Prevalence, Clinical Manifestations, Treatment, and Clinical Course of Chronic Urticaria in Elderly: A Systematic Review

Figures & data

Figure 1 Flow diagram of the literature review process in this systematic review. Eighty-five articles were suitable for the inclusion criteria and were included in our systemic review. There were three randomized controlled trials, 12 prospective cohorts, 34 retrospective cohorts, one case-control, 16 cross-sectional, eight case series, and 11 case reports.

Table 1 The Reported Prevalence of Chronic Urticaria, Chronic Spontaneous Urticaria, and Chronic Inducible Urticaria in Elderly Patients Relative to All Reported Cases of These Disorders

Study (year)	Study design	Country	Population	Elderly patients among all reported patients
				N/Total (%)
Chronic urticaria
Juhlin (1981)^Citation12	Retrospective cohort	Sweden	University Hospital	18/330 (5.5)
Greene et al (1985)^Citation244	Prospective cohort	USA	Department of Dermatology Mayo Clinic	9/50 (18.0)
Mekkes et al (1986)^Citation25	Retrospective cohort	Netherland	Dermatology clinic University Hospital	3/109 (2.8)
Barlow et al (1993)^Citation26	Retrospective cohort	UK	Urticaria clinic St John’s Dermatology Centre	1/135 (0.7)
Hashiro et al (1994)^Citation27	Cross-sectional	Japan	Outpatient clinic Hospital	5/30 (16.7)
Gaig et al ^a (2004)^Citation29	Cross-sectional	Spain	Spanish population National telephone directory survey	10/30 (33.3)
Chen et al ^b (2012)^Citation19	Retrospective cohort	Taiwan	Taiwan population National Health Insurance Research Database	3,615/12,720 (28.4)
Krupashankar et al (2012)^Citation28	Prospective cohort	India	University Hospital	5/80 (6.3)
Magen et al (2013)^Citation63	Retrospective cohort	Israel	Allergy consultation Secondary and tertiary care	124/1,319 (9.4)
Ban et al (2014)^Citation11	Retrospective cohort	South Korea	Allergy clinic University Hospital	37/837 (4.4)
Chuamanochan et al (2016)^Citation10	Retrospective cohort	Thailand	Urticaria clinic University Hospital	67/1,622 (4.1)
Chu ^b (2017)^Citation30	Retrospective cohort	Taiwan	Taiwan population National Health Insurance Research Database	40,816/177,879 (23.0)
Eun et al (2018)^Citation31	Prospective cohort	Korea	Korean Population National Health Insurance Service - National Sample Cohort	447/2,980 (15.0)
Seo et al ^c (2019)^Citation32	Retrospective cohort	Korea	Korean Population Health Insurance Review and Assessment Service database	41,882/174,579 (24.0)
Wertenteil et al ^d (2019)^Citation33	Cross-sectional	USA	Multihealth system data analytics and research platform	22,900/69,570 (32.9)
Jankowska-Konsur et al^e (2019)^Citation34	Cross-sectional	Poland	Poland Population Recruitment from multi centers all over the country	154/1,091 (14.1)
Chung et al (2020)^Citation74	Retrospective cohort	Korea	Outpatient clinic University Hospital	26/329 (7.9)
Napolitano et al (2021)^Citation45	Retrospective cohort	Italy	Dermatology unit University Hospital	153/1,970 (7.8)
Chronic spontaneous urticaria
Yang et al (2005)^Citation41	Cross-sectional	Taiwan	Dermatological Clinics University Hospital	5/75 (6.7)
Hiragun et al (2013)^Citation38	Retrospective cohort	Japan	University Hospital	22/117 (18.8)
Magen et al (2013)^Citation63	Retrospective cohort	Israel	Allergy consultation secondary and tertiary care	92/1,051 (8.8)
Vikramkumar et al (2014)^Citation42	Cross-sectional	India	Department of Dermatology	5/48 (10.4)
Lapi et al ^f (2016)^Citation35	Retrospective cohort	Italy	Italian population The Health Search IMS Health Longitudinal Patient Database	4,242/13,479 (31.5)
Curto-Barredo et al (2018)^Citation36	Retrospective cohort	Spain	Urticaria unit Hospital	119/549 (21.7)
Nettis et al (2018)^Citation40	Retrospective cohort	Italy	Secondary care centers	32/322 (9.9)
Curto-Barredo et al (2019)^Citation37	Retrospective cohort	Spain	Urticaria unit Hospital	99/549 (18.0)
Jankowska-Konsur et al ^e (2019)^Citation34	Cross-sectional	Poland	Poland Population Recruitment from multi centers all over the country	104/667 (15.6)
Jo et al (2019)^Citation39	Retrospective cohort	South Korea	University Hospital	79/970 (8.1)
Chronic inducible urticaria
Dover et al ^c (1988)^Citation43	Retrospective cohort	England	Dermatology Hospital	1/44 (2.3)
Katsarou-Katsari et al (2008)^Citation44	Retrospective cohort	Greece	Skin allergy division Hospital	10/62 (16.1)
Seo et al ^g (2019)^Citation32	Retrospective cohort	Korea	Korean Population Health Insurance Review and Assessment Service database	3,290/20,191 (16.3)
Jankowska-Konsur et al ^e (2019)^Citation34	Cross-sectional	Poland	Poland Population Recruitment from multi centers all over the country	46/383 (12.0)
Napolitano et al (2021)^Citation45	Retrospective cohort	Italy	Dermatology Unit University Hospital	26/451 (5.8)

Notes: ^aGaig et al conducted a population-based study among adults in Spain. Population sample was randomly selected from a national telephone directory. The phone survey was performed with each individual employing the Computer-assisted Telephone Interview technique. ^bThe database from National Health Insurance Research of Taiwan represented approximately 99.9% of Taiwan’s population. ^cDover et al reported the prevalence of delayed pressure urticaria in hospital for diseases of the skin and the dermatology institute. ^dElectronic health records data for a demographically heterogenous population-based sample of >55 million patients. The database is from 27 participating integrated health care organizations, representing over 55 million unique persons (17% of the population across all four census regions of the United States). ^eThis nationwide, multi-center, cross-sectional questionnaire-based study was performed under the auspices of the Polish Dermatological Society. Ten chronic urticaria patients were recruited by each of 102 dermatologists and allergists from different regions of Poland to achieve a good representation of patients from the whole country. ^fThe database from the Health Search IMS Health Longitudinal Patient Database (HSD) contained the computer-based patient records from about 1,000 general practitioners (GPs) throughout Italy. Included in this study were almost 1 million electronic patient records which met standard quality criteria. They were selected on a geographical basis to represent the whole Italian population. ^gThe database from Health Insurance Review and Assessment Service covers 97.0% of the Korean population. Not all types of urticaria were included in the study of Seo et al. The reported subtypes of chronic inducible urticaria were cholinergic urticaria and cold/heat urticaria, as shown in this table. Prevalence of dermographism was also reported but not included in this current study, as it was not symptomatic dermographism, which is chronic inducible urticaria subtypes.

