A Beacon in the Dark: Canakinumab. A New Therapeutic Perspective in Chronic Tophaceous Gout
A Beacon in the Dark: Canakinumab. A New Therapeutic Perspective in Chronic Tophaceous Gout
Davide Firinu . Stefano Del Giacco 0 1 2 3
0 D. Firinu S. Del Giacco Department of Medical Sciences and Public Health, University of Cagliari , Cagliari , Italy
1 A. De Santis D. Chessa Department of Medical Sciences and Public Health , Assl Olbia, Olbia , Italy
2 D. Marotto (&) Rheumatology, Department of Medical Sciences and Public Health , Assl Olbia, Olbia , Italy
3 Funding: Novartis Farma , Italy
Gout is the most common form of arthritis in adults. It is often associated with other comorbidities, which contraindicate the use of conventional therapies. The discovery of the role of interleukin-1b (IL-1b) in orchestrating the monosodium urate crystal-induced inflammatory response offered new therapeutic prospects to refractory patients, or to those in whom standard therapies are contraindicated. This paper describes a clinical case of a 65-year-old man with chronic tophaceous gouty arthropathy and subintrant flares, who had comorbidities contraindicating the use of conventional gout therapies-to which he did not respondwho was treated with canakinumab, a monoclonal selective inhibitor of IL-1b. The patient reported a gradual, rapid, and significant reduction in pain, with a response observed within 12 h of the administration of the drug. Consistent with previous clinical studies, canakinumab appeared to be a viable, safe, and effective alternative to conventional therapies in this patient with gout who had limited therapeutic options.
Canakinumab; Chronic tophaceous gout; Interleukin-1b; Refractory gouty arthropathy; Treatment options
Known since ancient times, gout is the most
common form of arthritis among the adult
population, with a prevalence of 4% in the USA
and 0.46% in Italy; it affects approximately 8.3
million people in America alone [
economic burden of gout is significant, not only
because epidemiological data show an increase
in its prevalence and incidence worldwide but
also because it has a high level of disability and
Gout is caused by the deposit of
monosodium urate crystals inside the joints and
tissues. The drugs conventionally used for the
treatment of acute gout are non-steroidal
antiinflammatory drugs (NSAIDs), including
cyclooxygenase (COX)-2 inhibitors, colchicine,
and corticosteroids [
]. However, an increasing
number of patients with gout are intolerant or
refractory, or have contraindications, to the use
of conventional drugs.
Recently, studies have highlighted the key
role of interleukin-1b (IL-1b) in the
inflammatory process related to the tissue and articular
deposit of monosodium urate crystals in
patients with gout [
]. According to this
theory, at the start of a bout of acute gout,
monosodium urate crystals activate inflammasome
NLRP3, leading to the release of IL-1b and
consequently an inflammatory response, with
vasodilation and recruitment of immune cells,
preferentially neutrophils, in the site of the
crystal deposit. Based on the identification of
the role of IL-1b in gout, development of drugs
that inhibit IL-1 signal transduction was
initiated, expanding the small number of
therapeutic options available for the management of
the acute attack in the patient with gouty
Among currently available IL-1 inhibitors are
anakinra, an IL-1 receptor human antagonist,
rilonacept, an inhibitor of both IL-1b and IL-1a,
and canakinumab, a fully human monoclonal
antibody selectively inhibiting IL-1b. Several
publications have demonstrated the efficacy of
these drugs in patients with gout for whom
conventional therapies are contraindicated or
Reported here is the case of a patient with
chronic tophaceous gout refractory to
conventional therapies, to the use of which he also
presented contraindications, who responded to
treatment with canakinumab.
