Use of intravenous immunoglobulin in toxic epidermal necrolysis and Stevens-Johnson syndrome: our current understanding

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN, Lyell's disease, syndrome) are considered to be part of a spectrum of adverse cutaneous drug reactions with increasing severity and extent of skin detachment, ranging from SJS (less than 10% body surface area skin detachment, 1-5% mortality) to TEN (greater than 30% skin detachment, 25-35% mortality). Both SJS and TEN are characterized morphologically by ongoing apoptotic keratinocyte cell death that results in the separation of the epidermis from the dermis. Recent evidence is supportive of a role for the death receptor Fas and its ligand FasL, in the pathogenesis of keratinocyte apoptosis during TEN. This Fas-mediated keratinocyte apoptosis that causes epidermal detachment in TEN can be inhibited in vitro by antagonistic monoclonal antibodies to Fas and by intravenous immunoglobulins (IVIG) which have been shown to contain natural anti-Fas antibodies. Over the last 6 years, numerous case reports and 8 non-controlled clinical studies containing 9 or more patients have analyzed the therapeutic effect of IVIG in TEN. Taken together, although each study has its potential biases, 6 of the 8 studies point towards a benefit of IVIG used at doses greater than 2 g/kg on the mortality associated with TEN. Hopefully, these studies will serve as the basis for designing a prospective controlled trial in the near future; as such, an approach appears the only way to definitively determine the therapeutic potential of IVIG in TEN.     

帕博利珠单抗致严重免疫相关皮肤不良反应的文献分析

目的: 探讨帕博利珠单抗致Stevens-Johnson综合征(SJS)、中毒性表皮坏死松懈症(TEN)严重皮肤反应的临床特点,旨在为临床合理使用帕博利珠单抗提供参考。方法: 检索中国知网、维普、万方、PubMed、Web of Science 和Medline 等数据库,收集整理自数据库建库至2022年2月关于帕博利珠单抗致SJS/TEN的个案报道,分析该药致SJS/TEN的临床特点。结果: 共收集25例病例,其中帕博利珠单抗致SJS病例13例,TEN7例,SJS/TEN重叠征5例。3种类型SJS/TEN反应中TEN发生最早,中位发生时间为16(3,39)d;其次为SJS/TEN重叠征,发生时间为30(22.5,115)d;SJS反应最晚为55(7,106.5)d。25例中有22例(88.0%)伴随着黏膜受累,17例(68.0%)在黏膜受累或皮肤脱落之前出现前驱性皮疹。25例患者24例(96.0%)接受了全身性糖皮质激素治疗,9例(36.0%)接受静脉注射免疫球蛋白,4例(16.0%)接受免疫抑制剂。最终,25例患者中17例(68.0%)好转或痊愈,5例(20.0%)死亡,3例(12.0%)预后未知。结论: 帕博利珠单抗可诱发SJS/TEN,应注意黏膜损伤,异常皮疹等可能为SJS/TEN发生信号,除了全身性糖皮质激素治疗以外,静脉注射免疫球蛋白和环孢素治疗证实是有益补充。     

Lamotrigine-induced Stevens-Johnson syndrome.

PURPOSE: A case of lamotrigine-induced Stevens-Johnson syndrome (SJS) is reported. SUMMARY: A 29-year-old woman with a medical history of schizoaffective disorder arrived at the emergency department with a severe generalized skin reaction. Three to four days prior she had noticed bumps on her lips that had spread to her oral mucosa. She had also developed a diffuse, erythematous, pruritic full-body rash involving the palms of her hands and the soles of her feet and began to feel feverish. Her medications at admission included aripiprazole 30 mg p.o. daily, escitalopram 10 mg p.o. daily, and lamotrigine 75 mg p.o. daily. Lamotrigine was the only new medication, initiated four weeks before this admission. The dermatology service confirmed the diagnosis of SJS using punch biopsy. Lamotrigine was suspected to be the culprit and was discontinued immediately. The patient was given oral prednisone 40 mg and intravenous fluids. Hydroxyzine was given for pruritis, and petroleum jelly and viscous lidocaine were applied to her lips. On hospital day 2, her symptoms and dermatological manifestations improved, but she continued to complain about irritation and slight pain of the mouth. She then received a mouthwash consisting of diphenhydramine, viscous lidocaine, and sodium bicarbonate. On hospital day 3, the patient had improved substantially and was discharged home. Reports of these dermatological reactions in patients receiving lamotrigine for the treatment of bipolar disorder are limited. Dosing, prompt recognition, and patient education are crucial for preventing morbidity and mortality associated with the development of serious cutaneous reactions. CONCLUSION: SJS was associated with lamotrigine use, despite appropriate dosing and dosage adjustment.     

