Stevens Johnson Syndrome and Toxic Epidermal Necrolysis: Maternal and Foetal Outcomes in Twenty-Two Consecutive Pregnant HIV Infected Women

Introduction

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) form a spectrum of a rare and life-threatening cutaneous drug reaction. SJS/TEN in pregnancy poses largely unknown risk factors and outcomes for both the mother and foetus compared to the general population.

Methods

We conducted a study of consecutive pregnant women admitted to single tertiary referral centre in South Africa with SJS/TEN over a 3 year period. They were all managed by the same medical team using the same protocols. We evaluated their underlying illnesses, offending drugs and the course of pregnancy and outcomes to determine factors influencing maternal and foetal outcomes.

Results

We identified twenty-two women who developed SJS/TEN while pregnant, all of them HIV-infected. Their median age was 29 years. The majority 16/22 (73%) had SJS, the milder variant of the disease affecting < 10% body surface area. Nevirapine was the offending drug in 21/22 (95%) cases. All 22 of the mothers survived with 3/22 (14%) developing postpartum sepsis. Pregnancy outcomes were known in 18/22 women and 9/18 (50%) babies were delivered by caesarean section. There were 2 foetal deaths at 21 and 31 weeks respectively and both were associated with post-partum sepsis. Postnatal complications occurred in 5 cases, 3 involving the respiratory system and the other two being low birth weight deliveries. Eight placentae and one foetus were sent for histology and none showed macroscopic or microscopic features of SJS/TEN. On follow-up, only 12/20 children were tested for HIV at 6 weeks post-delivery and none of them were HIV-infected. All had received prophylactic ARVs including nevirapine.

Conclusions

TEN, the severe form of the disease, was associated with poorer foetal outcomes. SJS/TEN-associated mortality is not increased in HIV-infected pregnant women. Maternal SJS/TEN does not seem to commonly manifest in the foetus.     

Cost-Effectiveness Analysis of HLA-B*5801 Testing in Preventing Allopurinol-Induced SJS/TEN in Thai Population

Background

Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), caused by allopurinol therapy, are strongly associated with the human leukocyte antigen (HLA), HLA-B*5801. Identification of HLA-B*5801 genotype before prescribing allopurinol offers the possibility of avoiding allopurinol-induced SJS/TEN. As there is a paucity of evidence about economic value of such testing, this study aims to determine the cost-effectiveness of HLA-B*5801 testing compared with usual care (no genetic testing) before allopurinol administration in Thailand.

Methods and Finding

A decision analytical and Markov model was used to estimate life time costs and outcomes represented as quality adjusted life years (QALYs) gained. The model was populated with relevant information of the association between gene and allopurinol-induced SJS/TEN, test characteristics, costs, and epidemiologic data for Thailand from a societal perspective. Input data were obtained from the literature and a retrospective database analysis. The results were expressed as incremental cost per QALY gained. A base-case analysis was performed for patients at age 30. A series of sensitivity analyses including scenario, one-way, and probabilistic sensitivity analyses were constructed to explore the robustness of the findings. Based on a hypothetical cohort of 1,000 patients, the incremental total cost was 923,919 THB (USD 29,804) and incremental QALY was 5.89 with an ICER of 156,937.04 THB (USD 5,062) per QALY gained. The cost of gout management, incidence of SJS/TEN, case fatality rate of SJS/TEN, and cost of genetic testing are considered very influential parameters on the cost-effectiveness value of HLA-B*5801 testing.

Conclusions

The genetic testing for HLA-B*5801 before allopurinol administration is considered a highly potential cost-effective intervention in Thailand. The findings are sensitive to a number of factors. In addition to cost-effectiveness findings, consideration of other factors including ethical, legal, and social implications is needed for an informed policy decision making.     

HLA-A*0206 with TLR3 Polymorphisms Exerts More than Additive Effects in Stevens-Johnson Syndrome with Severe Ocular Surface Complications

Background

Stevens-Johnson syndrome (SJS) is an acute inflammatory vesiculobullous reaction of the skin and mucosa, often including the ocular surface, and toxic epidermal necrolysis (TEN) occurs with its progression. Although SJS/TEN is thought to be initiated by certain types of medication coupled with possible infection. In the present study we examined the multiplicative interaction(s) between HLA-A*0206 and 7 Toll-like receptor 3 (TLR3) Single-nucleotide polymorphisms (SNPs) in patients with SJS/TEN.

Principal Findings

We analyzed the genotypes for HLA-A and 7 TLR3 SNPs in 110 Japanese SJS/TEN patients with severe ocular complications and 206 healthy volunteers to examine the interactions between the two loci. We found that HLA-A*0206 exhibited a high odds ratio for SJS/TEN (carrier frequency: OR = 5.1; gene frequency: OR = 4.0) and that there was a strong association with TLR3 rs.5743312T/T SNP (OR = 7.4), TLR3 rs.3775296T/T SNP (OR = 5.8), TLR3 rs.6822014G/G SNP (OR = 4.8), TLR3 rs.3775290A/A SNP (OR = 2.9), TLR3 rs.7668666A/A SNP (OR = 2.7), TLR3 rs.4861699G/G SNP (OR = 2.3), and TLR3 rs.11732384G/G SNP (OR = 1.9). There was strong linkage disequilibrium (LD) between rs.3775296 and rs.5743312 and between rs.7668666 and rs.3775290. The results of interaction analysis showed that the pair, HLA-A*0206 and TLR3 SNP rs3775296T/T, which exhibited strong LD with TLR3 rs.5743312, exerted more than additive effects (OR = 47.7). The other pairs, HLA-A*0206 and TLR3 rs.3775290A/A SNP (OR = 11.4) which was in strong LD with TLR3 rs7668666A/A SNP, and TLR3 rs4861699G/G SNP (OR = 7.6) revealed additive effects. Moreover, the combination HLA-A*0206 and TLR3 rs3775296T/T was stronger than the TLR3 rs6822014G/G and TLR3 rs3775290A/A pair, which reflected the interactions within the TLR3 gene alone.

