AIRO INTERNATIONAL JOURNAL VOLUME 6 ISSN 23203714



Role of Autologus Serum in Chronic Idiopathic Urticaria Submitted by: Dr. B.C. Ghiya (Associate Professor, SPMC Bikaner, Rajasthan ) ????????????????????????? Dr. Prasoon Soni? (Assistant Professor SPMC Bikaner, Rajasthan) ABSTRACT Chronic Idiopathic Urticaria is thought to affect at least 0.1% of population1,2 and has a chronic relapsing course, with approximately 20% of patients still having the disease after 10 years. Until recently, all cases of chronic urticaria (CU) were considered idiopathic in nature, since no definite cause is known in those cases. This issue was partially resolved in 1993 when Hide?et al3 reported that auto-antibodies against the high-affinity IgE receptor, FCERI,?cause histamine release in a subset of patients with CU. Subsequent reports established that 27-61%4-7?of CU patients, depending on the method of antibody detection, had these circulating antibodies in their blood. Patients with these circulating antibodies are considered under category of chronic autoimmune urticaria.(CAU) The Basophil histamin release assay is currently the “gold standard” for detecting patients of chronic autoimmune urticaria. However, this bioassay is confined mainly to research centers. Western blotting and other assays, including enzyme linked immunosorbent assay and flow cytometry are tedious tests requiring specialist services and still need to be validated. ASST is the simplest method to identify the patients of chronic autoimmune urticaria. Background : Chronic urticaria (CU) is a common and distressing dermatosis characterized by the appearance of evanescent wheals almost daily, continuously for six or more weeks. Chronic urticaria is a clinical diagnosis. Aim : To evaluate efficacy of autologous serum therapy in autologous serum skin test(ASST) (+) and (-) patients of chronic urticaria. Material & Methods: A prospective randomized clinical study was conducted on 40 patients of chronic urticaria, attending outpatient department of Skin, STD and Leprosy of our institute. Out of which 20 patients were ASST (+) and 20 patients were ASST (-). All the patients were treated with 2ml intramuscular injection of autologous serum weekly for 9 weeks and followed up for 12 weeks after completion of therapy. Results : Our results at 21 weeks showed, out of total 20 ASST (+) group, 7, 5 and 4 patients had complete, marked and moderate improvement respectively while 4 cases had no improvement. In ASST (-) group, 4 patients each had complete and marked improvement while 3 cases had moderate improvement and 9 cases had no improvement at all. Mean improvement in ASST (+) cases was 6.106.03 and in ASST (-) cases it was 8.506.01 and the difference was found to be statistically insignificant (p>0.05). Conclusion : We conclude that autologous serum therapy is effective treatment in chronic urticaria irrespective of their auto-reactive urticaria status. Key Words : Chronic Urticaria, Autologous serum therapy, Autologous serum skin test. INTRODUCTION Chronic Idiopathic Urticaria is thought to affect at least 0.1% of population1,2 and has a chronic relapsing course, with approximately 20% of patients still having the disease after 10 years. Until recently, all cases of chronic urticaria (CU) were considered idiopathic in nature, since no definite cause is known in those cases. This issue was partially resolved in 1993 when Hide?et al3 reported that autoantibodies against the high-affinity IgE receptor, FCERI,?cause histamine release in a subset of patients with CU. Subsequent reports established that 27-61%4-7?of CU patients, depending on the method of antibody detection, had these circulating antibodies in their blood. Patients with these circulating antibodies are considered under category of chronic autoimmune urticaria.