Allergy 2004: 59: 869–873 Copyright Ó Blackwell Munksgaard 2004

Printed in UK. All rights reserved ALLERGY

Original article

Clinical and laboratory parameters in predicting chronic urticaria

duration: a prospective study of 139 patients

Background: Despite the disabling nature of chronic urticaria (CU), little is E. Toubi1, A. Kessel1, N. Avshovich1,
known about the disease’s duration or the efficacy of adopting aggressive E. Bamberger1, E. Sabo1, D. Nusem2,
therapeutic regimens such as cyclosporine A. J. Panasoff2
Objectives: The aim of this study was to evaluate whether parameters such as 1
Division of Allergy and Clinical Immunology, Bnai-
angioedema, autologous serum test, anti-thyroid antibodies, and total IgE could Zion Medical Center, Faculty of Medicine, Technion;
2
predict both CU duration and severity. Lin Medical Center, Clalit Health Services, Haifa,
Patients and methods: One hundred and thirty-nine patients suffering from CU Israel
were prospectively followed over a 5-year period for disease duration, severity
and the presence of angioedema. Also investigated was the association between
these clinical parameters and the subsequent detection of autologous serum test,
anti-thyroid antibodies, and total IgE.
Results: CU lasted over 1 year in more than 70% of cases and in 14% it still
existed after 5 years. Angioedema co-existed or appeared during the course of
CU in 40% of patients and was associated with disease duration. Autologous
serum test and anti-thyroid antibodies were found positive in 28 and 12% of
patients, respectively, compared to none of normal individuals, P ¼ 0.001. CU Key words: autoimmunity; chronic urticaria duration;
duration was associated with the presence of both autologous serum test and severity; treatment.
anti-thyroid antibodies; however, autologous serum test and not anti-thyroid
antibodies was found in association with CU severity. Elias Toubi, MD
Conclusion: We demonstrate for the first time that CU duration is associated Division of Allergy and Clinical Immunology
with clinical parameters such as severity and angioedema, and with laboratory Bnai-Zion Medical Center
47, Golomb Str., P.O.B. 4940
parameters such as autologous serum test and anti-thyroid antibodies. The Haifa 31048
ability to predict CU duration may facilitate decisions regarding the possible Israel
early initiation of cyclosporine A as a means by which to reduce disease severity
and duration. Accepted for publication 25 November 2003

Chronic urticaria (CU) is a common disabling disorder possibility that CU is at least partially autoimmune is
occurring in 0.1% of the population, with an average consistent with previous findings of increased frequency
duration of 3–5 years in adults (1). Physical urticaria and of anti-thyroid antibodies (ATA) and other autoimmune
intolerance to food additives account for 20% and nearly markers such as rheumatoid factor (9, 10).
5% of such patients, respectively, with the remaining Although most investigators concur that laboratory
defined as chronic idiopathic urticaria (CIU). Neverthe- tests such as CBC, chemistry panel, complement levels
less, in 40% of patients, physical urticaria such as delayed and skin test are noncontributory, autoimmune markers
pressure urticaria and dermographism were shown to such as anti-nuclear (ANA), AST, ATA, and total IgE
co-exist with CIU (2–4). are worthy of consideration and were subsequently
In 1986, Grattan et al. (5) reported the presence of a obtained routinely by most clinicians for the evaluation
serum factor that caused whealing upon autologous of CU. In practice, most specialists who deal this
intradermal injection (autologous serum test, AST) in disabling disorder are mainly concerned with the man-
some patients with CIU. However, the autoimmune agement of these patients. H1 anti-histamine treatment is
dimension of CU became apparent only in 1993 when beneficial for mild–moderate CU patients. However,
Greaves and colleagues (6) identified this factor as an IgG when CU is severe and short courses of corticosteroids
with specificity for the a-chain of the high-affinity IgE are unavoidable, low dose of cyclosporine A (CsA) was
receptor (FceRIa). The presence of anti-FceRIa, ranging reported by many to be both safe and beneficial (11–13).
from 25 to 45% of the total patients with CIU, was The natural history of CIU becomes particularly
demonstrated by many to be the causative autoantibody important when such forms of treatment are considered,
that results in mast cell degranulation (7, 8). The given that the efficacy of such treatment modalities are

