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MEDICINE® 80: 37-44, 2001
Copyright © 2001 by Lippincott Williams & Wilkins, Inc.
The Schnitzler Syndrome
Four New Cases and Review of the Literature
DAN LIPSKER, YOLANDE VERAN, FABIENNE GRUNENBERGER, BERNARD CRIBIER, ERNEST HEID,
AND EDOUARD GROSSHANS
Introduction
The Schnitzler syndrome is defined by a unique
and particular constellation of clinical and biologic
signs including chronic urticaria, intermittent fever,
bone pain, arthralgia or arthritis, and a monoclonal
IgM gammopathy. The syndrome was described by
Schnitzler, a French dermatologist, in 1972 (42) and
since then more than 40 other patients have been re-
ported. The syndrome is often underdiagnosed, and
the delay to diagnosis is more than 5 years in most
cases. Because of the variety of clinical signs, this
syndrome is of concern to the dermatologist, the in-
ternist, the rheumatologist, and the hematologist.
Many patients have seen all these specialists before
the diagnosis is established. In this study, we report
4 new patients with this syndrome and review all
cases in the English, German, and French literature.
Patients and Methods
We report here 4 new cases and the results of a literature review
of the Schnitzler syndrome. A MEDLINE (National Library of Med-
icine, Bethesda, MD) search was performed using the key words
“urticaria” and “monoclonal gammopathy”; “urticaria” and “IgM”;
“urticaria” and “macroglobulinemia”; and “Schnitzler syndrome.”
The search period was 1966–2000. Both English and non-English
literature were retrieved. Only patients with chronic urticaria and
a monoclonal IgM gammopathy, in the absence of any other dis-
ease that might explain these findings, were included.
Case Reports
From 1992 to 2000, we investigated 4 patients with the Schnitz-
ler syndrome. None of these patients have been reported previ-
From Clinique Dermatologique (DL, BC, EH, EG) and Service
de Médecine Interne (FG), Hôpitaux Universitaires, Strasbourg,
and Hôpital d’Instruction des armées Legouest (YV), Metz, France.
Address reprint requests to: D. Lipsker, Clinique Derma-
tologique, 1, Place de l’hôpital, F-67091 Strasbourg Cedex, France.
Fax: 33 3 88 11 60 40; e-mail: dlipsker@noos.fr.
37
Vol. 80, No. 1
Printed in U.S.A.
ously. Two of these patients were followed in the dermatology de-
partment of a university hospital (Patients 1 and 2), 1 in the inter-
nal medicine department of a university hospital (Patient 3), and 1
in the dermatology department of a military hospital (Patient 4).
Patient 1
A 67-year-old man had a 6-year history of persistent, antihista-
mine-resistant urticaria. He had been examined already by 5 physi-
cians, including dermatologists and hematologists, but no diagnosis
had been established. Usually, individual lesions resolved within
24–48 hours. They consisted of moderately pruritic rose macules or
maculopapules with varying topography (Figures 1 and 2). The face,
the soles, and the palms were spared. He never experienced an-
gioedema. Concomitant with the urticaria, he had experienced
arthralgia affecting the shoulders and recurrent episodes of fever.
The fever, which could reach 39 C, was well tolerated, and was ac-
companied by an exaggeration of the skin rash. Alcohol ingestion
also aggravated the skin rash. He reported occasional night sweats.
On examination, he had a widespread, edematous, maculopapular
rash, as well as palpable inguinal and axillary lymph nodes.
Histologic examination of a biopsy from an urticarial lesion
showed edema and a perivascular infiltrate of neutrophils and
eosinophils in the papillary dermis. Fibrinoid deposits were seen
around dilated superficial blood vessels. However, fibrinoid necro-
sis, the hallmark of fully developed leukocytoclastic vasculitis,
was not seen. Immunofluorescence studies were negative.
