Severe gynecologic sequelae of Stevens-Johnson syndrome and toxic epidermal necrolysis caused by ibuprofen: a case report.

BACKGROUND: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a serious, drug-induced, life-threatening condition characterized by an epidermal blistering rash with necrosis, desquamation and mucosal surface involvement. This patient represents the youngest and most significant case report in the literature of gynecologic damage due to TEN. CASE: A 31/2-year-old girl developed TEN involving 90% of her body surface area after exposure to pediatric ibuprofen. After onset of puberty she required surgery to treat vulvar, vaginal and cervical adhesions, stenosis and hematometra. CONCLUSION: While delaying evaluation and treatment of the extremely young child with this disorder until puberty has been the standard, consideration should be given to earlier evaluation and intervention.

Risk of nevirapine-associated Stevens-Johnson syndrome among HIV-infected pregnant women: the Medunsa National Pharmacovigilance Centre, 2007 - 2012.

BACKGROUND: Stevens-Johnson syndrome (SJS) is an acute life-threatening condition often elicited by drugs. The government's indecisiveness in deciding to stop the use of nevirapine (NVP) in HIV-infected pregnant women owing to the increase of SJS among this population group in South Africa prompted this investigation. OBJECTIVES: To investigate if pregnancy is a risk factor for SJS among HIV-infected women taking NVP-containing regimens and registered within the Medunsa National Pharmacovigilance Centre database. METHODS: A matched case-control study with 5:1 matching was conducted. Women with SJS (cases) taking NVP-containing regimens were matched with women without SJS (controls) taking NVP-containing regimens. Controls were randomly selected and matched to cases by hospital, age, treatment duration and CD4 count. Conditional logistic regression was used to determine if pregnancy was a risk factor for SJS. RESULTS: Six SJS cases were identified and 30 controls selected. The median age of both cases and controls was 29 years and the average CD4 counts were 237 and 234 cells/microl respectively. Subjects were on NVP treatment for 18 - 31 days before the onset of SJS. Controls did not develop SJS after treatment of between 1 and 365 days. Pregnancy increased the chances of developing SJS 14-fold (OR 14.28, p = 0.006, 95% CI 1.54 - 131.82). CONCLUSIONS: NVP-containing ARV regimens taken during pregnancy increase the risk of developing SJS. Healthcare workers are advised to offer informed consent to patients and recommend effective contraception methods if NVP treatment is considered. In the light of our findings, further studies of the association between NVP, pregnancy and SJS are necessary before general conclusions can be reached.

Relationship between the HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis.

IMPORTANCE: The US Food and Drug Administration recommends screening for the HLA-B*1502 allele before initiation of carbamazepine therapy in patients of Asian ancestry, but there remains unclear evidence of a relationship between HLA-B*1502 and Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) among carbamazepine users, especially in some racial/ethnic populations. OBJECTIVE: To determine the relationship between the HLA-B*1502 allele and carbamazepine-induced SJS and TEN. DATA SOURCES: A comprehensive search of the following data sources was performed without language restriction from the inception of the database until January 8, 2013: EMBASE, PubMed, clinicaltrials.gov, Cochrane Library, IPA (International Pharmaceutical Abstracts), HuGENet (Human Genome Epidemiology Network), and CINAHL (Cumulative Index to Nursing and Allied Health Literature), and the reference lists of identified studies. STUDY SELECTION: Inclusion criteria were studies that investigated the relationship between HLA-B*1502 and carbamazepine-induced SJS and TEN and that reported sufficient data for calculating the frequency of HLA-B*1502 carriers among cases and controls. The search yielded 525 articles, of which 16 met the inclusion criteria. The studies included 227 SJS or TEN cases, 602 matched control subjects, and 2949 population control subjects. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted the following data: study design, eligibility criteria, diagnostic criteria, patient demographics, genotype distribution, HLA-B genotyping technique, selection of cases and controls, dosage of carbamazepine and duration of use, and results of Hardy-Weinberg equilibrium in the control group. The Newcastle-Ottawa Scale was used to assess the quality of studies. The overall odds ratios (ORs) with corresponding 95% CIs were calculated using a random-effects model. The primary analysis was based on matched control studies. Subgroup analyses by race/ethnicity were also performed. MAIN OUTCOME AND MEASURE: The primary outcome was carbamazepine-induced SJS and TEN. The outcome measure is given as an overall OR. RESULTS: The summary OR for the relationship between HLA-B*1502 and carbamazepine-induced SJS and TEN was 79.84 (95% CI, 28.45-224.06). Racial/ethnic subgroup analyses yielded similar findings for Han-Chinese (115.32; 18.17-732.13), Thais (54.43; 16.28-181.96), and Malaysians (221.00; 3.85-12 694.65). Among individuals of white or Japanese race/ethnicity, no patients with SJS or TEN were carriers of the HLA-B*1502 allele. CONCLUSIONS AND RELEVANCE: We found a strong relationship between the HLA-B*1502 allele and carbamazepine-induced SJS and TEN in Han-Chinese, Thai, and Malaysian populations. HLA-B*1502 screening in patients requiring carbamazepine therapy is warranted.