Table 2 The Reported Prevalence of Chronic Urticaria in the Elderly Population

Study (year)	Study design	Country	Population	Reported chronic urticaria among all elderly patients N/Total (%)
Chronic urticaria
Gaig et al^a (2004)^Citation29	Cross-sectional	Spain	Spanish population National telephone directory survey	10/1,047 (1.0)
Lapi et al^b (2016)^Citation35	Retrospective cohort	Italy	Italian population The Health Search IMS Health Longitudinal Patient Database	13,476/488,145 (2.8)
Wertenteil et al^c (2019)^Citation33	Cross-sectional study	USA	Multihealth system data analytics and research platform	22,900/9,757,210 (0.2)
Gaber et al (2020)^Citation46	Prospective cohort	Egypt	Outpatient clinic University Hospital	2/260 (0.8)

Notes: ^aGaig et al conducted a population-based study among adults in Spain. Population sample was randomly selected from a national telephone directory. The phone survey was performed with each individual employing the Computer-assisted Telephone Interview technique. ^bThe database from the Health Search IMS Health Longitudinal Patient Database (HSD) contained the computer-based patient records from about 1,000 general practitioners (GPs) throughout Italy. Included in this study were almost 1 million electronic patient records which met standard quality criteria. They were selected on a geographical basis to represent the whole Italian population. ^cElectronic health records data for a demographically heterogenous population-based sample of >55 million patients. The database is from 27 participating integrated health care organizations, representing over 55 million unique persons (17% of the population across all four census regions of the United States).

Table 3 The Reported Demographic and Clinical Characteristics of Elderly Patients with Chronic Urticaria (CU), and Compared Between the Two Subtypes of CU – Chronic Spontaneous Urticaria and Chronic Inducible Urticaria

Clinical features: N/Total (%)	CU^a	CSU	CIndU
	(N=1,112,066)	(N=891)	(N=1,568)
Gender
Female	61,170/106,669 (57.4)	276/432 (63.9)	873/1,509 (57.9)
Age at presentation, mean±SD, years	70.4±6.2	71.6±6.7	69.9±3.8
Symptoms
Wheal alone	305/413 (73.9)	236/312 (75.6)	NA
Wheal with angioedema	107/413 (25.9)	76/312 (24.4)	NA
Wheal with anaphylaxis	1/413 (0.2)	0/312 (0.0)	1/1 (100.0)
Duration of disease prior diagnosis, mean±SD, years	1.9±3.6	1.9±3.7	NA
Personal history of atopy^b
Allergic rhinitis	44/233 (18.9)	9/100 (9.0)	9/27 (33.3)
Asthma	84,519/982,862 (8.6)	4/101 (4.0)	2/27 (7.4)
Atopic Dermatitis	57,163/985,228 (5.8)	15/162 (9.3)	4/27 (14.8)
Allergic conjunctivitis	2/73 (2.7)	0/7 (0.0)	1/27 (3.7)
Unspecified atopy	18/144 (12.5)	8/105 (7.6)	0/1 (0.0)
Family history of atopy
Allergic rhinitis	5/74 (6.8)	0/1 (0.0)	0/2 (0.0)
Asthma	2/74 (2.7)	0/1 (0.0)	0/2 (0.0)
Atopic Dermatitis	1/74 (1.4)	0/1 (0.0)	0/2 (0.0)
Types of chronic inducible urticaria
Cold urticaria	18/165 (10.9)	NA	7/154 (4.6)
Symptomatic dermographism	25/344 (7.3)	NA	25/344 (7.3)
Cholinergic urticaria	1,468/42,006 (3.5)	NA	3/124 (2.4)
Delayed pressure urticaria	4/126 (3.2)	NA	2/124 (1.6)
Heat urticaria	3/154 (2.0)	NA	2/153 (1.3)
Solar urticaria	2/125 (1.6)	NA	1/124 (0.8)
Aquagenic urticaria	1/153 (0.7)	NA	1/153 (0.7)
Comorbidity^b,c
Gastrointestinal diseases	708,417/985,284 (71.9)	1/5 (20.0)	NA
Coronary and other vascular diseases
Cardiac/cerebral vascular diseases	72/196 (36.7)	52/169 (30.8)	19/26 (73.1)
Atrial fibrillation	1/5 (20.0)	1/5 (20.0)	NA
Metabolic diseases
Dyslipidemia	3/7 (42.9)	2/6 (33.3)	1/1 (100.0)
Hypertension	183,473/986,035 (18.6)	103/264 (39.0)	20/27 (74.1)
Obesity	5/30 (16.7)	0/4 (0.0)	5/26 (19.2)
Diabetes Mellitus	34/271 (12.6)	34/271 (12.6)	NA
Unspecified metabolic syndrome	21/67 (31.3)	21/67 (31.3)	NA
Musculoskeletal diseases
Osteoporosis	3/7 (42.9)	3/7 (42.9)	NA
Gout	1/5 (20.0)	0/4 (0.0)	NA
Avascular hip necrosis	1/5 (20.0)	1/5 (20.0)	NA
Thyroid diseases
Hyperthyroidism	1/1 (100.0)	NA	NA
Hypothyroidism	5/9 (55.6)	1/5 (20.0)	NA
Grave’s disease	4/9 (44.4)	2/6 (33.3)	NA
Hashimoto’s thyroid diseases	22/106 (20.8)	21/105 (20.0)	NA
Parathyroid adenoma	1/5 (20.0)	1/5 (20.0)	NA
Unspecified thyroid diseases	28/142 (19.7)	24/116 (20.7)	4/26 (15.4)
Systemic diseases
Raynaud phenomena	2/6 (33.3)	0/4 (0.0)	NA
Systemic lupus erythematosus	1/5 (20.0)	1/5 (20.0)	NA
Anemia	1/5 (20.0)	0/4 (0.0)	NA
Unspecified autoimmune diseases	8/70 (11.4)	8/69 (11.6)	0/1 (0.0)
High myopia	1/5 (20.0)	0/4 (0.0)	NA
Genitourinary disorders
Benign prostate hyperplasia	3/30 (10.0)	3/30 (10.0)	3/26 (11.5)
Chronic kidney diseases	6/96 (6.3)	6/96 (6.3)	NA
Chronic obstructive pulmonary diseases	2/31 (6.5)	1/5 (20.0)	1/26 (3.8)
Psychiatric problems
Dementia	4/67 (6.0)	4/67 (6.0)	NA
Unspecified psychiatric problems	5/130 (3.9)	2/103 (1.9)	2/26 (7.7)
Dermatologic diseases
Psoriasis	4/96 (4.2)	4/96 (4.2)	NA
Contact dermatitis	3/96 (3.1)	3/96 (3.1)	NA
Malignancy
Gastrointestinal cancer	6/10 (60.0)	0/4 (0.0)	NA
Genitourinary cancer	2/6 (33.3)	0/4 (0.0)	NA
Bronchioalveolar cancer	2/6 (33.3)	0/4 (0.0)	NA
Thyroid cancer	2/6 (33.3)	2/6 (33.3)	NA
Malignant melanoma	1/5 (20.0)	0/4 (0.0)	NA
Hematologic malignancy	35/3,625 (1.0)	0/8 (0.0)	NA
Unspecified malignancy	459/3,714 (12.4)	11/99 (11.1)	NA
Possible causes of urticaria
Stress	27/99 (27.3)	27/99 (27.3)	NA
Aspirin intolerance	8/42 (2.0)	1/5 (20.0)	0/4 (0.0)
Parasitic infection	6/129 (4.7)	0/4 (0.0)	NA
Collagen vascular disease	4/124 (3.2)	NA	NA
Insect bite	3/126 (2.4)	1/1 (100.0)	1/27 (3.7)
Paronychia	1/1 (100.0)	NA	NA
Unspecified drug allergy	12/132 (9.1)	1/8 (12.5)	NA
Unspecified food allergy	1/33 (3.0)	0/7 (0.0)	1/26 (3.9)
Laboratory investigations
Positive ASST	125/263 (47.5)	107/195 (54.9)	1/3 (33.3)
Positive SPT	1/9 (11.1)	0/4 (0.0)	1/1 (100.0)
Positive Basophil histamine release test	5/13 (38.5)	4/9 (44.4)	NA
Leukocytosis	4/82 (4.9)	4/70 (5.7)	0/1 (0.0)
Positive HBsAg	8/75 (10.7)	8/68 (11.8)	0/1 (0.0)
Positive anti-HCV	0/70 (0.0)	0/68 (0.0)	0/2 (0.0)
Total serum IgE
Elevated IgE	8/19 (42.1)	7/16 (43.8)	1/1 (100.0)
IgE level, mean±SD, kU/L
ImmunoCAP method (normal range 0–119 kU/L) ^d	477.3±288.8	477.3±288.8	NA
Pharmacia CAP System IgE FEIA method^e (normal range 0–100 kU/L)	164.9±210.4	194.5±269.7	NA
Nephelometry method^f (normal range 0–100 kU/L)	125	125	NA
Elevated erythrocyte sedimentation rate	22/82 (26.8)	18/71 (25.4)	0/1 (0.0)
Elevated D-dimer	2/4 (50.0)	NA	NA
Elevated prothrombin fragment	3/4 (75.0)	NA	NA
Abnormal C3	0/18 (0.0)	0/7 (0.0)	0/1 (0.0)
Abnormal C4	2/18 (11.1)	0/7 (0.0)	0/1 (0.0)
Abnormal CH50	1/11 (0.0)	0/5 (0.0)	NA
Abnormal C1-INH	0/13 (0.0)	0/7 (0.0)	NA
Positive antinuclear antibodies	13/81 (16.0)	13/69 (18.8)	0/2 (0.0)
Positive anticentromere antibodies	2/2 (100.0)	NA	NA
Positive Anti-FcεRI antibodies	2/3 (66.7)	2/3 (66.7)	NA
Abnormal free T3	0/22 (0.0)	0/9 (0.0)	0/1 (0.0)
Abnormal free T4	4/31 (12.9)	3/20 (15.0)	0/1 (0.0)
Abnormal TSH	6/33 (18.2)	3/19 (15.8)	0/2 (0.0)
Positive antithyroid peroxidase antibodies	40/150 (26.7)	25/110 (22.7)	1/2 (50.0)
Positive antithyroglobulin antibodies	42/124 (33.9)	31/86 (36.1)	0/1 (0.0)
Abnormal urinalysis	10/64 (15.6)	10/63 (15.9)	NA
Abnormal stool examination	6/85 (7.1)	4/77 (5.2)	NA

