Studies on Lupus Nephritis

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease characterized by multiple organ involvement, production of autoantibodies to nuclear components and local formation or deposition of immune complexes in different organs. Lupus nephritis (LN) is a common and severe manifestation of SLE. A renal biopsy is the “gold standard” for diagnosis of LN and the basis for treatment strategies. However there is no consensus whether a repeat biopsy should be performed to define response to treatment. Biomarkers available for renal disease activity are insufficient and LN patients may have inflammatory lesions in renal tissue despite of clinical quiescent disease. The aim of this thesis was to study clinical, laboratory and histopathological findings in LN-patients with repeated renal biopsies performed after immunosuppressive treatment. I aimed to investigate the role of second renal biopsies in evaluation of treatment response, and to identify novel biomarkers for renal disease activity. We also studied long-term outcome and predictors of response in a subset of patients with severe LN who were treated with B-cell depletion therapy (rituximab). In paper I we studied renal expression and serum levels of High Mobility Group Box 1 protein (HMGB1), a nuclear protein that can act as a proinflammatory mediator and is proposed to be involved in multiple inflammatory diseases. We found high serum levels and increased expression in renal tissue of HMGB1 in LN at both active disease and after immunosuppressive treatment. The study indicates a role for HMGB1 in LN and also supports previous findings of persistent inflammation in the renal tissue despite treatment. In paper II we compared clinical and histopathological findings in LN patients with repeated renal biopsies performed after induction immunosuppressive treatment. A substantial proportion of patients had persistent inflammatory lesions in renal tissue despite an apparent clinical good response. Repeated biopsies may thus add important information that is not captured by routine laboratory markers which in turn may have impact on long-term renal outcome. In paper III we studied serum cytokines in association to clinical and histopathological response in LN. We found high baseline levels of interleukin (IL)-17 in patients with a poor histopathological outcome and high IL-23 in clinical non-responding patients. Immunostainings revealed increased expression of IL-17 in areas with inflammatory CD3+ T-cell infiltrates in renal tissue. The study indicates a Th-17 phenotype in a subset of patients with severe LN. In paper IV we studied long-term (mean 36 months) renal outcome in 25 patients, with previously refractory or relapsing LN, who had been treated with rituximab (RTX). A majority of the patients achieved a complete remission. A long time of B-cell depletion was associated with a faster response. The study supports the use of RTX in patients with refractory LN. In conclusion, repeated renal biopsies after induction treatment revealed persisting active nephritis in many patients despite clinically inactive disease. Consistently, HMGB1 was increased in renal tissue at both active disease and after treatment. A subset of patients with severe LN had high levels of Th-17 associated cytokines which may be of use as biomarkers. LN patients refractory to standard therapy had overall good response at long term follow-up after B-cell depleting therapy. LIST OF PUBLICATIONS This thesis is based on the following papers, which will be referred to in the text by their Roman numerals. I. Zickert A, Palmblad K, Sundelin B, Chavan S, Tracey KJ, Bruchfeld A, Gunnarsson I. Renal expression and serum levels of high mobility group box 1 protein in lupus nephritis. Arthritis Res Ther. 2012 Feb 20;14(1):R36 II. Zickert A, Sundelin B, Svenungsson E, Gunnarsson I. Role of early repeated renal biopsies in lupus nephritis. Submitted. III. Zickert A, Amoudruz P, Sundstrom Y, Ronnelid J, Malmstrom V, Gunnarsson I. IL-17 and IL-23 in lupus nephritis association to histopathology and response to treatment. Submitted. IV. Jonsdottir T, Zickert A, Sundelin B, Welin Henriksson E, van Vollenhoven R, Gunnarsson I. Long-term follow-up in Lupus nephritis patients treated with rituximabclinical and histopathological response. Rheumatology (Oxford). 2013 Jan 3. (Epub ahead of print) Related publication based on the patient cohort, not included in the thesis Sjowall C, Zickert A, Skogh T, Wettero J, Gunnarsson I. Serum levels of autoantibodies against C-reactive protein correlate with renal disease activity and response to therapy in lupus nephritis. Arthritis Res Ther. 2009;11(6):R188.