HCP5 genetic variant (RS3099844) contributes to Nevirapine-induced Stevens Johnsons Syndrome/Toxic Epidermal Necrolysis susceptibility in a population from Mozambique

Purpose

Nevirapine (NVP) is an anti-retroviral drug used for the treatment of HIV infection, that may cause several severe adverse events, including Stevens Johnsons Syndrome/Toxic Epidermal Necrolysis (SJS/TEN). A recent whole genome association study highlighted a strong association with allopurinol-induced SJS/TEN within the HCP5 and PSORS1C1 genes in the Japanese population. Our aim was to verify the contribution of these two genes in the susceptibility to NVP-induced SJS/TEN in a population from Mozambique.

Methods

Genotyping of PSORS1C1 rs2233945 and HCP5 rs3099844 SNPs was performed in a sample of 27 patients with SJS/TEN and 76 controls. A case–control and a haplotype analysis were performed.

Results

The HCP5 rs3099844 variant allele was significantly associated with the SJS/TEN susceptibility (OR?=?2.03 and P?=?0.039). The TA haplotype, carrying both the variant alleles of the two genes, showed a higher risk for developing SJS/TEN (OR?=?3.44and P?=?0.003). The regression analysis confirmed the contribution of HCP5 rs3099844 SNP (OR?=?2.05, P?=?0.047). By a log-linear model, we also investigated for interaction between HCP5 rs309844 and PSORS1C1 rs2233945 SNPs with respect to SJS/TEN risk, and we observed a strong interaction between the two SNPs (P?=?0.005).

Conclusions

We confirmed the association of HCP5 with the SJS/TEN susceptibility in a population from Mozambique treated with NVP.     

Exploratory study on biomarkers associated with severe cutaneous adverse reactions

Most of adverse drug reactions (ADRs) occur as an extension of pharmacological effects. They occur dependently on their blood concentrations and can be potentially reduced by controlling their dose. On the other hand, ADRs categorized as Type B usually occur irrelevantly to their pharmacological effects at different organs from their target, and are often life-threatening and unpredictable. The incidences of Type B ADRs are very low. Severe cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are delayed allergic reactions in which T-cells are involved and categorized as Type B ADRs. Recent progress of pharmacogenomic studies has revealed that particular types of human leukocyte antigen (HLA) class I antigens have strong associations with severe cutaneous adverse reactions and that the associations are specific to causative drugs, phenotypes of adverse reactions and ethnic groups. We established a research group in 2006 with professionals of pharmacogenomics, dermatologists, ophthalmologists and psychiatrists to explore genetic biomarkers associated with Japanese SJS/TEN patients. To date, we have collected more than 100 Japanese SJS/TEN patients through participating institutes and a case-collecting system covering all over Japan constructed by us. No carriers of HLA-B*1502 which was reported to have extremely strong association with carbamazepine-induced SJS/TEN in Han Chinese and south Asians, although a moderate association between allopurinol-induced SJS/TEN and HLA-B*5801 detected in Han Chinese was observed.     

Spontaneous reports of drug-induced erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis in Denmark 1968-1991

Spontaneous reporting systems (SRS) have been established to monitor drug safety problems after marketing, especially rare, but serious adverse drug reactions (ADRs). Among these are the skin disorders erythema multiforme (EM), Stevens- Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The purpose of this study has been to evaluate the data on these serious skin disorders available in a SRS. All reports concerning these diseases submitted to the Danish Committee on ADRs during the period 1968 to 1991 were reviewed according to predefined criteria. Information was often scarce,and the diagnosis of the reporter had to be accepted at face value in 28% of cases. Two hundred cases of EM, 74 of SJS and 29 of TEN were identified. More than 60% of cases were hospitalized. The diseases had fatal outcome in six patients with TEN, three with SJS and a single patient suffering from EM. One hundred and twenty-eight different drugs were reported as causal agents. Major drug groups involved were antibiotics (sulphonamides and penicillins), non-steroidal anti-inflammatory drugs, anti-epileptics and analgesics. Incidence estimates based on spontaneous reports were compared to the incidence according to the literature and data from a nationwide hospital discharge diagnosis register. The reporting fraction for EM and SJS is estimated to 10-30%, and for TEN to 25-50%, but the validity of reports is in some cases difficult to assess owing to lack of detail.     

