Systemic lupus erythematosus : biomarkers and biologics

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, predominantly affecting women of childbearing age. The pathogenesis of SLE is multifactorial, and the clinical phenotype and course vary considerably within the SLE population. Multiple organs can be involved, lupus nephritis (LN) being one of the most severe manifestations. Immunologic abnormalities constitute a hallmark of SLE, and hyperactivity of the B cell lineage plays an important role in the pathogenesis, resulting in a prominent production of autoantibodies to nuclear components and immune complex depositions. The heterogeneity of SLE makes its management and the development of new therapies challenging. Belimumab is a monoclonal antibody targeting the B cell activating cytokine BAFF, also known as BLyS, approved for the treatment of SLE.

In the studies included in this thesis, we focused on biomarkers in lupus nephritis and effects of belimumab treatment in SLE. For the purpose of the first part, immune components that have been implied to be important in lupus nephritis were evaluated as biomarkers of activity, response to treatment and long-term prognosis. In the second part, we investigated the clinical and immunologic effects of belimumab in a prospective, real-life clinical setting.

We identified an association of antiphospholipid antibodies with short-term renal function impairment during LN flares, but we found no association with the long-term renal prognosis. In contrast, soluble TNF receptor 2 was predictive of kidney tissue damage and long-term renal function deterioration. Soluble TNF receptor 2 was shown to predict treatment response in patients with membranous nephritis, whereas a role of APRIL, a plasma cell survival cytokine, was implicated in proliferative glomerulonephritis. Finally, low baseline serum concentrations of BLyS were predictive of response to induction treatment for LN.

We demonstrated decreased disease activity and corticosteroid usage, and no significant damage progression in patients with SLE during belimumab treatment. We observed rapid effects on naïve B cells and B cells of earlier developmental stages, whereas later stage B cells showed delayed or no changes. High baseline disease activity and steroid dose were associated with beneficial treatment outcomes, whereas smoking and established organ damage predicted reduced treatment efficacy. While high BLyS levels predicted clinical improvements, high B cell counts predicted unfavourable outcomes, implying that patients with a high B cell activity and, therefore, suppressed BLyS activity may benefit from B cell depletion preceding BLyS inhibition.

Based on our results from the studies of belimumab, smokers who qualify for treatment with this biologic agent should actively be encouraged to quit smoking. An important implication for the use of belimumab is that early treatment evaluation might underestimate delayed clinical improvements occurring as a consequence of late therapy-associated B cell changes.

List of scientific papers

I. Ioannis Parodis, Laurent Arnaud, Jakob Gerhardsson, Agneta Zickert, Birgitta Sundelin, Vivianne Malmström, Elisabet Svenungsson, Iva Gunnarsson. Antiphospholipid antibodies in lupus nephritis. PLoS One. 2016;11(6): e0158076.
https://doi.org/10.1371/journal.pone.0158076

II. Ioannis Parodis, Huihua Ding, Agneta Zickert, Laurent Arnaud, Anders Larsson, Elisabet Svenungsson, Chandra Mohan, Iva Gunnarsson. Serum soluble Tumour Necrosis Factor Receptor 2 (sTNFR2) as a biomarker of kidney tissue damage and long-term renal outcome in lupus nephritis. Scandinavian Journal of Rheumatology. 2016: 1-10.
https://doi.org/10.1080/03009742.2016.1231339

III. Ioannis Parodis, Agneta Zickert, Birgitta Sundelin, Magnus Axelsson, Jakob Gerhardsson, Elisabet Svenungsson, Vivianne Malmström, Iva Gunnarsson. Evaluation of B lymphocyte stimulator and a proliferation inducing ligand as candidate biomarkers in lupus nephritis based on clinical and histopathological outcome following induction therapy. Lupus Science and Medicine. 2015;2(1): e000061.
https://doi.org/10.1136/lupus-2014-000061

IV. Ioannis Parodis, Christopher Sjöwall, Andreas Jönsen, Daniel Ramsköld, Agneta Zickert, Martina Frodlund, Azita Sohrabian, Laurent Arnaud, Johan Rönnelid, Vivianne Malmström, Anders A Bengtsson, Iva Gunnarsson. Smoking and pre-existing organ damage reduce the efficacy of belimumab in systemic lupus erythematosus. [Accepted]
https://doi.org/10.1016/j.autrev.2017.02.005

V. Ioannis Parodis, Daniel Ramsköld, Tadepally Lakshmikanth, Yang Chen, Agneta Zickert, Natalie Sippl, Jaromir Mikes, Khaled Amara, Adnane Achour, Petter Brodin, Iva Gunnarsson, Vivianne Malmström. B cell alterations during BAFF inhibition with belimumab in SLE. [Manuscript]