Introduction
Cold-induced urticaria (ColdU) is a common form of chronic inducible urticaria. It
is characterized by the development of wheals and, sometimes, angioedema upon skin
exposure to cold air, liquids, or objects.
1
Although considerable progress has been made over the last years in the understanding
of the condition and its treatment, ColdU remains a challenging clinical problem.
Patients often suffer from ColdU for years before they are diagnosed, and treatment
requires a personalized approach. Similar to other forms of chronic urticaria, ColdU
has a significant impact on quality of life.
1
Here, we describe a case of severe and refractory ColdU associated with cryoglobulinemia
and successfully treated with rituximab.
Case report
A 60-year-old woman was referred to our Urticaria Center of Reference and Excellence
2
because of ColdU, from which she suffered since the age of 30. Localized pruritic
wheals occurred when the ambient temperature was below approximately 18 °C for longer
than 3-4 minutes, upon exposure to cold wind, or when touching cold objects. A cold
provocation test (TempTest) was positive at a temperature of 18 °C and lower (Fig
1). The dermatology life quality index was 16, indicating a large impact on her quality
of life.
Fig 1
TempTest results at baseline (T0) showed a clear wheal-and-flare reaction between
4 °C (A) and 16-18 °C (B). Three months after rituximab therapy, the TempTest was
negative (C).
Her general medical history included hypertension and monoclonal B-cell lymphocytosis.
The latter was diagnosed 7 years prior to presentation. A wait-and-see policy was
maintained, since lymphocyte counts were stable during follow-up. The family history
was negative for chronic urticaria and auto-inflammatory diseases. Treatment with
at least 3 different H1-antihistamines at up to 4-fold of the standard dose, omalizumab
dosed up to 600 mg every 4 weeks subcutaneously, and cyclosporin up to 5 mg/kg was
unsuccessful. Because of the severe and refractory nature of her ColdU, further investigations
were performed. This revealed type I cryoglobulins (monoclonal IgG), which were associated
with the monoclonal B-cell lymphocytosis. No mutations associated with auto-inflammatory
conditions were found with whole exome sequencing.
We hypothesized that, in this patient, the cryoglobulins detected were of pathophysiologic
importance for her ColdU and started treatment with rituximab, a therapeutic monoclonal
antibody directed against CD20 that reduces autoantibody production via depletion
of memory B-lymphocytes. The patient received 2 intravenous administrations of 1000 mg
rituximab with a 2-week interval. Three months later, the patient reported a remarkable
improvement of her symptoms. She could now walk outside at a temperature of 8 °C for
3 hours and was able to touch cold objects without developing signs or symptoms of
ColdU. Also, the cold provocation test was now negative (Fig 1), the lymphocyte count
normalized, and the cryoglobulin level decreased to 0.05 g/L (Table I). At the time
of writing, the complete response was still maintained 7 months after rituximab treatment,
and cryoglobulin levels were decreased further, to 0.02 g/L.
Table I
Laboratory results before and after treatment with rituximab
Lab test [reference values/intervals]
Before rituximab
3 months after rituximab
7 months after rituximab
Cryoglobulins [<0.03 g/L]
0.18 g/L, type I monoclonal IgG
0.05 g/L
0.02 g/L
IgE [<100 kU/L]
8
-
-
IgA [0.76-3.9 g/L]
0.67
0.71
0.73
IgG [7.0-16.0 g/L]
10.7
8.9
7.0
IgM [0.45-2.30 g/L]
0.27
0.25
0.27
C-reactive protein [<10 mg/L]
3.9
-
4.3
Erythrocyte sedimentation rate [0-30 mm/h]
17
-
-
Hemoglobin [7.5-9.5 mmol/L]
7.9
7.9
8.2
Leukocytes [3.5-10.0 × 109/L]
12.0
6.0
6.6
Lymfocytes [15%-50%]
73.9
37.2
36.9
Ig, Immunoglobulin.
