morel J., Zarnitsky C., Dubost J.J., Pers J.O., Nowak E., Saraux A. Treatment of primary Sjogren syndrome with rituximab: a randomized trial. Ann Intern Med. 2014 Feb 18; 160(4): 233–42.

  15. Bowman S.J., Everett C.C., O’Dwyer J.L., Emery P., Pitzalis C., Ng W.F., Pease C.T., Price E.J., Sutcliffe N., Gendi N.S.T., Hall F.C., Ruddock S.P., Fernandez C., Reynolds C., Hulme C.T., Davies K.A., Edwards C.J., Lanyon P.C., Moots R.J., Roussou E., Giles I.P., Sharples L.D., Bombardieri M. Randomized controlled trial of rituximab and cost-effectiveness analysis in treating fatigue and oral dryness in primary Sjogren’s syndrome. Arthritis Rheumatol. 2017 Jul; 69(7): 1440–50.

  16. Lavie F., Miceli-Richard C., Quillard J., Roux S., Leclerc P., Mariette X. Expression of BAFF (BLyS) in T cells infiltrating labial salivaryglands from patients with Sjogren’s syndrome. J Pathol. 2004; 202: 496–50.

  17. Mackay F., Woodcock S.A., Lawton P., Ambrose C., Baetscher M., Schneider P., Tschopp J., Browning J.L. Mice transgenic for Baff develop lymphocytic disorders along with autoimmune manifestations. J Exp Med. 1999 Dec 6; 190(11): 1697–1710.

  18. Daridon C., Devauchelle V., Hutin P., Le Berre R., Martins-Carvalho C., Bendaoud B., Dueymes M., Saraux A., Youinou P., Pers J.O. Aberrant expression of BAFF by B lymphocytes infiltrating the salivary glands of patients with primary Sjogren’s syndrome. Arthritis & Rheumatism. 2007 April; 56(4): 1134–44.

  19. Mariette X., Roux S., Zhang J., Bengoufa D., Lavie F., Zhou T., Kimberly R. The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjogren’s syndrome. Ann Rheum Dis. 2003; 62: 168–71.

  20. Schneider P., MacKay F., Steiner V., Hofmann K., Bodmer J.L., Holler N., Ambrose C., Lawton P., Bixler S., Acha-Orbea. H, Valmori D., Romero P., Werner-Favre C., Zubler R.H., Browning J.L., Tschopp J. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med. 1999; 189: 1747–56.

  21. Quartuccio L., Salvin S., Fabris M., Maset M., Pontarini E., Isola M., De Vita S. BLyS upregulation in Sjogren’s syndrome associated with lymphoproliferative disorders, higher ESSDAI score and B-cell clonal expansion in the salivary glands. Rheumatology 2013; 52: 276–81

  22. Quartuccio L., Fabris M., Moretti M., Barone F., Bombardieri M., Rupolo M., Lombardi S., Pitzalis C., Beltrami C.A., Curcio F., De Vita S. Resistance to rituximab therapy and local BAFF overexpression in Sjogren’s syndrome-related myoepithelial sialadenitis and low-grade parotid B-cell lymphoma. Open Rheumatol J. 2008; 2: 38–43.

  23. Pollard R., Abdulahad W., Vissink A. et al. Serum levels of BAFF, but not APRIL, are increased after rituximab treatment in patients with primary Sjogren’s syndrome: data from a placebo-controlled clinical trial. Annals of the Rheumatic Diseases. 2012; 72(1): 146–48.

  24. Gualtierotti R., Borghi M.O., Gerosa M., Schioppo T., Larghi P., Geginat J., Meroni P.L. Successful sequential therapy with rituximab and belimumab in patients with active systemic lupus erythematosus: a case series. Clin Exp Rheumatol. 2018 Jul–Aug; 36(4): 643–47.

  25. Carter L.M., Isenberg D.A., Ehrenstein M.R. Elevated serum BAFF levels are associated with rising anti-double-stranded DNA antibody levels and disease flare following B cell depletion therapy in systemic lupus erythematosus. Arthritis Rheum. 2013 Oct; 65(10): 2672–79.

  26. Quartuccio L., Salvin S., Corazza L., Gandolfo S., Fabris M., De Vita S. Efficacy of belimumab and targeting of rheumatoid factor-positive B-cell expansion in Sjogren’s syndrome: follow-up after the end of the phase II open-label BELISS study. Clin Exp Rheumatol. 2016 Mar–Apr; 34(2): 311–14.

  27. Mariette X., Seror R., Quartuccio L. et al. Efficacy and safety of belimumab in primary Sjogren’s syndrome: results of the BELISS open-label phase II study. Ann Rheum Dis. 2015; 74: 526–31.

  28. De Vita S., Quartuccio L., Salvin S., Picco L., Scott C.A., Rupolo M., Fabris M. Sequential therapy with belimumab followed by rituximab in Sjogren’s syndrome associated with B-cell lymphoproliferation and overexpression of BAFF: evidence for long-term efficacy. Clin Exp Rheumatol. 2014 Jul–Aug; 32(4): 490–94.