Laboratory investigations showed a moderately increased ery-
throcyte sedimentation rate (ESR) of 32 mm/h; C reactive protein
level was 17.8 mg/dL. Interleukin (IL)-6 level was increased to 97.1
pg/mL (normal  20 pg/mL), IL-2 receptor level was slightly in-
creased to 230 pg/mL (normal  190 pg/mL), while tumor necrosis
factor (TNF)  and IL-8 levels were within normal range. Serum pro-
tein electrophoresis demonstrated a monoclonal IgM component
with kappa light chains on immunofixation. No Bence-Jones pro-
teinuria was detectable. Total IgM was 5.4 g/L (normal, 0.4–3.1 g/L);
IgG, IgA, IgD, complement hemolytic assay (CH) 50, C3, C4, and C1-
inh were in normal range. There were no antinuclear antibodies,
cold agglutinins, cryofibrinogen, or cryoglobulins. Antibodies to
myelin glycoprotein were absent. An IgM anti-IgG rheumatoid fac-
tor was present at 30.8 U/mL (normal  11 U/mL). Hepatitis C was
excluded. Creatinine, complete blood count, and serum calcium
were in normal range. Skeletal X-rays were normal. Bone marrow
aspirates and histology showed no abnormality. The histologic ex-
amination of an axillary lymph node showed inflammatory hyper-
plasia. Cerebral and thoracic scans and abdominal sonography
were normal.
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38 LIPSKER ET AL
FIG. 1. Patient 1. Moderately pruritic rose macules and macu-
lopapules with varying topography that usually resolved within
24–48 hours.
His symptoms proved difficult to control. Antihistamines (lorata-
dine, terfenadine, dexchlorpheniramine, hydroxyzine), colchicine (1
mg/d), dapsone (100 mg/d), aspirin (3 g/d), and ibuprofen (1,200
mg/d) were ineffective. Psoralens and ultraviolet A (PUVA) therapy
allowed moderate improvement of the rash.
This patient was followed for 7 years and still had a daily rash. IgM
levels increased steadily from 2.55 g/L in 1993 to 11 g/L in 2000, but
the monoclonal spike remained stable about 7 g/L in the last 3 years.
Patient 2
A 41-year-old woman was admitted for chronic urticaria. The
eruption began 3 years earlier and consisted of a daily, mildly pru-
ritic rash involving mainly the trunk (Figure 3), but also the face on
occasion. Two years earlier, she had been hospitalized elsewhere to
investigate the rash and inflammatory arthralgia of the hands and
knees. An extensive workup was negative at that time, except for a
slightly increased ESR of 22 mm/h and the presence of traces of a
monoclonal IgM gammopathy. No diagnosis was established. Re-
cently, she developed intermittent fever, night sweats, and chills
and was therefore referred to us. She was in good general condition,
and skin examination revealed numerous red pale macules and
maculopapules mainly on the trunk. Individual lesions resolved
FIG. 2. Patient 1. Pale rose macules and maculopapules.
FIG. 3. Patient 2. Daily, mildly pruritic rash involving mainly the
trunk.
within 24 hours. Fever reached as high as 40 C. Otherwise, exami-
nation was unremarkable except for a single left palpable axillary
lymph node.
A skin biopsy showed edema of the upper dermis with an in-
flammatory infiltrate rich in neutrophils, which was consistent
with the diagnosis of neutrophilic urticaria. Direct skin immuno-
fluorescence studies were negative.
Laboratory investigations showed an elevated ESR of 121 mm/h.
IL-6 level was increased to 50.6 pg/mL (normal  20 pg/mL), IL-2 re-
ceptor level was increased to 249 pmol/L (normal  190 pmol/L),
and TNF level was within normal range. Blood count revealed
leukocytosis of 21.69  109/L with 18.63  109/L neutrophils, slight
eosinophilia of 0.58  109/L, thrombocytosis of 559  109/L, and ane-
mia (hemoglobin 99 g/L). Serum protein electrophoresis demon-
strated a monoclonal IgM component with kappa light chains on
immunofixation. No Bence-Jones proteinuria was detectable. The
monoclonal component was estimated at 6.1 g/L. Total IgM was 5.35
g/L (normal, 0.4–3.1 g/L); IgG, IgA, IgD, CH 50, C3, C4, and C1-inh
were in normal range. There were no antinuclear antibodies, rheu-
matoid factor, cold agglutinins, cryofibrinogen, or cryoglobulins.
Hepatitis C was excluded. Creatinine and serum calcium were in
normal range. Skeletal X-rays were normal. Bone marrow aspirates
and histology showed slight plasmacytosis (8%). Abdominal and
thoracic scans were normal.
