Original Article. Barvaliya M, Sanmukhani J, Patel T, Paliwal N, Shah H 1, Tripathi C

Transcription

1

2 Original Article Drug-induced Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS-TEN overlap: A multicentric retrospective study Barvaliya M, Sanmukhani J, Patel T, Paliwal N, Shah H 1, Tripathi C Department of Pharmacology, Government Medical College, Bhavnagar, 1 Department of Dermatology, Venerology and Leprosy, Sir Takhtsinhji General Hospital and Government Medical College, Bhavnagar, Gujarat, India Address for correspondence: Dr. C.B. Tripathi, cbrtripathi@yahoo. co.in Received : Review completed : Accepted : ABSTRACT Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare immunemediated severe cutaneous adverse reactions with incidence rate of 0.05 to 2 persons per million populations per year. Drugs are the most commonly implicated in 95% of cases. Aims: To audit the causative drugs, clinical outcome, and cost of management in SJS, TEN, and SJS-TEN overlap. Setting and Design: Tertiary care hospitals-based multicentric retrospective study (case series). Materials and Methods: Indoor case papers of SJS, TEN, and SJS-TEN overlap admitted between January 2006 and December 2009 in four tertiary care hospitals of Gujarat were scrutinized. Data were collected for demographic information, causative drugs, investigations, treatment given, duration of hospital stay, time interval between onset of symptoms and drug intake, clinical outcome, and complications. Data were analyzed to find out proportion of individual drugs responsible, major complications, and clinical outcome in SJS, TEN, and SJS-TEN overlap. Total cost of management was calculated by using cost of drugs, investigations, and consumables used during entire hospital stay. Statistical Analysis: One-way Analysis of Variance followed by Tukey-Kramer multiple comparison test was used for comparison of incubation period, duration of hospital stay, and cost of management. Results: Antimicrobials (50%), nonsteroidal anti-inflammatory drugs (22.41%), and antiseizure drugs (18.96%) were the most commonly associated groups. Nevirapine (28.12%) was the most common drug. Antiseizure drugs were more often associated with serious form of adverse reaction (TEN: 81.8%) than other drugs. Duration of hospital stay (20.6 vs 9.7 days) and cost of management (` 7 910/- vs ` 2 460/-) were significantly higher in TEN than SJS (P=0.020 and P<0.001, respectively). Time duration between drug intake and onset of symptoms (17.7 vs 27.5 days) was nonsignificantly lower in TEN as compared with SJS. Secondary infection (28.12%) was the most common complication noted. Mortality rate was 15.6% among all cases; 9% in SJS and 26.7% in TEN. Conclusion: Antimicrobial drugs are the most commonly implicated drugs and cost of managing these adverse drug reactions is higher than other serious ADRs. KEY WORDS: Adverse drug reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis A dverse Quick Response Code: Introduction drug reactions (ADRs) hold special importance in healthcare as they account for 6% of total hospital Access this article online Website: DOI: / PubMed ID: Journal of Postgraduate Medicine April 2011 Vol 57 Issue 2 *** admissions, increase in economic burden on healthcare system, withdrawal of drugs from market, and death. [1-3] Among the various ADRs, cutaneous adverse reactions like skin rashes, urticaria, itching, fixed drug eruption, angioedema, erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) are the common ones. [4,5] In this wide spectrum of cutaneous reactions, SJS and TEN are rare but serious form of ADRs affecting patient s life. [4] SJS and TEN are immune-mediated reactions, due to various etiological factors like drugs, infections, malignancy, and radiation therapy. [5] Drugs are the most commonly implicated in 95% of cases. [5] Incidence of SJS and TEN is 0.05 to 2 persons per million populations per year. [6,7] Incidence is higher in HIV patients than general 115