869
Toubi et al.

likely to vary with the disease course. Yet, reports on the Autologous serum test
natural history of CU are very limited, and for the most
AST was performed in all the individuals studied (in patients after
part fail to cover the possible association between the antihistamine washout) as previously described (22). Briefly, 0.1 ml of
clinical course of CU and laboratory analyses (14–17). sterile autologous serum was injected intradermaly, and the wheal/
Consequently, we still know little about the average flare size was determined at 30 min and followed for a total of 60 min.
duration of CU and the prevalence of CU lasting longer Saline was used as a negative control and histamine (1 mg/ml) served
than 1 year. We also know little about the efficacy of CsA as a positive control. The wheal/flare diameter was measured and
treatment among severe patients symptomatic for longer scored from 0 to +3 as follows: 0 ¼ negative control; +1 ¼ wheal
1.5 mm >negative control, flare ¼ 15 mm; +2 wheal ¼ 3–5 mm,
than 1 year, not to mention the efficacy of early initiation
flare >15 mm; +3 ¼ wheal ¼ 6–10 mm. A widely used simplifica-
of CsA in particularly severe cases. tion of this test was suggested by the same group, that is, AST is
The current study was designed to analyze whether considered positive when the wheal attained is at least 1.5 mm greater
urticaria duration could be predicted by various clinical than the negative control (23).
and laboratory parameters such as AST, ANA, ATA,
total IgE, and others in a large cohort of patients who
Statistical analyses
were prospectively followed in our referral outpatient
clinic over a period of 5 years. Associations between categorical groups were assessed using the chi-
square test or Fisher’s exact test as appropriate. The relation
between urticaria duration and disease severity, angioedema, AST
and ATA was evaluated using the log-rank test. Kaplan–Meier
Patients and methods curves were constructed and displayed for the relation between
urticaria duration and each of the above variables. Two-tailed
This prospective study included 145 CIU patients (92 females and
P-values of 0.05 or less were considered to be statistically significant.
53 males, age range 17–66 years, mean 41 years) who were fol-
lowed by four senior allergists in two large referral outpatient
allergy clinics from 1998 until 2003. The follow-up time ranged
between 3 and 5 years. Exclusion criteria included pure physical Results
urticaria, infectious diseases, and food or food additive hyper-
sensitivity. Chronic infection was excluded on the basis of a Patient characteristics
detailed history, physical examination, and related laboratory At commencement of the study and during the following
analyses such as stool culture and eosinophils for parasites,
3 months of follow-up, 28/139 (20%) patients were
C-reactive protein, and antibodies to Helicobacter pylori when
suspected (18). Food and food additive hypersensitivity were scored as mild CU, whereas 45/139 (32%) and 66/139
excluded on the basis of skin prick tests for a wide panel of food (47%) were scored as suffering from moderate to severe
allergens and a trial of mono-allergen elimination diet. When CU, respectively. Angioedema (at least three episodes of
highly suspected, oral food additive provocation tests were initi- angioedema during a month) co-existed or appeared
ated (19, 20). during the course of CU in 56/139 (40%) of patients.
All patients underwent the following laboratory workup: CBC, Patients with mild CU were treated periodically with
chemistry panel, protein-electrophoresis (PEP) and complement
levels. ANAs were detected by using indirect fluorescent antibody
antihistamines, whereas most patients with moderate to
technique on HEP-2 commercial slides (Zeus Scientific, Inc., New severe CU were on antihistamines most of the time and
Jersey, USA), anti-thyroglobulin and thyroid microsomal antibod- frequently needed short courses of corticosteroids.
ies were detected by ELISA commercial kits (Orgentec Diagnostika,
GmbH, Mainz, Germany), and total IgE was detected by a Rida-
screen, ELISA kit (Darmstadt, Germany). AST was detected upon Duration of CU
entry in only 127 patients. All laboratory tests were compared with
After 6 months of follow-up, 94% of patients were still
those analyzed in 60 age- and sex-matched healthy individuals
(employees of both medical centers), who served as normal controls. found to be CU-positive. At the end of 12 months CU
During follow-up, six patients dropped out, leaving a sample of 139 was still ongoing in 75% of patients, whereas towards the
patients for whom complete information was available. end of 24 months CU was present in 52% of patients.
Informed consent was obtained from each patient and the study After 36 months of follow-up CU was still present in
protocol conformed to the ethical guidelines of the 1975 Declaration 43% of patients, and by the end of the study (5 years)
of Helsinki as reflected in a priori approval by the Bnai Zion 14% of patients were still suffering from CU.
Medical Center Human Research Committee.

