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Journal of Pakistan Association of Dermatologists 2013; 23 (4): 378-383. Original Article Comparative evaluation of autologous serum skin test and autologous plasma skin test in chronic urticaria Sohail Ali Baig, C Balachandran, Sudhir Nayak Department Of Dermatology, Kasturba Medical College, Manipal, Manipal University, India Abstract Objective To compare autologous serum skin test (ASST) and autologous plasma skin test (APST) in the diagnosis of autoimmune urticaria Patients and methods A prospective study was done in patients with chronic urticaria. Autologous plasma and serum skin tests were performed in all patients who were meeting the inclusion and exclusion criteria and readings were taken at the end of 30 minutes. Results Fifty-nine patients (Males-25 and Females-34) were enrolled in the study. ASST was positive in 24 (40.7%) and APST was positive in 27 (45.8%) out of 59 patients. 20 (33.9%) were positive to both ASST and APST, 28 (47.5%) were negative to both ASST and APST. Conclusion ASST and APST are two simple, inexpensive and easy to do in-office procedures which can be used to diagnose autoimmune urticaria. APST was slightly superior to ASST in diagnosing autoimmune urticarial in our study. Although many patients showed positivity to both tests, significant numbers of patients were positive to only one test. We thus recommend the performance of both ASST and APST in all patients of chronic urticaria to detect those patients of chronic autoimmune urticaria. Key words Autologous serum skin test, autologous plasma skin test, autoimmune chronic urticaria Introduction Chronic urticaria is one of the commonest dermatological problems encountered in clinical practice which is characterized by wheals occurring daily or almost daily for duration of more than 6 weeks. The term chronic idiopathic urticarial is used when no definitive cause for urticarial can be ascertained.1 Autoimmune urticarial is used to refer to those patients with Address for correspondence Dr. Sudhir Nayak U.K., Assistant Professor, Department of Dermatology, Kasturba Medical College, Manipal University, Manipal-576104, India Ph#: 9900412394 Email: [email protected] chronic urticaria who tend to have histamine releasing autoantibodies and who tend to develop wheal and flare response on intradermal testing with their own sera.2 The gold standard tests for the detection of autoimmune urticaria are the basophil histamine release assay and flow cytometric basophil activation test.3 The commonly utilized clinical test for detection of autoantibodies is the autologous serum skin test (ASST) which has a sensitivity of 70% and specificity of 80% and is considered as a screening test.3,4 Another test which has found favour among clinicians in detection of autoimmune urticarial is the autologous plasma skin test (APST), which is considered to be more sensitive.4 378 Journal of Pakistan Association of Dermatologists 2013; 23 (4): 378-383. This study was undertaken to investigate skin autoreactivity in chronic idiopathic urticaria by using plasma anticoagulated with sodium citrate and compare autologous plasma skin test (APST) with autologous serum skin test (ASST). Patients and methods A case-control study was conducted at the department of dermatology in a tertiary care hospital. Inclusion criteria of study were: patients with history of wheals of more than 6 months duration. Following patients were excluded: patients on oral corticosteroids for past 1 month, patients on oral anti-histamines for past 72 hours, pregnant and lactating women, patients with urticarial vasculitis, patients with a history of type I hypersensitivity, patients with physical urticaria other than simple dermographism. Patients selected on the basis of inclusion and exclusion criteria were enrolled in the study and an informed written consent was obtained. 