De novo lupus nephritis during treatment with belimumab.

OBJECTIVE: In light of reports of de novo LN during belimumab (BLM) treatment, we sought to determine its frequency and contributing or protective factors in a real-life setting. METHODS: Patients with SLE who received BLM between 2011 and 2017 at five European academic practices were enrolled (n = 95) and followed longitudinally for a median time of 13.1 months [interquartile range (IQR): 6.0-34.7]; 52.6% were anti-dsDNA positive, 60.0% had low complement levels, and 69.5% had no renal involvement prior to/at BLM initiation [mean disease duration at baseline: 11.4 (9.3) years]. Age- and sex-matched patients with non-renal SLE who had similar serological profiles, but were not exposed to BLM, served as controls (median follow-up: 132.0 months; IQR: 98.3-151.2). RESULTS: We observed 6/66 cases (9.1%) of biopsy-proven de novo LN (4/6 proliferative) among the non-renal BLM-treated SLE cases after a follow-up of 7.4 months (IQR: 2.7-22.2). Among controls, 2/66 cases (3.0%) of de novo LN (both proliferative) were observed after 21 and 50 months. BLM treatment was associated with an increased frequency and/or shorter time to de novo LN [hazard ratio (HR): 10.7; 95% CI: 1.7, 67.9; P = 0.012], while concomitant use of antimalarial agents along with BLM showed an opposing association (HR: 0.2; 95% CI: 0.03, 0.97; P = 0.046). CONCLUSION: Addition of BLM to standard-of-care did not prevent LN in patients with active non-renal SLE, but a favourable effect of concomitant use of antimalarials was implicated. Studies of whether effects of B-cell activating factor inhibition on lymphocyte subsets contribute to LN susceptibility are warranted.

Biologic Sequencing in Systemic Lupus Erythematosus: After Secondary Non-response to Rituximab, Switching to Humanised Anti-CD20 Agent Is More Effective Than Belimumab.

Background: Rituximab is commonly used for systemic lupus erythematosus (SLE) but secondary non-depletion and non-response (2NDNR) associated with anti-drug antibodies is a notable problem with repeat rituximab cycles. Other B cell-targeted therapies include other anti-CD20 monoclonal antibodies or belimumab. Objective: To compare efficacy of switching to alternative anti-CD20 agents vs. belimumab in SLE patients with 2NDNR to rituximab. Methods: One hundred and twenty five patients received rituximab and had evaluable data. 77/125 received repeat rituximab cycles. Of these, 14/77 (18%) had 2NDNR. 8/14 patients were switched to belimumab (CD20-to-belimumab group) and 6/14 patients were switched to an alternative humanised anti-CD20 agent (CD20-to-CD20 group, ocrelizumab n = 3, ofatumumab n = 2, obinutuzumab n = 1). Efficacy was assessed using the BILAG-2004, SLEDAI-2K, SRI-4, and daily prednisolone requirement at baseline and 6 months. Results: In the CD20-to-belimumab group, only one patient achieved an SRI-4 and 2/8 patients had new/worsening BILAG-2004 grade A for lupus nephritis. There was no improvement in SLEDAI-2K; median (IQR) was 11.0 (9.5-14.8) at baseline and 10 (9.5-15.5) at 6 months. Median (IQR) prednisolone dose increased from 7.5 mg (4.4-12.5) to 10 mg (6.3-10). In the CD20-to-CD20 group, all 6 patients achieved an SRI-4. Median (IQR) SLEDAI-2K improved from 16.0 (10.3-24.0) at baseline to 5.0 (2.5-6.0) at 6 months. Median (IQR) prednisolone dose decreased from 15 mg (15-15) to 10.5 mg (5.3-15.0). Conclusion: This is the first assessment of belimumab's efficacy in a post-rituximab population. Our data suggests that patients with 2NDNR to rituximab, which constituted 11% of all patients initiated on this drug, should be switched within the same biologic class to another anti-CD20 agent.

Cyclooxygenase expression and prostaglandin levels in central nervous system tissues during the course of chronic relapsing experimental autoimmune encephalomyelitis (EAE).

OBJECTIVE: Multiple sclerosis (MS) and its animal counterpart experimental autoimmune encephalomyelitis (EAE) have a major inflammatory component that drives and orchestrates both diseases. One particular group of mediators are the prostaglandins (PGs), which we have previously shown, through quantitation and pharmacological intervention, to be closely involved in the pathology of MS and EAE. The aim of the current study was to determine the expression of the PG-generating cyclooxygenase (COX) enzymes and the profile of PGE(2) and PGD(2), in selected central nervous system (CNS) tissues, with the development of the chronic relapsing (CR) form of EAE. In particular, the work investigates the possible relationship between the expression of COX isoenzymes and PG levels during the neurological phases of CR EAE. METHODS: CR EAE was induced in Biozzi mice with inoculum containing lyophilised, syngeneic spinal cord emulsified in complete Freund's adjuvant. The cerebral cortex, cerebellum and spinal cord were dissected from mice during the acute, remission and relapse stages of disease with a minimum of five animals per treatment. The expression of COX-1, COX-1b variant and COX-2, in pooled samples, was determined by Western blotting. PGE(2) and PGD(2) levels in extracted samples were measured using commercial enzyme immunoassay kits. RESULTS: COX-2 expression in spinal cords during acute disease remained unaltered and was in contrast to an enhancement of the enzyme, together with COX-1 and COX-1b, in all other sampled areas. PGE(2) and PGD(2) levels remained unchanged during the acute phase and the subsequent remission of symptoms. COX-1 and COX-1b expression was elevated in tissues during the relapse stage of CR EAE and concentrations of the prostanoids were markedly increased. CONCLUSIONS: The study examines the implications of COX isoenzyme expression over the course of CR EAE and discusses the reported relationship between PGE(2) and PGD(2) in the instigation and resolution of CNS inflammation. Consideration is also given to the treatment of CR EAE and suggests that drugs designed to limit the inflammatory effects of the PGs should be administered prior to or during the relapse phase of the disease.