Notes: ^aIt should be noted that the CU group included all CU patients aged above 60 years. Studies that reported specifically for CSU or CIndU subtypes were also included in the subgroups of CSU and CIndU. ^bOne patient could have more than one personal history of atopy or one comorbidity. Comorbidity and history of atopy were only showed information from papers which mentioned about each disease. ^cIt should be noted that the studies of Urbach, Lindelof et al, and Chen et al reported only the number of patients with malignancy, other comorbidities were not identified. ^dTotal IgE level measured by ImmunoCAP method were reported in three studies, Ban et al (n=37), Romano et al (n=1), and Nettis et al (n=32), which reported about CU, CSU, and CSU, respectively. Referring to the National Center for Health Statistics, Centers for Disease Control and Prevention, the normal range of total IgE based on ImmunoCAP method is 0–119 kU/L. ^eTotal IgE level measured by Pharmacia CAP method was reported in only one study, Staubach et al (n=4), which reported about CSU. ^fTotal IgE level measured by Nephelometry method was reported in only one study, Kulthanan et al (n=1), which reported about CSU.

Abbreviations: Anti-FcεRI, anti-FcepsilonRI; ASST, autologous serum skin test; C3, complement C3; C4, complement C4; CH50, total hemolytic complement; C1-INH, complement 1 esterase inhibitor; CIndU, chronic inducible urticaria; CSU, chronic spontaneous urticaria; CU, chronic urticaria; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; Ig, immunoglobulin; NA, not available/not applicable; SD, standard deviation; SPT, skin prick test; TSH, thyroid stimulating hormone.

Table 4 The Reported Treatment for and Clinical Course of Chronic Urticaria in the Elderly