(CAU) The Basophil histamin release assay is currently the “gold standard” for detecting patients of chronic autoimmune urticaria. However, this bioassay is confined mainly to research centers. Western blotting and other assays, including enzyme linked immunosorbent assay and flow cytometry are tedious tests requiring specialist services and still need to be validated. ASST is the simplest method to identify the patients of chronic autoimmune urticaria. MATERIAL AND METHODS A prospective randomized clinical study was conducted on 40 patients of chronic urticaria, attending outpatient department of Skin, STD and Leprosy. The cases of chronic urticaria were diagnosed on the basis of typical clinical manifestation. Physical drug-induced and infection-related urticaria was diagnosed by thorough history-taking and relevant investigations.?Patients with CIU were screened and autologous serum skin test (ASST) was done in all. After screening for inclusion and exclusion criteria, ASST (+) patients and ASST (-) patients were recruited for the study.?History (current, past, family and other illnesses), details about lesion (number, site and size) & urticaria total severity score, treatment taken and follow-up were recorded in a printed proforma. Patient’s Selection Criteria Patients willing for weekly injections, in the age group of 18 to 60 years, having total severity score of more than 13 and almost daily appearance of wheals for ≥ 2months without antihistamines were included in study. Exclusion criteria Pregnant women and patients with physical urticaria, drug-induced and infection-related urticaria, patients on systemic corticosteroid or immunosuppressive drug in the past 6 weeks or taking treatment for other systemic illnesses were excluded.? Autologous Serum Skin Test (ASST) All antihistamines were withdrawn 2 days prior to skin test. Venous blood was taken into sterile glass tubes without clotting accelerators and allowed to clot at room temperature for 10 minutes. Serum was separated by centrifugation at 2000 rpm for 10 minutes.0.1cc of autologous serum and sterile saline were injected into volar aspects of forearm leaving a gap of 5cms between each injection site using a 31-gauge needle avoiding areas involved in spontaneous wheals in the last 24 hours. Wheal and flare responses were measured at 30 minutes after injection. ASST was considered positive when the average of two perpendicular diameters of the autologous serum wheal was ≥1.5 mm more than the normal saline wheal. A scoring system was used to evaluate the therapeutic response to autologous serum therapy8. Parameters Scores 0 1 2 3 Number of wheals None <10 11-50 >50 Size of wheals None < 1cm 1-3cm >3cm Intensity of pruritus None Mild Moderate Severe Duration of persistence None < 1hr 1-12hr >12hr Frequency of appearance None Once a week 2-3 times a week Daily/ almost daily Frequency of antihistamine use None Once a week 2-3 times a week Daily/ almost daily ? Based on 0-18 Total Severity Score (TSS) was generated and overall disease severity classified as ????????? Clear (TSS = 0), ????????? Mild (TSS 1-6), ????????? Moderate (TSS 7-12), ????????? Severe (TSS 13-18). To account for the powerful placebo effect of weekly injections, we attached less importance to the response immediately after the 9-week treatment period. A period of 12weeks longer than the treatment duration was allowed to elapse before the follow-up assessment to ascertain actual long-lasting improvement/remission. The main outcome measure was the fall in total severity scores at the 21 week follow-up visit. Treatment given The baseline parameters were recorded after a week's run-in period in which patients were allowed to take a short-acting antihistamine orally (pheniramine 25 mg) only when wheals appeared. Thereafter, every week for nine consecutive weeks, 5 ml blood was drawn, serum separated and a 2-ml deep intramuscular injection was given in alternate buttocks. Rescue antihistamine was permitted as in the run-in period; no other drugs were permitted. At 21 weeks of follow-up, score were assessed as ????????? 0 = complete remission, ????????? 1-6 = marked improvement, ????????? 7-12 = moderate improvement, ????????? 