Biologic agents currently in use or under investigation can roughly be divided into:- Anti-cytokine [anti-tumor necrosis factor-alpha (TNF-a), anti-interleukin (IL)-1,
anti-IL-6, anti-ILs-12 and -23] - Transcription factor interference [anti-Janus kinase 3 (JAK3)]
- Interference of immune cell migration and entry into sites of inflammation (alefacept,
natalizumab) - B-cell depletion (rituximab)
- T-cell interference (abatacept)
Therapeutic Targets
TNF-ais a multifunctional cytokine that is a chief mediator of inflammation and an integral
component to a healthy immune response against infection and malignancy. It is a protein
secreted by T cells, natural killer cells, and mast cells but mainly from activated
mononuclear phagocytes in response to antigen presentation. Most cells possess TNF
receptors. Receptors are either membrane bound or freely circulating. The soluble form acts
to neutralize excess circulating TNF. TNF-ahas profound pathologic complexity mediating
both systemic effects and local damage present in serious systemic complications of
infection like sepsis and the destruction seen in many auto-inflammatory diseases. Its effects
are as follows (6–9):
l On the hypothalamus causing fever
l On muscle to produce catabolism with resultant weight loss and malaise
l On liver to synthesize acute-phase reactants
l Macrophage recruitment to site of infection
l Stimulation of granulocyte colony–stimulating factor
l Production of nitric oxide in macrophages needed for killing organisms
l Induction of IL-1, another key component in the inflammatory cascade
l Activation of inflammatory and coagulation processes of endothelial cells
l Apoptosis of various tumor cellsThere are several approved anti-TNF therapies in use and under investigation (Table 1)
for a wide spectrum of disease: amyloidosis, ankylosing spondylitis, Behcet’s disease,
inflammatory bowel disease, periodic fever syndromes, psoriasis, psoriatic arthritis, RA, and
uveitis.
IL-1is a key cytokine in the inflammatory cascade that mediates fever, systemic and local
inflammation, as well as being associated with bone and cartilage destruction. It is recognized
as important in stimulating macrophages, fibroblasts, and hematopoiesis in bone marrow. The
IL-1 receptor blocker, anakinra, is used in RA, Still’s disease, periodic fever syndromes, and
Behcet’s disease. It appears that there is no increased risk of infection over placebo (10,11).
IL-6is a key pro-inflammatory cytokine that is important in the mediation of fever and
acute-phase responses. It is secreted by T cells, macrophages, and fibroblasts in response to
tissue damage and presence of antigenic material. It is required for resistance against
Streptococcus pneumoniae.The IL-6 receptor blocker, tocilizumab, is under investigation for use
in RA and Castleman’s disease, which is a lymphoproliferative disorder.
ILs-12 and -23 are pro-inflammatory targets of combined inhibition by the drug
ustekinumab. This is in use and under investigation for inflammatory bowel diseases,
multiple sclerosis, psoriasis, and psoriatic arthritis.
JAK3is a tyrosine kinase responsible for intracellular signaling of hematopoietic cells
especially lymphocytes, natural killer cells, and monocytes. This signaling lies upstream of
major cytokine expression and adaptive immunity mechanisms such as T- and B-cell
proliferation and signaling. Mutations for JAK3 result in severe combined immunodeficiency
syndrome (SCID) rendering severe defects in T- and B-cell function. JAK3 is currently under
investigation, alone, and in combination with anti-TNF therapy, as a target for several
autoimmune and auto-inflammatory diseases of which RA is the most common.
378 Saketkoo and Espinoza