Antihistamines (cetirizine, hydroxyzine), aspirin (3 g/d), and di-
clofenac (150 mg/d) did not alleviate the skin rash. PUVA therapy
partly improved the skin rash. Naprosyn (1 g/d) controlled the
joint pain but did not prevent the fever or the skin rash. An in-
crease in intensity and duration of the inflammatory symptoms
(fever and arthralgia) and a symptomatic inflammatory anemia
(6.5 g Hb/dL) necessitated immunosuppressive treatment with
chlorambucil (4 mg/d) and dexamethasone 20 mg/d for 5 days
every 3 weeks. Although this treatment corrected the anemia, and
partially the fever, it did not control skin rash or joint pain. This
patient was followed for 6 years and still had a daily rash. IgM lev-
els steadily increased from 5.35 g/L in 1994 to 17.9 g/L in 2000. The
monoclonal component increased more slightly during the last 3
years from 6.1 g/L to 8.1 g/L.
Patient 3
A 74-year-old man had an erythematous widespread eruption of
3 years’ duration. Individual lesions resolved within 24–48 hours.
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THE SCHNITZLER SYNDROME
They consisted of rose pale macules or maculopapules with vary-
ing topography (Figure 4). The face, the palms, and the soles were
not affected by the eruption, which was not pruritic until recently.
He never experienced angioedema. The patient concomitantly de-
veloped recurrent fever with peaks above 39.5 C, and he had lost
7 kg in the past 7 months. He complained about morning stiffness
affecting the hands and feet. On examination, he had bilateral pal-
pable axillary lymph nodes.
A cutaneous biopsy showed neutrophilic urticaria rich in eos-
inophils. Direct cutaneous immunofluorescence studies showed
granular IgM deposits in the papillary dermis. Laboratory investi-
gations showed a moderately increased ESR of 40 mm/h; C reac-
tive protein level was 47.7 mg/dL. Serum levels of IL-6, IL-8 and
TNF were in normal range, but the level of the IL-2 receptor was
increased to 460 pmol/L (normal  190 pmol/L). Serum protein
electrophoresis demonstrated a monoclonal IgM component with
kappa light chains on immunofixation. No Bence-Jones protein-
uria was detectable. The monoclonal IgM spike was 2.6 g/L (nor-
mal, 0.4–3.1 g/L); IgG and IgA were in normal range. An undosable
IgM monoclonal spike had been detected 2 years earlier. CH 50,
C3, C4, and C1-inh were in normal range. Ferritin and IgD levels
were in normal range. There were no cold agglutinins, cryofib-
rinogen, or cryoglobulins. An IgM anti-IgG rheumatoid factor was
present at 43.5 U/mL (normal  11 U/mL). The search for antinu-
clear antibodies was positive at 1:320. Hepatitis C was excluded.
Creatinine and serum calcium were in normal range. Complete
blood count revealed moderate anemia. Bone marrow aspirates
and histology showed medullary hypoplasia. Skeletal X-rays were
normal. Morphologic studies of the thorax, abdomen, and pelvis
revealed no abnormality.
Prednisone (20 mg/d), chlorambucil (4 mg/d), ketoprofen (300
mg/d), cetirizine (10 mg/d), and hydroxyzine (50 mg/d) proved in-
effective to control his symptoms.
This patient was followed for 4 years and still had a daily rash.
His monoclonal IgM gammopathy slightly increased about 0.5 g/L
every 6 months in the last 3 years.
Patient 4
A 49-year-old man was referred for a rash of 2 years’ duration.
His eruption started 2 years ago and consisted of erythematous,
nonpruritic, slightly elevated red plaques. Individual lesions ap-
FIG. 4. Patient 3. Pale rose macules and maculopapules with
varying topography. Individual lesions resolved within 24–48
hours.
39
peared daily, lasted about 12 hours, and resolved without sequel.
The eruption involved the whole body, including the face, but the
patient never experienced angioedema. The patient noticed that
the rash was triggered when he ingested alcohol and spicy food. A
few months after the eruption started, other clinical signs ap-
peared. He developed fever about twice a week, up to 39.8 C, of-
ten preceded by chills as well as inflammatory arthralgia of the
knees and ankles and pain in both tibias. His examination was oth-
erwise unremarkable except for a xanthelasma at the right eyelid.
