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ORIGINAL ARTICLE
Year : 2022  |  Volume : 67  |  Issue : 5  |  Page : 518-523
Open-label non-blinded cohort study on anti-histaminic resistant chronic idiopathic urticaria in Western India


1 Allergologist and Pulmonologist, Department of Pulmonary Medicine, The Lung Centre, Office No 404, 4th Floor Marathon Chambers, P K Road, Mulund West, Mumbai, Maharashtra, India
2 Allergologist and Pulmonologist, The Lung Centre, Office NO 104, First Floor Trinity Apartments, Uthalsar Road, Thane West, Maharashtra, India

Date of Web Publication29-Dec-2022

Correspondence Address:
Subramanian Natarajan
Allergologist and Pulmonologist, The Lung Centre, Office No 404, 4th Floor Marathon Chambers, P K Road, Mulund West, Mumbai - 400 080, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.ijd_718_21

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   Abstract 


Introduction: Chronic idiopathic urticaria (CIU) is a chronic relapsing disease with hives for a period of six weeks or more. It has a significant impact on the physical and mental well-being of patients. Aims and Objectives: Open-label non-blinded study of over 600 patients diagnosed with CIU was done. The aim of the study was to observe the following: 1. Characteristics of patients of anti-histaminic resistant CIU, 2. Efficacy of cyclosporin and any adverse events in the study population and 3. Prognosis and relapse rates of these patients at the end of one year. Methods: Detailed history taking and guided clinical evaluation were done to include chronic resistant urticarias in the study and their clinical characteristics and prognosis were studied. Results: A total of 610 patients were diagnosed with CIU over a period of four years. Of these, 47 patients (7.7%) were diagnosed with anti-histaminic resistant urticaria. Of these, 30 patients (4.9%) who took treatment with cyclosporin at the above dosages were included in group 1. Rest 17 patients were in group 2 that were continued on anti-histaminics. Patients in cyclosporin group 1 showed a significant reduction in symptom scores as compared with group 2 at the end of six months. A lower need for corticosteroid therapy was noted in the cyclosporin group. Conclusion: Cyclosporin in low doses is very useful in anti-histaminic resistant urticaria with the duration of therapy being six months. It is cost-effective in low and medium-income countries and easily available.


Keywords: Chronic, cyclosporin, relapse, resistant, urticaria


How to cite this article:
Natarajan S, Subramanian P. Open-label non-blinded cohort study on anti-histaminic resistant chronic idiopathic urticaria in Western India. Indian J Dermatol 2022;67:518-23

How to cite this URL:
Natarajan S, Subramanian P. Open-label non-blinded cohort study on anti-histaminic resistant chronic idiopathic urticaria in Western India. Indian J Dermatol [serial online] 2022 [cited 2023 Jan 31];67:518-23. Available from: https://www.e-ijd.org/text.asp?2022/67/5/518/366140





   Introduction Top


Chronic spontaneous urticaria (CSU) or chronic idiopathic urticaria (CIU), is defined by the presence of urticaria (hives) on most days of the week,[1] for a duration of six weeks or longer. Urticaria is a mast cell-driven disease with the release of multiple mediators like histamine, platelet-activating factors and cytokines. Chronic urticaria (CU) causes a significant physical and psychosocial impact on patients.[2] It markedly affects objective functioning and subjective well-being. Also, many patients have lower subjective satisfaction due to the chronic relapsing nature of the disease and dependency on the medicines. The prevalence of CIU in the general population,[3],[4] has been estimated to range from 0.5% to 5%; however, the true point prevalence, cumulative prevalence and lifetime prevalence of CU have not been established even in the United States. The prevalence and incidence in India have still not been estimated.


   Aims and Objectives Top


This was an open-label non-blinded study of over 600 patients diagnosed with CIU. The study aimed to observe the following characteristics: 1. Characteristics of patients of anti-histaminic resistant CIU, 2. Efficacy of cyclosporin and any adverse events in the study population and 3. Prognosis and relapse rates of these patients at the end of one year.


