. Author manuscript; available in PMC: 2013 Jun 6.

Published in final edited form as: Nat Med. 2012 Jun 6;18(6):871–882. doi: 10.1038/nm.2752

Table 1.

Therapeutic strategies for SLE

	Lessons from animal models of SLE^128,142

Knockout mice can be used to study disease initiation.	Molecules involved in the clonal expansion of lymphocytes and/or germinal center functions are necessary for the initiation of disease in most models. Some molecules, such as type I IFNs and FcR, are involved in disease initiation or tissue damage only in certain strains, showing the effect of genetic heterogeneity on disease mechanisms. Some molecules, such as TLR9, TNF-α and IL-10, have pleiomorphic functions and therefore may be either protective or pathogenic, depending on the disease stage.
Specific targeting of immune pathways has proved less effective in attenuating disease than is observed in the knockouts.	Nearly all drugs are more effective at preventing disease onset than treating established disease. As disease progresses, higher drug doses and combination therapies are required to achieve remission. Different strains have different stringencies for therapeutic responses, and not all strains respond to each therapy.

	Recent approaches to SLE therapies^81–83

Innate immunity	Approaches include targeting TLRs and their downstream signaling molecules and effector cytokines, improving clearance mechanisms using exogenous IgM and delivering exogenous DNase to compensate for intrinsic defects of this enzyme in SLE. Some aspects of TLR signaling are protective against autoimmunity in animal models. Circulating DNA in SLE may be resistant to digestion. These approaches are mostly experimental or are in development for human use. Phase 2 studies of IFN-α inhibition are pending.
Adaptive immunity—B cells	Approaches include B cell depletion, modulation of co-receptor function and alteration of B cell selection. These approaches rarely target all subsets of B cells and may lead to counterproductive homeostatic expansion of other subsets. Approaches that alter selection may have different effects on naive and antigen-activated immunoglobulin repertoires and may need to be given continuously to achieve clinical efficacy. Clinical trials have so far only shown efficacy for belimumab; new trials of individual treatments and drug combinations are underway.
Adaptive immunity—T cells	Approaches include co-stimulation blockade, cytokine inhibitors, kinase inhibitors and induction of regulatory subsets. Clinical trials of co-stimulatory inhibitors have so far either failed to show efficacy or were terminated because of toxicity; new trials of additional agents or drug combinations are underway. Effects of broad inhibitors of T cell activation may result in immune suppression.
Tissue injury and inflammation	Approaches include inhibitors of the complement cascade, cytokine blockade and nonimmunological approaches to preserve renal function. Nonimmunological approaches may prevent end-stage organ damage but have no effects on systemic immune dysfunction. Because of the pleiomorphic effects of cytokines, cytokine blockade may improve some aspects of disease but worsen others. Early clinical studies of cytokine blockade have produced promising results but have also shown adverse effects in several cases. Many new approaches are in development.

New therapies for SLE primarily target one of four major pathogenic pathways: innate immunity, B cells, T cells or tissue injury and inflammation. Although animal studies provide valuable insights into the therapeutic potential of experimental drugs for SLE, additional considerations are needed when predicting the probable outcomes of treatments in human patients.