Discussion
In this report we describe a case of complete clinical remission of ColdU associated
with type I cryoglobulinemia after treatment with rituximab in a patient with monoclonal
B-cell lymphocytosis.
Cryoglobulins are immunoglobulins that precipitate at temperatures below 37 °C. Precipitation
can cause occlusion of vessels, sometimes leading to immune-complex vasculitis and
tissue damage. Cryoglobulins can be classified into 3 types according to clonality
and type of immunoglobulin. Type 1 consists of monoclonal immunoglobulins, mostly
IgG or immunoglobulin M and is mostly seen in clonal B-cell diseases. Type 2 describes
a mixture of monoclonal immunoglobulin M and polyclonal IgG and is associated with
autoimmune diseases and hepatitis C infection. A mixture of polyclonal immunoglobulin
M and IgG can be classified as type 3 cryoglobulins. Dermatological findings in patients
with cryoglobulinemia can include skin purpura, necrotic ulcers, cold-induced acrocyanosis,
and the Raynaud phenomenon.
3
ColdU is a very rare manifestation of cryoglobulinemia, and the pathophysiology has
not yet been elucidated. Our patient had classical, cursory wheals matching urticaria
rather than vasculitis, which would be expected in typical cryoglobulinemic skin lesions.
Potentially, the cryoglobulins in this particular case are matching an epitope on
mast cells and basophils, causing IgG mediated degranulation.
4
Unfortunately, we did not perform a basophil or mast cell activation test, mostly
because of the technical difficulties of working with cryoglobulins in vitro. However,
the striking effect of B-cell depletion with rituximab corroborates the hypothetical
presence of autoreactive immunoglobulins in this patient, and the clear association
with ColdU suggests a pathophysiologic role for the cryoglobulins.
Although rare, cryoglobulinemia should be considered in refractory ColdU. In a large
French cohort study, 5 of 104 patients had cryoglobulinemia,
5
and a recent systematic review and meta-analysis of 14 relevant studies with a total
of 1151 ColdU patients showed that 3.0% (19/628) of patients had detectable levels
of cryoglobulins.
6
Furthermore, we identified 2 case reports of relevance to our case. One described
a 13-year-old boy with hepatitis B-associated type 2 cryoglobulinemia who developed
ColdU. Upon clearance of the hepatitis B infection, his ColdU disappeared together
with the cryoglobulins.
7
The other published case concerned a patient with cryoglobulinemia associated with
chronic lymphocytic leukemia and ColdU as the only clinical manifestation. The patient
was treated with chlorambucil 10 mg once daily for 6 weeks, followed by 2 mg/day maintenance
and steroids. Hematologic remission ensued, and the ColdU improved, although complete
remission was not achieved.
8
Lastly, in a cohort of 35 patients with ColdU, 46% had detectable cold agglutinins,
and 27% had cryoglobulins.
9
None of these studies explored the potential of rituximab as treatment for cryoglobulin-associated
ColdU.
Rituximab is a monoclonal antibody that targets B-cells and has a position in the
treatment of both autoimmune disorders; eg, rheumatoid arthritis and hematologic diseases.
10
The use of rituximab for ColdU is off-labeled and was administered in the setting
of an academic hospital after multiple on-label treatments had proven to be unsuccessful.
Off-label use of rituximab should at any time be carefully considered, as rituximab
may provide serious adverse events. Infusion reactions are most common and can range
from headache and fever up to bronchospasm, hypotension, and, in rare cases, anaphylaxis-like
reactions.
11
In conclusion, cryoglobulinemia may underlie some cases of ColdU. The role of cryoglobulins
in the pathophysiology of ColdU has not yet been elucidated in detail and requires
further investigation. Until then, we propose testing for cryoglobulinemia in patients
with refractory ColdU, and B-cell depleting therapy can be considered when cryoglobulins
are detected.
Conflicts of interest
None disclosed.