|Ahead of print publication
Evaluation of different therapies in indian patients with chronic urticaria: A systematic review of randomized controlled trials in the last decade
Anant D Patil1, Ganesh Bingewar2
1 Department of Pharmacology, Dr. DY Patil Medical College, Navi Mumbai, Maharashtra, India
2 Burjeel Medical Center, Abu Dhabi, UAE
|Date of Submission||10-May-2020|
|Date of Decision||23-Jul-2020|
|Date of Acceptance||07-Aug-2020|
Anant D Patil,
Department of Pharmacology, Dr. DY Patil Medical College, Nerul, Navi Mumbai - 400 706, Maharashtra
Source of Support: None, Conflict of Interest: None
The objective of this study was to perform a systematic review of randomized controlled trials (RCTs) related to chronic urticaria in Indian patients evaluating different treatment options published in the last decade. A systematic literature search of PubMed/Medline was performed using keywords “Study(ti) OR trial(ti) AND urticaria(ti) AND “2009”(Date-Publication): “2020”(Date-Publication). All the selected articles were screened for author information and study design. Only RCTs from India were considered for the final analysis. Out of 205 articles retrieved, 11 RCTs were selected for the systematic review. Six RCTs evaluated the effects of antihistamines (loratadine, levocetirizine, rupatadine, and olopatadine) in Indian patients with chronic urticaria. The results show that these agents are effective and well tolerated in the treatment of chronic urticaria. Other therapies evaluated through RCTs included levocetirizine plus montelukast, add-on methotrexate, azathioprine, cyclosporine, narrowband ultraviolet B, psoralen plus ultraviolet A, and vitamin D. Levocetirizine 5 mg plus montelukast 10 mg combination was found to be as effective as levocetirizine 10 mg in patients not responding to levocetirizine 5 mg/day. A small trial did not prove the benefit of methotrexate add-on therapy with antihistamine. Azathioprine trials show that it can be a useful option in resource-limited settings. Second-generation antihistamines represent the most commonly investigated therapies through RCTs in India, and they represent a valuable option in the management of chronic urticaria.
Keywords: Randomized controlled trials, research, urticaria
|How to cite this URL:|
Patil AD, Bingewar G. Evaluation of different therapies in indian patients with chronic urticaria: A systematic review of randomized controlled trials in the last decade. Med J DY Patil Vidyapeeth [Epub ahead of print] [cited 2021 Jun 13]. Available from: https://www.mjdrdypv.org/preprintarticle.asp?id=316634
| Introduction|| |
Urticaria is a complex heterogeneous group of dermatological disorder characterized by the presence of hives, angioedema, or both. The disease is associated with a significant burden related to health-care costs. There have been significant developments in the field of urticaria over the last few years, especially in the last decade. The European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded network of excellence, the Global Allergy and Asthma European Network (GA2LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO) (EAACI/GA2 LEN/EDF/WAO) guideline on the management of urticarial was published in 2009. This was followed by the publication of a consensus statement on the management of urticaria by expert dermatologists in India (2011). The update on the EAACI/GA2 LEN/EDF/WAO guideline was published in 2013. A position statement for the use of omalizumab in chronic spontaneous urticaria in Indian patients was published in 2016 and a update on the consensus statement for the diagnosis and management of urticaria in Indian patients was published in 2018. The literature suggests that scientific urticaria updates in India are keeping pace with global developments.
Randomized controlled trials (RCTs) are considered the gold standard in clinical research. Evidence generated from such trials plays a very important role in the development of guidelines and policies. With this background, a systematic review of urticaria-related RCTs in Indian patients with chronic urticaria published in the last decade was performed.
| Review|| |
Article search strategy and selection criteria
A systematic search of Medline through PubMed was performed for retrieving eligible articles for the review. Keywords “Study[ti] OR trial[ti] AND urticaria[ti] AND “2009”[Date-Publication]: “2020”[Date-Publication]) were used for searching the articles.
Data abstraction and analysis
Abstracts of all the retrieved articles were screened by both the authors. All the retrieved articles having authors from India were selected for further screening. Articles other than terms “study” or “trial” in the title were excluded from the analysis. All the selected articles were screened for study design, and only RCTs from India were considered for qualitative synthesis. Disagreements were resolved by mutual discussion.