5ml of venous blood was obtained in two different containers. To one of the containers, sodium citrate was pre-added to obtain plasma. Both the containers were centrifuged at 2500 rpm for 5 minutes within 5 minutes of blood withdrawal. Using an insulin syringe 0.05ml of thus obtained serum, plasma and saline were administered intradermally on the volar aspect of the forearm and reading was taken at the end of 30mins. The formation of wheal of at least 3mm with simultaneous development of erythema was considered as a positive reaction when accompanied with a negative reaction to saline. Results Fifty-nine patients were included in the study of whom 25 were males and 34 were females. The mean age of the patients was 34 years. Routine laboratory investigations like complete blood picture, urine examination, renal, liver and thyroid function tests were normal in all patients. ASST was positive in 24 (40.7%) and APST was positive in 27 (45.8%) out of 59 patients. 20 (33.9%) were positive to both ASST and APST, 28 (47.5%) were negative to both ASST and APST. Seven patients were APST positive and ASST negative, and 4 negative for APST and positive ASST (Table 1). McNemar test showed no statistical significance. Table 1 Frequency of positive results with autologous plasma skin test (APST) with autologous serum skin test (ASST). APST positive APST negative Total ASST positive 20 (33.9%) 4(6.8%) 24 (40.7%) ASST negative 7 (11.9%) 28 (47.4%) 35 (59.3%) Total 27 (45.8%) 32 (54.2%) 59 (100%) Table 2 Frequency of positive results with autologous plasma skin test (APST) in patients with history of angioedema. APST positive APST negative Total Angioedema history present 16 8 24 Angioedema history absent 11 24 35 Total 27 32 59 Table 3 Frequency of positive results with autologous serum skin test (ASST) in patients with history of angioedema. ASST positive ASST negative Total Angioedema history present 15 9 24 Angioedema history absent 9 26 35 Total 24 35 59 379 Journal of Pakistan Association of Dermatologists 2013; 23 (4): 378-383. 16 14 12 10 8 Males 6 Females 4 2 0 APST ASST Figure 1 Gender wise positivity of autologous plasma skin test (APST) with autologous serum skin test (ASST). Table 4 Autologous serum skin test (ASST) positivity in various studies. Study Year of ASST positives publication Sajedi et al..[1] 2011 38/58 (65.5%) Irinyi et al. [3] 2012 34/46 (74%) Sabroe et al. [6] 1999 38/54 (70%) # Nettis et al. [7] 2003 54/125 (43%) Yildiz et al. [8] 2011 26/42 (62%) Krupashankar et al. [9] 2012 47/80 (58.7%) Bakos et al. [10] 2003 26/48 (54.2%) George et al. [11] 2008 34/100 (34%) Godse [12] 2008 14/30 (46.7%) Asero et al. [13] 2006 51/96 (53%)* Metz et al. [14] 2009 75/200 (37.5%) Nettis et al. [15] 2002 42/102 (41.2%) Staubach [16] 2006 53/135 (39.2%) Bajaj [17] 2007 195/394 (49.5%) Present study 24/59 (40.7%) Note: # ASST was measured with varying diameters in the study, but 38/54 were for the criteria of serum wheal diameter ≥ 1.5mm Table 5 Comparative analysis of autologous serum skin test (ASST) and autologous plasma skin test (APST) in various studies. Study ASST positives APST positives Both ASST and ASST alone APST alone Both ASST APST positive positive positive and APST negative Sajedi et al. [1] 38/58 (65.5%) 45/48 (77.6%) 37/58 (63.8%) 1/58 (1.7%) 8/58 (13.8%) 12/58 (20.7%) Yildiz et al. [8] 26/42 (62%) 28/42 (67%) 26/42 (61.9%) 0 2/42 (4.8%) 14/42 (33.3%) Godse [12] 14/30 (46.7%) 14/30 (46.7%) 14/30 (46.7%) 0 0 16/30 (53.3%) Asero et al. [13] 51/96 (53%)* 61/71 (86%) 40/41 (98%) 1 21/30 (70%) 9 Metz et al. [14] 75/200 (37.5%) 86/200 (43%) 57/200 (28.5%) 18/200 (9%) 29/200 (14.5%) 96/200 (48%) Present study 24/59 (40.7%) 27/59 (45.8%) 20/59 (33.9%) 4/59 (6.8%) 7/59 (11.9%) 28/59 (47.4%) Note: * only 71 out of 96 patients were subjected to APST with sodium citrate. 25 patients were subject to potassium EDTAAPST-potassium, but as potassium EDTA led to non-specific reactions, these patients were excluded. Only the remaining 71 patients were subject to APST- sodium citrate. 