Laboratory analyses
Urticaria score
All patients presented normal chemistry panel, CBC,
All patients were scored on a four-point scale as detailed previously
PEP, and complement levels. ANA were found positive in
by Breneman et al. (21). Briefly, this scale takes into account the
number of lesions, number of separate episodes, average size of 6/139 (4%) of patients compared to 1/60 (1.7%) of
lesions, average duration of lesions and pruritus as follows: 0 ¼ no normal controls, P ¼ 0.6. Both duration and severity
symptoms; 1 ¼ mild urticaria (1–4 points); 2 ¼ moderate urticaria were not associated with ANA positivity. ATAs were
(5–9 points); 3 ¼ severe urticaria (¼10 points). detected positive in 17/139 (12%) of patients compared to

870
 Parameters in predicting chronic urticaria duration

none of the normal controls P ¼ 0.004. In three of these In relation with AST: AST was defined positive in 36/
patients disthyroidism was detected by low TT4 and high 126 (28%) of patients and in none among the normal
TSH; however, thyroid replacement did not change the individuals, P ¼ 0.0001. In this regard, when CU dur-
course of CU. Total IgE was found elevated (considered ation was analyzed in relation to AST, significant
elevated only when >200 U + 2 SD) in 32/139 (23%) differences were already present at 12 months of follow-
compared to 3/60 (5%) in the control group P ¼ 0.02. up: CU still existed in 94% of AST-positive patients, in
The association of CU duration with clinical param- contrast to 78% of AST-negative patients. At 24 months,
eters (angioedema and severity), and laboratory param- 72% of AST-positive patients were still suffering from
eters (AST, ATA, and total IgE) was analyzed in all CU, in contrast to 43% of AST-negative patients. Of
patients studied as follows: interest is that at 5 years of follow-up both AST-positive
Relation between CU duration and severity: Whereas and AST-negative patients presented similar rates. Dif-
urticaria resolved in all patients with mild CU within ferences in CU duration between AST-positive and AST-
24 months, moderate to severe CU persisted in 59% of negative were significant when considering the whole
patients up to 24 months, and in 32% up to 60 months, period, P ¼ 0.004 (see Fig. 2). Also, we could not
P < 0.0001 (Table 1). demonstrate a correlation between CU duration and
With angioedema: At 12 months of follow-up, 88 and AST score among patients with positive AST.
80% of angioedema-positive and angioedema-negative CU duration in relation to ATA: At 12 months differ-
patients were still suffering from urticaria attacks, ences in CU rates between ATA-positive and AST-
respectively. However, at 24 months of follow-up 64% negative patients were noticed (94 vs 82%, respectively).
of angioedema-positive patients in contrast to 43% of At 24 months, 70% of ATA-positive patients (as opposed
angioedema-negative patients were still presenting CU to 50% of ATA-negative patients) still suffered from CU.
hives. When this association was analyzed further up to At 5 years of follow-up, 52% of ATA-positive patients vs
5 years 45% of patients with existing angioedema were 16% of ATA-negative presented CU attacks, P ¼ 0.02
still having CU as compared to only 12% of angioedema- (see Fig. 3).
negative patients, P ¼ 0.002 (see Fig. 1). Though relative to normal individuals, total IgE was
found to be elevated among CU patients, this elevation
was not found to have a significant association with either
disease duration or CU severity.
Table 1. Rates of urticaria duration in relation to disease severity

Rates of urticaria duration (months) The association of CU severity with other parameters
Severity 12 24 36 60 P value Angioedema was documented in 47/111 patients suffering
from moderate to severe CU, and in 9/28 of mild CU
Mild (n ¼ 23) 68% 0% – – <0.0001
patients. ATA was found positive in 3/28 mild CU
Moderate to severe (n ¼ 116) 86% 59% 50% 32%
patients and in 14/111 of moderate to severe CU patients.