In October 2016, a 65-year-old male patient, who
had been hospitalized for acute heart failure, was
referred to our operative unit (OU) for a
consultation by the medicine OU of the same hospital
for a severe acute attack of gout. He had a history
of type 2 diabetes mellitus, arterial hypertension,
ischemic dilated cardiomyopathy, and chronic
atrial fibrillation. He had also experienced a
previous myocardial infarction, had chronic
grade III renal insufficiency for the last 3 years,
was obese, and was diagnosed with gouty
arthropathy in 2011. Since his diagnosis of gout
the patient had experienced over 15 acute
attacks, and was treated with colchicine,
highdose steroids, NSAIDs, and allopurinol (replaced
in 2016 with febuxostat). His family history was
negative for gout, and there was a personal
history of high dietary purine intake and previous
smoking and alcohol abuse.
At the time of referral, the patient had
swelling of multiple joints, including his right
knee, wrists, and the metacarpophalangeal
(MCP) and interphalangeal (IP) joints of his
hands, feet, and ankles. In the days prior to
hospitalization, he had progressive clinical
worsening of his gout, which he treated with
NSAIDs, colchicine (up to 3 mg/day), and
highdose steroids without any benefit. He presented
at the emergency room of our hospital where,
over several days additional boluses of steroids
were administered without clinical response,
but with a worsening of dyspnea, fatigue, poor
control of blood pressure, and onset of swelling.
At admission, he was receiving the following
therapies: bisoprolol 7.5 mg/day (5 ? 2.5 mg),
colchicine 1 mg twice daily, rivaroxaban
15 mg/day, prednisone 25 mg/day, tramadol as
needed, pantoprazole 40 mg/day, febuxostat
80 mg/day, and olmesartan 20 mg/day.
Upon physical examination, the patient was
in severe pain, numerous tophaceous nodules
were observed bilaterally on the hands, feet,
elbows, and knees (Figs. 1a, 2), and symmetric
arthritis of the feet, right knee, and right hand
was present, with the overlying skin warm and
erythematous. Walking was impossible.
Blood tests revealed elevated uric acid, blood
urea nitrogen, blood count, serum creatinine,
erythrocyte sedimentation rate, and C-reactive
protein (Table 1), while culture tests (blood
culture, urinoculture, stool test, synovial fluid
culture), tests for antinuclear antibodies,
antidouble stranded DNA, anti-citrullinated protein
antibody, extractable nuclear antigen
antibodies, rheumatoid factor, prostate-specific
antigen, hepatitis B and hepatitis C markers,
and his thyroid profile were all negative. The
examination of the right knee synovial fluid
showed the presence of monosodium urate
crystals, with marked leukocytosis.
An X-ray of the hands revealed multiple
asymmetrical thickening of periarticular soft
tissue, with increased nubecula-type density,
erosions of the interphalangeal joints, cystic
lesions and initial reduction of the
corresponding articular rimae, while a chest X-ray
was normal. Echocardiography showed widely
dilated left ventricular hypokinetic LV and an
ejection fraction of 20% while
electrocardiography (ECG) revealed full atrial fibrillation
arrhythmia, an average heart rate of 95 bpm,
and left bundle branch block.
Considering the failure to respond to
conventional gout therapies, to which the patient
by now had proved to be refractory, as well as
the contraindications to their use due to his
comorbidities, canakinumab was administered
subcutaneously, in a single dose of 150 mg.
The patient reported a gradual, rapid, and
significant reduction in pain (calculated using a
0–100 VAS scale), which was apparent 12 h after
the administration of the drug (Fig. 3a). After
24 h, the patient was able to walk
independently, without any help or support. Over the
next few days there was a progressive
improvement in the patient’s daily activities, as assessed
by the Barthel Index of Activities of Daily Living
and the Lawton–Brody Instrumental Activities
of Daily Living Scale, which improved from 30
to 100 and from 2/5 to 5/5 at 4 weeks after
treatment. In parallel with the reduction of
pain, the dose of his steroid (prednisone) was
gradually scaled down, until its complete
suspension, after 22 days (Fig. 3b). Blood tests
carried out 10 days after the administration
showed improvement of all parameters
previously elevated (Table 2).
Fourteen days after receiving canakinumab,
the patient was discharged from hospital. At
this time, the patient had a marked
improvement in his cardiac and renal function.
