Clinical Efficacy of Belimumab in Patients with Systemic Lupus Erythematosus and Headache. A Report of Two Cases

Intractable headache, one of the manifestations of neuropsychiatric systemic lupus erythematosus, is difficult to diagnose and determine an effective treatment. In addition to conventional therapy according to the type of headache, the treatment should be conducted considering the disease activity of systemic lupus erythematosus rather than the headache. We report two patients with intractable headache who were successfully treated using belimumab therapy. The headaches in both patients were relieved after 2 weeks of belimumab administration. The neutralization of B lymphocyte stimulator and reduced production of cytokines from B lymphocytes might contribute to the early effects. The potential benefits of using belimumab as an additional immunosuppressant for treating intractable headache complicated with systemic lupus erythematosus have been discussed.

TNFSF13B, the gene that encodes the B-cell activating factor and B-lymphocyte stimulator (BAFF/BLyS), is expressed differently in the blood of Crohn's disease patients

Crohn's disease and ulcerative colitis are examples of inflammatory bowel disorders (IBD) (1). We usedpublicly available microarray data to figure out how gene expression in the hematopoietic compartment ofCrohn's disease patients differs from healthy controls (2-4). We discovered that BAFF, also known as the Blymphocytestimulator (BLyS), encoded by the gene TNFSF13B (5), was differently expressed in the blood ofCrohn's Disease patients in two datasets (2, 3). BAFF was shown to be among the genes most differentlyexpressed in monocyte-derived macrophages from Crohn's Disease patients in a third dataset (4). Inindividuals with IBD, serum BAFF, fecal BAFF, and BAFF expression in the intestinal mucosa have all beenshown to be higher (6, 7). The expression of BAFF in the peripheral blood of Crohn's disease patients issimilarly enhanced, as seen below.

Don’t Miss Lupus

Chapter for Lupus Book Systemic lupus erythematosus is a well-recognized multi-system disease. Hallmarks of the disorder include the prevalence of antinuclear antibodies (ANA) and double stranded antibodies (DNA). The disease often presents with lupus rashes and/or arthritis or arthralgias. Lupus is “the great imitator,” as no organ system is excluded, when diagnosing and treating a lupus patient. While lupus remains evasive in novel therapies with true benefit; one issue has been consistent, in that the preponderance of the evidence thus far, leads to B cell dysfunction. More recently Belimumab was indicated for use in lupus patients. This is a BLyS-Specific inhibitor (B lymphocyte stimulator) medication. At this time, I would like to focus on lupus in a manner that you are not used to hearing. Typically, any practitioner who approaches a patient with a plethora of symptoms, would order blood tests, and conclude a diagnosis of lupus. In this chapter, I will point out and focus on the need to think “outside the box” and perhaps consider lupus as simply one of various other scenarios.

Post-translational modifications in T cells in systemic erythematosus lupus

Systemic erythematosus lupus (SLE) is a classic autoimmune disease characterized by multiple autoantibodies and immune-mediated tissue damage. The etiology of this disease is still unclear. A new drug, Belimumab, which acts against the B-lymphocyte stimulator (BLyS), can effectively improve the condition of SLE patients, but it cannot resolve all SLE symptoms. The discovery of novel, precise therapeutic targets is urgently needed. It is well known that abnormal T cell function is one of the most crucial factors contributing to the pathogenesis of SLE. Protein post-translational modifications (PTMs), including phosphorylation, glycosylation, acetylation, methylation, ubiquitination, and SUMOylation, have been emphasized for their roles in activating protein activity, maintaining structural stability, regulating protein-protein interactions and mediating signaling pathways, in addition to other biological functions. Summarizing the latest data in this area, this review focuses on the potential roles of diverse PTMs in regulating T cell function and signaling pathways in SLE pathogenesis, with the goal of identifying new targets for SLE therapy.

The gene encoding the B-cell activating factor and B-lymphocyte stimulator (BAFF/BLyS), TNFSF13B, is differentially expressed in the blood of patients with Crohn’s Disease.

Inflammatory bowel diseases (IBD) include Crohn’s Disease and Ulcerative Colitis (1). We mined published microarray data to understand how gene expression in the hematopoietic compartment of patients with Crohn’s Disease is most different from that of healthy controls (2-4). Across two datasets (2, 3), we found that BAFF, also known as the B-lymphocyte stimulator (BLyS), encoded by the gene TNFSF13B (5), was differentially expressed in the blood of patients with Crohn’s Disease . Analysis of a third dataset (4) revealed that BAFF was among the genes most differentially expressed in monocyte-derived macrophages from patients with Crohn’s Disease. Serum BAFF, fecal BAFF, and BAFF expression in the intestinal mucosa has been demonstrated to be increased in patients with IBD (6, 7). We show here that expression of BAFF in the peripheral blood of patients with Crohn’s Disease is also increased.