13-18 = poor/no improvement. RESULTS Mean age in ASST (+) cases was 29.809.67 years and in ASST (-) cases was 30.5511.09 and difference found to be statistically insignificant (p>0.05). No statistical significant difference in male and female patients. Most of the patients in both the groups were students. Mean duration of disease in ASST (+) cases was 28.9029.28 months and in ASST (-) cases, mean duration of disease was 27.7533.66 months and the difference was found to be statistically insignificant (p>0.05). ASST (+) patients had similar mean baseline TSS when compared to ASST (-) patients, but mean appearance of wheal and antihistamine use which were higher in ASST (+) cases as compared to ASST (-) cases. While no statistical significant difference was found in TSS at the 9th week and 21 weeks. Mean number of wheals and pill burden at 21 weeks declined more in ASST (+) patients than ASST (-). Patients in both the groups showed a downward trend in TSS from baseline to the end of treatment and to the 21 week. At the baseline all the patients were in severe grade in either group. At the final follow up Out of total 20 ASST (+) cases, 7, 5 and 4 had completely, marked and moderate improvement respectively, while 4 cases had no improvement. In ASST (-) group, 4 patients each had complete and marked improvement while 3 cases had moderate improvement and 9 cases had no improvement at all. Mean improvement in ASST (+) cases was 6.106.03 and in ASST (-) cases it was 8.506.01 and the difference was found to be insignificant (p>0.05). DISCUSSION The present study was undertaken to evaluate the effectiveness of Autologous serum therapy (AST) in ASST (+) and ASST (- ) patients of chronic urticaria. Chronic urticaria is a chronic, relapsing and recalcitrant disorder, which makes the patient to suffer not only physically but also psychologically. This could be an extremely disabling and difficult-to-treat condition and adversely affect the quality of life of the sufferer9. Autoimmune urticaria is a subset of chronic urticaria where the disease is caused by histamine releasing autoantibodies and hence these patients may benefits from the manipulation of the immune system. Independent of the likely heterogeneous identity of serum factors responsible for degranulating mast cells after intradermal injections in ASST (+) patients, it appeared feasible to attempt to tolerize such CU patients to their respective circulating mast cell secretagogues10. Although in literature the therapy consisted of intramuscular injection of autologous whole blood, we used serum instead of whole blood because of various factors: 1.????? It is the serum that is injected while performing ASST which shows positive response since it contains the autoantibodies. This suggests that the factor that causes positive ASST is present in the serum. Hence injection of serum would also result in similar response as would be expected with whole blood injection. The circulating autoreactive factor is present in the serum, not in the cellular components of blood. 2.????? Finer needles can be used for injecting serum compared to those with whole blood, reducing patient discomfort and increasing compliance. 3.????? Whole blood must be injected as quickly as possible after being drawn to avoid the possibility of clotting, requiring increased patient co-operation. We found that our results were somewhat similar to the study conducted by Bajaj et al8 and Patil et al11. In the present study at the final follow up visit i.e. at 21 weeks we found that, in ASST (+) group, 35% patients (n=7) were completely cured and 25% patients (n=5) showed marked improvement. In ASST (-) group, 20% patients (n=4) were completely cured and another 20% patients showed marked improvement, while Bajaj et al8 found that 35.5% patients were completely cured & 24.2 % had only mild disease in ASST (+) group and these figures were 23 % & 23 % in ASST (-) group. Staubach et al12 evaluated efficacy of autologous whole blood (AWB) in chronic urticaria. They used autologous whole blood injections weekly for 8 weeks and follow up evaluation done at 4 weeks after the last injection. They found that 70% ASST (+) patients showed a significant improvement in their signs and symptoms which is higher than that seen in present study (60%).However these two studies are not easily comparable since they used a somewhat different scoring system and shorter follow up period. In a study by Debbarman et al11 54 patients were given AST and 57 patients were given injection NS as a placebo. Out of the 54 patients who received AST, 20 patients were ASST (+) and 34 patients were ASST (-). They found that those who received AST had significant decline in TSS irrespective of their autoreactive urticaria status. Autoreactive urticaria took two weeks more time for significant decline from baseline TSS than non-autoreactive variety, though the intergroup