|Year : 2021 | Volume
| Issue : 2 | Page : 88-93
An open-labeled, single-centered, interventional, prospective study to determine the efficacy of autologous serum therapy in chronic spontaneous urticaria
Khushboo Arvind Minni1, GK Tharini2
1 Department of Dermatology, Venereology and Leprosy, Mumbai Port Trust Hospital, Mumbai, Maharashtra, India
2 Department of Dermatology, Madras Medical College, Chennai, Tamil Nadu, India
|Date of Submission||21-Feb-2021|
|Date of Acceptance||12-Jan-2022|
|Date of Web Publication||08-Jul-2022|
Dr. Khushboo Arvind Minni
Department of Dermatology, Venereology and Leprosy, Mumbai Port Trust Hospital, LM Nadkarni Marg, Nadkarni Park, Wadala East, Mumbai - 400 037, Maharashtra
Source of Support: None, Conflict of Interest: None
BACKGROUND: Chronic spontaneous urticaria (CSU) poses a therapeutic challenge by dermatologists and patients alike.
OBJECTIVES: This study aimed to find the prevalence of functional autoantibodies among patients using autologous serum skin test (ASST) and to evaluate the efficacy of autologous serum therapy (AST) as an adjuvant in CSU.
MATERIALS AND METHODS: An open-labeled, single-centered, prospective, interventional study of 1 year was performed after institutional ethical approval among 55 consenting patients of CSU. ASST was performed to find the prevalence of functional autoantibodies and those positive were given weekly intramuscular AST for the next 9 weeks. For clinical outcome, weekly urticaria activity score (UAS7) was recorded at baseline and at week 10. Any adverse effects were recorded. Wilcoxon sign-ranked test and Fisher's exact test were used to demonstrate equal variance.
Results: Fifty-five CSU patients consented to participate in the study; 41 were ASST+ and six were dropped out; hence, the prevalence of autoreactivity was 74.54%. Four of seven who presented with angioedema were ASST+. Thus, the prevalence of angioedema in ASST+ patients of CSU was 11.4%. At the end of 10th week, on comparing individual components of UAS7, there was a statistical significant difference (P < 0.05) in the number of wheals (P = 0.00001), pruritus (P = 0.00001), frequency of wheals (P = 0.00001), as well as the overall UAS7 (P = 0.0001) scores. The effect size is 1.23 (Cohen's d). On grading the improvement at week 10, marked (>75%), good (50%–74%), satisfactory (25%–49%), and poor (<25%) improvement were observed in 8 (22.9%), 12 (34.3%), 11 (31.4%), and 4 (11.4%) patients, respectively.
CONCLUSION: AST is effective in significantly reducing wheals and pruritus and improves quality of life. It can be tried as an adjuvant before switching patient to other immunosuppressants or expensive biologicals in this current COVID-19 pandemic. Large long-term prospective randomized controlled trials with follow-up are required to conclusively ascertain the efficacy of AST as an adjuvant in CSU.
Keywords: Autologous serum skin test, autologous serum therapy, chronic spontaneous urticaria, urticaria activity score
|How to cite this article:|
Minni KA, Tharini G K. An open-labeled, single-centered, interventional, prospective study to determine the efficacy of autologous serum therapy in chronic spontaneous urticaria. Indian J Allergy Asthma Immunol 2021;35:88-93
|How to cite this URL:|
Minni KA, Tharini G K. An open-labeled, single-centered, interventional, prospective study to determine the efficacy of autologous serum therapy in chronic spontaneous urticaria. Indian J Allergy Asthma Immunol [serial online] 2021 [cited 2022 Dec 2];35:88-93. Available from: https://www.ijaai.in/text.asp?2021/35/2/88/350086
| Introduction|| |
This description by Heberden in 1772, “…the greatest number (of patients) experience no other evil from it besides the intolerable anguish arising from the itching,” holds true even today as urticaria has a significant impact on patient quality of life. The availability of several treatment modalities and management guidelines on chronic spontaneous urticaria (CSU) management, the most common chronic urticaria (CU), highlights its therapeutic challenge to most dermatologists.,
Nowadays, two types of autoimmune mechanisms are held to be relevant in CSU: type I autoimmunity (autoallergy) with immunoglobulin E (IgE) autoantibodies to autoantigens and type IIb autoimmunity with immunoglobulin G autoantibodies to IgE or its high-affinity receptor, FceRI. Autologous serum skin testing (ASST) is used as a nonspecific screening test to evaluate the presence of histamine-releasing factors and functional autoantibodies in serum.,
We aimed to study the prevalence of these functional autoantibodies using ASST in CSU and also to evaluate the efficacy of autologous serum therapy (AST) as an adjuvant in CSU management.