喹诺酮类药物致Stevens-Johnson综合征和中毒性表皮坏死松解症文献分析

目的:分析喹诺酮类药物致Stevens-Johnson综合征(SJS)和中毒性表皮坏死松解症(TEN)不良反应的发生情况,为临床合理用药提供参考.方法:通过PubMed、Web of Science、Springer、Embase、Scopus、万方期刊论文数据库、维普期刊数据库、中国知网(CNKI)、中国生物医学文献...     

抗癫痫药物等引发药疹与人类白细胞抗原基因的相关性研究

目的探讨抗癫痫药物等引发药疹与HLA基因多态性的相关性,以期为药疹的预防和治疗提供依据。方法收集48例药疹患者,采用PCR-SSP方法检测HLA-B*1502、HLA-A*0206、HLA-A*3101、HLA-A*1101、HLA-B*5901、HLA-Cw*0704、HLA-Cw*0801、HLA-DRB1*1202等8个等位基因。采用RT-PCR检测HLA-B*1502基因阳性者中mRNA表达水平。结果药物引发的药疹可能与HLA-B*1502、HLA-Cw*0801、HLA-A*0206和HLA-Cw*0704等位基因相关(P<0.05);其中抗癫痫药物引发的重症药疹与HLA-B*1502等位基因的相关性最强(P<0.01);且抗癫痫药物引发的重症药疹HLA-B*1502 mRNA的表达水平明显高于耐受组及对照组(P<0.01)。结论抗癫痫药物引发的重症药疹与HLA-B*1502等位基因密切相关。HLA-B*1502mRNA表达水平可以作为预测抗癫痫药物诱发重症药疹的重要指标。     

Immunohistochemical expression of apoptotic markers in drug-induced erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are considered to be severity variants of the same disease, which is almost always associated with drug intake. In contrast, erythema multiforme (EM) is a disorder regarded as only rarely caused by drugs. Keratinocyte apoptosis has been shown to play an important part in the pathogenesis of SJS and TEN, whilst its role in EM remains controversial. To determine the expression of apoptosis-associated molecules Fas, Fas ligand (FasL), Bcl-2 and Bax in the above disorders, an immunohistochemical analysis was performed. We studied both lesional skin from thirty patients having drug-induced EM and 5 cases classified within the SJS/TEN spec nottrum and normal skin samples. We found a keratinocyte overexpression of Fas antigen, an important molecule mediating apoptosis, not only in SJS and TEN but also in EM. Another noteworthy finding was the strong expression of Bcl-2, a protein known as blocking apoptosis, along the basal layer and in the dermal infiltrate both in SJS/TEN and in EM. Taken together, these findings suggest that Fas-dependent keratinocyte apoptosis may play a part in the pathogenesis of both SJS/TEN and EM. Fas-mediated cell death may be partially suppressed by the Bcl-2 protein.     

头孢菌素类药物致史蒂文斯-约翰逊综合征和中毒性表皮坏死松解症的文献分析

目的： 分析头孢菌素类药物致史蒂文斯-约翰逊综合征（SJS）和中毒性表皮坏死松解症（TEN）不良反应发生情况及其临床特点,为临床安全用药提供参考。方法： 检索Web of Science、PubMed、中国知网数据库、维普数据库和万方数据库关于头孢菌素类药物致SJS/TEN的文献报道并进行分析。结果： 共纳入文献25篇,26例不良反应,其中,男性15例（57.69%）,女性11例（42.31%）;年龄最小5岁,最大85岁,中位年龄61.5岁;SJS 9例（34.62%）,TEN 17例（65.38%）;发生时间集中在用药后3 d内的13例（50.01%）;临床表现以皮肤伴有或不伴渗出多型红斑、斑丘疹为主的皮疹伴发热、口腔、生殖器和或眼黏膜破溃,随着病程进展进而出现皮肤水疱破裂及脱落,常伴有继发性感染及多脏器损害,以肝肾损害较常见。结论： 临床应用头孢菌素类药物存在SJS/TEN的风险,医务人员应了解其发病特点及早期鉴别SJS/TEN症状,一旦发生应根据患者严重程度尽早给予对症治疗,降低SJS/TEN的病死率,加强后期随访及患者用药教育。     

实例探讨药物引起SJS或TEN的评分方法——Naranjo评分与ALDEN评分比较

药物引起的史蒂文斯-约翰逊综合征（SJS）和中毒性表皮坏死松解症（TEN）是一种罕见严重的不良反应,其特征是广泛性的皮肤表皮剥离和黏膜侵犯。当评估可疑药物和SJS或TEN之间的因果关系时,除了Naranjo评分外,最近根据两个大型的病例对照研究结果所衍生的ALDEN评分也提供了新思路。本文结合1例同时服用对乙酰氨基酚和头孢拉定导致中毒性表皮坏死综合征的案例,应用ALDEN评分及Naranjo评分分析两种药物与ADR间的关联性,并讨论此两种评分方法的差异性及适宜性。     

