Amazing response to Kineret in Muckle-Wells syndrome

[Guest guest]

Rheumawire

Feb 25, 2004

Amazing response to anakinra in Muckle-Wells syndrome

London, UK - The interleukin-1 receptor antagonist anakinra (Kineret®,

Amgen) has shown amazing results in patients with the autoinflammatory

disease Muckle-Wells syndrome (MWS).

" This is one of the most remarkable things I have ever seen, " lead

author Prof Philip Hawkins (National Amyloidosis Centre, Royal Free

Hospital, London, UK) told rheumawire. " The really incredible thing is

how specific and rapid the response was. These patients have been sick

every day of their lives, and within hours of taking the first dose of

anakinra they began to feel better. "

Hawkins and colleagues report their findings in the February 2004 issue

of Arthritis & Rheumatism [1]. In an accompanying editorial, Drs Hal M

Hoffman (University of California-San Diego, La Jolla) and Dhavalkumar D

Patel (University of North Carolina, Chapel Hill) say that Hawkins's

work confirms " the central role of IL-1 in this disease and [provides] .

. a potentially life-saving therapy for this group of patients. "

Hawkins and colleagues also report that the 3 patients with MWS in their

study had several interesting clinical features that imply that the

disease may be part of a clinical spectrum of autoinflammatory

conditions.

MWS is very rarethere are perhaps only " a few dozen patients " in the UK,

Hawkins says. It is a dominantly inherited autoinflammatory disease

characterized by rashes, fever, arthralgia, progressive sensorineural

deafness, and, in some cases, the development of systemic AA

amyloidosis. " These patients are ill from within a few hours of being

born, " he notes.

Previously, there has been no effective treatment for patients with MWS,

Hawkins says. " Corticosteroids work to some extent, but only in high

doses that are unacceptable in the long term. " For the one fifth of MWS

patients who develop amyloidosiswhich can occur either within a few

years of diagnosis or not for several decadesprognosis is poor, Hawkins

says, and most will die within 5 to 10 years.

Following the discovery of the gene associated with the disease, CIAS1,

less than 2 years ago (see sidebar), it was determined that the protein

this gene encodes was involved in regulating interleukin-1, hence the

decision to try anakinra in these patients.

The British researchers treated 3 patients with MWS who were all members

of the same familya 42-year-old woman, her 22-year-old son, and her

15-year-old daughter. All patients were started on the dose of anakinra

licensed for use in rheumatoid arthritis (RA)100 mg subcutaneously once

a day. " This completely and utterly turned off their symptoms within

hours of the first injection, " Hawkins noted, adding that the patients

" relapsed within 48 hours when the treatment was stopped. "

None of the patients experienced any adverse side effects, other than a

slight injection-site reaction, which resolved after a few weeks in all

3 patients, he added. Also, because the response was so remarkable, the

dose of anakinra was tapered down to at least half the RA dose50 mg

subcutaneously a day. The 3 patients are still taking anakinra, he says.

Currently, a 100-mg dose every day costs around £500 to £600 a month,

but the fact that MWS patients can be maintained on half this dose

reduces the cost by 50%. So far, Hawkins has been able to obtain funding

from the UK National Health Service for anakinra for MWS; he thinks it

is unlikely that Amgen will seek to obtain a license to market the

product for this disease, given its rarity.

Hawkins and colleagues have also previously reported on 2 patients with

MWS in whom nephrotic syndrome due to amyloidosis had developed [3]. In

both patients, symptoms of inflammation ceased within hours of the first

injection of anakinra, and plasma SAA concentrations, the most sensitive

objective marker of inflammation, normalized within 3 days " and have

remained normal for 6 months, " they note in the new paper.

Both Hawkins et al and Hoffman and Patel say that these findings taken

together indicate the need for further studies of anakinra in this and

other autoinflammatory disorders. The editorialists add that many

questions remain to be answered and that " the rapid progression from

gene identification to effective therapy in such disorders is an

indication that these . . . can be answered sooner rather than later. "

MWS: part of a clinical continuum of autoinflammatory

diseases?

Hawkins's patients with MWS have all reported

exacerbation of symptoms after cold exposure, a trait commonly seen in

familial cold autoinflammatory syndrome (FCAS), and some have had

neurologic and ocular findings characteristic of neonatal-onset

multisystem inflammatory disease (NOMID).

Less than 2 years ago, the gene responsible for MWS

was discovered. Known as CIAS1, NALP3, or PYPAF1, the gene encodes a

protein called cryopyrin. Mutations in CIAS1 were initially identified

in patients with FCAS and MWS, Hawkins et al note, and 40% to 50% of

patients with NOMID also have mutations in CIAS1.

" We suspect that the clinical features of patients

with CIAS1 mutations overlap much more than has previously been

recognized and that the correlation of phenotype and CIAS1 genotype may

prove to be quite broad in terms of disease characteristics, penetrance,

and severity, " they note.

In their editorial, Hoffman and Patel say: " This

report and others are making it increasingly clear that the disorders

caused by CIAS1 mutations are not distinct diseases but actually

represent a clinical continuum of subphenotypes, with FCAS being the

mildest, MWS of intermediate severity, and NOMID being the most severe. "

" It is still not understood how these patients can

have such different clinical presentations but can all possess mutations

in CIAS1, " they add, noting that this finding " challenges the concept of

these conditions as single-gene disorders. " Also, many questions remain

to be answered, they say. For example, " What are the genetic or

environmental influences that determine the clinical presentation in

patients with CIAS1mutations? "

Interestingly, remarkable results have also been seen

with anakinra in patients with NOMID, as reported by rheumawire. The US

National Institute of Arthritis and Musculoskeletal and Skin Diseases is

currently enrolling for an open-label international trial of anakinra in

NOMID, led by Dr Raphaela Goldbach-Mansky (e-mail:

goldbacr@...). Rheumawire understands that Amgen is not

supplying anakinra for this study; it was initially prepared to provide

the drug but could not reach agreement with the researchers.

Hawkins says he has recently discussed this study with

the NIAMS researchers: " My understanding is that it is going very well. "

Hawkins told rheumawire he also has another article in press in

Arthritis & Rheumatism " in which we report the same extremely rapid and

complete response to anakinra in a patient with NOMID. " And the

researchers have another paper in press in Immunity further elucidating

the CIAS1 pathway.

Nainggolan

Sources

1. Hawkins PN, Lachmann HJ, Aganna E, McDermott MF. Spectrum of clinical

features in Muckle-Wells syndrome and response to anakinra. Arthritis

Rheum 2004 Feb; 50(2):607-12.

2. Hoffman HM, Patel DD. Genomic-based therapy: targeting interleukin-1

for autoinflammatory diseases. Arthritis Rheum 2004 Feb; 50(2):345-9.

3. Hawkins PN, Lachmann HJ, McDermott MF. Interleukin-1-receptor

antagonist in the Muckle-Wells syndrome. N Engl J Med 2003 Jun 19;

348(25):2583-4.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org