The systematic search yielded 205 articles, of which 196 were considered for further analysis, whereas nine were excluded from the initial analysis as they did not satisfy the inclusion criteria. The reasons for exclusion of these articles are depicted in [Figure 1]. Eleven RCTs included in the qualitative analysis are listed in [Table 1].
|Table 1: Randomized controlled trials in India evaluating the efficacy of different therapies|
Click here to view
Out of the 11 RCTs, six investigated the effects of second-generation antihistamines (loratadine, levocetirizine, rupatadine, and olopatadine) in chronic urticaria. Other than antihistamines, methotrexate as add-on therapy, azathioprine, cyclosporine, narrowband ultraviolet B, and psoralen plus ultraviolet A were evaluated through RCTs. In the following section, we briefly discuss the results of these RCTs.
Randomized controlled trials with second-generation antihistamine
In an open-label study, Anuradha et al. compared the efficacy and safety of loratadine versus levocetirizine administered for 4 weeks in sixty patients with chronic idiopathic urticaria. In this study, changes in differential and absolute eosinophil count were significant with levocetirizine. Better symptom control as evaluated by total symptom score was observed with levocetirizine than loratadine. The incidence of adverse events was also lesser with levocetirizine. Overall, levocetirizine was found to have better efficacy and safety than loratadine.
In another single-blind study involving seventy patients with chronic idiopathic urticaria, Maiti et al. compared the efficacy and safety of rupatadine versus levocetirizine administered for 4 weeks. In this study, the global efficacy score of rupatadine was significantly better than that of levocetirizine. Similarly, the incidence of adverse events was less with rupatadine.
In another single-center study, Sil et al. compared the efficacy and safety of olopatadine 5 mg twice daily versus levocetirizine 5 mg every day in 120 patients with chronic urticaria. The treatment duration was 9 weeks, in which antihistamines were administered continuously for the first 4 weeks and as required for the next 5 weeks. Urticaria Activity Score (UAS) and urticaria Total Severity Score (TSS) were the primary outcome measures in this study. Results of data from 105 patients (olopatadine, n = 54; levocetirizine, n = 51) showed a significant reduction in UAS and TSS with both the drugs. A comparative analysis showed better efficacy with olopatadine without a difference in adverse event profiles between the two drugs.
Dakhale et al. compared cetirizine and rupatadine in chronic spontaneous urticaria in a randomized double-blind controlled trial. This study involved seventy patients and the duration of treatment was 6 weeks. Efficacy parameters included mean number of wheals, pruritus, mean total symptom score, and wheal size. The results suggested better efficacy with rupatadine than cetirizine.
In a 6-week, randomized, double-blind trial, Dakhale et al. compared the efficacy and safety of rupatadine versus olopatadine in patients with chronic spontaneous urticaria. Rupatadine as well as olopatadine significantly decreased the mean total symptom score and other parameters of efficacy including number of wheals and size of wheal. The results of this study involving sixty patients showed better efficacy with olopatadine with a significantly higher reduction in the mean total symptom score, number of wheals, size of wheals, intensity of erythema, and change in eosinophil count. Olapatadine also resulted in lesser rates of adverse event than rupatadine. The cost-effectiveness ratio was less with olopatadine.
A randomized, double-blind trial compared levocetirizine 10 mg versus combination of levocetirizine 5 mg and montelukast 10 mg in patients with chronic urticaria not responding to levocetirizine 5 mg. In this study, 120 patients were enrolled. Patients in one group received a double dose of levocetirizine, whereas for those in the other group, montelukast 10 mg was added with levocetirizine 5 mg. The duration of treatment was 4 weeks. The primary outcome measures, that is, UAS and urticaria TSS, had significantly reduced in both groups. There was no significant difference between the two groups. Significant improvement in the quality of life was observed among patients receiving a combination of levocetirizine and montelukast. Sedation was more in levocetirizine 10-mg group.
The overall results of this systematic review confirm the efficacy, safety, and valuable role of second-generation antihistamines in the treatment of chronic urticaria.
Other therapies in the treatment of chronic urticaria
In a small randomized study, Sharma et al. compared the efficacy of oral methotrexate 15 mg/week versus placebo given for 12 weeks in patients with chronic spontaneous urticaria not responding to H1 antihistamine. The study included 29 patients of whom 14 were randomized to receive methotrexate and the remaining 15 to receive placebo. Levocetirizine 5 mg was given to patients in both groups for control of symptoms. After terminating the treatment of 12 weeks, the patients were followed up to check relapse. Reduction by more than two-third of baseline urticaria scores was the primary outcome of this study. In this study, methotrexate treatment for 3 months did not result in any additional benefit. One of the major limitations of this study was the large number of dropouts. Twelve patients discontinued the trial. Both groups had similar effects on the primary outcome parameter. Out of ten patients who were followed up after completion of trial treatment, 70% had relapse. As far as safety is concerned, one patient who received methotrexate was discontinued from the study due to severe nausea and vomiting. No patient in the placebo group reported any adverse event.