comparison showed no significant difference at every follow up. In the present study we also found similar results as the intergroup comparison of baseline TSS, at 9 weeks and at 21 weeks showed no significant difference. In the present study AST was well tolerated. Three patients were reported to have acneform eruptions that may due to any other cause. In a study by Bajaj et al8 none of the patients reported any side effects except local soreness lasting from 12 to 24 hours. In a study by Debbarman et al11 sedation, dryness of mouth, epigastric pain, nausea and diarrhea were spontaneously reported adverse events. Table 1 Comparative Total Severity Score (TSS)? 0 Week 9 week 21 weeks Positive Negative p Positive Negative p Positive Negative P Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD Number of Wheals 2.40 0.50 2.65 0.49 0.119 0.95 0.69 1.30 1.03 0.214 1.10 1.17 1.65 1.14 0.139 Size of Wheals 2.55 0.60 2.65 0.49 0.569 1.00 0.73 1.15 0.81 0.542 1.05 1.10 1.50 1.05 0.194 Pruritus 2.65 0.59 2.60 0.60 0.791 1.10 0.91 1.10 0.91 1.000 0.95 0.99 1.25 1.16 0.387 Persistent 1.65 0.59 2.00 0.56 0.062 1.00 0.73 1.15 0.88 0.559 0.80 0.77 1.35 0.93 0.049 Appearance 2.90 0.31 2.55 0.60 0.027 1.25 0.97 1.35 1.04 0.754 1.15 1.14 1.50 1.05 0.318 Antihistamine Use 2.90 0.31 2.55 0.60 0.027 1.00 0.86 1.25 1.12 0.433 1.05 1.19 1.25 1.16 0.594 Total Score 15.05 1.82 15.00 1.62 0.927 6.30 0.41 7.30 5.39 0.525 6.10 6.03 8.50 6.01 0.251 ? ?Advantages of AST Inexpensive and easy modality of treatment which can be used in resource poor set up for autoimmune urticaria patients and less time consuming when centrifuge is available for sera separation. Disadvantages of AST An invasive procedure which involves needle prick. The procedure consumes time for sedimentation and separation of sera unless a centrifuge is used to quicken the process. It is logistically difficult for patients to follow up weekly for therapy. CONCLUSION We conclude that autologous serum therapy is effective treatment in chronic urticaria irrespective of their auto-reactive urticaria status. REFERENCES 1.????????? Greaves MW. Chronic urticaria. N Engl J Med 1995;332:1767-72. 2.????????? Hellgren L. The prevalence of urticaria in the total population. Acta Allergol 1972;27:236-40 3.????????? Hide M, Francis DM, Grattan CE, Hakimi J, Kochan JP, Greaves MW. Autoantibodies against the high affinity IgE receptor as a cause of histamine release in chronic urticaria. N Engl J Med 1993;328:1599-604. 4.????????? Godse KV. Autologous serum skin test in chronic idiopathic urticaria. Indian J Dermatol Venereol Leprol 2004;70:283-4.? 5.????????? Fiebiger E, Maurer D, Holub H et al.?Serum IgG autoantibodies directed against the alpha chain of Fc epsilon RI: A selective marker and pathogenetic factor for a distinct subset of chronic urticaria patients? J Clin Invest 1995;96:2606-12. 6.????????? Ferrer M, Kinet JP, Kaplan AP. Comparative studies of functional and binding assays for IgG anti Fc epsilon Riα (α-subunit) in chronic urticaria. J Allergy Clin Immunol 1998;101:672-8.? 7.????????? Piconi S, Trabattoni D, Iemoli E, Fusi ML, Villa ML, Milazzo F?et al.?Immune profiles of patients with chronic idiopathic urticaria. Int Arch Allergy Immunol 2002;128:59-66.? 8.??????????? Bajaj AK, Saraswat A, Upadhyay A, Damisetty R, Dhar S, Autologous serum therapy in chronic urticaria : Old wine in new bottle.Indian J Dermatol Venereol Leprol 2008;74:109-13 9.????????? Mori O, Hashimoto T. Autologous whole blood intramuscular injection as a cure for chronic urticaria: report of a patient in whom intradermal injection of autologous serum continued to cause a weal-and-flare response. Br J Dermatol 1999;140:1192-1193. 10.????? Debbarman P, Sil A, Datta PK, Bandyopadhyay D, Das NK. Autologous serum therapy in chronic urticaria: A promising complement to antihistamines. Indian J Dermatol 2014;59:375-82. 11.????? Patil S, Sharma N, Godse K. Autologous serum therapy in chronic urticaria. Indian J Dermatol 2013;58:225-6. 12.????? Staubach P, Onnen K, Vonend A, Metz M, Siebenhaar F, Tschentscher I?et al.?Autologous whole blood injections to patients with chronic urticaria and a positive autologous serum skin test: A placebo-controlled trial. Dermatology 2006;212:150-9.? ................
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