A cutaneous biopsy showed neutrophilic urticaria. Direct cuta-
neous immunofluorescence studies revealed no immunoglobulin
or complement deposition. Laboratory investigations showed an
increased ESR of 66 mm/h; C reactive protein level was 53 mg/L.
Serum level of TNF was in normal range, but the level of the IL-
2 receptor was increased to 514 pmol/L (normal  190) and IL-6
level was increased to 41 pg/mL (normal  20 pg/mL). Serum pro-
tein electrophoresis demonstrated a monoclonal IgM component
with kappa light chains on immunofixation. No Bence-Jones pro-
teinuria was detectable. The monoclonal IgM spike was 5.3 g/L
(normal, 0.4–3.1 g/L); IgG and IgA levels were moderately in-
creased to 16.4 g/L and 4.79 g/L, respectively. An undosable IgM
monoclonal spike had been detected 2 years earlier. CH 50, C3, C4,
and C1-inh were normal. Ferritin level was increased to 424 ng/mL
(normal  284 ng/mL), and IgD level was in normal range. There
were no cold agglutinins, cryofibrinogen, or cryoglobulins. No an-
tinuclear antibodies were detected. Hepatitis C was excluded. Cre-
atinine and serum calcium were in normal range. Complete blood
count revealed a moderate anemia (10.5 g Hb/dL) and leukocyto-
sis (11.41  109/L leukocytes, 8  109/L neutrophils), and throm-
bocytosis (442  109/L). Bone marrow aspirates and histology
were normal. Skeletal X-rays were normal. Morphologic studies of
the thorax, abdomen, and pelvis revealed no abnormality.
Prednisone (20 mg/d) and ibuprofen (800 mg/d) proved inef-
fective to control his symptoms. This patient was followed for 2
years and still had a daily rash.
Discussion
The Schnitzler syndrome is a rare and probably un-
derdiagnosed disorder. Including the 4 patients re-
ported here, 52 patients with this syndrome have
been reported to date (1–9, 10–26, 29–32, 35–40,
42–44, 46–50). The mean delay to diagnosis was 5.4
years (SD 4.9 yr). Mean age at diagnosis was 60 years
(SD 12 yr) and the male to female ratio is 1.45. Of
note, most cases were reported in Europe, mainly in
France and Spain. Only 3 North American patients
with this syndrome have been reported so far (6, 26).
Clinical signs
The nature and frequency of the different clinical
signs reported in patients with the Schnitzler syn-
drome are shown in Table 1. The presence of the skin
rash and the monoclonal IgM component, which de-
fine this syndrome, are constant, although the possi-
bility of the Schnitzler syndrome without rash has
been advocated in a patient with bone pain, bone
densification, and a monoclonal IgM component
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40 LIPSKER ET AL

TABLE 1. Frequency of clinical findings in 52 patients urticaria is the most common histopathologic find-
with the Schnitzler syndrome ing. The 4 patients we followed had neutrophilic ur-
Frequency in % (% of ticaria. Fully developed vasculitis is rare (only 2
Sign Patients in whom this patients in the review by de Castro et al), and there-
Information was Reported)
fore this syndrome should not be classified with the
Skin rash 100/100 urticarial vasculitides. When immunofluorescence
Pruritus 29/79 studies were performed, deposition of immunoreac-
Fever 90/92
Arthralgia and/or arthritis 59/94 tants, mainly IgM, could be found around the super-
Bone pain 59/79 ficial dermal vessels in about 30% of patients (1, 6, 8,
Liver and/or spleen enlargement 33/83 9, 32). In a few noteworthy observations, IgM de-
Palpable lymph nodes 50/85 posits were found along the dermal-epidermal junc-
Elevated ESR (30 mm/h) 98/87
Leukocytosis (10  109/L) 89/85
tion (21, 35, 37). We recently demonstrated, by means
Monoclonal IgM component 100/100 of immunoelectron microscopic studies and immu-
Kappa light chain 89/87 noblotting on epidermal and dermal skin extracts,
Abnormalities in IgG and/or IgA levels 26/67 that IgM-skin interactions play a major role in the
Bence-Jones proteinuria 44/62 pathophysiology of the skin lesion (27). Indeed, anti-
IgM 10 g/L 33/87
IgM deposition in skin 35/71 skin IgM autoantibodies of the same isotype as their
Abnormal bone marrow findings 20/79 monoclonal gammopathies can be present in the
Abnormal bone morphology 56/79 serum of some patients with the Schnitzler syn-
Abbreviations: ESR erythrocyte sedimentation rate. drome. These IgM autoantibodies seem to deposit in
vivo in the epidermis and at the dermal-epidermal
junction, in the region of the anchoring fibrils, and
(45). The other 2 most characteristic clinical signs they could thus trigger a local inflammatory response
are fever and joint and/or bone pain. that could induce the skin lesions (27).