Study (year)	N = Elderly CU/ Total	Treatment									Duration of treatment	Treatment response	Follow-up after treatment and outcome	Side-effects after treatment
		AH1			Corticosteroids		LTRA	Omalizumab	Immunosuppressant	Others
		fgAH1	sgAH1	Unspecified AH1	Systemic	Topical
Prospective Cohort Studies
Leznoff et al (1983)^Citation67	N = 1 of 17	NA	NA	NA	NA	NA	NA	NA	NA	- Levothyroxine (dose: 0.2 mg/d) for euthyroid patient who had autoimmune thyroiditis	NA	Partial improvement	NA	NA
Rumbyrt et al (1995)^Citation88	N = 1 of 7	NA	NA	NA	Previous use of - Prednisolone (dose: NA) with no improvement	NA	NA	NA	NA	Previous use of - Famotidine (dose: NA) with no improvement - Doxepin (dose: NA) with no improvement -Thyroxine (0.05 mg/d) for euthyroid patient who had autoimmune thyroiditis	At least 4 weeks	Complete control then discontinued thyroxine	Longer than 1 year of rare hive, with use of Hydroxyzine (dose: NA, as needed)	NA
O’Donnell et al (1998)^Citation54	N = 1 of 10	NA	- Cetirizine (dose: 10 mg twice daily)	Previous use of 0 (dose: NA) with no improvement	NA	NA	NA	NA	No	- IVIG (dose: 0.4 g/kg/d for 5 days)	5 days	Partial improvement	6 months	Headache
Sanada et al (2005)^Citation242	N = 5 of 25	NA	Previous use of - Ebastine (dose: 20 mg/d) with no improvement - Ebastine (dose: 20 mg/d)	NA	NA	NA	- All cases: Montelukast (dose: 10 mg/d)	NA	NA	NA	NA	Complete control	NA	NA
		NA	Previous use of - Ebastine (dose: 20 mg/d) with no improvement - Ebastine (dose: 20 mg/d)		Previous use of - Betamethasone (dose: 0.5 mg/d orally) with no improvement							Marked improvement
		Previous use of - Hydroxyzine (dose: 50 mg/d) with no improvement	Previous use of - Homochlorcyclizine (dose: 30 mg/d) with no improvement - Homochlorcyclizine (dose: 30 mg/d)		NA							No improvement
		NA	Previous use of - Olopatadine (dose: 20 mg/d) with no improvement - Olopatadine (dose: 20 mg/d)		Previous use of - Betamethasone (dose: 0.5 mg/d orally) with no improvement							No improvement
		NA	Previous use of - Loratadine (dose: 10 mg/d) - Ebastine (dose: 10 mg/d) with no improvement - Loratadine (dose: 10 mg/d) - Ebastine (dose: 10 mg/d)		NA							No improvement
Kaplan et al ^a (2008)^Citation50	N = 2 of 12	- Hydroxyzine (dose: 25–50 mg every 6 hours as needed, total 100–175 mg/d)	NA	NA	NA	NA	NA	- All cases: Omalizumab 150 mg sc every 2 weeks or every 4 weeks	No	NA	4 months	No improvement	NA	NA
		- Hydroxyzine (dose: 25–50 mg every 6 hours as needed, total 175 mg/d in the first 4 week then tapered dose until stop at week 8)										Complete control
Uysal et al (2014)^Citation61	N = 3 of 27	NA	All cases: - Desloratadine or fexofenadine; (dose: recommended dose for 3–4 times)	NA	NA	NA	NA	- Omalizumab 150 mg sc every 2 weeks then extend to 5 weeks	Previous use of - MTX (dose: NA) with no improvement	NA	112 days	Complete control then discontinued omalizumab	NA	NA
								- Omalizumab 150 mg sc every 2 weeks then extend to 7 weeks	Previous use of - AZA (dose: NA) with no improvement		78 days
								- Omalizumab 150 mg sc every 2 weeks then extend to 7 weeks	Previous use of - AZA (dose: NA) with no improvement		62 days
Retrospective cohort studies
McGirt et al (2006)^Citation94	N = 2 of 19	Previous use of - Hydroxyzine (dose: maximum 25 mg nightly) with no improvement	Previous use of - Cetirizine (dose: maximum 10 mg/d) with no improvement	NA	Previous use of - Prednisolone (dose: 10 mg/d for 3 days; 2–3 times) with no improvement - Prednisolone (dose: 10 mg/d once for 5 months)	NA	NA	NA	NA	- Sulfasalazine (dose: start at 500 mg/d then increased by 500 mg each week until 2 g/d) for total 12 months	12 months	Complete control then tapered off of sulfasalazine, sgAH1	3 months	NA
		NA	Previous use of - Cetirizine (dose: 10 mg/d) with no improvement		Previous use of - Prednisolone dose pack (dose: NA) for 5 courses with no improvement					- Sulfasalazine (dose: start at 500 mg/d then increased by 500 mg each week until 2 g/d) for total 11 months	11 months	Complete control then discontinued sulfasalazine	NA
Perez et al (2010)^Citation241	N = 1 of 16	NA	Previous use of - sgAH1 (unmentioned name, dose: above the recommended dose) with no improvement	NA	Previous use of - Prednisolone (dose: 20 mg/d) with no improvement	NA	NA	NA	Previous use of - CsA (dose: NA) with no improvement - MTX (dose: 5 mg weekly)	Previous use of 0 (unmentioned name, dose: NA) with no improvement - Folic acid (dose: 5 mg weekly)	NA	Marked improvement	NA	NA
Mitzel-Kaoukhov et al (2010)^Citation53	N = 2 of 6	NA	Previous use of - sgAH1 (unmentioned name, dose: 4-fold of the recommended dose) with no improvement	NA	NA	NA	All cases: previous use of - LTRA (unmentioned name, dose: NA) with no improvement	NA	All cases: previous use of - CsA (dose: NA) with no improvement	Previous use of - Histaglobin (dose: NA) with no improvement - IVIG (dose: 2 mg/kg every 4 weeks) for 11 cycles	10 months	Complete control then discontinued	14 months	No
			Previous use of - sgAH1 (unmentioned name, dose: 8-fold of the recommended dose) with no improvement		Previous use of - Systemic corticosteroid (unmentioned name, dose: high dose) with no improvement				NA	Previous use of - Dapsone (dose: NA) with no improvement - IVIG (dose: 2 mg/kg every 4 weeks) for 4 cycles then remission but 4 months later	11 months	Complete control then discontinued	2 months then relapse occurred so IVIG was reinitiated for other 5 cycles	Impairment of pre-existing HT, disappeared after extending the treatment period of IVIG from 2 to 3 days
Sagi et al (2011)^Citation83	N = 5 of 8	All cases: previous use of - fgAH1 (unmentioned name, high dose) with no improvement	All cases: previous use of - sgAH1 (unmentioned name, high dose) with no improvement	NA	Previous use of - Systemic corticosteroid (unmentioned name, dose: NA) with no improvement - Systemic corticosteroid (dose: 30–40 mg/d) for multiple courses then tapered down (dose: NA) - Systemic corticosteroid (dose: 30–40 mg/d) for multiple courses then tapered down (dose: NA) - Systemic corticosteroid (dose: 30–40 mg/d) for multiple courses then tapered down until off	NA	NA	NA	- MTX (dose: 15 mg weekly) for 1 month then tapering down to 10 and 5 mg oral weekly for 1 and 1 month, respectively)	- Folic acid (dose: 5 mg weekly)	3 months	Complete control then discontinued MTX and folic acid	8 months	No
									- MTX (dose: 15 mg weekly) for 3 months then currently in the process of tapering down to 10 mg oral weekly for 2 months, without recurrence of urticaria)		5 months	Complete control (still in the MTX tapering process)	NA	Elevated liver enzyme (Twice the normal values) – resolved after reducing MTX dosage
									- MTX (dose: 15 mg oral weekly) for 3 months		3 months	Complete control then discontinued MTX and folic acid	2 months	No