Association between adverse reactions to allopurinol and exposures to high maintenance doses: implications for management of patients using allopurinol.

OBJECTIVE: The objective of this study was to estimate the association between adverse drug reactions (ADRs) and exposure to allopurinol maintenance doses higher than those in the 1984 suggested limits of Hande et al. adjusted for level of renal function. METHODS: We conducted a retrospective review of electronic health records of patients prescribed allopurinol from January 1, 2004, to June 30, 2011, to identify those who had a definite or possible ADR to allopurinol. The associations of ADRs with maintenance doses of allopurinol 1 to 1.5 times and more than 1.5 times the suggested limits of Hande et al. compared with doses within the suggested limits of Hande et al. were estimated using logistic regression models. RESULTS: Of 4755 patients prescribed allopurinol, 2946 had a serum creatinine measured within 6 months of starting allopurinol, and of these, 1268 patients' records were reviewed. Forty-eight patients had a definite ADR to allopurinol, 2 of which were allopurinol hypersensitivity syndrome. The odds ratios of definite ADRs with maintenance doses of allopurinol 1.0 to 1.5 times and more than 1.5 times suggested compared with doses within suggested limits were, respectively, 1.42 (95% confidence interval [CI], 0.66-3.04) and 2.04 (95% CI, 0.87-4.77). Among those with an allopurinol maintenance dose more than 1.5 times suggested limits, the proportion of patients with a definite ADR was 2.6% (95% CI, 1.0%-5.2%). CONCLUSIONS: There is no significant association of high maintenance doses of allopurinol with ADRs, and the absolute risk of ADRs at doses higher than 1.5 times the 1984 suggested limits of Hande et al. is low. Cautious, gradual increases in allopurinol maintenance doses above the suggested limits of Hande et al. are warranted if necessary to achieve a serum uric acid level less than 6 mg/dL.

HLA-B alleles associated with severe cutaneous reactions to antiepileptic drugs in Han Chinese.

PURPOSE: HLA-B*15:02 screening is recommended before starting carbamazepine in Han Chinese and Southeast Asians because the allele is strongly predictive of Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) induced by the drug. We examined whether other HLA-B alleles are also involved and whether the association extends to other antiepileptic drugs (AEDs). METHODS: Cases of SJS/TEN induced by any AEDs were recruited and matched (1:5) with AED-tolerant controls. Carrier rates of HLA-B alleles, determined by direct sequencing, were compared between cases and controls. Results were meta-analyzed with previous studies to examine the associations between HLA-B*15:02 and SJS/TEN induced by phenytoin and lamotrigine. KEY FINDINGS: A total of 55 cases (27 carbamazepine, 15 phenytoin, 6 lamotrigine, 7 other AEDs) and 275 controls were recruited. In drug-specific analysis, the carrier rate of HLA-B*15:02 was significantly higher in carbamazepine-SJS/TEN cases compared with carbamazepine-tolerant controls (92.3% vs. 11.9%; p = 3.51 × 10(-18) ; odds ratio (OR) 89.25; 95% confidence interval (CI) 19.25-413.83), and also in phenytoin-SJS/TEN cases compared with phenytoin-tolerant controls (46.7% vs. 20.0%; p = 0.045; OR 3.50; 95% CI 1.10-11.18). Meta-analyses showed a strong association of HLA-B*15:02 with phenytoin-SJS/TEN (p < 3 × 10(-4) ; OR 4.26; 95% CI 1.93-9.39) and, to a lesser extent, lamotrigine-SJS/TEN (p = 0.03; OR 3.59; 95% CI 1.15-11.22). Compared with drug-tolerant controls, the carrier rates of HLA-B*40:01 and HLA-B*58:01 were lower in cases of SJS/TEN induced by carbamazepine (p = 0.004) and other AEDs (p = 0.009), respectively. SIGNIFICANCE: SJS/TEN induced by carbamazepine and phenytoin is strongly and moderately associated with HLA-B*15:02 in Han Chinese, respectively. Possible protective associations with HLA-B*40:01 and HLA-B*58:01 warrant further investigation.