Echocardiography revealed post-ischemic
dilated hypokinetic cardiomyopathy, severe
dilation of the left ventricle, moderate reduction in
global kinetics, moderate–severe diastolic
dysfunction, biatrial enlargement (severe in left
atrium), mild pulmonary hypertension, mild
mitral insufficiency, ectasia of the aortic root
and ascending aorta, and an injection fraction
The patient was discharged with instructions
to take tramadol three times per day as needed,
which he did not (as reported at the follow-up
visits made on days 30, 45, 60, and 90); the
patient also reported no new acute attacks or
Four weeks after the administration of
canakinumab, he presented for a follow-up,
where the number and size of tophi observed at
hospitalization were reduced (Figs. 1c and 2).
Informed consent was obtained from the
patient for his information to be used in this
To date, canakinumab is the only drug to have
obtained approval from the Italian Medicines
Agency (AIFA) for the symptomatic treatment
of adult patients with gouty arthritis.
Canakinumab is approved by the European Medicines
Agency for the treatment of adult patients with
frequent attacks of gouty arthritis refractory to
NSAIDs, colchicine, and repeated courses of
]. The efficacy of
canakinumab was investigated in two phase 2
variabledose studies [
] and in two phase 3,
randomized, multicenter, double-blind studies
(bRELIEVED and b-RELIEVED-II) [
showed that a single dose of canakinumab
(150 mg) can control new exacerbations and
causes a rapid reduction of the pain and
inflammatory state in patients with gout who
have contraindications, intolerance, or
non-responsiveness to colchicine and/or to NSAIDs.
Long-term follow-up studies with canakinumab
have also reported similar efficacy [
]. Post hoc
analysis of the phase 3 studies to determine the
safety and efficacy of canakinumab in a
subgroup of patients refractory to NSAIDs and
colchicine reported similar results to the main
]. Canakinumab is also reported to
improve health-related quality of life in patients
with difficult-to-treat gouty arthritis [
safety profile of canakinumab from the phase 3
studies showed that the treatment is well
tolerated and the main adverse events reported
with treatment include infections,
hypertension, headache, and back pain [
canakinumab is not approved by the US Food
and Drug Administration for the treatment of
gouty arthritis because of concerns regarding its
safety, particularly related to the incidence of
infections and hypertension with its use [
Despite the presence of multiple
comorbidities (diabetes, hypertension, heart failure)
contraindicating the use of conventional therapies,
the baseline characteristics of the patient in the
present case report were globally similar to the
patients enrolled in the phase 3 studies with
]. Our case, which appears to
be the first in Italy in which a patient with
gouty arthropathy refractory to conventional
therapies was treated with canakinumab,
supports the findings of the clinical trials by
demonstrating how a single dose of
canakinumab 150 mg results in a rapid and significant
improvement of the pain, the inflammatory
state, and thus the patient’s quality of life. A
single dose of canakinumab (150 mg) also
seemed to reduce the number and size of tophi
in the patient, and further studies are required
to confirm this effect.
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CRP C-reactive protein, ESR erythrocyte sedimentation
Funding. The study and article processing
charges were funded by Novartis Farma, Italy.
All authors had full access to all of the data in
this study and take complete responsibility for
the integrity of the data and accuracy of the
Authorship. The named authors meet the
International Committee of Medical Journal
Editors (ICMJE) criteria for authorship for this
manuscript, take responsibility for the integrity
of the work as a whole, and have given final
approval for the version to be published.
Medical Writing and/or Editorial
Assistance. We would like to thank Simone Boniface
and Nishad Parkar, PhD, of Springer Healthcare
Communications who edited the English of the
manuscript prior to submission and helped with
the peer review comments post submission,
respectively. This medical writing support was
funded by Novartis Farma, Italy.
Disclosures. Daniela Marotto, Antonella De
Santis, Donatella Chessa, Davide Firinu, and
Stefano Del Giacco have nothing to disclose.
Compliance with Ethics Guidelines.
Informed consent was obtained from the patient
for his information to be used in this case
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