									- MTX (dose: 7.5 mg oral weekly) for 2 months		2 months	No improvement then discontinued MTX and folic acid due to poor compliance	2 months	Fatigue
									- MTX (dose: 15 mg oral weekly) for 1 month then change to 15 mg IM weekly for 4 months		5 months	Complete control then tapering MTX down but relapse occurred and required a constant dose of MTX 15 mg/week	NA	Gastrointestinal discomfort – resolved after changing to MTX IM route
Magen et al (2013)^Citation20	N = 49 of 92	- fgAH1 (unmentioned name; dose: NA) in 8 of 46 patients	- sgAH1 (unmentioned name; dose: NA) in 49 of 49 patients	NA	- Systemic corticosteroid (unmentioned name, dose: NA) in 2 of 49 patients	NA	NA	NA	NA	NA	12 months	Complete control in 34 of 46 patients	NA	NA
Magen et al (2013)^Citation63	N = 1 of 9	NA	NA	NA	NA	NA	NA	NA	NA	- Amoxicillin (dose: 2 g/d) - Clarithromycin (dose: 1 g/d) - Omeprazole (dose: 40 mg/d) for treatment of H. pylori infection	2 weeks	Complete control then discontinued H. pylori infection treatment	NA	NA
Song et al (2013)^Citation55	N = 4 of 16	NA	All cases: previous use of - Cetirizine (dose: 60–80 mg/d) with no improvement	NA	Previous use of - Prednisolone (dose: 15 mg/d) for 10 courses with no improvement - Prednisolone (dose: NA) for short courses Previous use of - Prednisolone (dose: 10 mg/d) for >20 courses with no improvement - Prednisolone (dose: NA) Previous use of - Prednisolone (dose: 5–20 mg/d) for >20 courses with no improvement - Prednisolone (dose: NA) tapered dose then off shortly after start omalizumab Previous use of - Prednisolone (dose: 5–10 mg/d) for >20 courses with no improvement - Prednisolone (dose: NA) tapered dose then off shortly after start omalizumab	NA	NA	All cases: - Omalizumab 150 mg sc every 4 weeks	NA	NA	24 months	Complete control and continued with omalizumab 150 mg sc every 4–8 weeks	NA	No
											2 months	No improvement then discontinued omalizumab and went into spontaneous remission then discontinued prednisolone		Flare of urticaria after first dose of omalizumab injection
											2 months	No improvement then discontinued omalizumab		No
											24 months	Complete control and continued with omalizumab 150 mg sc every 4–8 weeks		No
Romano et al (2015)^Citation62	N= 1 of 9	Previous use of - Cinnarizine (dose: NA) with no improvement	NA	Previous use of -AH1 (unmentioned name, dose: NA) with no improvement	Previous use of - Systemic steroid (unmentioned name, dose: NA) with no improvement	NA	Previous use of - LTRA (unmentioned name, dose: NA) with no improvement	- Omalizumab 150 mg sc every 4 weeks	Previous use of - CsA (dose: NA) with no improvement	NA	5 months	No improvement then discontinued omalizumab	42 months	Pain at injected site
Sugiyama et al (2015)^Citation73	N = 2 of 40	NA	Previous use of - Olopatadine (dose: 5 mg/d) with partial improvement - Olopatadine (dose: 5 mg/d) NA	NA	NA	NA	NA	NA	NA	All cases: - Triiodothyronine (dose: 25 g/d) for Hashimoto’s disease	3 months	Complete control then discontinued triiodothyronine	>10 months of complete control then recurrence occurred after triggered by upper respiratory tract infection; symptom was well-controlled with olopatadine 2.5 mg/d	NA
													NA
Kulthanan et al (2017)^Citation57	N = 1 of 13	NA	Previous use of - Desloratadine (dose: 20 mg/d) - Levocetirizine (10 mg/d) with no improvement - Desloratadine (dose: 5–10 mg/d)	NA	Previous use of - Prednisolone (5–10 mg/d) with no improvement	NA	Previous use of - Montelukast (dose: NA) with no improvement	- Omalizumab 150 mg sc every 4 weeks	Previous use of - CsA (dose: NA) - HCQ (dose: NA) with no improvement	Previous use of 0 (unmentioned name, dose: NA) with no improvement	4 months	Complete control then discontinued omalizumab	NA	No
Napolitano et al (2018)^Citation93	N = 1 of 1,493	NA	NA	Previous use of 0 (dose: 4 times of licensed dose) with no improvement	Previous use of - Prednisolone (dose: NA) with partial improvement	NA	NA	NA	NA	- Chemotherapy for small cell lung cancer	NA	Complete control	NA	NA
Napolitano et al (2021)^Citation45	N = 26 of 451	NA	- sgAH1 (unmentioned name, recommended dose) in 23 of 26 patients - sgAH1 (unmentioned name, double dose) in 3 of 26 patients with SD	NA	NA	NA	NA	NA	NA	NA	NA	Complete control in 26 of 26 patients	NA	No
Martina et al (2021)^Citation90	N = 62 of 62	NA	NA	NA	NA	NA	NA	- Omalizumab 300 mg sc every 4 weeks	NA	NA	3 months	- Complete control in 44 of 62 patients - Partial improvement in 11 of 62 patients - No improvement in 7 of 62 patients	NA	asthenia; spontaneously resolved within 48 hours (2 patients)
Case Series
Manganoni et al (2007)^Citation89	N = 1 of 4	Previous use of - Oxatomide (dose: 60 mg/d) with no improvement	NA	NA	Previous use of - Betamethasone (dose: 2 mg/d orally) with no improvement	NA	NA	NA	NA	- Surgery: total thyroidectomy for papillary thyroid carcinoma	NA	Complete control	60 months	NA
Godse (2011)^Citation48	N = 1 of 5	NA	Previous use of - sgAH1 (unmentioned name, dose: 4 times of recommended dose) with no improvement	NA	Previous use of - Systemic corticosteroid (dose: NA) with no improvement	NA	NA	- Omalizumab 300 mg sc every 4 weeks	NA	NA	4 months	Complete control then discontinued omalizumab	NA	NA
Groffik et al (2011)^Citation49	N = 1 of 9	NA	Previous use of - sgAH1 (unmentioned name, dose: 4 times of recommended dose) with no improvement	NA	Previous use of - Systemic corticosteroid (dose: NA) for long-term with no improvement	NA	NA	- Omalizumab 300 mg sc every 2 weeks	NA	NA	2 months	Complete control then discontinued omalizumab	NA	NA
Metz et al (2011)^Citation52	N = 1 of 7	NA	Previous use of - Loratadine (recommended dose) - Cetirizine (recommended dose) - Desloratadine (2–6 fold of recommended dose) - Ebastine (recommended dose) - Rupatadine (2–6 fold of recommended dose) - Levocetirizine (recommended dose) with no improvement	NA	NA	NA	Previous use of - Montelukast (dose: NA)	- Omalizumab 300 mg sc every 2 weeks	NA	Previous use of - Ranitidine (dose: NA) - Antibiotics (unmentioned name, dose: NA) with no improvement	3 months	No improvement then discontinued omalizumab	NA	NA
Kirkpatrick et al (2012)^Citation51	N = 1 of 6	NA	NA	Previous use of 0 (dose: NA) with no improvement	Previous use of - Systemic corticosteroid (unmentioned name, dose: NA) with no improvement	NA	NA	NA	No	- Levothyroxine (dose: 150 g/d) for hypothyroidism due to post I^131 for Grave’s disease	1 month	Complete control, then continue levothyroxine same dose	24 months. After that, levothyroxine was tapered to 125 g/d but relapsed occurred within 3 weeks, so dose was increased to 150 g/d again; complete control	NA
Ivyanskiy et al (2012)^Citation76	N = 3 of 19	NA	NA	All cases: previous use of 0 (dose: NA) with no improvement	NA	NA	NA	All cases: - Omalizumab 150 mg sc every 2 weeks	No Previous use of - CsA (dose: NA) with no improvement Previous use of - CsA (dose: NA) - AZA (dose: NA) - MMF (dose: NA) with no improvement in all treatment	No Previous use of - TNF-α inhibitor (dose: NA) with no improvement Previous use of - TNF-α inhibitor (dose: NA) with no improvement	6 months	Complete control then discontinued omalizumab	NA	No
