Immunomodulators in SLE: Clinical evidence and immunologic actions

Abstract

Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease. Current treatment strategies rely heavily on corticosteroids, which are in turn responsible for a significant burden of morbidity, and immunosuppressives which are limited by suboptimal efficacy, increased infections and malignancies. There are significant deficiencies in our immunosuppressive armamentarium, making immunomodulatory therapies crucial, offering the opportunity to prevent disease flare and the subsequent accrual of damage. Currently available immunomodulators include prasterone (synthetic dehydroeipandrosterone), vitamin D, hydroxychloroquine and belimumab. These therapies, acting via numerous cellular and cytokine pathways, have been shown to modify the aberrant immune responses associated with SLE without overt immunosuppression. Vitamin D is important in SLE and supplementation appears to have a positive impact on disease activity particularly proteinuria. Belimumab has specific immunomodulatory properties and is an effective therapy in those with specific serological and clinical characteristics predictive of response. Hydroxychloroquine is a crucial background medication in SLE with actions in many molecular pathways. It has disease specific effects in reducing flare, treating cutaneous disease and inflammatory arthralgias in addition to other effects such as reduced thrombosis, increased longevity, improved lipids, better glycemic control and blood pressure. Dehydroeipandrosterone is also an immunomodulator in SLE which can have positive effects on disease activity and has bone protective properties. This review outlines the immunologic actions of these drugs and the clinical evidence supporting their use.

Effects of Hydroxychloroquine on Proteinuria in Immunoglobulin A Nephropathy

“…The efficacy of HCQ may result from its ability to inhibit the activation of toll-like receptors (TLRs) and numerous cytokines [7], which are also crucial in the abnormal mucosa-kidney axis in IgAN [8]. Gao et al [9] found that HCQ reduced proteinuria to 65.9 ± 25.5% ( p = 0.002) of the baseline level (0.90 ± 0.45 g/day) in patients with IgAN; however, there was no statistically significant difference in proteinuria levels between the HCQ and losartan groups.…”

No evidence of clinical efficacy of hydroxychloroquine in patients hospitalised for COVID-19 infection and requiring oxygen: results of a study using routinely collected data to emulate a target trial

“…23 Drugs decreasing virus shedding may therefore be inadequate at this stage; this is why many anti-inflammatory drugs are currently being tested, such as tocilizumab, corticosteroids, and others. Despite the immunomodulatory properties of HCQ, which include regulation of the production of pro-inflammatory cytokines such as IL-2, IL-1, IL-6 and TNFα, 24 and endosomal inhibition of toll-like receptors, which play a major role in innate immune response, 2 5…”

The Systemic Activation of Programmed Death 1-PD-L1 Axis Protects Systemic Lupus Erythematosus Model from Nephritis

“…Lupus nephritis started from the deposition of anti-dsDNA antibody immune complexes in the kidney parenchyma, which activated the complement system via classical pathway, induced the leucocytes infiltration to release inflammatory mediators (chemokines, proinflammatory cytokines, enzymes, and nitric oxide), and finally rendered the renal damage [2,3]. Although the initiating events are not completely understood, it is generally accepted that abnormally autoreactive T lymphocytes play an important role in disease pathogenesis and progress.…”