Figure 1. A Kaplan–Meier curve demonstrating the relation- Figure 2. A Kaplan–Meier curve demonstrating the relation-
ship between chronic urticaria duration and the presence of ship between chronic urticaria duration and the detection of
angioedema during the course of disease in these patients. autologous serum test in these patients.

871
Toubi et al.

munity and CU severity and duration has not been

investigated in the past.
Interest in the possible autoimmune origin of CU was
further strengthened with the identification of IgG
autoantibodies directed against FceRIa or IgE on mast
cells (29, 30). But since these disease-specific histamine-
releasing autoantibodies were found in not more than
50% of cases, other circulatory factors were proposed to
play a role in mast cell degranulation such as metallo-
proteinases and cytokines such as TNF-a and IL-10
(31, 32). The production of various and unrelated
autoantibodies in CU (AST and ATA) might be driven
by polyclonal T-helper-cell activity, rather than distinct
monoclonal auto-reactive T-cells and therefore were
suggested to be only associate autoimmune markers.
We propose that our current finding of total IgE elevation
is a part of this polyclonal activity rather than due to a
specific trigger. This is consistent with our previous
Figure 3. A Kaplan–Meier curve demonstrating the relation- documentation of increased proliferation and over-
ship between chronic urticaria duration and the detection of expression of Bcl-2 in both B and T lymphocytes derived
anti-thyroid antibodies. from CU patients (33). Following this understanding of
CU being a T-cell-dependent disorder, the beneficial
Whereas neither parameter was found in association with effects of CsA in severe CU become highly reasonable, in
CU severity, both were found to have a significant addition to its histamine-releasing inhibitory effect.
association with CU duration. Positive AST was docu- In this study, we demonstrate that CU lasted over 1 year
mented in 33/104 moderate to severe CU patients; in more than 70% of patients. After 36 months of follow-
however, only 3/22 patients with mild CU were AST up, 43% of patients were still suffering from CU, and by
positive, thus AST positivity presents a trend towards a the end of the study, 14% of patients were still suffering
significant association with CU severity, P ¼ 0.08. from CU. In this regard, the natural history of urticaria
reveals that management should be directed toward
allowing the patient to maintain an acceptable quality of
life, until the episode resolves. Since most reports on CsA
Discussion
treatment suggest its initiation only when severe CU lasts
The wide clinical spectrum of urticaria (i.e. distribution of over 1 year, we propose that, as it is customary in the
hives, the invariable intensity of itch, and the duration of management of autoimmune diseases, the early initiation
disease) indicate that multiple mediators are involved in of CsA be considered in severe CU cases.
the polymorphism and variable behavior of this disorder The early identification of patients in whom urticaria is
(24, 25). The occasional appearance of angioedema expected to be long lasting and/or severe is desirable.
during the course of CU occurred in approximately A significant contribution of the current study is that our
50% of patients. However, neither angioedema nor CU findings suggest a strong association between CU dur-
severity, have been evaluated in conjunction with other ation with the presence of angioedema, AST, and ATA.
laboratory parameters as possible predictors of CU Whereas our results reinforce earlier findings suggesting
duration or as means by which to distinguish between an association between AST and CU severity (34), the
autoimmune and nonautoimmune CU. current study is the first to associate AST with CU
The reports of Leznof (26) were the first to show an duration. Based on these findings, the early initiation of
association between thyroid autoimmunity and CU. Such CsA among patients exhibiting severe CU along with
an association was further supported in other studies in AST positivity may be considered, especially when
which both thyroglobulin and thyroid microsomal anti- angioedema and ATA are also present, since in such
bodies were found increased (27). The prevalence of patients one may predict CU to also be long standing.
thyroid function alterations in such patients as well as the Just how autoimmunity is related to CU duration and
efficacy of correcting these alterations has been discussed severity remains unclear and requires further investiga-
in many studies but remains questionable (9). In a most tion. One possibility is that long-lasting CU is the result
recent report (28), higher incidence of ATA was found in of a prolonged stimulation of T-cells followed by
CU patients in whom anti-IgE receptor antibodies were prolonged polyclonal activation, and the production of
positive. This is compatible with our finding of the various cytokines that could possibly induce the secretion
association between AST positivity and the presence of of the autoantibodies discussed above. We are cognizant
ATA. However, the association between thyroid autoim- of the high incidence of moderate to severe CU among

