Case Report

Dermatology 2011;222:123–127 Received: November 1, 2010

Accepted after revision: February 16, 2011
DOI: 10.1159/000326112
Published online: April 5, 2011

Efficacy of Anti-Interleukin-1 Receptor

Antagonist Anakinra (Kineret쏐) in a Case
of Refractory Sweet’s Syndrome
Nicolas Kluger a, b Déborah Gil-Bistes a Bernard Guillot a Didier Bessis a
       

a
Service de Dermatologie, Hôpital Saint-Eloi, CHU de Montpellier, Université Montpellier I, Montpellier, France;
 

b
Departments of Dermatology, Allergology and Venereology, Institute of Clinical Medicine, University of Helsinki,
 

Skin and Allergy Hospital, Helsinki University Central Hospital, Helsinki, Finland

Key Words ological analysis reveals a neutrophilic tuating circulating monoclonal IgG-kap-
Sweet’s syndrome ⴢ Neutrophilic dermal infiltrate. Systemic corticosteroid pa gammopathy was detected, but bone
dermatosis ⴢ Anakinra ⴢ Interleukin-1 therapy remains the mainstay of treatment marrow aspirate and biopsies failed to dis-
receptor antagonist [1, 2]. We report a patient with SS who was close an underlying hematologic malig-
unresponsive to numerous treatments and nancy. A diagnosis of monoclonal gam-
who had a dramatic response to anakinra. mopathy of unknown significance was
Abstract therefore considered. The patient had pre-
Sweet’s syndrome is a neutrophilic dermato- viously received the following treatments
sis characterized by fever, an elevated neu- Case Report without efficacy: prednisone, colchicine
trophil count, and painful erythematous cu- (1 mg/day), methotrexate (15 mg/week),
taneous lesions. Histopathological analysis A 66-year-old Caucasian male had had and disulone (50–150 mg/day). In January
reveals a neutrophilic dermal infiltrate. Sys- recurrent flares of neutrophilic dermatosis 2010, rituximab (375 mg/m2 weekly for 4
temic corticosteroid therapy remains the since the summer of 2005. Urticaria-like weeks) was administered to the patient
mainstay of treatment. We report the case of infiltrated papules, pustules, erosions, based on the hypothesis of a physiopatho-
a 66-year-old male patient who had a 5-year crusts, and sometimes necrotic lesions of logical relationship between neutrophilic
history of Sweet’s syndrome refractory to the limbs and trunk (fig. 1) were erupted. dermatosis and circulating monoclonal
various conventional treatments. Anti-inter- Lesions were mildly itchy and sometimes gammopathy. After 2 months of follow-up
leukin-1 receptor antagonist anakinra was associated with a burning sensation. How- there was no improvement in the skin le-
initiated and this resulted in a dramatic clini- ever, the patient never displayed any extra- sions. Based on recent published reports
cal and biological improvement. Anakinra is cutaneous manifestations such as weight [2, 3], interleukin (IL)-1 receptor antago-
a promising treatment for neutrophilic der- loss, fever, night sweats, arthralgias, or oc- nist (anakinra or Kineret쏐, 100 mg/day
matoses and sheds light on the interleukin-1/ ular or mucosal lesions. Moreover, leu- subcutaneously) was initiated at the end of
inflammasome pathway as central in the kocytosis was consistently absent during April 2010. White blood cells and the
physiopathology of neutrophilic dermatosis. the flares. Repeated cutaneous biopsies erythrocyte sedimentation rate (ESR)
Copyright © 2011 S. Karger AG, Basel showed a dense infiltrate of neutrophils lo- were within the normal range while C-re-
cated in the dermis, associated with edema active protein (CRP) was elevated to 16
in favor of SS (fig.  2). No clinical, radio- mg/l (n !5) before treatment. The patient
Introduction logical, or laboratory signs of any autoim- acknowledged stabilization of the erup-
mune condition, systemic disease, or ma- tion within 4–5 days of beginning with
Sweet’s syndrome (SS) is a neutrophilic lignancy were found. It is important to anakinra, followed by progressive resolu-
dermatosis characterized by fever, an ele- note that there was no clinical argument tion of the skin lesions (fig.  3) and a sig-
vated neutrophil count, and painful ery- for inflammatory bowel disease, but no nificant reduction of CRP levels (table 1).
thematous cutaneous lesions. Histopath- colonoscopy was performed. Only a fluc- After a month, only a few pustules of the
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© 2011 S. Karger AG, Basel Nicolas Kluger

1018–8665/11/2222–0123$38.00/0 Department of Skin and Allergic Diseases
Fax +41 61 306 12 34 Helsinki University Central Hospital
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 Color version available online
a b

Fig. 1. a Urticaria-like infiltrated papules on the back. b Necrotic papules, pustules, and erosions on the lower limbs.

