HDAC Inhibitors as Epigenetic Regulators

Targeting JAKs in SLE would be a logical therapeutic option which can be studied further starting with trials to determine the safety, pharmacodynamics and efficacy of these drugs in SLE. Fostamatinib (Syk inhibitor) Spleen tyrosine kinase (Syk) is implicated in the B cell immunopathogenesis of SLE and is a potential therapeutic target. 10 mg/kg with AP1903 standard therapy (= 0.10 and = 0.021, respectively) [23]. However, at 76 weeks, there was no significant difference in responder rates between the belimumab and placebo groups. The BLISS-52 and BLISS-76 clinical trials both excluded patients with active lupus nephritis. BLISS-LN is usually a phase III, randomized, double-blind, placebo-controlled study to evaluate the efficacy and security of belimumab plus standard of care versus placebo plus standard of care in adult subjects with active lupus nephritis which will provide clinically relevant information about the use of belimumab in lupus nephritis “type”:”clinical-trial”,”attrs”:”text”:”NCT01639339″,”term_id”:”NCT01639339″NCT01639339 (http://www.clinicaltrials.gov). An exploratory analysis of belimumab use in patients of black ethnicity in the BLISS-52 and BLISS-76 trials (n = 148) reported lower clinical effectiveness in this group as compared to other ethnic groups. A phase III/IV AP1903 multi-center, randomized, double-blind, placebo-controlled, 52-week study to evaluate the efficacy and security of belimumab in adult AP1903 subjects of black race with SLE is usually planned as a future study “type”:”clinical-trial”,”attrs”:”text”:”NCT01632241″,”term_id”:”NCT01632241″NCT01632241 (http://www.clinicaltrials.gov). Belimumab may be more effective in specific sub-groups of lupus patients. Published data show that Fyn belimumab is usually significantly more efficacious in SLE patients who are ds-DNA positive, hypocomplementemic or have high disease activity as measured by SELENA-SLEDAI score 10 [24]. In 2012, fatal anaphylaxis was reported in a patient treated with belimumab and it is now known that there is a risk of a delayed acute hypersensitivity reaction to belimumab, especially in patients with multiple drug allergies. Long-term observational data will provide further security and tolerability data on belimumab. At present the FDA Center for Drug Evaluation and Research has examined the security labeling for belimumab (http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm299628). The increased susceptibility to contamination after belimumab treatment may be as a consequence of alterations in the signaling pathways including BAFF/BLys and the TACI receptor. The TACI molecule has a complex role in host AP1903 immunity including activation of B cells and T cell impartial immune regulation; however, this is yet to be completely comprehended [25]. In light of this, it has been postulated that this post-belimumab low BAFF/BLys levels result in a reduction in TACI signaling and hamper the host immune defenses against pathogens, such as polysaccharide encapsulated bacteria. Patients treated with belimumab have an increased susceptibility to contamination, the commonest being pharyngitis, bronchitis, cystitis and viral gastroenteritis [23]. In the clinical trials serious infections have been reported in 6% of belimumab-treated patients as compared to 5.2% in placebo controls but there have been no reports to date of PML in belimumab treated patients [26]. Although belimumab received regulatory approval from the US FDA and the EMEA, its use in some countries has been restricted until approval by national drug evaluation businesses. The German Institute for Quality and Efficiency in Health Care (IQWiG) has recommended evaluation of belimumab for additional benefit over optimized immune-suppression rather than over standard therapy prior to full approval (http://www.iqwig.de). In 2012 The National Institute for Health and Clinical Superiority (Good) provided a draft national guidance on the use of belimumab for SLE in the United Kingdom. NICE did not recommend belimumab within its licensed indication as add-on therapy to standard immune-suppressive drugs in adult patients with active auto-antibody positive SLE. In making this decision, Good considered the clinical trial evidence, clinical specialist and patient opinions. NICE concluded that the use of belimumab was not sufficiently cost-effective to the National Health Support (NHS) in relation to its reported clinical.