  29. Меснянкина А.А., Соловьев С.К., Александрова Е.Н., Алексанкин А.П., Асеева Е.А., Насонов Е.Л.. Двойная терапия генно-инженерными биологическими препаратами у пациентов с системной красной волчанкой. Научно-практическая ревматология. 2016; 54(3): 281–288.

  30. Hofmann K., Clauder A.K., Manz R.A. Targeting B cells and plasma cells in autoimmune diseases. Front Immunol. 2018; 9: 835.

  31. Verstappen G.M., van Nimwegen J.F., Vissink A., Kroese F.G.M., Bootsma H. The value of rituximab treatment in primary Sjogren’s syndrome. Clin Immunol. 2017 Sep; 182: 62–71.


About the Autors

Stanislava S. Benevolenskaya, rheumatologist of V.A. Almazov National medical scientific research Center, postgraduate student of V.A. Almazov National medical scientific research Centre of the Ministry of Healthcare of Russia. Address: 197341, St. Petersburg, 2 Akkuratova Str. Tel.: +7 (812) 702-37-03. E-mail: stsebe@mail.ru
Anastasia Al. Korolkova, rheumatologist, postgraduate student with rheumatology specialization of the Department of internal medicine of V.A. Almazov National medical scientific research Centre of the Ministry of Healthcare of Russia. Address: 197341, St. Petersburg, 2 Akkuratova Str. Tel.: +7 (812) 702-37-03. E-mail: ana9099588@ya.ru
Valentina Yu. Myachikova, rheumatologist of V.A. Almazov National medical scientific research Centre, postgraduate student of V.A. Almazov National medical scientific research Centre, junior research worker of scientific research laboratory of rheumatology of V.A. Almazov National medical scientific research Centre of the Ministry of Healthcare of Russia. Address: 197341, St. Petersburg, 2 Akkuratova Str. Tel.: +7 (812) 702-37-03. Email: myachik9191@gmail.com
Evgeny S. Kuvardin, rheumatologist, postgraduate student of V.A. Almazov National medical scientific research Centre of the Ministry of Healthcare of Russia. Address: 197341, St. Petersburg, 2 Akkuratova Str. Tel.: +7 (812) 702-37-03. E-mail: evgenkuv23@yandex.ru
Kira Ev. Zotkina, rheumatologist, junior research worker of scientific research laboratory of rheumatology of V.A. Almazov National medical scientific research Centre of the Ministry of Healthcare of Russia. Address: 197341, St. Petersburg, 2 Akkuratova Str. Tel.: +7 (812) 702-37-03. Email: kira.zotkina@gmail.com
Irina N. Grigorieva, rheumatologist of V.A. Almazov National medical scientific research Centre of the Ministry of Healthcare of Russia. Address: 197341, St. Petersburg, 2 Akkuratova Str. Tel.: +7 (812) 702-37-03.
Email: irina3shina@gmail.com
Alexander K. Khadzhidis, PhD, Chief clinical pharmacologist of St. Petersburg, President of the Professional medical Association of clinical pharmacologists of St. Petersburg, associate professor of the Department of allergology with a course of clinical pharmacology of St. Petersburg State pediatric medical University of the Ministry of Healthcare of Russia. Address: 194100, St. Petersburg, 2 Litovskaya Str. Tel.: +7 (812) 295-06-46. E-mail: a_khadjidis@mail.ru
Irina An. Bekhtereva, MD, associate professor, pathologist at the pathology Department of the clinical molecular morphology of the hospital named after E.E. Eichwald of I.I. Mechnikov North-western State medical University of the Ministry of Healthcare of Russia. Address: 191015, St. Petersburg, 41 Kirochnaya Str. Tel.: +7 (812) 303-50-50. Email: biapatan@yahoo.com
Yuri Al. Krivolapov, MD, professor, head of the Department of clinical molecular morphology of the hospital named after E.E. Eichwald of I.I. Mechnikov North-western State medical University of the Ministry of Healthcare of Russia. Address: 191015, St. Petersburg, 41 Kirochnaya Str. Tel.: +7 (812) 303-50-50. Email: krivolapov.yuri@gmail.com
Alexander M. Lila, MD, professor, director of V.A. Nasonova research institute of rheumatology. Address: 115522, Moscow, 34 A Kashirskoye Shosse Str. Tel.: +7 (495) 109-29-10.
Aleksei L. Maslyansky, MD, associate professor, rheumatologist, head of the scientific research laboratory of rheumatology of V.A. Almazov National medical scientific research Centre of the Ministry of Healthcare of Russia. Address: 197341, St. Petersburg, 2 Akkuratova Str. Tel.: +7 (812) 702-37-03. E-mail: esc_4@mail.ru

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