Effects of azathioprine were evaluated in a placebo-controlled, randomized trial among chronic urticaria patients. Patients having positive result for autologous serum skin test were treated with azathioprine 50 mg/day or placebo for 8 weeks. The patients were followed up till 36 weeks. Levocetirizine 5 mg was allowed as and when required. Urticaria was assessed by TSS. Azathioprine treatment resulted in a significant decrease in the intensity of chronic urticaria and need of rescue antihistamine. Except few gastrointestinal side effects during initial therapy, there were no abnormal hematological or biochemical changes.
Recently, Pathania et al. compared the effects of azathioprine versus cyclosporine in patients with chronic spontaneous urticaria, not responding to antihistamine. In this randomized, noninferiority trial, forty patients each received cyclosporine and azathioprine for 3 months and were further followed up for the next 3 months. Azathioprine was not inferior to cyclosporine in this study. The primary end point of at least 75% reduction in UAS after 3 months was achieved by an almost equal percentage of patients (cyclosporine 79.5%; azathioprine 80%). However, at 6 months, it was maintained by 47.95% and 60% of patients in cyclosporine and azathioprine groups, respectively. The reduction in the number of patients maintaining at least 75% reduction in UAS was significant in patients receiving cyclosporine but not in the azathioprine group. UAS reduction at 3 months was significant in both groups. However, after 6 months, the score increased significantly in the cyclosporine but not in the azathioprine group. The overall results suggested the usefulness of azathioprine as an adjuvant therapy for the treatment of refractory chronic spontaneous urticaria, especially in resource-limited settings.
In a study, 192 patients stratified based on 25(OH) 2D levels received Vitamin D3 alone, antihistamine and systemic corticosteroid or Vitamin D3, antihistamine, and systemic corticosteroid. The treatment duration was 6 weeks. Serum Vitamin D levels of the patients were compared with that of 130 healthy controls. The percentage of patients with low serum levels of 25(OH) 2D was statistically significantly higher in patients with chronic urticaria than that of healthy controls (91% vs. 64%; P < 0.0001). Visual analog score and 5-D itch scores significantly decreased in all the three groups. Reduction was more in patients receiving a combination of Vitamin D3, antihistamine, and systemic corticosteroid.
Another study compared phototherapy, that is, narrowband ultraviolet B versus psoralen plus ultraviolet A, in patients with steroid-dependent antihistamine refractory chronic urticaria (n = 50). Phototherapy (narrowband ultraviolet B) worked better than psoralen plus ultraviolet A.
Overall, second-generation antihistamines (loratadine, levocetirizine, rupatadine, and olopatadine),,,,, antihistamine plus montelukast, double dose of levocetirizine, Vitamin D, immunosuppressants (methotrexate, cyclosporine, and azathioprine,), and narrowband ultraviolet B have been evaluated through RCTs in Indian patients with chronic urticaria.
Inclusion of only PubMed articles for a systematic literature search is one of the limitations of this systematic review. Although it is one of the largest databases, the chances of missing other RCTs published in journals not indexed with PubMed cannot be ruled out. Second, articles published before 2009 were not included in the analysis.
| Conclusion|| |
In RCTs, second-generation antihistamines including loratadine, levocetirizine, rupatadine, and olopatadine have been evaluated for their efficacy and safety in chronic urticaria. The results suggest that second-generation antihistamines represent a valuable treatment option for the treatment of chronic urticaria. Other therapies evaluated through RCTs include levocetirizine plus montelukast, methotrexate, cyclosporine, azathioprine, and narrowband ultraviolet B.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Antia C, Baquerizo K, Korman A, Bernstein JA, Alikhan A. Urticaria: A comprehensive review: Epidemiology, diagnosis, and work-up. J Am Acad Dermatol 2018;79:599-614.
Zuberbier T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK, Giménez-Arnau A, et al
. EAACI/GA(2)LEN/EDF/WAO guideline: Definition, classification and diagnosis of urticaria. Allergy 2009;64:1417-26.
Godse KV, Zawar V, Krupashankar D, Girdhar M, Kandhari S, Dhar S, et al
. Consensus statement on the management of urticaria. Indian J Dermatol 2011;56:485-9.