380 Journal of Pakistan Association of Dermatologists 2013; 23 (4): 378-383. Table 6 Diagnostic criteria for positive autologous serum skin test (ASST) and autologous plasma skin test (APST) in various studies. Study and year of Criteria for ASST positive Criteria for APST positive publication Sajedi et al. [1], 2011 Wheal at least 3mm more than saline and Patients with saline wheal >3mm and patients histamine wheal also at least 3mm more than with difference in wheal diameter < 3mm saline between histamine and saline were excluded. Wheal of plasma not mentioned Irinyi et al. [3], 2012 Wheal with diameter ≥1.5mm of saline at 30 Not done min Sabroe [6], 1999 Wheal with diameter ≥1.5mm of saline at 30 Not done min (Recommended). Other diameter ranging from 0.5mm to 2.5mm was also considered. Nettis et al. [7], 2003 Wheal with diameter ≥1.5mm of saline at 30 Not done min Yildiz et al. [8], 2011 Wheal red and diameter ≥1.5 mm of saline at Wheal more than 3mm and ASST, sodium 30 min citrate skin test and saline skin test negative Krupashankar et al. [9], Wheal red and with diameter ≥ 1.5 mm of Not done 2012 saline at 30 min. Bakos et al. [10], 2003 Wheal at least 1.5mm diameter more than Not done saline at 30 min George et al. [11], 2008 Wheal red with diameter ≥ 1.5mm of saline at APST not done 30 min Godse [12], 2008 Wheal and flare reaction with wheal diameter Wheal and flare reaction with wheal diameter at at least 1.5mm more than saline at 30 min least 1.5mm more than saline at 30 min Nettis et al. [15], 2002 Wheal of serum at least 1.5 mm more than APST not done saline induced wheal at 30 min and reassessed at 60 min Staubach [16], 2006 Wheal at least 1.5mm more than wheal of APST not done human serum albumin at 30 min Bajaj [17], 2007 Average of 2 perpendicular diameters of APST not done serum ≥1.5mm of saline at 30 min Present study, 20013 Wheal of at least 3mm with accompanying Wheal of at least 3mm with accompanying flare flare and no wheal with saline at the end of and no wheal with saline at the end of 30mins 30mins 13 (52%) of 25 male patients were positive for ASST. 11 (32.4%) of the 34 female patients were positive for ASST. There was no statistical significance as per Pearson Chi-square test. However statistical significance as per Pearson Chi-square test (0.071) was noted in the APST results, with 15 (60%) males and 12 (35.3%) female patients being positive for APST. Out of the 59 patients, twenty four patients had associated angioedema. Out of the 24 patients, APST and ASST were positive in 16 and 15 patients respectively, which was statistically significant (Tables 2 and 3). Discussion Autoimmune urticaria comprises nearly 35% of all chronic urticaria patients.5 Autoimmune urticaria is often associated with other autoimmune diseases and is often refractory to standard doses of anti-histamines. Ruling out autoimmune urticaria is therefore prudent before labeling a person as having chronic idiopathic urticaria. Tests like western blot, basophil histamine release assays and enzyme-linked immunosorbent assay (ELISA) for detection of functional autoantibodies are expensive and not easily available.6 ASST and ASPT are two inexpensive, easy to do common tests that can be performed clinical set up. The sensitivity and specificity of the tests tend to vary from study to do. ASST is considered to be positive only 381 Journal of Pakistan Association of Dermatologists 2013; 23 (4): 378-383. during stage of clinically activity.2 APST on the other hand tends to remain positive even after cessation of clinical activity.4 Plasma contains complements, coagulation factors and proteins than serum and thus plasma is considered to be more autoreactive than serum.1,8 (62.5%) patients, respectively. Angioedema was present in 9/35 (25.7%) ASST-negative and 8/32 (25%) APST-negative patients. A previous study reported 29/42 (69%) of angioedema patients with a positive ASST and angioedema in 26/60 (43.3%) patients.15 In our study ASST was positive in 24/49 (40.7%). This is similar to earlier reported studies which have reported a positive ASST ranging from 34% to 74% (Table 4). In our study a positivity of APST was seen in 27/59 (45.8%) patients was seen. This was almost similar to previous studies which showed a positivity of 43% to 86%.1,8,12-14 Our study had values similar to Godse et al.12 (46.7%) and Metz et al.14 (43%). Conclusion Eleven out of the fifty nine patients were positive to either ASST or APST (Table 5). Thus if only one of these were performed, then a significant percentage of patients would miss the diagnosis of autoimmune urticaria and would have been erroneously labeled as idiopathic. Variation in the diagnostic criteria for size of wheals has been cited as a reason for the variation in positivity in various studies (Table 6). Most studies for ASST have used the development of wheal at least 1.5 mm more in diameter than saline as the diagnostic