Autologous Serum Therapy in Recalcitrant Chronic Spontaneous Urticaria: Experience from Three Dermatology Clinics in Malaysia

Abstract

Autohemotherapy is a commonly used treatment for recalcitrant chronic urticaria in some countries. Herein we report our experience using autologous serum therapy in eight patients with recalcitrant chronic spontaneous urticaria. Autologous serum therapy was initiated weekly for nine weeks followed by every fortnightly. Urticaria Activity Score (UAS) 7, Dermatology Life Quality Index (DLQI), and reduction of antihistamine usage were used to assess the treatment response. Eight patients (age range: 25–76 years old; four females and four males) had one to ten years of duration of recalcitrant chronic spontaneous urticaria. All failed to respond to high doses of second-generation antihistamines and five to immune-modulating agents. Three did not respond to omalizumab. At week nine, the reduction of UAS7 ranged from 76.2% to 100%. There was more than an 80% improvement in DLQI in all patients. The number of wheals seemed to be reduced first followed by pruritus. Three patients had stopped antihistamines by week eight of treatment. No adverse events were reported in all eight patients. Autologous serum therapy may serve as an alternative treatment for recalcitrant chronic spontaneous urticaria. Apart from the practicality, which requires frequent clinic visits, venipuncture, and centrifugation, it is cheap and effective with minimal adverse events.

Introduction

Chronic spontaneous urticaria (CSU) is thought to be an autoimmune disorder and, is linked to the presence of mast cell-degranulating autoantibodies, either immunoglobulin (Ig) E autoantibodies directed to autoallergens (type I autoimmunity) or IgG autoantibodies to the high-affinity IgE receptor or IgE itself (type IIb autoimmunity).[1] At least 21–67% of CSU patients have circulating autoantibodies against high-affinity IgE receptors that result in mast cell degranulation. We describe the use of autohemotherapy-autologous serum therapy (AST) in eight patients with recalcitrant CSU.

Methodology

AST was initiated weekly for nine weeks and if there was improvement, continued for another week followed by every fortnightly until week 20. The blood was drawn from the cubital fossa into a serum vial free from any coagulation-inducing substances and centrifuged at 1300 g for 15 minutes. The serum obtained was subsequently injected intramuscularly with up to 0.05 ml/kg body weight (BW) following the protocol by Yu et al.[1] into the gluteal muscle, as shown in Figure 1. Urticaria Activity Score (UAS) 7 at baseline, week five and week nine (weekly UAS7 diary was given to the patient to score before the visit), Dermatology Life Quality Index (DLQI) at baseline and week nine, and reduction of antihistamine usage were recorded to assess the treatment response. Antihistamines were continued throughout the study period and were allowed to be adjusted based on the patient’s responses.

Figure 1.

AST procedure. (a) Blood was taken from the cubital fossa, (b) put into plain tubes and let clotted for a few minutes, (c and d) sent for centrifugation, (e) serum was separated and ready to be aspirated, and (f) autologous serum was ready to be injected

Results

The eight patients were aged between 25 and 76 years. They suffered from a recalcitrant CSU for one to ten years. The male-to-female ratio was 1:1. They had multiple medical conditions including hypertension, diabetes mellitus, dyslipidemia, fatty liver, benign prostate hyperplasia, allergic contact dermatitis, atopic dermatitis (AD), essential thrombocytosis, gout, inverse psoriasis, allergic rhinitis and bronchial asthma. Five patients had baseline serum IgE measured and were raised between 105 and 4900 kU/L. All failed to improve with high doses of second-generation antihistamines. Five patients did not respond to immune-modulating agents, such as cyclosporine, prednisolone, methotrexate, and colchicine. Three did not respond to omalizumab, a recombinant humanised IgG1 monoclonal antibody targeting human IgE. The clinical characteristics of the patients are summarised in Table 1.

Table 1.