872
 Parameters in predicting chronic urticaria duration

our study population which could be explained by the ted in order to further confirm the efficacy of utilizing
higher referral rate of such patients to specialized immunological indices as a basis for therapeutic decision-
outpatient clinics. Additional studies should be conduc- making.

References
1. Greaves M. Chronic urticaria. J Allergy 13. Toubi E, Blant A, Kessel A, Golan 24. Champion RI, Roberts SOB, Carpen-
Clin Immunol 2000;105:664–672. TD. Low-dose-cyclosporin-A in the ter RG, Roger JH. Urticaria and
2. May CD. Are confusion and contro- treatment of severe chronic idiopathic angioedema a review of 554 patients.
versy about food hypersensitivity really urticaria. Allergy 1997;52:312–316. Br J Dermatol 1969;81:588–597.
necessary? J Allergy Clin Immunol 14. Quaranta JH, Rohr AS, Rachelefsky 25. Beltrani VS. An overview of chronic
1985;75:329–333. CS, Siegal SC, Katz RM, Spector SL. urticaria. Clin Rev Allergy Immunol
3. Black AK, Lawlor F, Greaves MW. The natural history and response to 2002;23:147–169.
Consensus meeting on the definition of therapy of chronic urticaria and angi- 26. Leznoff A. Chronic urticaria. Can Fam
physical urticaria and urticarial vasculi- oedema. Ann Allergy 1989;62:421–424. Physician 1998;44:2170–2176.
tis. Clin Exp Dermatol 1996;21:424–426. 15. Schnyder B, Helbling A, Pichler WJ. 27. Zauli D, Grassi A, Ballardini G,
4. Barlow RJ, Warburton F, Watson K, Chronic idiopathic urticaria: natural Contestabile S, Zucchini S, Bianchi
Black AK, Greaves MW. The diagnosis course and association with Helicobacter FB et al. Thyroid autoimmunity in
and incidence of delayed pressure urtic- pylori infection. Int Arch Allergy chronic urticaria: implications for
aria in patients with chronic urticaria. Immunol 1999;119:60–63. therapy. Am J Clin Dermatol 2002;3:
J Am Acad Dermatol 1993;24:954–958. 16. van der Valk PG, Moret G, Kiemeney 525–528.
5. Grattan CEH, Wallington TB, LA. The natural history of chronic 28. Kikuchi Y, Fann T, Kaplan AP.
Warin RP. A serological mediator in urticaria and angioedema in patients Antithyroid antibodies in chronic
chronic idiopathic urticaria: a clinical visiting a tertiary referral centre. Br J urticaria and angioedema. J Allergy
immunological and histological evalua- Dermatol 2002;146:110–113. Clin Immunol 2003;112:218.
tion. Br J Dermatol 1986;114:583–590. 17. Kozel MM, Mekkes JR, Bossuyt PM, 29. Hide M, Francies DM, Grattan CEH,
6. Hide M, Francies DM, Grattan CEH, Bos JD. Natural course of physical and Barr RM, Winkelman RK, Greaves
Hakimi J, Kacham JP, Greave MW. chronic urticaria and angioedema in 220 MW. The pathogenesis of chronic idio-
Autoantibodies against the high affinity patients. J Am Acad Dermatol pathic urticaria: new evidence suggests
IgE receptor as a cause of histamine 2001;45:387–391. an autoimmune basis and implications
release in chronic urticaria. N Engl J 18. Bakos N, Fekete B, Prohaszka Z, for treatment. Clin Exp Allergy