3 population. [8] Clinically, SJS and TEN are characterized by polymorphic lesions like erythematous macules, papules, plaque, vesicles, and bullae predilected to distal extremities with Nikolsky s sign positive. Target lesion with bull s eye appearance is characteristic of SJS and TEN. Oral, genital, and conjunctival mucosa is often involved in the form of erosion or ulceration. [9] The basic difference between SJS and TEN is the percentage of body surface area (BSA) involved: <10% in SJS; >30% in TEN; 10 to 30% in SJS-TEN overlap. [5,9] No confirmatory in vivo or in vitro tests are available for identifying offending agents in SJS and TEN. [9] Moreover, a rechallenge in a case is not ethically justified as these are the life-threatening reactions. So, to identify the drugs associated with risk of causing severe skin reactions, retrospective epidemiological data are required. This study was aimed to audit the causative drugs, clinical outcome, and economic burden due to these serious ADRs. This study also helped us to know the changing pattern of most common causative agents for SJS and TEN. Materials and Methods This multicentric study was started after approval from Institutional Review Board, Government Medical College, Bhavnagar, Gujarat. Permission for data collection at other centers was taken from the head of the respective institutions. Indoor case papers of SJS, TEN, and SJS-TEN overlap admitted between January 2006 and December 2009 in Sir Takhtsinhji General Hospital, Bhavnagar; Pandit Deendayal Upadhyay Civil Hospital, Rajkot; New Civil Hospital, Surat; and Sir Sayaji General Hospital, Vadodara were scrutinized. Data were collected for demographic information, causative drugs, time duration between drug intake and onset of symptoms, BSA involvement, duration of hospital stay, treatment given, complications, and clinical outcome. Cases with doubtful diagnosis and insufficient data were excluded from the study. Data were analyzed to find out the proportion of individual drugs involved, major complications, and cost of management for SJS, TEN, and SJS-TEN overlap. Total cost of management was calculated by using cost of drugs (average cost of drugs from IDR-triple i Drug Compendium), investigations, and consumables used during entire hospital stay. [10] Ward and nursing charges were not included in the management cost. SCORTEN score was calculated for each case at the time of admission and its relation with mortality was compared in the study. [11] Results are expressed as percentages and mean (95% confidence interval [CI]). Comparisons between the three groups were performed by using One-way Analysis of Variance (ANOVA) followed by Tukey-Kramer multiple comparison test. A P value of less than 0.05 was considered significant. All statistical analyses were performed with GraphPad InStat 3 (demo version). Results Of the 46 cases scrutinized, 32 cases were included in the study, whereas 14 cases were excluded from the study. Among the 32 cases, we found 11 cases of SJS, 15 cases of TEN, and 6 cases of SJS-TEN otverlap. Of the 32, 17 patients were male and 15 were female between age group of 7 to 60 years. Total 58 drugs were found as suspected causative agent. In 20 cases, multiple drugs were suspected, whereas in 12 cases, single drug was implicated. In all the 32 cases, drugs were the probable cause of eruptions, as determined by Naranjo s algorithm. [12] Antimicrobials (50%) were the most commonly associated group followed by nonsteroidal anti-inflammatory drugs (NSAIDs) (22.41%) and antiseizure drugs (18.96%) [Table 1]. Nevirapine (9 of 32 cases), paracetamol (8 of 32 cases), cotrimoxazole (7 of 32 cases), and phenytoin (7 of 32 cases) were found to be the most commonly associated drugs. Phenytoin (4 of 12 cases) was the most common drug among the single drug culprit cases. Associated diseases were present in 13 cases (HIV infection - 12 cases [37.5%] and malignancy - 1 case [3.1%]). In 12 HIV patients, nevirapine (9 of 12 cases), cotrimoxazole (6 of 12 cases), zidovudine (1 of 12 cases), and stavudine (1 of 12 cases) were found responsible for causing this reaction. Antiseizure drugs were more often associated with serious form of adverse reaction (TEN: 81.8%) than other drugs. Time duration between drug intake and onset of symptoms was 27.5 days (95% CI: ) in SJS, 17.7 days (95% CI: ) in TEN, and 15.3 days (95% CI: ) in SJS-TEN overlap. Table 1: Drug groups and individual drugs responsible for SJS, TEN, and SJS-TEN overlap Drugs SJS TEN SJS-TEN overlap Total Antimicrobials 12 (20.7) 10 (17.2) 07 (12) 29 (50) Cotrimoxazole Amoxicillin Erythromycin Quinine Ampicillin Cefixime Amikacin Gentamicin Levofloxacin Chloroquine Nevirapine Stavudine Zidovudine NSAIDs 03 (5.1) 07 (12) 03 (5.1) 13 (22.4) Paracetamol Nimesulide Diclofenac Aspirin Antiseizure 01 (1.7) 09 (15.5) 01 (1.7) 11 (19.0) Phenytoin Carbamazepine Phenobarbitone Others (8.6) (8.6) Ondansetron Domperidone Famotidine Pantoprazole Data are expressed in absolute numbers of cases and value expressed in () is in percentage; SJS: Stevens-Johnson syndrome; TEN: Toxic epidermal necrolysis; NSAIDs: Nonsteroidal anti-inflammatory drugs 116 Journal of Postgraduate Medicine April 2011 Vol 57 Issue 2