] [Full text]
Zuberbier T, Aberer W, Asero R, Bindslev-Jensen C, Brzoza Z, Canonica GW, et al
. Methods report on the development of the 2013 revision and update of the EAACI/GA2 LEN/EDF/WAO guideline for the definition, classification, diagnosis, and management of urticaria. Allergy 2014;69:e1-29.
Godse K, Rajagopalan M, Girdhar M, Kandhari S, Shah B, Chhajed PN, et al
. Position statement for the use of omalizumab in the management of chronic spontaneous urticaria in Indian patients. Indian Dermatol Online J 2016;7:6-11.
] [Full text]
Godse K, De A, Zawar V, Shah B, Girdhar M, Rajagopalan M, et al
. Consensus Statement for the Diagnosis and Treatment of Urticaria: A 2017 Update. Indian J Dermatol 2018;63:2-15.
] [Full text]
Spieth PM, Kubasch AS, Penzlin AI, Illigens BM, Barlinn K, Siepmann T. Randomized controlled trials-a matter of design. Neuropsychiatr Dis Treat 2016;12:1341-9.
Anuradha P, Maiti R, Jyothirmai J, Mujeebuddin O, Anuradha M. Loratadine versus levocetirizine in chronic idiopathic urticaria: A comparative study of efficacy and safety. Indian J Pharmacol 2010;42:12-6.
] [Full text]
Maiti R, Jaida J, Raghavendra BN, Goud P, Ahmed I, Palani A. Rupatadine and levocetirizine in chronic idiopathic urticaria: A comparative study of efficacy and safety. J Drugs Dermatol 2011;10:1444-50.
Sil A, Tripathi SK, Chaudhuri A, Das NK, Hazra A, Bagchi C, et al
. Olopatadine versus levocetirizine in chronic urticaria: An observer-blind, randomized, controlled trial of effectiveness and safety. J Dermatolog Treat 2013;24:466-72.
Dakhale GN, Shinde AT, Mahatme MS, Hiware SK, Mishra DB, Mukhi JI, et al
. Clinical effectiveness and safety of cetirizine versus rupatadine in chronic spontaneous urticaria: A randomized, double-blind, 6-week trial. Int J Dermatol 2014;53:643-9.
Sharma VK, Singh S, Ramam M, Kumawat M, Kumar R. A randomized placebo-controlled double-blind pilot study of methotrexate in the treatment of H1 antihistamine-resistant chronic spontaneous urticaria. Indian J Dermatol Venereol Leprol 2014;80:122-8.
] [Full text]
Rasool R, Masoodi KZ, Shera IA, Yosuf Q, Bhat IA, Qasim I, et al
. Chronic urticaria merits serum vitamin D evaluation and supplementation; a randomized case control study. World Allergy Organ J 2015;8:15.
Bhanja DC, Ghoshal L, Das S, Das S, Roy AK. Azathioprine in autologous serum skin test positive chronic urticaria: A case-control study in a tertiary care hospital of eastern India. Indian Dermatol Online J 2015;6:185-8.
] [Full text]
Dakhale GN, Wankhede SS, Mahatme MS, Hiware SK, Mishra DB, Dudhgaonkar SS. Comparison of efficacy, safety and cost-effectiveness of rupatadine and olopatadine in patients of chronic spontaneous urticaria: A randomized, double-blind, comparative, parallel group trial. Indian J Dermatol 2016;61:63-9.
] [Full text]
Bishnoi A, Parsad D, Vinay K, Kumaran MS. Phototherapy using narrowband ultraviolet B and psoralen plus ultraviolet A is beneficial in steroid-dependent antihistamine-refractory chronic urticaria: A randomized, prospective observer-blinded comparative study. Br J Dermatol 2017;176:62-70.
Sarkar TK, Sil A, Pal S, Ghosh C, Das NK. Effectiveness and safety of levocetirizine 10 mg versus a combination of levocetirizine 5 mg and montelukast 10 mg in chronic urticaria resistant to levocetirizine 5 mg: A double-blind, randomized, controlled trial. Indian J Dermatol Venereol Leprol 2017;83:561-8.
] [Full text]
Pathania YS, Bishnoi A, Parsad D, Kumar A, Kumaran MS. Comparing azathioprine with cyclosporine in the treatment of antihistamine refractory chronic spontaneous urticaria: A randomized prospective active-controlled non-inferiority study. World Allergy Organ J 2019;12:100033.