Hoffman_Layout 1 03/12/2009 11:42 Page 57
Management of Cryopyrin-associated Periodic Syndromes
CAPS have been associated with heterozygous mutations, either Figure 1: The Disease Severity Spectrum of
inherited in an autosomal-dominant manner or developed
Cryopyrin-associated Periodic Syndromes
spontaneously in the NLRP3 gene, although mutations have not been
detected in all patients.
7–9
The
Mild Intermediate Severe
NLRP3-encoded cryopyrin operates as
phenotype phenotype phenotype
part of a larger complex called the Nalp3 inflammasome, forming a
molecular platform regulating the IL-1 pathway. Specifically, cryopyrin
and other adaptor proteins bring together the molecules of the IL-1β-
converting enzyme caspase 1, thereby resulting in the activation of
MWS
caspase and ultimately the processing of pro-IL-1β to its active FCAS Urticaria-like rash NOMID
proinflammatory mature form
10
(see
Cold-induced urticaria Amyloidosis Urticaria
Figure 2).
Fever Deafness CNS disease
Arthralgia Arthralgia Arthropathy
Various potential triggers have been proposed for this pathway,
Arthritis
including muramyl dipeptide, adenosine triphosphate, toxins,
Cryopyrin-associated periodic syndromes (CAPS) encompass the related disorders
Staphylococcus aureus or Listeria monocytogenes, bacterial RNA,
familial cold auto-inflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and
viral infection/viral RNA, gout-associated or pseudo-gout-associated
neonatal-onset multisystem inflammatory disorder (NOMID), which lie on a spectrum
of disease severity.
crystals,= and antiviral compounds.
11–15
These suggest that cryopyrin
acts as a sensor of pathogens or danger signals.
Figure 2: Pathogenesis of Cryopyrin-associated
Periodic Syndromes
Although the exact mechanism underlying the dysregulation of the
IL-1 pathway in CAPS is unclear, it appears that mutant cryopyrin
Pathogen-derived danger signals, inflammation:
results in an increase in the release of active IL-1β, consistent with
muramyl dipeptide, ATP, toxins, bacterial RNA,
disease-associated inflammatory symptoms including fever,
Staphylococcus aureus, Listeria monocytogenes,
viral RNA/infections, gout/pseudo-gout crystals,
arthralgias, and rash. Monocytes from CAPS patients also antiviral compounds
spontaneously secrete IL-1β due to spontaneous activation of
caspase 1 and subsequent secretion of active IL-1β.
16,17
Taken
together, NLRP3 mutations are believed to result in a constitutively
active or hyperactive form of the Nalp3 inflammasome complex that,
Cryopyrin
Nalp3
in turn, causes activation of caspase 1 and hypersecretion of IL-1β.
2 inflammasome
Caspase 1
Activation of caspase-1
This article will focus on the
(IL-1β-converting enzyme)
pathogenesis of cryopyrin-associated
Rilonacept,
periodic syndromes and inhibitors of
canakinumab
Pro-IL-1β IL-1β
interleukin-1β signalling that have
(inactive form) (active form)
IL-1 receptor
demonstrated efficacy in treating
Anakinra
Cell membrane
these conditions.
Inflammation
Activation of immune cells
Treatment Options
Tissue injury
CAPS and their associated symptoms have traditionally been treated
with antihistamines, non-steroidal anti-inflammatory drugs (NSAIDS),
corticosteroids, and other immunosuppressants. However, the results
Various triggers lead to the activation of the Nalp3 inflammasome and the subsequent
activation of caspase 1 resulting in secretion of active interleukin-1β (IL-1β)and
have been disappointing as high doses of these drugs lead to only
inflammatory symptoms. Anakinra, rilonacept, and canakinumab work to inhibit excess
slight improvements in symptoms. Moreover, the side effects of these
IL-1β signalling in cryopyrin-associated periodic syndromes (CAPS).
treatments are often worse than the disease itself.
treated with an IL-1Ra were compared with untreated subjects
FCAS patients have the option of partially controlling their disease by following general cold exposure.
18
After the cold challenge, untreated
meticulously controlling their environment and limiting their exposure patients developed clinical symptoms. Significant increases in serum
to cold conditions. This can be achieved by wearing many layers concentrations of IL-6 and white blood cell counts were observed.
of clothes, maintaining warm temperatures in their homes and Conversely, when IL-1Ra was administered prior to cold exposure, no
remaining indoors without air conditioning as much as possible. such symptoms or increases in inflammatory markers were detected.
18
Obviously, this may have a significant impact on their quality of life.
Anakinra, Rilonacept and Canakinumab
With the success of recent translational research, CAPS can now be Treating patients with IL-1β-blocking drugs has provided encouraging
treated with IL-1β blockers that counter the effects of an overactive results. Several medications are currently available, including
inflammasome; drugs of this nature have proved highly effective in anakinra, rilonacept and canakinumab. Although all three work by
eliminating symptoms. A proof-of-concept study evaluated the effects blocking IL-1 signalling in the affected pathway, there are slight
of an IL-1 receptor antagonist (IL-1Ra) on FCAS where patients pre- differences in their specific mechanisms of action (see Figure 2).
19
EUROPEAN MUSCULOSKELETAL REVIEW 57
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100 |
Page 101 |
Page 102 |
Page 103 |
Page 104 |
Page 105 |
Page 106 |
Page 107 |
Page 108 |
Page 109 |
Page 110 |
Page 111 |
Page 112 |
Page 113 |
Page 114 |
Page 115 |
Page 116