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doi: 10.5606/ArchRheumatol.2016.6000
Arch Rheumatol 2016;31(4):377-380
CASE REPORT
Different Therapeutic Paths (Colchicine vs. Anakinra) in Two Patients
With Schnitzler’s Syndrome
Marko BAREŠIĆ,1 Joško MITROVIĆ,2 Jadranka MOROVIĆ VERGLES, 2 Branimir ANIĆ 1
1Department of Internal Medicine, Division of Clinical Immunology and Rheumatology,
University Hospital Center Zagreb, Zagreb, Croatia
2Department of Internal Medicine, Division of Clinical Immunology and Rheumatology,
Dubrava University Hospital, Zagreb, Croatia
Received: April 20, 2016 Accepted: April 25, 2016 Published online: July 11, 2016
Correspondence: Marko Barešić, MD. Department of Internal Medicine, Division of Clinical Immunology and Rheumatology, University Hospital Center Zagreb,
10000 Zagreb, Croatia. Tel: +385 12 388 330 e-mail: markobaresic@gmail.com
©2016 Turkish League Against Rheumatism. All rights reserved.
Schnitzler’s syndrome is an uncommon disorder
characterized by urticarial rash and monoclonal
gammopathy. It was first described by a French
dermatologist Lilian Schnitzler and named
after her. 1 The disease is thought to be an
adult onset autoinflammatory syndrome with
unknown etiology and unknown pathogenesis. 2,3
The diagnosis is reached after excluding all
other more common causes 4 taking into account
the Strasbourg diagnostic criteria (Table 1). 2
Treatment strategies depend on several factors,
the most important being the general condition
of the patient and levels of acute phase reactants.
In this article, we aimed to evaluate the different
treatment strategies by comparing the clinical
courses of two patients, one achieving remission
with colchicine and the other with interleukin 1
(IL-1) receptor blockade after failing to respond to
the conventional immunosuppressants.
CASE REPORT
Case 1- A 50-year-old female patient with
unremarkable medical history had an eight-year
history of intermittent urticarial rash (localized,
later on generalized) and periodic high fevers
with chills and shivering, accompanied by
generalized myalgia and malaise. Laboratory
work-up registered elevated acute phase reactants,
leukocytosis with neutrophilia, and elevated
immunoglobulin M (IgM). Tests for antinuclear
antibodies, complement levels, C1 esterase
inhibitor, anti-neutrophil cytoplasmic antibodies,
IgE and eosinophil cationic protein were negative.
Skin allergy and inhaled allergens testing were
also unremarkable. We treated the patient with
antihistamines with no effect. During a routine
check-up, we detected IgM kappa monoclonal
gammopathy and performed additional tests
ABSTRACT
Schnitzler’s syndrome is a rare autoinflammatory syndrome with unidentified mechanism of disease and etiology with unknown definitive treatment
algorithm. The two obligatory criteria for the diagnosis of Schnitzler’s syndrome include chronic urticarial rash and monoclonal gammopathy
(immunoglobulin M or immunoglobulin G). In this article, we describe two patients with different courses of disease with different average lengths
of time between initial symptoms and the final diagnosis (6 months to 8 years). Exclusion of more common conditions is needed to ensure the correct
diagnosis. Treatment strategy depends on the patient’s constitutional symptoms (fever, malaise, generalized myalgia, and arthralgias) and laboratory
tests of inflammation. Treatment includes usage of conventional drugs and cytokine blockade (interleukin-1 and interleukin-6). Further studies are
needed to determine the precise mechanism of disease and the appropriate targeted therapy.
Keywords: Anakinra; canakinumab; colchicine; glucocorticoids; Schnitzler’s syndrome.
Arch Rheumatol378
(analysis of bone marrow, computed tomography
of the thorax, abdomen, and pelvis) and excluded
lymphoproliferative disease. We controlled the
urticarial rash and high fever only with higher
doses of prednisone (0.5 mg per kg or more).
The attempt to use other immunosuppressants
(azathioprine, cyclophosphamide, mycophenolate
mofetil) as steroid sparing drugs was also
ineffective. The patient developed side effects
of glucocorticoid therapy - diabetes mellitus and
depression - and stopped the regular follow-up
visits and had to retire. Two years later, she was
hospitalized during a period of prolonged high
fever and generalized urticarial rash. Once again,
we performed detailed work-up. Skin biopsy
showed elements of neutrophilic dermatosis
(Figure 1). After excluding all other possible
causes of the symptoms, we reached a diagnosis of
Schnitzler’s syndrome. Due to prominent general
constitutional symptoms and ineffectiveness of
antihistamines, several immunosupressants and
steroid-dependent disease the treatment with
anakinra was started with a prompt and excellent
result. Patient has been in remission in the follow-
up period with no need for prednisone.