Clinical characteristics of 8 patients on AST

Patient, age, gender	Comorbid	Presence of angioedema	Atopy history	Family history of CSU	Family history of atopy	Duration of CSU (years)	Previous medications	Serum IgE level (kU/L)	UAS7			DLQI		Time to stop anti- histamine	Current status
									Baseline	Week five	Week nine	Baseline	Week nine
1, 56, F	Hypertension, diabetes mellitus, dyslipidemia, fatty liver	Yes	Bronchial asthma Atopic eczema	Nil	Nil	Five	Ciclosporin (not tolerating) Omalizumab (5 months)	1356	42 Wheals 21 Itch 21	15 (64.3% reduction) Wheals 6 Itch 9	10 (76.2% reduction) Wheals 4 Itch 6	8	1 (87.5% improve)	Ongoing	In remission
2, 70, M	Benign prostate hyperplasia, allergic contact dermatitis	No	Nil	Nil	Nil	Three	Methotrexate (4 months) Ciclosporin 6 months	-	32 Wheals 14 Itch 18	12 (62.5% reduction) Wheals 6 Itch 6	4 (87.5% reduction) Wheals 2 Itch 2	8	1 (87.5% improve)	Stopped at week eight	Three weekly
3, 76, M	Essential thrombocytosis, gout, hypertension, inverse psoriasis	No	Nil	Nil	Nil	Eight	Ciclosporin (15 months) Omalizumab (5 years)	-	42 Wheals 21 Itch 21	14 (66.7% reduction) Wheals 6 Itch 8	8 (81% reduction) Wheal 1 Itch 7	9	1 (88.9% improve)	Stopped at week 5	Weekly
4, 25, F	Thalassemia trait	Yes	Nil	Nil	Yes	One	Ciclosporin (5 months)	116	22 Wheals 17 Itch 8	14 (36.4% reduction) Wheals 6 Itch 9	0 (100% reduction)	5	0 (100% improve)	Stopped at week eight	In remission
5, 62, F	Gout, allergic contact dermatitis	Yes	Bronchial asthma	Nil	Nil	Two	Ciclosporin (9 months) Omalizumab (9 months)	4594	33 Wheals 16 Itch 17	27 (18.2% reduction) Wheals 11 Itch 16	9 (72.7% reduction) Wheals 5 Itch 4	11	10 (9% improve)	Ongoing	Weekly
6, 70, M	Hypertension, dyslipidemia	No	Nil	Nil	Yes	Two	High dose cetirizine (14 months) Colchicine (1 month)	105	35 Wheals 14 Itch 21	16 (54.3% reduction) Wheals 2 Itch 14	2 (93.3% reduction) Wheals 0 Itch 2	8	0 (100% improve)	Stopped at week four	In remission
7, 35, F	Allergic rhinitis, asthma	Yes	Allergic rhinitis Bronchial asthma	Nil	Yes	Three	High dose desloratadine (36 months) Colchicine (2 months)	1115	30 Wheals 12 Itch 18	22 (26.7% reduction) Wheals 7 Itch 15	0 (100% reduction)	9	0 (100% improve)	Stopped at week eight	In remission
8, 56, M	Allergic rhinitis, dyslipidaemia		Allergic rhinitis	Yes	Nil	10	Double antihistamines (cetirizine and loratadine) Intermittent prednisolone	-	21 Wheals 9 Itch 12	12 (42.9% reduction) Wheals 7 Itch 5	6 (71.4% reduction) Wheals 3 Itch 3	9	2 (77.8% improve)	Ongoing, high dose	Two weekly

All our patients showed good responses to AST. The earliest symptom reduction was experienced after the second therapy session. By week nine, there was a 71.4% to 100% reduction of UAS7 from baseline [Table 1]. Improvement of quality of life (QoL) assessed using DLQI was observed in more than 90% of patients. The number of wheals seemed to reduce first followed by pruritus. Three patients ceased antihistamines by week eight of treatment, while three patients achieved symptoms-free by week nine of treatment. The QoL of six patients (75%) improved remarkably at the end of the ninth treatment. Three patients achieved complete remission and had been antihistamine-free for at least nine months. No serious adverse events were reported in all eight patients.

Discussion

Autologous serum skin test (ASST) has been used to detect patients who have autoimmune urticaria.[2] These patients tend to have a greater number of wheals with wider distribution, pruritus with greater intensity, more frequent systemic symptoms, and a slower response to omalizumab.[3] ASST was not performed in our patients due to the difficulty in stopping antihistamines before ASST.

Autohemotherapy has been utilised in some countries, such as China, Germany, India, Iran, South Korea, Turkey, Mexico, and the United States of America, in the treatment of CSU.[4] The mechanisms of action behind AST remain to be elucidated and its efficacy remains a subject of controversy due to limited evidence. It was hypothesised that AST might be able to reduce the levels and effects of mast cell-degranulating IgE autoantibodies, such as IgE-anti-interleukin (IL)-24.[1] Interestingly, AST was shown to reduce the IgE autoantibodies level but not the IgG autoantibodies.[4] Staubach et al.[5] have shown that the result of ASST did not affect the efficacy of AST. There was no difference in terms of clinical improvement (graded as >30% reduction of UAS and DLQI scores) between ASST(+) and ASST(−) patients at weeks 0, 10, and 16.[5]

Kocatürk et al.[6] compared autologous whole blood (AWB), AST and placebo (normal saline) in ASST(+) and ASST(−). The AWB resulted in a significant improvement in UAS scores during treatment, but the efficacy was lost after treatment was discontinued. Notably, four of our patients experienced a recurrence of symptoms immediately after two weeks of cessation of AST. These observations could possibly be explained by the transient immune tolerance or improvement of the regulatory pathway of the immune system induced by the ‘desensitisation’ process. These patients required resumption of AST at an interval of two to three weeks.

The efficacy of AST in our study was consistent with other published observations.[1,5] CSU significantly affects patients’ QoL. Except for one patient, all our patients experienced a significant improvement in their QoL. Interestingly, the improvement of wheals and pruritus following AST was associated with a worsening of AD in two patients. Both of patients had underlying AD. This negative finding was in contrast with several other reports.[7,8] AST has been used as a complementary and alternative treatment modality for AD for more than 100 years in many regions, including Europe, Russia, Japan, India, China, and South America. However, a study conducted by Nahm et al.[9] showed that there were no significant differences in the changes in clinical severity of AD assessed by the Eczema Area and Severity Index (EASI) score. There are still limited data on the mechanism of AST in the adaptive immune system. Further studies are required to investigate the cellular and molecular mechanisms of AST in CSU.

Furthermore, the optimum length of treatment period from previous authors was somewhat arbitrary, with AST instituted up to a 12-, 16- or 20-week period. However, most of these authors agreed that therapy should be discontinued if there were no improvements by the eighth or ninth week.[1,10] Additionally, the dosage of serum injection was also somewhat arbitrary ranging from 0.025 ml/kgBW to 0.05 ml/kgBW.[1] Both of these issues should be further elucidated in future studies.

Conclusion

AST offers a promising alternative to refractory CSU, providing an affordable and effective approach with minimal adverse effects. Overall, 75% of our patients responded clinically and experienced significant improvement in QoL. Further research is necessary to better understand its mechanism of action, length of treatment period, dosage to be instituted and its effects on other dermatoses.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.