criteria.3,612 In our study, we had wheal with more than 3mm with plasma and serum with an accompanying flare and an absence of wheal with saline as diagnostic criteria. This strict absence of reaction to negative control as diagnostic criteria was in comparison to other studies. In spite of such stringent diagnostic criteria, we had results which were comparable with previous studies. Out of 24 patients with angioedema, ASST and APST were positive in 16 (66.7%) and 15 ASST is perhaps the commonest test performed for evaluation of patients with chronic autoimmune urticaria. Both ASST and APST are inexpensive, easy to perform office based procedures with relatively low downtime for results. In our study, we found out that APST was positive in more patients than ASST. Although patients positive for one test were positive for the other test in majority of the patients in our study there was a significant number of patients who were positive to only one test. We thus recommend the performance of both ASST and APST in all patients of chronic urticaria to detect those patients of chronic autoimmune urticaria. Further studies with a larger sample size are advocated. References 1. 2. 3. 4. Sajedi V, Movahedi M, Aghamohamadi A et al. Comparison between sensitivity of autologous skin serum test and autologous plasma skin test in patients with chronic idiopathic urticaria for detection of antibody against IgE or IgE receptor (FcεRIα). Iran J Allergy Asthma Immunol. 2011;10:111-7. Haldar B, Ghosh S, Haldar S. Cutaneous vascular responses. In: Valia RG, Valia AR, editors. IADVL Textbook of Dermatology.3rd ed. Mumbai: Bhalani Publishing House; 2008. p. 665-6 Irinyi B, Gyimesi E, Garaczi E et al. Extended diagnostic value of autologous serum test and basophil CD63 expression assay in chronic urticarial. Br J Dermatol. 2012; doi: 10.1111/j.1365-2133.2012.11179. Nichols KM, Cook-Bolden FE. Allergic skin disease: Major highlights and recent 382 Journal of Pakistan Association of Dermatologists 2013; 23 (4): 378-383. advances. Med Clin North Am. 2009;93:1211-24. 5. Amar SM, Dreskin SC. Urticaria. Prim Care Clin Office Pract. 2008;35:141-57. 6. Sabroe RA, Grattan CEH, Francis DM et al. The autologous serum skin test: a screening test for autoantibodies in chronic idiopathic urticaria. Br J Dermatol. 1999;140:446-52. 7. Nettis E, Pannofino A, D’ Aprile C et al. Clinical and aetiological aspects in urticaria and angio-edema. Br J Dermatol. 2003;148:501-6. 8. Yildiz H, Karabudak O, Doğan B, Harmanyeri. Evaluation of autologous plasma skin test in patients with chronic idiopathic urticaria. Br J Dermatol. 2011;165:1205-9. 9. Krupashankar KS, Shashikala K, Madala R. Clinical and investigative assessment of patients with positive versus negative autologous serum skin test. Indian J Dermatol. 2012;57:434-8. 10. Bakos M, Hillander M. Comparison of chronic autoimmune urticaria with chronic idiopathic urticaria. Int J Dermatol. 2003;42:613-5. 11. George M, Balachandran C, Prabhu S. Chronic idiopathic urticaria: Comparison of clinical features with positive autologous serum skin test. Indian J Dermatol Venereol Leprol. 2008;74:105-8. 12. Godse KV. Autologous serum skin test v/s autologous plasma skin test. Indian J Dermatol Venereol Leprol. 2008;74:496-7. 13. Asero R, Tedeschi A, Riboldi P et al. Plasma of patients with chronic urticarial shows signs of thrombin generation and its intradermal injection causes wheal and flare reactions more frequently than autologous serum. J Allergy Clin Immunol. 2006;117:1113-7. 14. Metz M, Gime´nez-Arnau A, Borzova E et al. Frequency and clinical implications of skin autoreactivity to serum versus plasma in patients with chronic urticaria. J Allergy Clin Immunol. 2009;123:705-6. 15. Nettis E, Dambra P, D'Oronzio L et al. Reactivity to autologous serum skin test and clinical features in chronic idiopathic urticaria. Clin Exp Dermatol. 2002;27:2931. 16. Staubach P, Onnen K, Vonend A et al. Autologous whole blood injections to patients with chronic urticaria and a positive autologous serum skin test: A placebocontrolled trial. Dermatology. 2006;212:150-9. 17. Bajaj AK, Saraswat A, Upadhyay A et al. Autologous serum therapy in chronic urticaria: Old wine in new bottle. Indian J Dermatol Venereol Leprol. 2008;74:109-13. 383