HLA-A 31:01 and HLA-B 15:02 as genetic markers for carbamazepine hypersensitivity in children.

The occurrence of hypersensitivity reactions including rare but life-threatening Stevens-Johnson syndrome (SJS) and drug-induced hypersensitivity syndrome (HSS) limits the use of the anticonvulsant carbamazepine (CBZ). Human leukocyte antigen-B (HLA)-B 15:02 and HLA-A 31:01 have been identified as predictive genetic markers for CBZ hypersensitivity in Asian and European patients. To replicate these genetic associations in pediatric patients from North America with a diverse ethnic background, we investigated HLA-A 31:01 and HLA-B 15:02 in 42 children with CBZ hypersensitivity and 91 CBZ-tolerant children from across Canada. HLA-A 31:01 was significantly associated with CBZ-HSS (odds ratio (OR): 26.4, P = 0.0025) and maculopapular exanthema (MPE) (OR: 8.6, P = 0.0037) but not with CBZ-SJS. Conversely, HLA-B 15:02 was associated with CBZ-SJS (OR: 38.6, P = 0.002) but not HSS or MPE. This study is the first to demonstrate the association of HLA-A 31:01 with CBZ hypersensitivity in children, providing important replication of this association and highlighting the importance of HLA-A 31:01 as a predictive biomarker across various ancestries.

Co-amoxiclav-induced Stevens Johnson syndrome in a child.

Stevens-Johnson syndrome is an uncommon life threatening disease generally induced by drugs. Antibiotics, mainly sulphonamides, are the most involved drugs in Stevens-Johnson syndrome in children. Co-amoxiclav is a well tolerated antibiotic. It has never been reported to cause, lonely this syndrome in children. Herein, we report a co-amoxiclav-induced Stevens-Johnson syndrome occurring in an 18-month-old child. The diagnosis of SJS is often challenging in children and other possible diseases should be ruled out. The etiology of this syndrome is not yet fully understood. It is thought to be mediated by an immunologic mechanism. Management involves early identification, withdrawal of the culprit drug and rapid initiation of supportive therapies.

Telaprevir-related dermatitis.

OBJECTIVE: To evaluate the incidence, type, and severity of telaprevir-associated skin reactions. DESIGN: Three dermatologists assessed available information including photographs, biopsy results, and clinical summaries of all cases with skin eruptions reported as moderate or severe during the telaprevir clinical development program. For cases from placebo-controlled trials, they were masked to exposure. SETTINGS: Phase 1 to 3 studies of telaprevir combination therapy for hepatitis C. PATIENTS: All patients with skin eruptions enrolled in telaprevir clinical trials prior to 2011 MAIN OUTCOME MEASURES: Incidence, diagnosis, morphologic features, extent, and severity of skin eruption. RESULTS: Skin eruptions were more frequent in patients who received telaprevir as part of hepatitis C treatment compared with pegylated interferon (peginterferon) and ribavirin alone (56% vs 34% overall; 3.7% vs 0.4% severe). Occurring at any time during the 12 weeks of telaprevir combination regimen, in more than 90% of cases, this eruption is pruritic eczematous dermatitis. None of the clinical or genetic factors examined were substantial risk factors for dermatitis. Three cases of Stevens-Johnson Syndrome (SJS), and 11 cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) were suspected, with 2 SJS and 3 DRESS cases considered likely. CONCLUSIONS: Telaprevir-related dermatitis occurs in a majority of telaprevir-treated patients. It is an eczematous dermatitis that differs in timing and appearance from the eruptions usually associated with drug reactions. The strong signal for an increased risk of DRESS or SJS requires particular vigilance in telaprevir-treated patients.

Retrospective analysis of Steven Johnson syndrome and toxic epidermal necrolysis over a period of 5 years from northern Karnataka, India.

OBJECTIVE: Cutaneous drug reactions are the most common type of adverse drug reactions. Adverse cutaneous drug reactions form 2-3% of the hospitalized patients. 2% of these are potentially serious. This study aims to detect the drugs commonly implicated in Steven Johnson Syndrome-Toxic Epidermal Necrosis (SJS-TEN). MATERIALS AND METHODS: A retrospective analysis was done in all patients admitted in the last five years in SDM hospital with the diagnosis of SJS-TEN. RESULTS: A total of 22 patients with SJS-TEN were studied. In 11 patients anti-epileptics was the causal drug and in 7, anti-microbials was the causal drug. Recovery was much faster in case of anti epileptics induced SJS-TEN as compared to that induced by ofloxacin. CONCLUSION: SJS-TEN induced by ofloxacin has a higher morbidity and mortality compared to anti convulsants.