重症多形红斑型药疹25例和中毒性表皮坏死松解症17例回顾性分析

对1990年12月~2013年4月本院收治的25例重症多形红斑（SJS）和17例中毒性表皮坏死松解症（TEN）患者的临床资料进行回顾性分析。探讨SJS和TEN的致敏因素、发生规律、临床特征和治疗措施。药物是引起SJS和TEN的最主要病因。致敏药物以抗菌药物为主（52.38%）,其次是抗癫痫药（28.57%）。黏膜损害和肝功能损害是最常见的并发症。 SJS和TEN均系统应用糖皮质激素治疗,SJS组8例和TEN组4例给予激素联合人免疫球蛋白治疗。系统应用糖皮质激素尤其是联合人免疫球蛋白治疗SJS和TEN有效。     

Toxic epidermal necrolysis after celecoxib therapy

Toxic epidermal necrolysis (TEN) is a rare disease that is defined by extensive detachment of full-thickness epidermis. It most often is related to an adverse drug reaction. The drugs implicated in most cases of TEN have been sulfonamides, anticonvulsants, allopurinol, and some of the conventional nonsteroidal antiinflammatory agents. We describe a patient who developed a generalized desquamating rash after therapy with celecoxib.     

Pharmacogenetics of toxic epidermal necrolysis

Importance of the field: Toxic epidermal necrolysis (TEN) and Stevens–Johnson Syndrome (SJS) are two of the most severe drug-induced cutaneous reactions. Advances in genome technologies have allowed researchers to identify genetic markers associated with this drug-associated event and these have provided a potential tool for prevention.

Areas covered in this review: Current updates of genetic biomarkers that have been identified as being associated with TEN/SJS induced by several drugs, and the associations of these markers in different populations, are discussed.

What the reader will gain: The strong association of HLA-B*1502 and carbamazepine (CBZ)-induced TEN/SJS have been reported by several independent studies. This association was mostly observed in patients of Southeast Asian ancestry; it was not observed in populations with low HLA-B*1502 allele frequency. Studies also suggest that drugs with a similar chemical structure to CBZ might also induce TEN/SJS in patients with HLA-B*1502. In addition to CBZ, HLA-B*5801 was also found to associate with allopurinol-induced TEN/SJS. This strongly suggests that the associations of these markers with TEN/SJS are drug specific.

Take home message: The strong association between CBZ and HLA-B*1502 has prompted the US Food and Drug Administration to update the label for CBZ to include genetic information and to recommend genetic testing before prescribing CBZ. Patients with Asian ancestry or who are from regions prevalent in HLA-B*1502 should be screened before CBZ treatment.     

Evaluation of minoxidil

The chemistry, pharmacokinetics, mechanism of action, clinical studies, adverse effects, toxicology, indications, contraindications, drug interactions, and dosing of minoxidil, a recently approved antihypertensive agent, are reviewed. Minoxidil is an orally effective vasodilator that selectively relaxes peripheral arteriolar smooth muscle, Reflex tachycardia, renin stimulation, and sodium retention occur when minoxidil is used and so it requires the concomitant use of a diuretic and a sympathoplegic agent, usually a beta blocker. Hirsutism and pericardial effusions are additional adverse effects. Minoxidil is indicated in the management of severe hypertension in patients who do not respond to standard antihypertensive agents. In controlled and unctrolled studies, minoxidil was effective in patients with hypertension secondary to renal or renovascular disease and in patients with essential hypertension. Minoxidil is a potent antihypertensive agent with adverse effects that limit its use to patients resistant or intolerant to other drugs.     

Association between HLA and Stevens–Johnson Syndrome Induced by Carbamazepine in Southern Han Chinese: Genetic Markers besides B*1502?