   Methods Top


Our study was based in two urban allergy outpatient department centers over four years starting from 2016 January. Recruitment of patients in the study was undertaken only for four years. All patients were initially screened for any history of hives of any cause.

The following sample questions were asked with the help of trained nurses and printed questionnaires and the responses were recorded.

  1. Time of onset of disease
  2. Shape, size, frequency/duration and distribution of wheals
  3. Associated angioedema
  4. Associated symptoms, for example, bone/joint pain, fever, abdominal cramps
  5. Family and personal history regarding wheals and angioedema
  6. Induction by physical agents or exercise
  7. Occurrence in relation to daytime, weekends, menstrual cycle, holidays and foreign travel
  8. Occurrence in relation to foods or drugs (e.g. non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors)
  9. Occurrence in relation to infections, stress
  10. Previous or current allergies, infections, internal/autoimmune diseases, gastric/intestinal problems or other disorders
  11. Social and occupational history, leisure activities
  12. Previous therapy and response to therapy including dosage and duration
  13. Previous diagnostic procedures/results


History-taking was also directed at excluding the inducible causes of urticaria. All efforts were made to find out whether any factors contributing to the inducible causes of urticaria were revealed. However, specific tests could not be performed due to the unavailability of the test agents. The most important question asked was, “Can you make your wheals come? Can you bring out your wheals? If yes, then it was noted in the Case Record Form (CRF). All patients with a history of atopy as a causative factor for urticaria were excluded. Patients with a history of hives after consumption of particular foodstuff, which recurred on repeat ingestion, were also excluded.

Patients were asked for detailed family history and the age of onset of disease. Also, a history of sudden deaths in the family was probed to rule out the possibility of hereditary angioneurotic oedema. Drug history was the most important history elicited. Specific drugs like ACE inhibitors like enalapril, ramipril, gliptins and sulphonylureas for diabetes and aspirin were enquired. These medications were either stopped and replaced with suitable and safe alternatives in consultation with their primary physicians. A detailed flowchart in [Table 1] shows the screening process and inclusion of subjects in the case study.
Table 1: Flowchart for case study inclusion:

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Patients diagnosed with the idiopathic cause of urticaria were included in the study and their details were recorded in their Case Record Forms (CRFs). Second-generation anti-histaminics were started as first-line medication, namely, desloratadine or fexofenadine. Dosage was increased up to four times the baseline dosage daily depending on the response to these medications. Of these, those responding to anti-histaminics were excluded from the study. Patients not responding to anti-histaminics even after six to eight weeks,[1] of four-fold anti-histaminic dosages were included in the study. Anti-histaminic resistant urticaria CRFs were further analysed. All these patients underwent evaluation with urticaria total severity score (UTSS) and urticaria activity score (UAS),[1],[5],[6] scoring at the start and end of one month of the treatment and subsequently every month till the end of a year or end of treatment, whichever is later. UTSS and UAS scores are easy-to-use, self-assessment clinical tools, which can easily help the patient and researchers to assess the clinical response to the treatment and guide any interventions that are required in the treatment. They are pointwise measurements of wheals and itching over a period of four weeks. [Table 2] and [Table 3] show the detailed pointwise assessment of wheals and itching using UTSS and UAS scoring systems. Patients were monitored for their symptoms and signs and a detailed medications history was taken in every follow-up. Whether they required additional medications from their general practitioner or whether they have self-medicated themselves for abatement of symptoms were also recorded.
Table 2: Urticaria total severity scores

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Table 3: Urticaria activity scores

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Investigations

All patients underwent a complete blood count; C-reactive protein, thyroid hormone levels Triiodothyronine (T3), Thyroxine (T4) Thyroid stimulating Hormone (TSH), anti-thyroglobulin antibodies (ATA) and anti-mitochondrial antibodies (AMA), anti-nuclear antibodies (ANA) by immunofluorescence method were also tested in all patients. Some patients who gave a history of urticaria in siblings or parents, severe undiagnosed abdominal pain and sudden deaths in the family were also tested with C1 esterase inhibitor levels. Serum immunoglobulin E levels were not done as a routine evaluation.