Rash
The rash of the syndrome is distinctive. In the 4 pa-
tients we had the opportunity to follow, it consisted of
pale rose, slightly elevated, papules and plaques (see
Figures 1–4). Individual lesions measure 0.5 to 2 or 3
cm in diameter. The rash is monomorphic and lesions
can be confluent. New lesions appear daily. They last
12–24 hours and then disappear without sequel. The
presence of purpura within the plaques was reported
in 1 patient (40), but this is an exceptional finding.
Short periods ranging from 1 to 2 weeks without erup-
tion are possible. In the beginning of the disease, pru-
ritus is usually absent. After 3 or 4 years, lesions
become mildly pruritic in 29% of patients according to
the review of the literature, although this is not a major
complaint. Trunk and limbs are most frequently af-
fected and the head and neck area is usually spared.
Angioedema is possible, though exceedingly rare. Two
of the patients we followed reported edema of the lips
at 1 occasion. In some patients, the rash is triggered by
alcohol ingestion. One of the characteristics of the skin
rash is that it is difficult to treat. Antihistamines,
steroids, colchicine, dapsone, nonsteroidal antiinflam-
matory drugs (NSAIDs), and immunosuppressive
agents have all been tried and gave inconstant results,
although they were often effective in controlling other
signs of the syndrome.
Histopathologic examination of the lesions usually
reveals neutrophilic urticaria. de Castro et al (11) re-
viewed 25 skin biopsy specimens from 15 of the orig-
inally reported patients and showed that neutrophilic
Fever
Intermittent fever, with peaks over 40 C, is present
in 90% of patients and is a cardinal feature of the dis-
ease. The fever is usually well tolerated and chills are
rare. In most patients, there is no relation between the
fever and the skin rash. Fever usually responds to
NSAIDs or to steroids. The pathophysiology of the
fever and of the syndrome in general remain unclear.
The presence of anti-IL-1 antibodies was reported
with increased frequency in this syndrome by Saurat
et al (41), but this finding was not confirmed subse-
quently by other investigators (19, 31, 32, 37). We
found elevated IL-6 and/or IL-2 receptor levels in the 4
patients reported here, but TNF and IL-8 levels were
in normal range. Although IL-6 is an essential plasma
cell growth factor, it is also an acute phase reactant
and its increase during a systemic illness is therefore
not surprising. Thus, it remains to be established if the
clonal IgM proliferation is primary in nature or the re-
sult of a continuous antigenic stimulation. It also re-
mains to be established if the IgM plays a role in the
systemic features of the disease, although IgM de-
posits in the skin seem to be involved in the patho-
physiology of the rash (27).
Musculoskeletal involvement
Musculoskeletal involvement is another cardinal
feature of the disease, affecting 80% of patients. Bone
pain (59% of patients) is the most characteristic find-
ing, but arthralgia and sometimes fully developed
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THE SCHNITZLER SYNDROME 41

arthritis are also common (59% of patients). Joint de- ing the other features of the Schnitzler syndrome (28).
struction and/or deformities have not been reported Bence-Jones proteinuria was reported in 44% of pa-
so far. Bone pain affects mostly the iliac bone and the tients. In about 26% of patients, lowered levels of IgG
tibia. Femur, spine, forearm, and clavicle were less of- or IgA can be found. At the time of diagnosis, exami-
ten involved. Lecompte et al (26) reviewed the bone in- nation of bone marrow is normal in 80% of patients. In
volvement in this syndrome and its differential the remaining 20%, unspecific, polyclonal, lympho-
diagnosis. Bone densification is the most frequent ra- cytic, or plasmocytic infiltrates were reported.