Case 2- A 53-year-old male patient with
unremarkable medical history had a four-month
history of acute generalized rash followed by high
fever, shivers, and hives. Higher doses of parenteral
or oral glucocorticoids (0.3-0.5 mg per kg)
reduced the symptoms. Due to elevated acute
phase reactants (erythrocyte sedimentation rate
and C-reactive protein), we performed check-up
and excluded infection. Standard nutritive and
allergen inhalation tests were negative. We treated
the patient with prednisone and azathioprine as a
steroid sparing drug with little effect. Further work-
up in the rheumatology unit was also negative for
antinuclear antibodies, systemic antineutrophil
Table 1. Strasbourg diagnostic criteria for Schnitzler’s syndrome
Obligatory criteria
Chronic urticarial rash
Monoclonal immunoglobulin M or immunoglobulin G
Minor criteria
Recurrent fever >38 °C (+/- skin rash)
Objective findings of abnormal bone remodeling (+/- pain)
A neutrophilic dermal infiltrate on skin biopsy (neutrophillic urticarial dermatosis)
Neutrophils >10,000/mm3 and/or C-reactive protein >30 mg/L.
Definitive diagnosis
Two obligatory and at least two minor criteria if paraprotein immunoglobulin M and Three minor criteria if paraprotein immunoglobulin G
Probable diagnosis
Two obligatory and at least one minor criteria if paraprotein immunoglobulin M and two minor criteria if paraprotein immunoglobulin G
Figure 1. Skin biopsy - Periodic acid-Schiff staining - perivascular and intravascular cell infiltrates, predominantly
neutrophils (arrows). (a) 100x magnification, (b) 400x magnification.
(a) (b)
379Colchicine vrs. Anakinra for the Treatment of Schnitzler's Syndrome
cytoplasmic antibody-associated vasculitides and
there was no decrease in complement levels. After
obtaining the finding of IgM kappa monoclonal
gammopathy, additional tests (bone marrow
analysis and computed tomography) ruled out
lymphoproliferative disease. Having reviewed
all the symptoms, we reached a diagnosis of
Schnitzler’s syndrome. Due to relatively mild
general constitutional symptoms, we started the
patient on colchicine and sustained a low dose of
prednisone with rapid improvement of rash. The
patient has been tolerating colchicine well and has
remained stable with almost normal acute phase
reactants in the follow-up period.
DISCUSSION
Schnitzler’s syndrome, being a rare disease, is
often overlooked and not frequently included in
the differential diagnosis of patients presenting
with urticarial rash.
According to the literature, the time elapsed
from onset of symptoms to diagnosis is
approximately five years. 2,3 The first patient we
described had a latency of more than eight years
before the correct diagnosis was established.
Both described patients had similar presenting
symptoms (periodic urticarial rash and fever)
but with different symptom intensity and course
of disease. They presented with both major
criteria (chronic urticarial rash and monoclonal
gammopathy) and the majority of minor
criteria needed for the diagnosis of Schnitzler’s
syndrome.2,3
Rash (red macules, papules or plaques without
itching, with burning sensation) is present in
almost all patients with Schnitzler’s syndrome
and can occur on any part of the body. 5
Monoclonal IgM component is the second most
important criteria; it is associated with kappa
light chains in 90% of patients. Differential
diagnostic procedure should be carried out
to exclude lymphoproliferative disease such
as multiple myeloma and Waldenstrom’s
macroglobulinemia. 6 Both described patients
underwent detailed check-up to exclude the
hematologic disease.
In the diagnostic procedure, skin biopsy
plays an important role especially in excluding
the diagnosis of urticarial vasculitis with the
predominant elements of leukocytoclastic
vasculitis. 3,5
General constitutional symptoms and their
effect on patient’s quality of life determine
the treatment strategy - anakinra for patients
with more severe clinical and laboratory signs
and colchicine for less prominent clinical and
laboratory signs of the disease. Although the
mechanism of the disease is still unknown, the
efficacy of IL-1 blockade suggests that Schnizler’s
syndrome is an IL-1 driven disorder. 7,8 Long-term
efficacy and safety of anakinra have been proven
in a cohort of patients. 9
Positive response to colchicine in our patient
with less pronounced systemic constitutional
symptoms could suggest colchicine as a drug
of first choice in the treatment of Schnitzler’s
syndrome. In case of primary or secondary
inefficacy of colchicin, blockade of IL-1 receptor
(anakinra) and IL-1 beta receptor (canakinumab)
should be tried. 10 Inhibition of IL-6 receptor
with tocilizumab was proved to be useful in
certain patients supporting the role of IL-6 in
the pathogenesis of the disease. 11 Positive effects
of colchicine treatment suggest yet unknown
mechanisms of the action of colchicine,
prompting further studies to clarify the role of
the drug in the therapy of Schnitzler’s syndrome.
Regular follow-ups of patients with Schnitzler’s
syndrome are warranted due to higher risk
for the development of secondary amyloidosis
and lymphoproliferative disorders especially in
untreated and undertreated patients. 12
In conclusion, this article reports two diverse
clinical courses and different managements of
patients with Schnitzler’s syndrome, and indicates
that treatment strategies dependent on the patient’s
general condition and levels of acute phase
reactants. According to our limited experience,
colchicine may be used as the drug of first choice
in the treatment of Schnitzler’s syndrome and IL-1
blockade may be used as the second line therapy
in refractory Schnitzler’s syndrome patients in
whom other immunosuppressants fail.
Declaration of conflicting interests
The authors declared no conflicts of interest with
respect to the authorship and/or publication of this article.
Arch Rheumatol380
Funding
The authors received no financial support for the
research and/or authorship of this article.
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