4 In treatment, systemic steroids were given in 8 of 11 cases of SJS, 12 of 15 cases of TEN, and 5 of 6 cases of SJS-TEN overlap, whereas intravenous immunoglobulin (IVIG) was given in 1 of 6 cases of SJS-TEN overlap. Duration of hospital stay was 9.7 days (95% CI: ) in SJS, 20.6 days (95% CI: ) in TEN, and 16.1 days (95% CI: ) in SJS-TEN overlap, while cost of management was ` 2 460/- (95% CI: ) in SJS, ` 7 910/-(95% CI: ) in TEN, and ` 4 857/- (95% CI: ) in SJS-TEN overlap. Duration of hospital stay and cost of management were significantly higher in TEN than in SJS (P=0.020 and P<0.001, respectively) [Table 2]. Various complications noted in cases of SJS, TEN, and SJS- TEN overlap were secondary infection, septicemia, altered liver function test, electrolytes imbalance, leucocytosis, leucopoenia, thrombocytopenia, hyperglycemia, respiratory distress, and acute renal failure. Secondary infection was the most common complication (9 of 32 cases) noted [Figure 1]. Mortality rate was 15.6% among all cases; 9% in SJS and 26.7% in TEN. Higher mortality rate was noticed in patients with higher SCORTEN score at the time of admission [Table 3]. Table 2: Comparison of incubation period, duration of hospital stay, and cost of management between SJS, TEN, and SJS-TEN overlap Groups Incubation period (days) Duration of hospital stay (days) Cost of management (`) SJS (n = 11) 27.5 ( ) 9.7 ( ) ( ) TEN (n = 15) 17.7 ( ) SJS-TEN overlap (n = 06) P value F (df) (ANOVA) 20.6 ( )* ( )** 15.3 ( ) 16.1 ( ) ( ) (2,29) (2,29) (2,29) Data expressed as mean (95% CI); *P=0.020 and **P<0.001 as compared with SJS by Tukey-Kramer multiple comparisons test; SJS: Stevens-Johnson syndrome; TEN: Toxic epidermal necrolysis Table 3: Comparison between SCORTEN score, mortality rate in present study, and expected mortality rate SCORTEN score at admission No. of cases Discussion We had male preponderance (53.1% male and 46.9% female), unlike female preponderance in earlier studies. [13-15] All the cases had same frequency of occurrence throughout the year, no seasonal variation was noted. [16] Three most common groups of drugs causing eruptions were antimicrobials, NSAIDs, and antiseizure drugs. This is in agreement with the previous reports. [13,14,17] Nevirapine (28.1%) was the most commonly associated drug in our study, as against phenytoin and carbamazepine which have been mentioned in previous study. [14,15] Antiseizure drugs were the most common drugs causing TEN in our study. They had the higher chance (81.8%) of causing severe eruption, that is, TEN than NSAIDs (53.84%) and antimicrobials (34.48%). This is higher as compared with the previous report (70%). [14] Average number of drugs to be found as causative for SJS, TEN, and SJS-TEN overlap was Though antimicrobials have been the most common group of drugs involved, there has been change in the individual drugs involved. Nevirapine and cotrimoxazole are the most common antimicrobial associated as compared with cephalosporins in an earlier study. [14] In all, 37.5% patients were HIV positive, which indicates increase in incidence of SJS and TEN in HIV patients, which was 7.3% in European study. [18] Nevirapine was the most common causative drug among the HIV patients as Mortality rate in study (%) Expected mortality rate [11] (%) or more >90 Figure 1: Complications noted in SJS, TEN, and SJS-TEN overlap (SJS: Stevens-Johnson syndrome; TEN: Toxic epidermal necrolysis; LFT: Liver function test) Journal of Postgraduate Medicine April 2011 Vol 57 Issue 2 117

5 compared with the cotrimoxazole. [8] However, of 7 culprit cases with cotrimoxazole, 6 patients were HIV positive. This shows higher incidence of SJS and TEN with cotrimoxazole in HIVpositive patients than in general populations. [8] In last few years, HIV infection might have changed the trend of antimicrobials causing SJS, TEN, and SJS-TEN overlap. In 4 HIV cases, reaction appeared after change in regimen of antiretroviral therapy from ZLE (Zidovudine, Lamivudine, Efavirenz) to ZLN (Zidovudine, Lamivudine, Nevirapine). Arrival of new drugs like nevirapine and lamotrigine have changed current scenario of causative drugs for SJS, TEN, and SJS-TEN overlap and risk of severe skin reaction increases with use of these drugs. [19] However, we did not have lamotrigine as culprit