| Materials and Methods|| |
This was an open-labeled, single-centered, prospective, interventional study of 1-year duration performed at our dermatology outpatient department of a tertiary care hospital; written informed consent was taken from patients before enrollment. Fifty-five CSU patients with urticaria > 6 weeks with willingness for repeated weekly injections, normal dental and otolaryngopharyngeal examination, and normal complete blood count with normal absolute eosinophil count were included. Patients with a known etiology for urticaria, <18 years, pregnant/lactating, and systemic illness were excluded from the study. Probable etiology of urticaria was ruled out following detailed history regarding any environmental, food or drug as a trigger, probable triggers for physical urticaria, diurnal variation, or history of contact with any allergen for contact urticaria.
Prior confirmation was done that patients had not taken antihistamines for at least 1 week before performing ASST by withdrawing 2 mL of venous blood in a plain unheparinized sterile plastic tube from the antecubital vein [Figure 1]. The test was performed. 0.1 mL of the patient's serum was injected intradermally using insulin syringe on volar aspect of the patient's left forearm (test) and using 0.1 mL normal saline (control) on the right forearm at a site not previously affected by a wheal in the last 24 h. Readings were taken after 30 min for the reactive wheals. Patients were categorized into two groups based on reactivity as autologous serum skin test positive (ASST+) when the average of two perpendicular diameters of the autologous serum wheal was ≥1.5 cm than control. ASST+ patients were treated with weekly intramuscular injection (gluteus maximus muscle) of 2 ml autologous processed serum for 9 weeks from 5 ml of whole blood. For clinical outcome, urticaria activity score 7 (UAS7) [Table 1] was used for the quantification of response in terms of number of wheals and pruritus. UAS7 was recorded at baseline and on week 10. Based on UAS7 score, the CSU patients were classified as none (0), mild (1–13), moderate (14–26), and severe (27–42) CSU.
No other forms of therapeutic treatment were allowed during the treatment and follow-up period except for oral levocetirizine 5 mg as and when required at the time of flare. Follow-up period was weekly up to 10 weeks for therapy. However, adverse clinical effect was not expected as patient's own serum was being used for the therapy, if any apparent were recorded. Student's t-test was used where equal variance was demonstrated.
The data were entered and summarized using frequency, percentages, mean, and standard deviation in Microsoft Excel version 2010 and subjected to analysis in GraphPad Prism version 8.0.0 for Windows, GraphPad Software, San Diego, California, USA (www.graphpad.com) for Wilcoxon sign-ranked test and Fisher's exact test for quantitative and qualitative nonparametric analysis, respectively, with 5% level of significance (P < 0.05).
| Results|| |
Fifty-five CSU patients consented to participate in the study of which 41 were ASST+; hence, the prevalence of functional autoantibodies was 74.54%. Seven patients presented with angioedema with CSU; of these, 4 were ASST+. Thus, the prevalence of angioedema in ASST + patients of CSU was 11.4%.
Four patients were loss to follow-up, two patients had no response and discontinued therapy. Hence there were six(4+2) dropouts and statistical analysis was done on 35 patients. There were 17 males (48.6%) and 18 females (51.4%) included in the study. The mean of baseline UAS7 was 28.2 while it reduced to 14 on week 10. At the end of 10th week, on comparing individual components of UAS7, there was a statistical significant difference (P < 0.05) in the number of wheals (P = 0.00001), pruritus (P = 0.00001), frequency of wheals (P = 0.00001), as well as the overall UAS7 (P = 0.0001) scores. The effect size is 1.23 (Cohen's d). On grading the improvement at week 10, marked (>75%), good (50%–74%), satisfactory (25%–49%), and poor (<25%) improvement were observed in 8 (22.9%), 12 (34.3%), 11 (31.4%) and 4 (11.4%) patients, respectively [Table 2].
|Table 2: Grading of weekly urticaria activity score 7 at baseline and at week 10|
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No side effects were observed after ASST or AST in CSU patients.
| Discussion|| |
CU is defined as “itchy urticarial wheals present on most of the days for 6 weeks, and a single wheal resolving spontaneously within 24 h.”, It can be further classified as CSU or chronic inducible urticaria (CIU). In contrast to CIU, which has defined triggers, CSU is independent of any exogenous stimuli. CU substantially lowers patients' quality of life because of intense pruritus, sleep disturbances, and concerns about physical appearance. In 1986, Grattan et al. were the first to use ASST to differentiate autoimmune urticaria from CIU. ASST is a simple, office-based test to diagnose subset of patients with CSU having autoimmunity,,, while AST, a novel therapeutic modality for CSU. Induction of anti-idiotype and shifting of Th2 cytokine profile to Th1 have been the postulated mechanism of AST.