Color version available online

Fig. 2. Skin biopsy of a lesion showing a

dense infiltrate of neutrophils in the der-
mis with edema.

right heel subsisted. As efficacy could have and the ESR rose to 37.1 mg/l and 55 mm, any reaction at the injection site, but in
been related either to anakinra or to a de- respectively. After 15 days of arrest, September 2010 he stopped taking anakin-
layed effect of rituximab, anakinra was anakinra was started again and showed a ra because of nausea. When he was seen in
withdrawn intentionally at day 35. Lesions similar efficacy with regard to clinical December 2010, he did not have any nau-
recurred quickly within a week on the low- signs and biological parameters (table  1). sea and the neutrophilic dermatosis was
er limbs, with inflammatory pustules and The patient remained disease free for 6 quiescent. He was of course advised to
erosions and a sterile conjunctivitis. CRP months with anakinra. He did not develop consult quickly if a new flare-up occurred.
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124 Dermatology 2011;222:123–127 Kluger /Gil-Bistes /Guillot /Bessis

       
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 Color version available online
a b

Fig. 3. Clearance of the lesions on the back (a) and lower limbs (b) after 1 month of anakinra.

Table 1. K inetics of white cell count, ESR, and CRP during anakinra treatment

11/01/10 16/04/10 20/04/10a 27/04/10 07/05/10 25/05/10b 09/06/10c 02/07/10 08/09/10 29/10/10
D0 D7 D17 D35

Hb, g/dl 14.9 14.4 NP NP 14.5 13.5 12.2 14.2 14.9 15.4
WBC, n/mm3 6,400 5,900 NP NP 7,200 8,000 6,400 7,300 7,400 6,900
PNN, n/mm3 4,090 3,310 NP NP 4,536 5,048 3,738 3,212 3,108 3,658
Lymph, n/mm3 1,510 1,440 NP NP 1,656 1,616 1,568 1,825 1,628 1,674
ESR, mm 16 18 28 38 NP 13 55 NP NP 17
CRP, mg/l 12.9 16.3 21.9 20 6 3.5 37.1 6 10 7

D = Day; Hb = hemoglobin levels; Lymph = lymphocyte count; NP = not performed; PNN = polynuclear cell count; WBC = white
blood cell count.
a D0: before initiation of anakinra. b D35: before anakinra withdrawal. c Before anakinra reintroduction.

Discussion ond-line therapies include nonsteroidal bowel disorder or inflammatory rheuma-

inflammatory drugs such as indometha- tism [3–10]. The list of the local and sys-
We report an additional case demon- cine 100–150 mg/day, clofazimine 200 mg/ temic treatments available is summarized
strating the dramatic efficacy of anakinra day, ciclosporine 2–4 mg/kg/day and dap- in table 2 [1, 2].
in refractory ‘atypical’ SS. A wide number sone 100–200 mg/day. There have been re- The efficacy of anakinra in neutrophil-
of treatments are available for the manage- ports of efficacy with methotrexate, inter- ic dermatosis has been reported on 2 prior
ment of SS. First-line therapies include feron- ␣, intravenous immunoglobulins, occasions [11, 12]. Delluc et al. [11] report-
classically systemic corticosteroids at a and etetrinate [1, 2]. Lastly, biologics, and ed the case of a 55-year-old woman with
dose of 1 mg/kg/day with a rapid decrease primarily anti-TNF- ␣ blocking agents, idiopathic SS that responded dramatically
of dose within 4–6 weeks, sometimes pre- have been proposed. It is important to note to anakinra while it failed to respond to
ceded by intravenous pulse administra- that infliximab and etarnecept have been a large number of immunosuppressive
tion for 3 days, colchicine 1.5 mg/day, and mainly proposed for patients with an as- treatments. More recently, Lipsker et al.
oral potassium iodide 900 mg/day. Sec- sociated disease such as inflammatory [12] successfully treated a 61-year-old
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Efficacy of Anakinra in Sweet’s Dermatology 2011;222:123–127 125