											9 months	Complete control then discontinued omalizumab
											4 months	Partial improvement then discontinued omalizumab
Armengot-Carbo et al (2013)^Citation81	N = 5 of 15	NA	NA	Previous use of 0 (dose: NA) with no improvement	Previous use of - Systemic corticosteroid (unmentioned name, dose: NA) with no improvement NA Previous use of - Systemic corticosteroid (unmentioned name, dose: NA) with no improvement NA Previous use of - Systemic corticosteroid (unmentioned name, dose: NA) with no improvement	NA	NA	- Omalizumab 150 mg sc every 4 weeks for 3 months then 300 mg sc every 4 weeks for other 3 months	Previous use of - CsA (dose: NA) with no improvement	Previous use of -AH2 (unmentioned name, dose: NA) with no improvement Previous use of -AH2 (unmentioned name, dose: NA) with no improvement Previous use of -AH2 (unmentioned name, dose: NA) with no improvement NA Previous use of -AH2 (unmentioned name, dose: NA) with no improvement	6 months	Partial improvement	NA	Nausea
								- Omalizumab 150 mg sc every 4 weeks for 3 months			3 months	No improvement then discontinued omalizumab		Nausea
								- Omalizumab 150 mg sc every 2 weeks for 3 months then 150 mg sc every 4 weeks for other 3 months			6 months	Complete control		No
								- Omalizumab 300 mg sc every 4 weeks for 6 months			6 months	Complete control		No
								- Omalizumab 150 mg sc every 4 weeks for 3 months			3 months	No improvement then discontinued omalizumab		No
Zubrinich et al (2019)^Citation92	N = 1 of 4	NA	NA	Previous use of - unspecified AH1 (dose: NA) with partial improvement	Previous use of - Prednisolone (dose: NA) with partial improvement	NA	NA	NA	NA	- Ivermectin (dose: NA) for treatment of Strongyloides infection	NA	Complete control	10 months	NA
Case reports
Urbach (1942)^Citation97	N = 1 of 1	NA	NA	NA	NA	NA	NA	NA	NA	- Surgery: neoplasm removal for rectal carcinoma	NA	Complete control	NA	NA
Anderson et al (1991)^Citation95	N = 1 of 1	Previous use of - Hydroxyzine (dose: NA) with no improvement	- Terfenadine (dose: NA)	NA	Previous use of - Systemic corticosteroid (unmentioned name, dose: NA) for short course with no improvement	Previous use of - Hydrocortisone cream (dose: NA) with no improvement	NA	NA	NA	- Surgery: neoplasm removal for colon carcinoma	NA	Complete control	60 months	NA
Amoroso et al (1997)^Citation69	N = 1 of 1	NA	NA	NA	Previous use of - Betamethasone (dose: 4 mg IV) - Betamethasone (dose: 0.5 mg/d orally) with no improvement	NA	NA	NA	NA	- Surgery: total thyroidectomy for Hashimoto’s thyroiditis	NA	Complete control	18 months	NA
Zhang et al (2004)^Citation79	N = 1 of 1	Previous use of - Chlorpheniramine (dose: 12 mg/d) with no improvement	NA	NA	- Prednisolone (dose: 10 mg/d) for 3 months and 1 week	NA	NA	NA	- Melphalan (dose: 2 mg) for 1 week followed by - Cyclophosphamide (dose: 50 mg/d) for 3 months for IgA Myeloma	NA	3.25 months	Complete control then discontinued prednisolone, melphalan, and cyclophosphamide	NA, symptom relapsed when myeloma relapsed	NA
Wong et al (2010)^Citation56	N = 1 of 1	Previous use of - Diphenhydramine (dose: 50 mg once) with complete control	- Cetirizine (dose: 10 mg/d) for prophylaxis	NA	NA	NA	NA	NA	NA	- Epinephrine auto-injector (dose: NA)	24 months	Marked improvement but 2 months later she acquired another hymenoptera sting, and within 2 weeks developed systemic urticaria when exposing to cold temperature	NA	NA
Baroni et al (2012)^Citation85	N = 1 of 1	NA	NA	Previous use of 0 (dose: NA) with no improvement	Previous use of - Systemic corticosteroid (unmentioned name, dose: NA) with no improvement	Previous use of - Topical corticosteroid (unmentioned name, dose: NA) with no improvement	NA	NA	NA	- Surgery: radical prostatectomy for prostate adenocarcinoma	NA	Complete control	24 months	NA
Hui-Hui et al (2012)^Citation84	N = 1 of 1	NA	Previous use of - Loratadine (dose: NA, taken once every other day) for 4 months with partial improvement	NA	NA	NA	NA	NA	NA	- Surgery: right middle lobectomy for lung cancer removal	NA	Complete control	6 months	NA
Zimmer et al (2016)^Citation82	N = 1 of 1	NA	NA	Previous use of -AH1 (unmentioned name, dose: up to 4 times of licensed dose) with no improvement	NA	NA	NA	- Omalizumab 300 mg sc every 4 weeks	NA	NA	4 months	Marked improvement then discontinued omalizumab	5 months, then relapse occurred	No
Sussman et al (2016)^Citation60	N = 1 of 1	Previous use of - Hydroxyzine (dose: 25–200 mg/d) - Diphen-hydramine (dose: 25–200 mg/d) - Doxepin (dose: 25–125 mg/d) with no improvement in all treatment but caused sedation	Previous use of - Cetirizine (dose: 10–40 mg/d) - Loratadine (dose: 10 mg/d) with no improvement in all treatment - Cetirizine (dose: 20 mg/d)	Previous use of 0 (dose: NA dosage as needed) with no improvement	Previous use of - Prednisolone (dose: 5–40 mg/d) with no improvement - Prednisolone (dose: tapering doses from before study until discontinued)	NA	Previous use of - Montelukast (dose: 10 mg/d) with no improvement	- Omalizumab 150 mg sc every 4 weeks	Previous use of - HCQ (dose: 400 mg/d) for 2 months - CsA (dose: 300 mg/d) for 2 months with no improvement in all treatment	Previous use of - Ranitidine (dose: 300 mg/d) with no improvement - IVIG (dose: NA, discontinued due to hemolytic reaction) Both with partial improvement	36 months	Marked improvement after 1 week then continued same dose of omalizumab but stopped taking prednisolone, resulting in low daily UAS7 scores. After 36 months, symptoms became severe, required longer courses and doses of prednisolone. Moreover, omalizumab was increased to 300 mg sc every 4 weeks to maintain low UAS7.	NA	NA
Kasperska-Zajac et al (2016)^Citation91	N = 1 of 1	NA	NA	Previous use of 0 (high dose) with no improvement	Previous use of - Prednisolone (dose: up to 15 mg) for the past 3–10 years with no improvement	NA	NA	- Omalizumab 300 mg sc	NA	NA	NA	Complete control after 1 dose of omalizumab then continued with omalizumab 150–300 mg every 5–6 weeks	NA	No
Aldasouqi et al (2018)^Citation96	N = 1 of 1	NA	NA	NA	NA	NA	NA	NA	NA	- Surgery: parathyroidectomy for primary hyperparathyroidism caused by large parathyroid adenoma	NA	Complete control	NA	NA
Pannofino (2018)^Citation58	N = 1 of 1	NA	- Rupatadine (dose: 10 mg twice daily) for 20 days then continue with 10 mg/d for 6 months then discontinued	Previous use of - unspecified AH1 (dose: NA) with no improvement	Previous use of - Oral corticosteroid (unmentioned name, dose: NA) with no improvement	NA	NA	- Omalizumab 300 mg sc every 4 weeks	NA	NA	6 months	Complete control then discontinued omalizumab	12 months	NA