Treatment

Patients who were diagnosed as anti-histaminic resistant urticarias were given the option of cyclosporin and when consented were started on cyclosporin at the dose of 2 mg per kilogram body weight up to a maximum of 4 mg per kilogram of body weight.[4],[7],[8],[9] They were included in group 1. Patients were monitored for symptoms by UTSS and UAS scores every 4 weeks and called for in-person visits in the outpatient department. Patients were given anti-histaminics for the first two weeks if they had symptoms of itching and subsequentlyas and when required (p.r.n), only if they had intolerable itching. They were as ked to mark those dates when they came for follow-up visits. Subsequently, during follow up visits, blood pressure was recorded and monthly complete blood count, alanine transaminase, serum creatinine and a lipid profile detailing, serum triglycerides and low-density lipoprotein (LDL) cholesterol. All patients were administered cyclosporin at the above dosage for a period of twelve weeks. Once their symptoms had completely disappeared, they were gradually tapered off the dosage of cyclosporin over the following twelve weeks or if still symptomatic then continued on the same dosages for a further period of twelve weeks. All of the patients received cyclosporin for about six months or twenty-four weeks in total. Those patients who did not respond to cyclosporin were offered omalizumab as a treatment option and those who refused omalizumab were continued on four times the dosage of anti-histaminics. Some of them were given over and above short tapering doses of oral prednisolone when symptoms were unabating with anti-histaminics. The extra doses of prednisolone, montelukast and additional anti-histaminics that were needed were noted in the one-year follow-up.

Follow-up

All patients were followed up every month, symptoms recorded, UAS and UTSS scores recorded and vitals were checked. Additional medication requirements like oral prednisolone, montelukast and anti-histaminics were recorded in the CRF. Follow-ups were recorded for a period of one year.

Statistical analysis

Two table tests and Chi-square methods were used to determine the P values and statistical significance was recorded with the P value being less than 0.5. ANOVA (analysis of variance) test was used to determine the test of significance.

A written informed consent was taken from all the patients participating in the study.


   Results Top


A total of 610 patients were diagnosed with CIU over a period of four years. Of these, 47 patients (7.7%) were diagnosed with anti-histaminic resistant urticaria. The rest of the 563 patients were continued with anti-histaminics at four times the usual dosage and showed significant remission at the end of six months. Of these 47 patients, 30 patients (4.9%) who took treatment with cyclosporin at the above dosages were included in group 1. Rest 17 patients were in group 2 that were continued on anti-histaminics because they refused any change of medicines. Detailed comparisons between the groups have been enlisted in [Table 4]. The age range was 17 to 64 in group 1 and 22 to 65 in group 2. No paediatric patients were noted or included in our study. The average duration of symptoms was thirty-seven months in group 1 and ten months in group 2 (p-value 0.11). One-third (33%) of patients (n = 10) showed signs of dermatographia while 25% of patients from group 2 had dermatographia (n = 4). Group 2 had higher number of patients demonstrating antibodies (AMA, ATA, ANA) (n = 9) as compared to group 1 (p-value 0.11). Patients in the cyclosporin group showed a significant reduction in symptom scores as compared with the second group. However, at the end of three months, the symptoms score reduction was not statistically significant (p-value 0.911). At the end of six months and one year, this benefit was seen with statistical significance (p-value < 0.001). [Figure 1] and [Figure 2] clearly show the symptom scores assessed on UTSS and UAS scoring over one year. Most of the patients in the second group required extra doses of anti-histaminics besides the regular dosages that they were on. Almost 60% (n = 10) required two or more doses of oral prednisolone in the one-year study period in group 2. In the first group, two patients failed on cyclosporin and were started on omalizumab. More than half of the patients recorded adverse events in group 1 (n = 16, 53.33%). [Table 5] shows the adverse events recorded in group 1 in our study.
Figure 1: Urticaria Total Severity Scores (UTSS)

