Page 1238 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1200 ParT TEN Prevention and Therapy of Immunological Diseases

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potentially driving production of antibodies to nucleoproteins. Anakinra is a nonglycosylated recombinant IL-1 receptor
Binding of lymphotoxin-β by etanercept may alter the clearance antagonist (rIL-1Ra) that differs from the endogenous IL-1Ra
of apoptotic products by germinal center adjacent follicular DCs by a single amino acid addition at the amino terminus. Admin-
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and macrophages. Given these collective considerations, it is istered subcutaneously at daily (or for some indications more
generally recommended that TNF-α inhibitors be discontinued frequent) intervals because of its very short serum half-life,
in patients who develop autoimmune complications during treat- anakinra functions as a competitive inhibitor of IL-1α and IL-1β
ment with this class of biological therapy. Moreover, anti–TNF-α binding to IL-1 receptors.
therapy is not recommended for patients with established SLE Anakinra, presently approved for the treatment of RA,
or other overlap syndromes with lupus-like features associated inhibits joint erosions. However, compared with the clini-
with autoantibody production. cal responses observed with use of TNF inhibitors and IL-6
inhibitors (tocilizumab) with regard to tender and swollen
Interleukin-1β Inhibitors joints, such responses with anakinra are much more modest.
IL-1β is synthesized as an inactive precursor, with activation of Given these observations with biologicals that require much less
IL-1β occurring following engagement of nucleotide-binding frequent dosing, anakinra is used infrequently in the treatment
oligomerization domain (NOD)–like receptors (NLRs) by a variety of RA. With the increased understanding of the role of IL-1
of exogenous or endogenous danger signals, which then trigger inflammasome activation in crystal-induced arthropathies, such
formation of molecular platforms (NLR family domain containing as gout and systemic inflammatory disorders, such as soJIA
protein 3 [NALP] inflammasomes) that facilitate cleavage of and AoSD, anakinra has been gaining renewed interest as a
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the IL-1β precursor by IL-1–converting enzyme (ICE). IL-1β therapeutic option in the treatment of these disorders. Case
stimulates proliferation of lymphocytes, upregulates the expression reports support use of anakinra in managing acute flare-ups
of adhesion molecules, and triggers the release of a variety of of gout or flare-ups of calcium pyrophosphate–associated
inflammatory mediators from leukocytes, including chemotactic pseudogout when the use of corticosteroids or nonsteroidal
factors, prostaglandins, proteases, and procoagulants. In patients antiinflammatory drugs (NSAIDs) is not favored because of
with RA, IL-1β triggers the release of proteases from phagocytic comorbid conditions, such as uncompensated heart failure or
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cells and macrophages that are destructive to bone and cartilage. diabetes with significant renal impairment. Prompt resolution
Inflammasome activation has also been shown to mediate of inflammatory markers and clinical manifestations have been
acute flare-ups of arthritis in patients with gout or calcium reported in patients with severe flare-ups of AoSD and soJIA
pyrophosphate deposition. Dysregulation of NLRP3 as a result treated with anakinra, including those associated with MAS. 29,30
of gain-of-function mutations in inflammasome-related genes The relatively short half-life of anakinra may render its use
has been implicated in the pathogenesis of familial cryopyrin- feasible when short-term blockade of IL-1 may be of benefit in
associated periodic syndromes (CAPS, cryopyrinopathies), familial managing severe flare-ups of IL-1–driven inflammation when
Mediterranean fever (FMF), and the pyogenic arthritis, pyoderma there is a concern for intercurrent infection. The potential
gangrenosum, and acne syndrome (PAPA). Increased expression utility of anakinra in this context is supported by a recent
and levels of IL-1β are also noted during flare-ups of inflammation study reexamining the outcomes from a previous sepsis trial,
in patients with adult-onset Still disease (AoSD), systemic-onset where survival was shown to have improved in patients with
juvenile idiopathic arthritis (soJIA), and macrophage activation clinical features of MAS who were randomized to anakinra
syndromes (MAS) associated with these and other autoimmune treatment. 31
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or infectious disorders. The naturally occurring IL-1 receptor Rilonacept (also referred to as IL-1-Trap) is a recombinant
antagonist (IL-1Ra) prevents the binding of IL-1β and IL-1α to the fusion protein that comprises the extracellular domain of the
IL-1 receptor (IL-1R), but tissue levels of IL-1Ra in in the above IL-1 accessory protein and IL-1 receptor type 1 attached to the
disorders may be insufficient to counteract the effects of IL-1β. Fc portion of immunoglobulin G1 (IgG1). Rilonacept binds to
IL-1α and IL-1β with high affinity and is approved for the
treatment of CAPS. Similar to anakinra, rilonacept is dosed
KEY CONCEPTS subcutaneously, albeit at weekly intervals because of its longer
Interleukin Inhibitors half-life. It is generally well tolerated, with injection site reactions
being the most common adverse events.
• Interleukin (IL)-1β inhibitors are very effective in the treatment of Canakinumab is a human genome sequence–derived mAb
disorders associated with constitutional or secondary activation of the with specificity for IL-1β that also binds to IL-1α. Approved for
IL-1 inflammasome, including cryopyrin syndromes, familial Mediter-
ranean fever flare-ups, and flare-ups of crystal induced arthropathy the treatment of CAPS as well as soJIA, canakinumab has the
(gout and calcium pyrophosphate dihydrate [CPPD] crystal deposition longest half-life of the currently approved therapies that target
disease/pseudogout). IL-1. In a randomized clinical trial comparing the use of
• Use of IL-1β inhibitors with a short half-life may be of benefit in canakinumab with parenteral triamcinolone administration for
managing severe flare-ups of inflammation associated with macrophage acute gout flare-ups, canakinumab was shown to have greater
activation, such as systemic-onset juvenile idiopathic arthritis (soJIA), reductions in joint pain and swelling, decreased needs for rescue
adult-onset Still disease, and severe sepsis syndromes. 32
• IL-6 signaling is complex in the context of signaling that can occur medications, and a greater time to subsequent flare-ups.
through cell membrane bound IL-6R, which mediates primarily IL-6 However, given that the observed rates of serious infections were
homeostatic effects, or through many other cell receptors that engage twice as high in the canakinumab arm, a half-life that well exceeds
IL-6/sIL-6R complexes (trans-signaling), which mediate IL-6 inflammatory the duration of typical flare-ups, and the questionable cost-
effects. effectiveness of using an intervention 5000 times the cost of
• Inhibition of IL-6 binding to IL-6R mediated by monoclonal antibody current therapies that are, by and large, effective for managing
(mAb) reagents, such as tocilizumab, is very effective in suppressing
clinical manifestations of rheumatoid arthritis (RA). acute gout, the use of canakinumab has not found favor in
treatment paradigms for managing gout.