Notes: ^aIt should be noted that the study of Kaplan et al included 12 CU patients (with 2 elderly patients) to be received placebo for 4 weeks and then omalizumab for 16 weeks. Omalizumab was injected every 2 weeks or every 4 weeks, dosed according to the patient’s body weight, and serum IgE at the screening visit.

Abbreviations: AH1, H1-antihistamine; AH2, H2-antihistamine; AZA, azathioprine; CsA, cyclosporine; d, day; fgAH1, first generation antihistamine; HCQ, hydroxychloroquine; IM, intramuscular; IV, intravenous; IVIG, intravenous immunoglobulin; LTRA, Leukotriene-receptor antagonist; mg, milligram; MMF, mycophenolate mofetil; MTX, methotrexate; NA, not available/not applicable; sc, subcutaneous; SD, symptomatic dermographism; sgAH1, second generation antihistamine; TNF-α inhibitor, tumor necrosis factor-α inhibitors; UAS7, Weekly Urticarial Activity Score.

Figure 2 Treatments and responses to treatment among elderly with chronic urticaria.

Notes: Some patients received more than one type of treatment.

Abbreviations: AH₁,H_1-antihistamine; fgAH₁, first generation H₁-antihistamine; IVIG, intravenous immunoglobulin; LTRA, leukotriene receptor antagonist; MTX, methotrexate; NA, not available/not applicable; sgAH₁, second generation H₁-antihistamine.

Table 5 Comparison of the Reported Demographic and Clinical Characteristics of Elderly Patients with Chronic Urticaria (CU) with Those of Non-Elderly

Clinical features: N/Total (%)	Elderly (our systematic review)	Non-elderly
Demographic Data
Prevalence of CU in population	22,900/9,757,210 (0.2) – 13,476/488,145 (2.8)^Citation29,Citation33,Citation35,Citation46	6019/7,555,991 (0.1) – 90/2613 (3.4)^Citation9,Citation19,Citation29,Citation30,Citation33,Citation98,Citation134–140
CSU proportion in CU	127/153 (83.0) – 63/65 (96.9)^Citation10,Citation20,Citation45	145/220 (66.0) – 215/231 (93.1)^Citation26,Citation34,Citation74,Citation108–111,Citation141–146
CIndU proportion in CU	2/65 (3.1) – 26/153 (17.0)^Citation10,Citation20,Citation32,Citation45	17/329 (5.2) – 75/220 (34.0)^Citation26,Citation74,Citation108–111,Citation141–146
Sex ratio (Male: Female)	1: 0.9–3.3^Citation10–12,Citation20–25,Citation30–33,Citation37,Citation39,Citation40,Citation45,Citation90	1: 1.0–5.7^Citation10,Citation12,Citation19,Citation28–30,Citation33,Citation34,Citation36–38,Citation40,Citation41,Citation74,Citation100,Citation109,Citation114,Citation130,Citation131,Citation134,Citation136,Citation139,Citation142–144,Citation147–163
Clinical presentation
Wheal alone	10/30 (33.3) – 86/99 (86.9)^Citation10,Citation12,Citation20,Citation37,Citation40,Citation90	96/330 (29.1) – 77/102 (75.5)^Citation12,Citation20,Citation40,Citation107,Citation109,Citation136,Citation141,Citation143,Citation147,Citation149,Citation163–168
Wheal with angioedema	13/99 (13.1) – 20/30 (66.7)^Citation10,Citation12,Citation20,Citation37,Citation40,Citation90	17/248 (6.9) – 152/199 (76.4)^Citation12,Citation28,Citation36–40,Citation74,Citation109,Citation111,Citation120,Citation136,Citation141,Citation143,Citation147,Citation149,Citation158,Citation159,Citation163,Citation165–173
Wheal with anaphylaxis ^a	1/1 (100.0)^Citation56	0/2,175 (0.0)^Citation28,Citation174,Citation175
Personal history of atopy	2/92 (2.2) – 9/26 (34.6)^Citation10,Citation11,Citation20,Citation37,Citation45,Citation64,Citation90	171/13,479 (1.3) −101/147(68.7)^Citation11,Citation12,Citation28,Citation34–38,Citation74,Citation100,Citation106,Citation114,Citation147,Citation159,Citation160,Citation163,Citation176–179
Comorbidities
Gastrointestinal diseases	5/104 (4.8) – 708,415/985,278 (71.9)^Citation20,Citation64	127/12,185 (1.0) – 145/330 (44.0)^Citation12,Citation28,Citation100,Citation111,Citation131,Citation178,Citation180–182
Metabolic syndrome	21/63 (33.3) – 44/92 (47.8)^Citation20,Citation90	276/12/185 (2.3) – 1,741/11,261 (15.5)^Citation100,Citation114,Citation116
Thyroid diseases	1/67 (1.5) – 19/99 (19.2)^Citation10,Citation20,Citation37,Citation45	34/13,479 (0.3) – 20/47 (42.5)^Citation12,Citation28,Citation30,Citation35–37,Citation67,Citation70,Citation100,Citation153,Citation159,Citation165,Citation170–172,Citation178,Citation183,Citation184
Autoimmune diseases	8/63 (12.7)^Citation90	40/12,185 (0.3) –25/209 (12.0)^Citation30,Citation100,Citation153,Citation159,Citation170,Citation172
Psychiatric problems
Anxiety disorders	NA	266/13,479 (2.0) – 24/30 (80.0)^Citation35,Citation139,Citation185–189
Depression & other psychiatric problems	2/99 (2.0) – 2/26 (7.7)^Citation37,Citation45,Citation65	121/12,185 (1.0) – 21/30 (70.0)^Citation12,Citation30,Citation36,Citation37,Citation100,Citation139,Citation148,Citation154,Citation159,Citation185–187,Citation189–192
Malignancies
Hematologic malignancy ^b	33/3,615 (0.9)^Citation19	80/36,910 (0.2) – 25/9,105 (0.3)^Citation18,Citation19
Other	415/3,615 (11.5) – 11/92 (12.0)^Citation19,Citation20	231/9,105 (0.3) – 330/13,479 (2.5)^Citation18,Citation19,Citation35,Citation148
Most common subtype of CIndU	Symptomatic dermographism^Citation10,Citation20,Citation45	Symptomatic dermographism^Citation10,Citation36,Citation37,Citation74,Citation108,Citation111,Citation193–195
Laboratory investigations
Positive antinuclear antibodies	13/63 (20.6) of CSU^Citation10	248/12,778 (1.9) – 131/195 (67.2) of CSU^Citation10,Citation120,Citation155,Citation158,Citation160,Citation196,Citation197
Elevated erythrocyte sedimentation rate	18/63 (28.6)^Citation10	3/184 (1.6) – 65/133 (48.9)^Citation10,Citation74,Citation155,Citation160,Citation165,Citation172,Citation178,Citation198
Elevated total serum IgE ^c	NA	14/330 (4.2) – 34/62 (54.8)^Citation12,Citation28,Citation36,Citation74,Citation165,Citation199–201
Positive ASST	11/61 (18.0) – 3/5 (60.0) of CSU^Citation20,Citation37,Citation40,Citation42	12/45 (26.7) – 49/67 (73.1) of CSU^Citation10,Citation28,Citation36,Citation37,Citation40,Citation74,Citation108,Citation111,Citation130,Citation142,Citation150,Citation155,Citation156,Citation160,Citation168,Citation196,Citation202–211
Abnormal thyroid function test ^c	NA	20/330 (6.1) – 20/66 (30.3)^Citation12,Citation38,Citation67,Citation70,Citation78,Citation198,Citation212,Citation213
Abnormal free T3 ^c	NA	1/56 (1.8) – 99/165 (60.0)^Citation74,Citation214
Abnormal free T4 ^c	NA	97/165 (58.8)^Citation74
Abnormal TSH ^c	NA	2/56 (3.6) – 99/167 (59.3)^Citation74,Citation165,Citation171,Citation183,Citation214,Citation215
Positive thyroid autoantibodies	3/24 (12.5) – 21/63 (33.3)^Citation10,Citation11,Citation40	3/79 (3.8) – 27/47 (57.5)^Citation10,Citation11,Citation36,Citation40,Citation67,Citation70,Citation71,Citation73,Citation74,Citation106,Citation109,Citation120,Citation130,Citation153,Citation155–157,Citation160,Citation161,Citation163,Citation165,Citation168,Citation170–173,Citation183,Citation184,Citation196,Citation198,Citation199,Citation201–203,Citation207,Citation209–237
Positive HBsAg	8/63 (12.7)^Citation10	0/121 (0.0) – 2/56 (3.6)^Citation10,Citation28,Citation111,Citation128,Citation129,Citation192,Citation238
Duration of disease prior to diagnosis (years)	0.2–2.0^Citation39,Citation60,Citation67,Citation69,Citation79,Citation85,Citation87	3.2–6.3^Citation87,Citation172
Treatment
Response to 1^st line (standard dose AH1)	17.045/99 (45.5) – 23/26 (88.5)^Citation37,Citation38,Citation45	164/516 (31.8) – 163/248 (65.9)^Citation36–39,Citation160,Citation170
Needed 2^nd line	3/26 (11.5) – 24/96 (25.0)^Citation37,Citation45	36/335 (10.8) – 199/569 (34.9)^Citation36,Citation37,Citation170,Citation172
Needed 3^rd line	5/32 (15.6) – 28/95 (29.5)^Citation37,Citation40	36/361 (10.0) – 93/329 (28.3)^Citation36,Citation37,Citation40,Citation74,Citation108,Citation159,Citation172,Citation178