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Figure 2: Urticaria Activity Scores (UAS)

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Table 4: Inter-group comparisons with major characteristics. Numbers in the columns signify the total number of patients

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Table 5: Adverse events in group 1 patients

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   Discussion Top


We studied two groups of patients in an open-label cohort study comparing anti-histaminics to cyclosporin, the first of its kind. Our two groups had comparable characteristics as delineated in [Table 4]. Thirty of the total 47 patients were given treatment with cyclosporin. Our study showed that patients who received cyclosporin were having a longer duration of symptoms than those who chose to continue with anti-histaminics as treatment. There are no studies, which have studied the duration of urticaria before starting treatment with cyclosporin. Anti-histaminic resistant urticaria is predominantly a disease in females. Almost two-thirds of the patients are females (n = 31, 66%). The angioedema was seen in almost 45% of patients in this cohort (n = 17). Angioedema is usually associated with approximately 20% of patients with CIU.[3],[6] However, in our study we found this to be seen in higher percentages of patients. Probably, this signals the fact that these subsets of patients have more severe diseases and a distressing course unless intervened early.

A quick glance at our charts in [Figure 1] and [Figure 2] shows that the response to treatment starts after the duration of three months. This could probably signify that cyclosporin is a slow-acting drug with sustained effects for a period of at least six months even after stopping the drug. Cyclosporin has an easy dosing frequency and is readily available with relatively cheap generic versions, which drastically reduce the cost of therapy in these patients as compared to omalizumab.

In our study, more than fifty percentage of patients had adverse drug reactions (ADRs) related to cyclosporin. Non-serious reversible adverse events were found in 80% of patients (n = 13). Hypercholesterolaemia in the form of raised LDL of more than 130 mg/dL was completely reversible once the treatment with cyclosporin was stopped after symptom remission. Only three patients had systemic hypertension, which required medications in long term. Similarly, in other studies,[4] the percentage of ADRs varied from 4% to 95%. In the study by Hollander et al.,[9] 37% of patients had ADRs and in 6% of patients, the drug was withdrawn due to drug-induced hypertension. In our study, treatment interruption was seen in only one patient (3.3%) due to hypertension. In the twenty-week study of 30 patients by Boubouka et al.,[10] almost 13.3% of patients stopped their medications due to hypertension. However, barring three patients who had hypertension, the rest of the ADRs in our study were mild and did not require treatment interruption. Also, the drug was largely tolerated by most of the patients without many gastrointestinal adverse effects.

Our study clearly showed that the symptom score reduction of CIU patients in group 1 was statistically significant at the end of six months thus warranting at least six months of therapy with cyclosporin. Ours is one of the few studies, which followed up patients for a span of one year. Six months of adequate therapy with full-dose cyclosporin is required to prevent treatment failures and relapses. In the 30 patient study by Boubuka et al.[10] on autoimmune urticaria, the relapse rate was the least of about 13%, suggesting that a longer duration of six months would mean a better resolution of symptoms and reduced relapses. In the 46 patient study by Neverman et al.,[11] anti-histaminic resistant urticaria in children had complete remission in three months of treatment. However, the relapse was seen in five patients warranting repeat therapy. Relapse was seen between 13% and 75% in various studies in the meta-analysis by Kulthanan et al.[4] The treatment duration varied between 4 and 20 weeks in all the studies included in this meta-analysis. Vena et al.[12] in their study on 99 patients showed that the relapse rates with a 16 week treatment was lower than that with an eight week treatment. We gave six months of cyclosporin in all our patients with a failure rate of just 6% and a relapse rate of 0%. None of our patients had relapse in the one year of study period. This clearly shows that stopping treatment at the end of three months can lead to relapses warranting restarting of the treatment. The safest duration of therapy would be six months of cyclosporin with least chances of recurrences and relapses.