Syndrome
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Table 2. Current treatments available for woman with severe neutrophilic pannicu- ficiency, i.e. systemic-onset juvenile idio-
the management of SS [1, 2] litis. The patient received anakinra for 2 pathic arthritis, adult Still’s disease, and
weeks but relapsed quickly after with- systemic autoinflammatory disorders in-
Local treatments drawal. However, 5 additional injections cluding cryopyrin-associated periodic syn-
Topical corticosteroids controlled the disease. No flare-up was ob- dromes and Schnitzler’s syndrome [16, 17].
Intralesional corticosteroids served within the next 6 months. In the IL-1 is a neutrophil chemoattractant as it
Calcineurin inhibitors: tacrolimus, case described above, SS responded dra- stimulates macrophages to secrete more
pimecrolimus matically to anakinra. Nevertheless, the GM-CSF and IL-8 and may play an under-
response was neither as fast nor as com- estimated role in the physiopathology of
Systemic treatments plete as in autoinflammatory syndromes. neutrophilic dermatoses. Going [18] was
Corticosteroids Indeed, it seems that 1–2 weeks of treat- the first to speculate about the potential
Oral corticosteroids ment is necessary to determine whether central role of IL-1 during SS. Bourke et al.
Intravenous corticosteroids anakinra is efficient in cases of neutrophil- [19] hypothesized a potential release of
Antiinflammatory drugs ic dermatoses, while in the case of Schnitz- IL-1 into the dermis of SS skin lesions.
Potassium iodide ler’s syndrome or other autoinflammatory However, Bourke et al. [19] could not mea-
Nonsteroidal antiinflammatory drugs: disorders responses occur within the first sure the circulating levels of IL-1 in this
indomethacin 24 h [13, 14]. Besides, epidermal and der- retrospective study. Giasuddin et al. [20]
Colchicine mal lesions related to neutrophilic infiltra- found elevated levels of IL-1␣, IL-1␤, IL-2,
Dapsone tion may leave scars compared to the urti- and IFN-␥ in the serum of patients with
Immunosuppressive treatments carial lesions of autoinflammatory disor- SS compared to normal control subjects.
Azathioprine ders. Our point of view is that physicians More recently, Meng et al. [21] showed that
Cyclophosphamide should rely on the absence of new lesions NLRP3 knockin mice exhibited spontane-
Cyclosporine to the assess the efficacy of anakinra and ous and contactant-induced skin inflam-
Methotrexate may have to expect slow healing of previ- mation characterized by neutrophil infil-
Antibiotics ous skin lesions. Lastly, anakinra may have tration and a Th17-dominant response.
Clofazimine a prolonged efficacy, even after its with- The inflammation resulted from excess
Doxycycline, minocycline, tetracycline drawal, as observed by Lipsker et al. [12]. IL-1␤ production from antigen-presenting
Biologics In Schnitzler’s syndrome, the effects of cells, which augments Th17 differentia-
Etanercept anakinra are only suspensive and recur- tion. NLRP3 mutation leads to inflamma-
Infliximab rence occurs as soon as the treatment is some hyperactivation and consequently
Anakinra stopped. Our patient decided to stopped Th17-dominant inflammation in autoin-
Miscellaneous taking anakinra and no recurrence oc- flammatory diseases. Thus, there is a
Chlorambucil curred after 3 months. growing body of evidence showing that
Danazol IL-1 is a powerful proinflammatory cy- IL-1 and inflammasomes may play a cen-
Etetrinate tokine responsible for systemic manifesta- tral role in SS and neutrophilic derma-
Interferon-␣ tions such as fever, chills, skin rash, urti- toses.
Intravenous immunoglobulins caria, neutrophilia, anemia, and an elevat- Anakinra appears to be an effective
Thalidomide ed ESR [15]. Dysregulation of IL-1 secre- therapy for SS. It should be considered in
tion has been observed in inflammatory cases of SS or any neutrophilic dermatosis
diseases for which anakinra has proved ef- unresponsive to conventional therapies.

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