In various studies, over the years, the prevalence of presence of functional autoantibodies by ASST positivity has varied from 27% to 61%., However, in our study (74.5%), the prevalence was higher than that reported by Karn and Kc (36.2%), Bajaj et al. (49.5%), and Debbarman et al. (40.5%).
Vikramkumar et al. reported that 66% of the patients presented with a history of angioedema and 50% of them were ASST positive. In other studies, there was no significant difference between patients with or without functional autoantibodies with regard to angioedema and ASST positivity and its prevalence ranged from 7% to 87%.
In 1913, Ravaut and Spiethoff described the use of autohemotherapy (AHT) for various pruritic dermatologic conditions such as prurigo, blistering diseases, urticaria, and certain types of acne associated with pruritus. Staubach et al. have documented the use of whole blood to treat CSU. Lack of evidence led to its disuse over the years. However, over the last decade, interest in this modality has resurged. Bajaj et al. introduced the use of serum in the treatment of urticaria. However, AST is considered more effective than AHT in CSU owing to the presence of circulating autoreactive factors in serum which are not present in blood and also serum being less painful to inject. Furthermore, one has to inject AHT immediately to avoid clotting.
Majid et al. showed a marked decline in disease activity after the first few injections of autologous serum. Staubach et al. reported a persistent treatment effect of autologous whole-blood injections in ASST-positive CSU patients and reduced disease activity as early as after 4 weekly treatments as assessed by UAS7 with the use of on-demand antihistamines. Our findings are also in agreement with the previous studies by Chen et al., Godse et al., and Abdallah et al. [Table 3].
|Table 3: Review of literature for Autologous serum injections and autohemotherapy in Chronic Urticaria|
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At least 59.7% of ASST-positive and 46% ASST-negative patients showed significant improvements in signs and symptoms after 9 weekly AST in the study by Bajaj et al. This improvement was sustained for at least 3–4 months after the last injection. Elazab and Hessam also showed similar downward trend of declining disease severity following AST treatment method and normal saline administration as the placebo.
A systematic review and meta-analysis on eight studies reported that AST was not more effective than the placebo for CSU after weekly treatment for 9 weeks, but a borderline significant reduction in TSS in the AST group was noted at the end of follow-up. AWB therapy was also not significantly superior to the placebo treatment in response rates at the end of follow-up after 4–6 weeks of the final treatment. Furthermore, no significant difference in the efficacy of AST or AWB therapy for CSU was observed between the ASST+ and ASST− patients. This systematic review and meta-analysis had some limitations. First, only two studies were included in each meta-analysis because of high divergence in the clinical scoring systems and evaluations of outcomes for urticaria in each study; moreover, the risk of publication bias could not be assessed. Second, no meta-analysis was conducted for direct comparison of the efficacy between AWB therapy and AST for CSU because sufficient assessable data were not available. Finally, high heterogeneity across studies existed in most of the current analysis. Hence, more studies directed at efficacy of AST are required as this study.
However, Brewer in his systematic review of AHT as a treatment for urticaria stated that (1) AHT does not have major side effects and that minor adverse effects are short lived and similar in frequency to those from placebo injections, (2) overall, AHT tends to be somewhat more effective in reducing symptoms than control therapy across studies although the advantage is not statistically reliable, (3) AHT and AST appear to have similar effectiveness, and (4) urticaria patients who test positive on the ASST respond more favorably to AHT on average than those who test negative.
The limitations of our study were a small sample size, absence of control group, and long-term follow-up.
| Conclusion|| |
In our study, AST was effective by significantly reducing the wheal numbers and pruritus, thereby reducing the overall UAS7 significantly. Its use along with antihistamincs highlights its role as an adjuvant and not a sole mode of treatment. AST, being autologous, is usually free of sensitization, cheap, and easy to prepare. We recommend its use as an adjuvant in the treatment of ASST + patients to improve their quality of life as an armamentarium in management of CSU before subjecting patients to long-term immunosuppression or expensive biologicals in this current COVID-19 pandemic. Long-term prospective randomized controlled trials with follow-up and large sample size are required to conclusively ascertain the efficacy of AST as an adjuvant therapy in CSU.
We would like to mention special thanks to our laboratory technicians for helped us withdraw blood samples and prepared autologous serum injections and our department for channelizing patients to be included in the study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]