diologic finding. Lytic lesions were reported in 2 pa-
tients (17, 22), and 2 patients had periosteal apposition Laboratory findings and differential diagnosis
(18, 26). Radiologic differential diagnosis is broad and
During the course of the disease, elevated ESR is a
includes mastocytosis, POEMS syndrome, Erdheim-
constant feature. Complement levels are normal or in-
Chester disease, Camurati-Englemann or Van Buchem
creased in patients with this syndrome. When comple-
disease, Buschke-Ollendorf syndrome, osteopetrosis,
ment levels are lowered, another diagnosis must be
melorheostosis, ribbing disease, and hypertrophic os-
considered and the possibility of a genetic deficiency
teoarthropathy. Bone technetium scanning reveals hy-
of C4 should be addressed, since 2 patients with the
perfixation in the areas of radiologic involvement (26).
Schnitzler syndrome had a C4a deficiency (39). Throm-
Magnetic resonance imaging was performed in 3 pa-
bocytosis and an inflammatory anemia are present in
tients (18, 26, 50) and showed medullary bone in-
about 10% of patients. In 2 patients, inflammatory ane-
volvement and marrow infiltration without space-
mia was severe and symptomatic (6). One of these 2 pa-
occupying features in the affected areas in 2 patients
tients is reported here (Patient 2), and anemia was so
(26, 50). A bone biopsy was performed in 9 patients (4,
severe that this patient had to be treated with steroids
10, 14, 19, 29, 36, 37, 44, 50). It was normal in 3 patients
and an alkylating agent, to which the anemia re-
(14, 42, 48) and showed a nonspecific inflammation in
sponded well. It is noteworthy that persistent leukocy-
5 patients (4, 10, 19, 29, 36), sometimes associated
tosis (10  109/L), in the absence of any treatment,
with hyperactive osteoblasts. One patient had histo-
occurred in 90% of patients. In this regard, both adult-
logic evidence of osteosclerosis (37).
onset Still disease and the Schnitzler syndrome can be
associated with a skin rash, fever, palpable lymph
Palpable lymph nodes and hepatic nodes, spleen and liver enlargement, arthralgia, and
or splenic enlargement leukocytosis (46). However, ferritin levels are usually
more elevated in the former while a monoclonal IgM
Palpable lymph nodes are found in 50% of patients
component is present in the latter.
and hepatic or splenic enlargement occurs in 33% of
Other diseases that should be considered in the dif-
patients. Palpable lymph nodes are found in the ax-
ferential diagnosis of this syndrome are shown in Table
illa and inguinal sites and sometimes in the cervical
2. There is no biologic marker for this disease. Thus, di-
region. Those lymph nodes can be multiple, persis-
agnosis requires a combination of clinical, biologic,
tent, and up to 2 or 3 cm large and therefore suggest
and radiologic findings as well as exclusion of other
the diagnosis of lymphoma, but biopsy shows non-
diseases. In Table 3, we suggest a combination of cri-
specific inflammation.
teria that can be used to diagnose the Schnitzler syn-
drome. Although the criteria are useful for the positive
Monoclonal IgM component diagnosis of the syndrome, they are not intended to dis-
tinguish the Schnitzler syndrome from other diseases
The monoclonal IgM component is a defining fea-
that can closely mimic this syndrome. Therefore, ex-
ture of the syndrome. In 89% of patients, it is associ-
clusion of other diseases, mainly cryoglobulinemia,
ated with a kappa light chain. Usually, when diagnosis
hypocomplementic urticarial vasculitis, acquired C1
of the syndrome is made, IgM levels are low (10 g/L
inhibitor deficiency, hyper IgD syndrome, and adult-
in 67% of patients). IgM levels can remain stable or in-
onset Still disease, remains essential.
crease progressively at a rate of about 0.5–1.0 g/L per
Associated findings included pseudoxanthum elas-
year. High IgM levels should raise suspicion of Wal-
ticum in 2 patients (29, 49), peripheral neuropathy
denström disease. When patients are seen at the very
with the presence of monoclonal IgM with anti-MAG
beginning of the disease, monoclonal IgM component
(myelin-associated glycoprotein) in 1 patient (25), C4
can be present at very low (trace) levels. Nashan et al
deficiency in 2 patients (39), and nodular regenera-
(33) reported a patient with urticaria, fever, arthralgia,
tive hyperplasia of the liver in 1 patient (24).