Attainment of treat-to-target endpoints in SLE patients with high disease activity in the atacicept phase 2b ADDRESS II study

Objective Low disease activity (LDA) and remission are emerging treat-to-target (T2T) endpoints in SLE. However, the rates at which these endpoints are met in patients with high disease activity (HDA) are unknown. Atacicept, which targets B lymphocyte stimulator and a proliferation-inducing ligand, improved disease outcomes in SLE patients with HDA (SLEDAI-2K ≥10) at baseline in the phase 2b ADDRESS II study. This is a post hoc analysis of T2T endpoints in these patients. Methods Patients received weekly atacicept (75 or 150 mg s.c.) or placebo for 24 weeks (1:1:1 randomization). Attainment of three T2T endpoints, LDA (SLEDAI-2K ≤ 2), Lupus Low Disease Activity State (LLDAS) and remission (clinical SLEDAI-2K = 0, prednisone-equivalent ≤5mg/day and Physician’s Global Assessment <0.5), was assessed and compared with SLE Responder Index (SRI)-4 and SRI-6 response. Results Of 306 randomized patients, 158 (51.6%) had baseline HDA. At week 24, 37 (23.4%) HDA patients attained LDA, 25 (15.8%) LLDAS and 17 (10.8%) remission. Each of these endpoints was more stringent than SRI-4 (n = 87; 55.1%) and SRI-6 (n = 67; 42.4%). Compared with placebo (n = 52), at week 24, patients treated with atacicept 150 mg (n = 51) were more likely to attain LDA [odds ratio (OR) 3.82 (95% CI: 1.44, 10.15), P = 0.007], LLDAS [OR 5.03 (95% CI: 1.32, 19.06), P = 0.018] or remission [OR 3.98 (95% CI: 0.78, 20.15), P = 0.095]. Conclusion At week 24, LDA, LLDAS and remission were more stringent than SRI-4 and SRI-6 response, were attainable in the HDA population and discriminated between treatment with atacicept 150 mg and placebo. These results suggest that T2T endpoints are robust outcome measures in SLE clinical trials and support further evaluation of atacicept in SLE. Trail registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01972568.

Alopecia areata in patients with systemic lupus erythematosus treated with belimumab: a plausible association

Belimumab, an anti-B-lymphocyte stimulator monoclonal antibody, was recently approved for the treatment of systemic lupus erythematosus. Alopecia areata is characterized by an acute immune-mediated hair loss. Herein, we report on three adult systemic lupus erythematosus patients who developed alopecia areata in association with belimumab treatment. Alopecia areata was resolved in all three patients and belimumab was discontinued in two of them. Thus, in the current report, we explore the plausible link between alopecia areata and belimumab.

B lymphocyte stimulator modulates number and function of endothelial progenitor cells in systemic lupus erythematosus

Background Circulating endothelial progenitor cells (EPCs) are biologic markers of endothelial function. In patients with systemic lupus erythematosus (SLE), the numerical reduction and functional impairment of EPCs contribute to the endothelial dysfunction. Through ex vivo and in vitro studies, we aimed at evaluating the effects of B lymphocyte stimulator (BLyS) on EPC colonies and endothelial cells and also investigating BLyS receptor expression on these cells. Methods EPCs were isolated from peripheral blood mononuclear cells (PBMC). In order to evaluate their ability to form colonies, EPCs were cultured on fibronectin-coated dishes and incubated with BlyS alone or BlyS and belimumab. Apoptosis of EPCs and endothelial cell line EA.hy926 was evaluated after 6, 12, and 24 h of incubation with BLyS and after 6 h with BLyS and belimumab. The expression of B cell activating factor-receptor (BAFF-R), B cell maturation antigen (BCMA), and transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI) on EPCs and EA.hy926 was analyzed by cytofluorimetry. Results The number of EPC colonies was lower in patients than in controls. Moreover, the colonies from SLE patients were poorly organized compared to controls; the addition of belimumab restored the colony structure. Incubation with BLyS induced apoptosis of EPCs and EA.hy926 that was inhibited by the co-incubation with belimumab. BAFF-R and BCMA were expressed on both EPCs and EA.hy926, while TACI was expressed only on EPCs. Conclusions EPCs and endothelial cells preferentially express BAFF-R which could be involved in the pro-apoptotic effect of BlyS. Belimumab administration seems to restore the quantitative and qualitative changes of EPC colonies both ex vivo and in vitro.