Notes: ^aWheal with anaphylaxis in elderly was found in only one case report of cold urticaria. ^bIt should be noted that the only retrospective study which reported malignancy in population was from Chen et al ^cProportion of elevated IgE, abnormal thyroid function test, free T3, free T4, and TSH in elderly patients were reported in only case reports and case series. No prospective or retrospective cohort study was found.

Abbreviations: ASST, autologous serum skin test; CIndU, chronic inducible urticaria; CSU, chronic spontaneous urticaria; CU, chronic urticaria; HBsAg, hepatitis B surface antigen; NA, not available/not applicable; TSH, thyroid stimulating hormone.

Table 6 Quality and Risk of Bias Assessment of Included Articles in Systematic Review

A. Randomized controlled trials
Study, year ^Ref	Random sequence generation (selection bias)					Allocation concealment				Blinding of participants and personnel				Blinding of outcome assessment					Incomplete outcome data			Selective reporting
Staubach et al, 2016^Citation239	+					+				+				+					+			+
Kaplan et al, 2005^Citation240	?					?				+				+					+			+
Goldsobel et al, 1986^Citation68	+					+				+				+					+			+
B. Non-randomized controlled trials
Study, year ^Ref	Criteria															Additional criteria in the case of comparative study
	A stated aim of the study	Inclusion of consecutive patients		Prospective collection of data			End point appropriate to the study aim	Unbiased evaluation of end points			Follow-up period appropriate	Loss to follow-up not exceeding 5%	Prospective calculation of the study size			A control group having the criterion standard intervention		Contemporary groups		Baseline equivalence of groups	Prospective calculation of the sample size		Statistical analyses adapted to the study design	Total
Martina et al, 2021^Citation90	2	2		2			2	0			2	0	0			-		-		-	-		-	10
Napolitano et al, 2021^Citation45	2	2		2			2	0			2	0	0			-		-		-	-		-	10
Gaber et al, 2020^Citation46	2	2		2			2	0			2	2	0			-		-		-	-		-	12
Chung et al, 2020^Citation74	2	2		2			2	0			2	0	0			-		-		-	-		-	10
Seo et al, 2019^Citation32	2	2		2			2	0			2	0	0			-		-		-	-		-	10
Zubrinich et al, 2019^Citation92	1	1		1			2	0			2	0	0			-		-		-	-		-	7
Wertenteil et al, 2019^Citation33	2	2		2			2	0			0	0	0			-		-		-	-		-	8
Jankowska-Konsur et al, 2019^Citation34	2	2		2			2	0			0	0	0			-		-		-	-		-	8
Jo et al, 2019^Citation39	2	2		2			2	0			2	0	0			-		-		-	-		-	10
Curto-Barredo et al, 2019^Citation37	2	2		2			2	0			2	0	0			-		-		-	-		-	10
Eun et al, 2018^Citation31	2	2		2			2	0			2	2	0			-		-		-	-		-	12
Nettis et al, 2018^Citation40	2	2		2			2	0			2	0	0			-		-		-	-		-	10
Napolitano et al, 2018^Citation93	2	2		2			2	0			2	0	0			-		-		-	-		-	10
Chanprapaph et al, 2018^Citation160	2	2		2			2	0			2	0	0			-		-		-	-		-	10
Curto-Barredo et al, 2018^Citation36	2	2		2			2	0			2	0	0			-		-		-	-		-	10
Pannofino, 2018^Citation58	2	0		2			1	0			2	0	0			-		-		-	-		-	7
Aldasouqi, 2018^Citation96	2	0		2			1	0			1	0	0			-		-		-	-		-	6
Kulthanan et al, 2017^Citation57	2	2		2			2	0			2	0	0			-		-		-	-		-	10
Lee et al, 2017^Citation64	2	2		2			2	0			2	0	0			-		-		-	-		-	10
Chu et al, 2017^Citation30	2	2		2			2	0			2	0	0			-		-		-	-		-	10
Ali, 2016^Citation152	2	2		2			2	0			2	2	0			0		2		2	0		2	20
Chuamanochan et al, 2016^Citation10	2	2		2			2	0			2	0	0			-		-		-	-		-	10
Kasperska-Zajac et al, 2016^Citation91	2	2		2			2	0			2	0	0			-		-		-	-		-	10
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Urbach, 1942^Citation97	1		0		0		1		0		0	0	0			-		-		-	-		-	2

Notes: +, low risk of bias; -, high risk of bias; ?, unclear risk of bias; 0, not reported; 1, reported but inadequate; 2, reported and adequate.

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