In the recent review “Lupus Nephritis: the Evolving Role of Novel Therapeutics” published in AJKD, Rovin and Parikh summarize the current understanding of the pathogenesis of lupus nephritis (LN) and review the novel agents under study for treatment of LN.
The authors provide a useful construct for classifying the novel agents for LN by dividing treatments into those that are primarily anti-inflammatory and those that are anti-autoimmunity. A critical point of the review is that the mechanism of action of new treatments must be considered in trial design in particular with regard to efficacy endpoints. Without this, agents expected to have long-term anti-autoimmunity benefits might appear non-beneficial when assessed using shorter-term outcomes designed for agents that work by an anti-inflammatory mechanism. The authors suggest that treatment should focus on reducing inflammation for management of active LN and controlling autoimmunity to prevent future flares of LN, either simultaneously or shortly after remission.
Rovin and Parikh review the history of LN treatment by describing the evolution from corticosteroids to cyclophosphamide and later to mycophenolate mofetil (MMF). They discuss recent multi-target therapy and lower dose cyclophosphamide. The authors emphasize that the rates of complete remission in these studies are still unacceptable, and highlight the reliance on short-term rather than long-term outcomes.
In addition, Rovin and Parikh review the mechanism of action and clinical trial data for many of the novel anti-inflammatory and auto-immunity therapeutics presently under study. The anti-inflammatory agents include:
1) Laquinimod, a small molecule derivative of quinolone-3-carboxamide that reduces pro-inflammatory cytokines and favors the developed of Tregs in favor of Th1 and Th17 cells,
2) The synthetic retinoids, that increase Treg activity and decrease Th17 cells,
3) Eculizumab, a monoclonal antibody against the C5 component of the terminal complement cascade, 4) Anti-TWEAK therapies that block NF-κB, cytokine, and inflammatory chemokine production, and
5) Anti-IL6 therapies.
Reviewed anti-autoimmunity agents include:
1) Humanized antibodies to interferon-alpha (rontalizumab and sifalimumab),
2) Rituximab, the monoclonal antibody targeting CD20 expressed on B cells,
3) Proteasome inhibitors such as bortezomib which induce plasma cell apoptosis and reduce induction of NF-KB-dependent pro-inflammatory cytokines,
4) Belimumab, an anti-BAFF antibody which blocks B-cell proliferation and maturation, and
5) Abatacept, a fusion protein between CTLA4 and IgG heavy chain that blocks T cell co-stimulation.
Finally, the authors discuss fresolimumab, a monoclonal antibody that blocks TGF-beta, which may function as an anti-fibrotic agent.
In conclusion, the authors suggest current treatment regimens are inadequate, and that novel agents are required but should be studied using clinical endpoints appropriate to their mechanism of action. They emphasize that despite several recent negative studies, the future for LN treatment looks exciting.
Craig Gordon, MD, MS