Med 1993;328:1599–1604. Fust G, Kalabay L. High prevalence of 1994;24:624–627.
7. Niimi N, Francis DM, Kermani F, IgG and IgA antibodies to19-kDa 30. Fiebiger E, Hammerschmid F, Stingl
Greaves MW, Black AK, O’Donnell Helicobacter pylori-associated lipopro- G, Maurer D. Anti-FceRI autoanti-
BF et al. Dermal mast cell activation by tein in chronic urticaria. Allergy bodies in autoimmune-mediated disor-
autoantibodies against the high affinity 2003;58:663–667. der. Identification of a structure–
IgE receptor in chronic urticaria. J Invest 19. Werfel T. Skin manifestations in food function relationship. J Cin Invest
Dermatol 1996;106:1001–1006. allergy. Allergy 2001;56 (Suppl. 67): 1998;101:243–251.
8. Tong LJ, Balakrishnan G, Kochan 98–101. 31. Piconi S, Trabattoni D, Iemoli E, Fusi
JP, Kinet J-P, Kaplan AP. Assessment 20. Wuthrich B. Food-induced cutaneous ML, Villa ML, Milazzo F et al.
of autoimmunity in patients with chronic adverse reactions. Allergy 1998; Immune profiles of patients with chronic
urticaria. J Allergy Clin Immunol 53(Suppl. 46):131–135. idiopathic urticaria. Int Arch Allergy
1997;99:461–465. 21. Breneman D, Bronsky AK, Bruce S. Immunol 2002;128:59–66.
9. Turktas I, Gokcora N, Demirsoy S, Cetirizine and astemisone therapy for 32. Baram D, Vaday GG, Salamon P,
Cakir N, Onal E. The association of chronic urticaria: a double-blind, Drucker I, Hershkoviz R, Mecori
chronic urticaria and angioedema with placebo-controlled, comparative trial. YA. Human mast cells release metallo-
autoimmune thyroiditis. Int J Dermatol J Am Acad Dermatol 1995;33:192–198. proteinase-9 on contact with activated
1997;36:187–190. 22. Grattan CEH, Francies DM, Hide M, T cells: juxtacrine regulation by TNF-
10. Ryhal B, DeMera RS, Shoenfeld Y, Greaves MW. Detection of circulating alpha. J Immunol 2001;167:4008–4016.
Peter JB, Gershwin ME. Are autoan- histamine releasing autoantibodies, with 33. Toubi E, Adir-Shani A, Kessel A,
tibodies present in patients with subacute functional properties of anti-IgE in Shmuel Z, Sabo E, Hacham H. Immune
and chronic urticaria? J Invest Allergol chronic urticaria. Clin Exp Allergy aberrations in B and T lymphocytes
Clin Immunol 2001;11:16–20. 1991;21:695–704. derived from chronic urticaria patients.
11. Fradin MS, Ellis GN, Goldfarb MT, 23. Sabrone RA, Grattan CEI, Francis J Clin Immunol 2000;20:371–378.
Voorhees JJ. Oral cyclosporine for DM, Barr RM, Black AK, Greaves 34. Sabroe RA, Seed PT, Francis DM,
severe chronic idiopathic urticaria and MW. The autologous serum skin test: Bart RM, Black AK, Greaves MW.
angioedema. J Am Acad Dermatol a screening test for autoantibodies in Chronic idiopathic urticaria: comparison
1991;25:1066–1067. chronic idiopathic urticaria. of the clinical features of patients with
12. Barlow RJ, Black AK, Greaves MW. Br J Dermatol 1999;140:446–452. and without anti-FceRIa or anti-IgE
Treatment of severe chronic urticaria autoantibodies. J Am Acad Dermatol
with cyclosporine-A. Eur J Dermatol 1999;40:443–450.
1993;3:273–275.

873