elevated ESR, and a monoclonal IgG component and
suggested that their observation could be a variant of Course and treatment
the Schnitzler syndrome. We reported a patient in
whom urticaria seemed to be related to a myeloma- The disease pursues a chronic course. Sponta-
tous IgA monoclonal spike, but this patient was lack- neous or treatment-induced remissions have not
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42 LIPSKER ET AL

TABLE 2. Differential diagnosis of the Schnitzler syndrome

Disease Distinguishing Features
Adult-onset Still disease Absence of monoclonal IgM; elevated, low-glycosylated ferritin
levels
Hypocomplementemic urticarial vasculitis Cutaneous biopsy shows vasculitis; low complement levels; lupus
erythematosous is often associated
Acquired C1 esterase inhibitor deficiency, especially in the setting Usually angioedema; low C4 levels, low functional C1-inh levels
of lymphoma and/or paraproteinemia
Cryoglobulinemia Temperature-dependency of clinical signs, presence of cryo-
globulins
Hyper IgD syndrome Elevated IgD levels
Erythema marginatum Preceding streptococcal infection; elevated anti-streptococcal
antibodies
Systemic lupus erythematosus Clinical findings suggestive of lupus erythematosus; presence of
antinuclear antibodies
CINCA syndrome* Begins in childhood; neurologic involvement; joint deformities
Muckle-Wells syndrome Deafness and amyloidosis; absence of monoclonal component;
family history
Lymphoma, Waldenström disease Lymph node biopsy, bone marrow biopsy
*CINCA (chronic infantile neurologic cutaneous and articular syndrome) is also called NOMID (neonatal onset multisystem inflam-
matory disease).

been reported. Although the disease features chronic
inflammation and a monoclonal component, to our
knowledge no patient has developed systemic amy-
loidosis. Nevertheless, amyloidosis should be con-
sidered as a possible complication of the syndrome.
The prognosis of the Schnitzler syndrome depends
on the possible evolution into a lymphoproliferative
disorder, either a lymphoma, including lymphoplas-
macytic lymphoma, lymphoma of the Richter type,
IgM myeloma, or Waldenström disease. Fifteen per-
cent of the patients reported with this syndrome de-
veloped lymphoproliferative disorders (1, 9, 20, 30,
38, 39, 47, 48). However, the number of patients with
the syndrome who will eventually develop lympho-
proliferative disorder is probably much higher, since
the reports of most patients were published shortly
after diagnosis, and therefore follow-up was too
short to draw any conclusion about long-term out-
come. Lymphoma or Waldenström disease appears
more than 10–20 years after the beginning of the first
signs of the syndrome in most cases. Schnitzler’s
original patient died from diffuse lymphoplasmacytic
TABLE 3. Diagnostic criteria for the Schnitzler syndrome*
Urticarial skin rash, monoclonal IgM component, and at least 2
of the following criteria:
Fever
Arthralgia or arthritis
Bone pain
Palpable lymph nodes
Liver or spleen enlargement
Elevated erythrocyte sedimentation rate
Leukocytosis
Abnormal findings on bone morphologic investigations
*Another cause must be eliminated in all cases (see Table 2 for
differential diagnosis), most notably hyper IgD syndrome, adult-
onset Still disease, hypocomplementemic urticarial vasculitis, ac-
quired C1 inhibitor deficiency, and cryoglobulinemia.
infiltration of the liver and bone marrow 23 years af-
ter the first signs of the disease (47). However, in rare
cases, Waldenström disease was revealed by the
Schnitzler syndrome (9). There is no specific predic-
tive factor of the development of a lymphoprolifera-
tive disorder. Thus, initial workup of a patient with
this syndrome should include an examination of
bone marrow, immunoelectrophoresis of serum and
urinary proteins, and dosage of immunoglobulin sub-
types. The 2 latter examinations can then be used to
follow-up those patients on a biannual basis. Lymph
nodes should be biopsied when they enlarge.