in our study. This may be due to its limited utilization or different environmental or genomic factors in our population. However, highest occurrence with nevirapine suggests the requirement of monitoring the newer drugs for such type of severe reactions. [19] Among NSAIDs, paracetamol was the most common to cause the reaction in our study and as described in other Indian study. [14] We did not find any oxicam derivative as culprit which is mentioned as the most commonly responsible among NSAIDs in American study. [20] This may be due to different genomic factors or drug utility pattern influencing both the populations. Duration of hospital stay in TEN is higher than in SJS, which is same as in previous study. [21] The risk of SJS, TEN, and SJS-TEN overlap appears to be greater in the first month of initiation of treatment as revealed by incubation period. Incubation period is nonsignificantly lower in the TEN as compared with SJS and SJS-TEN overlap. In our study, majority of cases were treated with systemic steroids, and mortality rate was found similar to previous study in which patients were treated with steroids. [14] Though the role of steroids is controversial in treatment of SJS and TEN, beneficial effect may be there if steroids are started early in treatment with proper dose. [22] IVIG was given in one patient with SCORTEN score 2 and had recovered within 8 days. We could not make any conclusion about the use of IVIG in treatment of SJS and TEN as it was used only in one patient in our study. Complications were seen more frequently in TEN group (63.4%), the most common being secondary infection (28.1%). One patient died in SJS group, whereas no mortality was noted in SJS-TEN overlap. Mortality rate in TEN group was 26.66%, which is equal to earlier study (26%). [14] Our study showed that mortality rate was higher in patients with higher SCORTEN score, which shows importance of SCORTEN score as an important tool for predicting the clinical outcome in patients of SJS, TEN, and SJS-TEN overlap. [11] Average cost of management of SJS (` 2 460/-) is nearly equal to average cost of management of other severe ADRs in India (` 2 820/-), but the cost of management of SJS-TEN overlap (` 4 857/-) and TEN (` 7 910/-) is much higher. [10] Being retrospective in nature, we were not able to calculate direct nonmedical and indirect costs. Thirty percent cases have been excluded from the study due to insufficient data or improper records. Proper record keeping is required for such type of study involving disease of low incidence rate. In conclusion, SJS, TEN, and SJS-TEN overlap are serious cutaneous adverse reactions most commonly caused by antimicrobials, NSAIDs, and antiseizure drugs. Their cost of management is higher than other serious ADRs. Acknowledgement Our sincere thanks to Dr. Neela Bhuptani, Professor and Head, Department of Dermatology, Venerology and Leprosy and Dr. R.B.Deshmukh, Medical Superintendent (P.D.U. Civil Hospital and Medical College, Rajkot); Dr. N.D.Kanthariya, Professor and Head, Department of Pharmacology and Dr. M.K.Vadel, Medical Superintendent (Government Medical College and New Civil Hospital, Surat) and Dr. Yogesh Marfatiya, Professor and Head, Department of Dermatology, Venerology and Leprosy and Dr. R.N. Deveshvar, Medical Superintendent (Medical College and S.S.G. Civil Hospital, Vadodara) for giving permission for the data collection at their respective centers. References 1. Patel KJ, Kedia MS, Bajpai D, Mehta SS, Kshirsagar NA, Gogtay NJ. Evaluation of the prevalence and economic burden of adverse drug reactions presenting to the medical emergency department of a tertiary referral centre: A prospective study. BMC Clin Pharmacol 2007;7:8. 2. Brvar M, Fokter N, Bunc M, Mozina M. The frequency of adverse drug reaction related admissions according to method of detection, admission urgency and medical department specialty. BMC Clin Pharmacol 2009;9:8. 