Limitations

This is a retrospective observational study and requires a large scale randomized prospective study to establish the characteristics of anti-histaminic resistant urticaria and to establish it as a separate entity and lay down guidelines for safe treatment alternatives for such patients. A few pointers on the limitations of our study. 1. What is already known about this topic? Cyclosporin is a recognized form of therapy. 2. What does this article add to our knowledge? Six months duration of cyclosporin is required for significant improvement in symptoms. ADRs leading to treatment interruptions are uncommon. Cyclosporin is a cheaper alternative and readily available with high efficacy in anti-histaminic resistant CU. 3. How does this study impact current management guidelines? Anti-histaminic resistant urticaria needs to be recognized as a separate phenotype. It is important to identify such patients early and initiate early second line therapy. Cyclosporin is a reliable alternative to monoclonal antibodies, which are costly and not readily available in India and other lower socio-economic nations.


   Conclusion Top


Anti-histaminic resistant urticaria is an uncommon but distinct phenotype with limited treatment options. Cyclosporin in appropriate doses is very useful in these cases with duration of therapy being at least six months. It is cost effective without the need for injections in low and medium income countries and easily available. Adequate therapy leads to excellent symptom abatement with least relapses.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Zuberbier T, Aberer W, Asero R, Abdul Latiff AH, Baker D, Ballmer-Weber B, et al. The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy 2018;73:1393-414.  Back to cited text no. 1
    
2.
Maurer M, Abuzakouk M, Berard F, Canonica W, Oude Elberink H, Giménez-Arnau A, et al. The burden of chronic spontaneous urticaria is substantial: Real-world evidence from ASSURE-CSU. Allergy 2017;72:2005-16.  Back to cited text no. 2
    
3.
Bernstein JA, Lang DM, Khan DA, Craig T, Dreyfus D, Hsieh F, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol 2014:133;1270-7.  Back to cited text no. 3
    
4.
Kulthanan K, Chaweekulrat P, Komoltri C, Hunnangkul S, Tuchinda P, Chularojanamontri L, et al. Cyclosporine for chronic spontaneous urticaria: A meta-analysis and systematic review. J Allergy Clin Immunol Pract 2018:6;586-99.  Back to cited text no. 4
    
5.
Hawro T, Ohanyan T, Schoepke N, Metz M, Oberhag AP, Staubach P, et al. The urticaria activity score—Validity, reliability, and responsiveness. J Allergy Clin Immunol Pract 2018:6;1185-90.  Back to cited text no. 5
    
6.
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.  Back to cited text no. 6
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Godse KV. Cyclosporine in chronic idiopathic urticaria with positive autologous serum skin test. Indian J Dermatol 2008;53:101-2.  Back to cited text no. 7
[PUBMED]  [Full text]  
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Kessel A, Toubi E. Cyclosporine-A in severe chronic urticaria: The option for long-term therapy. Allergy 2010;65:1478-82.  Back to cited text no. 8
    
9.
Hollander SM, Joo SS, Wedner HJ. Factors that predict the success of cyclosporine treatment for chronic urticaria. Ann Allergy Asthma Immunol 2011;107:523-8.  Back to cited text no. 9
    
10.
Boubouka CD, Charissi C, Kouimintzis D, Kalogeromitros D, Stavropoulos PG, Katsarou A. Treatment of autoimmune urticaria with low-dose cyclosporin A: A one-year follow-up. Acta Derm Venereol 2011;91:50-4.  Back to cited text no. 10
    
11.
Neverman L, Weinberger M. Treatment of chronic urticaria in children with antihistamines and cyclosporine. J Allergy Clin Immunol Pract 2014;2:434-8.  Back to cited text no. 11
    
12.
Vena GA, Cassano N, Colombo D, Peruzzi E, Pigatto P. Cyclosporine in chronic idiopathic urticaria: A double-blind, randomized, placebo-controlled trial. J Am Acad Dermatol 2006;55:705-9.  Back to cited text no. 12
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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