Giant cell myocarditis in a patient with a spondyloarthropathy after a drug hypersensitivity reaction.

A young woman thought to have seronegative rheumatoid arthritis developed Stevens-Johnson syndrome after treatment with sulfasalazine; this resolved with prednisone. Later she was found to be HLA-B27-positive in keeping with a spondyloarthropathy. Soon afterward, she developed clinical myopericarditis and cardiogenic shock that responded initially to methylprednisolone and intravenous immunoglobulin, but recurred. An endomyocardial biopsy demonstrated active myocarditis with a mixed cell composition including rare giant cells, but not enough to classify it as giant cell myocarditis. Heart failure symptoms returned and she eventually required a heart transplant; the explanted heart showed giant cell myocarditis.

Drug-induced rash: nuisance or threat?

Drug-induced rash is the most commonly reported drug reaction and occurs in a dizzying array of presentations. Changes in lean and fat body tissue, gastrointestinal acid and mucosal permeability, cardiac output, and renal and hepatic metabolism can affect drug absorption, distribution, metabolism, and elimination. Elders may develop cutaneous eruptions from drugs or biologics and be more sensitive to topical medications. Almost all medications have been associated with rash to some degree. Consultant pharmacists should be able to distinguish between the rashes that are uncomfortable from those that are potentially life-threatening. Some drug therapies tend to induce or aggravate "companion" rashes. With select medications, rash is a clinical indicator that the medication is working. Extensive or unusually painful drug-induced skin conditions are rare, but often require fast action by health care providers to direct the patient to life-saving help. Many of these rashes are associated with high mortality, severe complications, and potential chronic disability. Awareness of the drugs that are most likely to cause a rash can help consultant pharmacists work with the clinical team to arrange appropriate care.

Stevens-Johnson Syndrome associated with mogamulizumab treatment of adult T-cell leukemia / lymphoma.

We report an adult T-cell leukemia/lymphoma patient suffering from Stevens-Johnson Syndrome (SJS) during mogamulizumab (humanized anti-CCR4 monoclonal antibody) treatment. There was a durable significant reduction of the CD4(+) CD25(high) FOXP3(+) regulatory T (Treg) cell subset in the patient's PBMC, and the affected inflamed skin almost completely lacked FOXP3-positive cells. This implies an association between reduction of the Treg subset by mogamulizimab and occurrence of SJS. The present case should contribute not only to our understanding of human pathology resulting from therapeutic depletion of Treg cells, but also alert us to the possibility of immune-related severe adverse events such as SJS when using mogamulizumab. We are currently conducting a clinical trial of mogamulizumab for CCR4-negative solid cancers (UMIN000010050), specifically aiming to deplete Treg cells.

Drug-induced severe adverse reaction enhanced by human herpes virus-6 reactivation.

Reactivation of certain latent viruses has been linked with a more severe course of drug-induced hypersensitivity reaction (HSR). For example, reactivation of human herpes virus (HHV)-6 is associated with severe organ involvement and a prolonged course of disease. The present study discusses an HSR developed in a previously healthy male exposed to ceftriaxone, doxycycline, vancomycin, and trimethoprim/sulfamethoxazole (co-trimoxazole; TMP/SMX). Initially, the patient presented clinical manifestations of HSR, as well as clinical and laboratory measurements compatible with liver and renal failure. Moreover, the patient presented skin desquamation compatible with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis. During the reaction, it was observed HHV-6 reactivation. The severity of clinical symptoms is correlated with HHV-6 titer, as well as with results of the in vitro lymphocyte toxicity assay (LTA). Serum levels of a large panel of cytokines are compared between the patient, a large population of SJS patients, and a cohort of healthy controls, using data collected by our laboratory over the years. HHV-6 was measured in the cell culture media from lymphocytes incubated with each of the 4 drugs. Moreover, we describe a new assay using cytokines released by patient lymphocytes following in vitro exposure to the incriminated drugs as biomarkers of HSR. Based on LTA results, HHV-6 reactivation and cytokine measurements, we establish that only doxycycline and TMP/SMX were involved in the HSR. As result of this analysis, the patient could continue to use the other 2 antibiotics safely.