Previous studies have demonstrated a strong association between carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (CBZ-induced SJS/TEN) and HLA-B*1502 in Chinese, and HLA-A*3101 but not HLA-B*1502 in Caucasians and Japanese. Cases with CBZ-induced SJS/TEN negative for HLA-B*1502 were reported recently in Southeast Asia. Negative correlations between CBZ-induced SJS/TEN and B*0702 or B*4001 have also been reported, suggesting a possible protective role. Here, we genotyped HLA-B and HLA-A in 18 cases with CBZ-induced SJS/TEN, in comparison with CBZ-tolerant and normal controls in Southern Han Chinese. A strong association between HLA-B*1502 and CBZ-induced SJS/TEN was found, with 72.2% sensitivity and 87.1% specificity. However, we also found five patients with SJS (5/18, 27.78%) who were negative for HLA-B*1502. HLA-A*2402 was present in nine of 16 cases with SJS (56.25%, including three of five cases negative for HLA-B*1502), which was significantly more frequent than that of CBZ-tolerant controls or the general southern population. Only one case with SJS carried HLA-A*3101. No statistical difference in the mean age, sex ratio and CBZ usage was found between the CBZ-induced SJS/TEN group and the CBZ-tolerant group. In search for possible protective genetic markers in HLA-B*1502-positive but CBZ-tolerant patients, we failed to find any significant factors in the HLA alleles observed. Given the association between HLA-B*1502 and CBZ-induced SJS/TEN, genetic testing before initiating CBZ therapy is suggested in Han Chinese population. However, physicians should also be vigilant about SJS/TEN in those negative for HLA-B*1502. Other factors for the development of CBZ-induced SJS/TEN in HLA-B*1502-negative patients and protective factors in CBZ-tolerant patients should be investigated further.     

Hla-B alleles and lamotrigine-induced cutaneous adverse drug reactions in the Han Chinese population

Abstract: Lamotrigine (LTG) is a commonly used antiepileptic drug. However, the use of LTG is limited because of its cutaneous adverse drug reactions (cADRs) ranging from mild maculopapular eruption (MPE) to severe Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). A strong association between HLA‐B*1502 and carbamazepine‐induced SJS/TEN has been identified in Chinese and Thai. Although three of seven cases with HLA‐B*1502 have been reported in LTG‐induced SJS/TEN so far, the relationship between HLA‐B*1502 and LTG‐induced SJS/TEN needs further investigation. It is also unclear whether there is a specific genetic marker associated with LTG‐induced MPE in Chinese. In this study, we genotyped 43 Han Chinese patients treated with LTG (14 cases with LTG‐induced cADRs and 29 LTG‐tolerant controls), using PCR‐SSP for HLA‐B*1502 testing and low‐resolution genotyping, as well as sequencing for four‐digit genotyping. The two cases with SJS were negative for HLA‐B*1502, with B1301/1301 and 4601/5610, respectively. Combining the data with previous studies, there was no significant difference in the frequency of subjects with HLA‐B*1502 between the LTG‐induced SJS/TEN group and the LTG‐tolerant group (p = 0.08, OR 4.23, 95% CI 0.94–18.97). In the MPE group, only one was positive for HLA‐B*1502. There was no significant difference in the frequency of a specific HLA‐B allele between the MPE group and the LTG‐tolerant group either. In this study, no significant association between HLA‐B*1502 and LTG‐induced SJS or MPE was found. Given the small sample size and only HLA‐B locus genotyping, further large‐scale studies are required to explore genetic associations with LTG‐induced cADRs.     

Lamotrigine and Stevens-Johnson Syndrome Prevention

Stevens-Johnson Syndrome (SJS) is a rare life-threatening condition characterized by severe mucocutaneous epidermal necrolysis and detachment of the epidermis. The condition centers around a delayed-type hypersensitivity reaction with a complex etiology stemming from a variety of causes. The number one cause is medication-related—common ones including sulfonamides, antiepileptics, allopurinol, and nonsteroidal anti-inflammatory drugs. Genetics also play a role as several human leukocyte antigen (HLA) genotypes within certain ethnic groups have been implicated in adverse reactions to specific drugs. HLAB*15:02 has been identified in the Chinese and others of Southeast Asian origin to increase susceptibility to lamotrigine and carbamazepine-induced SJS. Furthermore, patients of Japanese origin with HLAB*31:01 and Koreans with HLA-B*44:03 are also at increased risk of SJS after receiving the same two drugs. Of the antiepileptics, one most commonly associated with SJS is lamotrigine, a pre-synaptic voltage-gated sodium channel inhibitor. Lamotrigine is an antiepileptic drug of the phenyltriazine class that is indicated for the prevention of focal and generalized seizures in epileptic patients as well as monotherapy or adjunctive maintenance treatment for Bipolar disorder. The occurrence of SJS is not a rigid contraindication to lamotrigine reintroduction in the same patient. To facilitate this, manufacturers have developed a strict re-challenge dosing regimen to facilitate successful reintroduction of lamotrigine. In order to prevent the recurrence of SJS during a re-challenge, timing of re-dose and initial rash severity must be considered. Therefore, to prevent SJS recurrence, prime lamotrigine re-challenge patients are those with mild initial rash that has not occurred within the previous 4 weeks. The Federal Food and Drug Administration recommends the testing HLA subtypes for those associated with SJS prior to starting lamotrigine.