Treatment of the Schnitzler syndrome is difficult
and disappointing. No treatment is constantly effec-
tive in treating the skin rash. NSAIDs, most notably
ibuprofen (3  400 mg/d), should be tried first (15),
but in most patients those drugs will ameliorate the
skin rash only briefly or not at all (3, 7, 21, 23, 29, 32,
36, 50). Antihistamines do not control the skin rash (5,
7, 6, 21, 26), and, as the rash is not pruritic in most pa-
tients, they are not indicated. The use of inhibitors of
neutrophil migration like colchicine or dapsone ap-
pears to be logical in this syndrome characterized by
leukocytosis and neutrophilic urticaria, but results
were inconstant (7, 8, 18, 21, 29, 32, 35, 40). Hydroxy-
chloroquine and chloroquine also proved ineffective
(6, 21, 36). Steroids and immunosuppressive drugs
are not indicated to treat the rash and they are not ef-
fective at acceptable dosages (3, 5, 6, 8, 13, 14, 17, 18,
22, 31, 32, 35, 36, 37); plasmapheresis (6, 31, 35) and
intravenous immunoglobulins (25) also are not effec-
tive. Even chemotherapeutic regimens that were pre-
scribed to treat the associated hematologic disorders
did not relieve the skin rash. PUVA therapy did reduce
the intensity of the skin rash in 2 of the patients re-
ported here, and this has been reported (31). Fever,
although intermittent, can be disabling. NSAIDs, and
Lipsker-MD-0106-01/01 12/21/2000 2:15 PM Page 43 (Black plate)
THE SCHNITZLER SYNDROME
sometimes steroids or immunosuppressive agents (3,
7, 13, 14, 17, 21, 23, 29, 32, 35, 36, 37, 50), alleviate it.
Bone pain and arthralgia most often respond well to
short treatments with NSAIDs (3, 7, 21, 23, 29, 32, 36,
50). Pramidorate was reported to be an effective
treatment of bone pain in 1 patient (34). Thus, treat-
ment depends on the nature and intensity of symp-
toms. NSAIDs are the first choice in most patients and
can be associated with colchicine or dapsone. Ster-
oids and immunosuppressive agents are only indica-
ted when systemic symptoms like fever or arthralgia
are disabling and do not respond to the first-line treat-
ments. (When symptoms do not respond to first-line
treatments but are tolerable, those agents should not
be used.) In rare cases, disabling inflammatory ane-
mia can necessitate introduction of steroids and alky-
lating agents (6).
Summary
The Schnitzler syndrome is characterized by a
chronic urticarial eruption with a monoclonal IgM
gammopathy. The other signs of the syndrome include
intermittent elevated fever, joint and/or bone pain with
radiologic evidence of osteosclerosis, palpable lymph
nodes, enlarged liver and/or spleen, elevated erythro-
cyte sedimentation rate, and leukocytosis. The mean
delay to diagnosis is more than 5 years, and this syn-
drome is of concern to internists and many medical
specialists. Patients with this syndrome are often ini-
tially considered to have lymphoma or adult-onset Still
disease, which are the main differential diagnoses.
However, hypocomplementic urticarial vasculitis, sys-
temic lupus erythematosus, cryoglobulinemia, ac-
quired C1 inhibitor deficiency, hyper IgD syndrome,
chronic infantile neurologic cutaneous and articular
(CINCA) syndrome, and Muckle-Wells syndrome
should also be excluded, because diagnosis relies on a
combination of clinical and biologic signs and there is
no specific marker of the disease. The disease pursues
a chronic course, and no remissions have yet been re-
ported. Disabling skin rash, fever, and musculoskele-
tal involvement are the most frequent complications.
Severe anemia of chronic disease is another serious
complication. The most harmful complication, how-
ever, is evolution to an authentic lymphoplasmacytic
malignancy, which occurs in at least 15% of patients.
This hematologic transformation can occur more than
20 years after the first signs of the disease, thus pa-
tients deserve long-term follow-up. Treatment is symp-
tomatic and unsatisfactory. The skin rash is un-
responsive to treatment, and nonsteroidal antiinflam-
matory drugs, antihistamines, dapsone, colchicine,
and psoralens and ultraviolet A (PUVA) therapy give
inconstant results. Fever, arthralgia, and bone pain of-
ten respond to nonsteroidal antiinflammatory drugs.
43
In some patients, these symptoms and/or the presence
of severe inflammatory anemia require steroids and/or
immunosuppressive treatment, which ameliorate in-
flammatory symptoms but do not change the course of
the skin rash.
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