3. Suh DC, Woodall BS, Shin SK, Hermes-De Santis ER. Clinical and economic impact of adverse drug reactions in hospitalized patients. Ann Pharmacother 2000;34: Sharma VK, Sethuraman G, Kumar B. Cutaneous adverse drug reactions: Clinical pattern and causative agents - a 6 year series from Chandigarh, India. J Postgrad Med 2001;47: Sharma VK, Sethuraman G. Adverse cutaneous reactions to drugs: An overview. J Postgrad Med 1996;42: Borchers AT, Lee JL, Naguwa SM, Cheema GS, Gershwin ME. Stevens-Johnson syndrome and toxic epidermal necrolysis. Autoimmun Rev 2008;7: Li LF, MaC. Epidemiological study of severe cutaneous adverse drug reactions in a city district in China. Clin Exp Dermatol 2006;31: Khambaty MM, Hsu SS. Dermatology of the patient with HIV. Emerg Med Clin North Am 2010;28: Mockenhaupt M. Severe drug-induced skin reactions: Clinical pattern, diagnostics and therapy. J Dtsch Dermatol Ges 2009;7: Ramesh M, Pandit J, Parthasarathi G. Adverse drug reactions in a South Indian hospital- their severity and cost involved. Pharmacoepidemiol drug saf 2003;12: Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: A severity-of-illness score of Toxic Epidermal Necrolysis. J Investi Dermatol 2000;112: Naranjo CA, Busto U, Seller EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reaction. Clin. Pharmacol Ther 1981;30: Schopf E, Stuhmer A, Rzany B, Victor N, Zentgraf R, Kapp JF. Toxic epidermal necrolysis and Stevens-Johnson syndrome: An epidemiologic study from West Germany. Arch Dermatol 1991;127: Sharma VK, Sethuraman G, Minz A. Stevens Johnson syndrome, toxic epidermal necrolysis and SJS-TEN overlap: A retrospective study of causative drugs and clinical outcome. Indian J Dermatol Venereol Leprol 2008;74: Devi K, George S, Criton S, Suja V, Sridevi PK. Carbamazepine--the commonest cause of toxic epidermal necrolysis and Stevens- Johnson syndrome: A study of 7 years. Indian J Dermatol Venereol Leprol 2005;71: Wanat KA, Anadkat MJ, Klekotka PA. Seasonal variation of Stevens- Johnson syndrome and toxic epidermal necrolysis associated with trimethoprim-sulfamethoxazole. J Am Acad Dermatol 2009;60: Journal of Postgraduate Medicine April 2011 Vol 57 Issue 2

6 17. Leenutaphong V, Sivayathorn A, Suthipinittharm P, Sunthonpalin P. Stevens-Johnson syndrome and toxic epidermal necrolysis in Thailand. Int J Dermatol 1993;32: Fagot JP, Mockenhaupt M, Bouwes-Bavinck JN, Naldi L, Viboud C, Roujeau JC. Nevirapine and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. AIDS 2001;15: Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: Assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol 2008;128: Ward KE, Archambault R, Mersfelder TL. Severe adverse skin reactions to nonsteroidal antiinflammatory drugs: A review of the literature. Am J Health Syst Pharm 2010;67: Yap FBB, Wahiduzzaman M, Pubalan M. Stevens - Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) In Sarawak: A Four Years Review. Egyptian Dermatol Online J 2008; Kardaun SH, Jonkman MF. Dexamethasone pulse therapy for Stevens- Johnson syndrome/toxic epidermal necrolysis. Acta Derm Venereol 2007;87: How to cite this article: Barvaliya M, Sanmukhani J, Patel T, Paliwal N, Shah H, Tripathi C. Drug-induced Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS-TEN overlap: A multicentric retrospective study. J Postgrad Med 2011;57: Source of Support: Nil, Conflict of Interest: None declared. Author Help: Online submission of the manuscripts Articles can be submitted online from For online submission, the articles should be prepared in two files (first page file and article file). Images should be submitted separately. 1) First Page File: Prepare the title page, covering letter, acknowledgement etc. using a word processor program. All information related to your identity should be included here. Use text/rtf/doc/pdf files. Do not zip the files. 2) Article File: The main text of the article, beginning with the Abstract to References (including tables) should be in this file. Do not include any information (such as acknowledgement, your names in page headers etc.) in this file. Use text/rtf/doc/pdf files. Do not zip the files. Limit the file size to 1 MB. Do not incorporate images in the file. If file size is large, graphs can be submitted separately as images, without their being incorporated in the article file. This will reduce the size of the file. 3) Images: Submit good quality color images. Each image should be less than 4096 kb (4 MB) in size. The size of the image can be reduced by decreasing the actual height and width of the images (keep up to about 6 inches and up to about 1800 x 1200 pixels). JPEG is the most suitable file format. The image quality should be good enough to judge the scientific value of the image. For the purpose of printing, always retain a good quality, high resolution image. This high resolution image should be sent to the editorial office at the time of sending a revised article. 4) Legends: Legends for the figures/images should be included at the end of the article file. Journal of Postgraduate Medicine April 2011 Vol 57 Issue 2 119