Significance

By interaction analysis, HLA-A*0206 and TLR3 SNP rs3775296T/T, which were in strong LD with TLR3 SNP rs5743312T/T, manifested more than additive effects that were stronger than the interactions within the TLR3 gene alone. Therefore, multiplicative interactions of HLA-A and TLR3 gene might be required for the onset of SJS/TEN with ocular complications.     

Prostaglandin E receptor subtype EP3 expression in human conjunctival epithelium and its changes in various ocular surface disorders

Background

In our earlier genome-wide association study on Stevens-Johnson Syndrome (SJS) and its severe variant, toxic epidermal necrolysis (TEN), we found that in Japanese patients with these severe ocular surface complications there was an association with prostaglandin E receptor 3 (EP3) gene (PTGER3) polymorphisms. We also reported that EP3 is dominantly expressed in the ocular surface-, especially the conjunctival epithelium, and suggested that EP3 in the conjunctival epithelium may down-regulate ocular surface inflammation. In the current study we investigated the expression of EP3 protein in the conjunctiva of patients with various ocular surface diseases such as SJS/TEN, chemical eye burns, Mooren’s ulcers, and ocular cicatricial pemphigoid (OCP).

Methodology/Principal Findings

Conjunctival tissues were obtained from patients undergoing surgical reconstruction of the ocular surface due to SJS/TEN, chemical eye burns, and OCP, and from patients with Mooren''s ulcers treated by resection of the inflammatory conjunctiva. The controls were nearly normal human conjunctival tissues acquired at surgery for conjunctivochalasis. We performed immunohistological analysis of the EP3 protein and evaluated the immunohistological staining of EP3 protein in the conjunctival epithelium of patients with ocular surface diseases. EP3 was expressed in the conjunctival epithelium of patients with chemical eye burns and Mooren’s ulcer and in normal human conjunctival epithelium. However, it was markedly down-regulated in the conjunctival epithelium of SJS/TEN and OCP patients.

Conclusions

We posit an association between the down-regulation of EP3 in conjunctival epithelium and the pathogenesis and pathology of SJS/TEN and OCP, and suggest a common mechanism(s) in the pathology of these diseases. The examination of EP3 protein expression in conjunctival epithelium may aid in the differential diagnosis of various ocular surface diseases.     

Factors Associated with Increased Mortality in a Predominantly HIV-Infected Population with Stevens Johnson Syndrome and Toxic Epidermal Necrolysis

Introduction

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening drug reactions with a higher incidence in HIV-infected persons. SJS/TEN are associated with skin and mucosal failure, predisposing to systemic bacterial infection (BSI), a major cause of death. There are limited data on risk factors associated with BSI and and mortality in HIV-infected people with SJS/TEN.

Methods

We conducted a retrospective study of patients admitted to a university hospital with SJS/TEN over a 3 year period. We evaluated their underlying illnesses, eliciting drugs, predictive value of bacterial skin cultures and other factors associated with mortality and BSI in a predominantly HIV-infected population by comparing characteristics of the patients who demised and those who survived.

Results

We admitted 86 cases during the study period and 67/86(78%) were HIV-infected. Tuberculosis was the commonest co-morbidity, diagnosed in 12/86(14%) cases. Skin cultures correlated with BSI by the same organism in 7/64(11%) cases and 6/7 were Gram-negative. Two of the 8 cases of Gram-negative BSI had an associated Gram-negative skin culture, although not always the same organism. All 8 fatalities had >30% epidermal detachment, 7 were HIV-infected, 6 died of BSI and 6 had tuberculosis.

Conclusions

Having >30% epidermal detachment in SJS/TEN carries an increased risk of BSI and mortality. Tuberculosis and BSI are associated with higher risk of death in SJS/TEN. Our data suggests there may be an association between Gram-negative BSI and Gram-negative skin infection.     

ABC Transporters and the Proteasome Complex Are Implicated in Susceptibility to Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis across Multiple Drugs

Stevens–Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) represent rare but serious adverse drug reactions (ADRs). Both are characterized by distinctive blistering lesions and significant mortality rates. While there is evidence for strong drug-specific genetic predisposition related to HLA alleles, recent genome wide association studies (GWAS) on European and Asian populations have failed to identify genetic susceptibility alleles that are common across multiple drugs. We hypothesize that this is a consequence of the low to moderate effect size of individual genetic risk factors. To test this hypothesis we developed Pointer, a new algorithm that assesses the aggregate effect of multiple low risk variants on a pathway using a gene set enrichment approach. A key advantage of our method is the capability to associate SNPs with genes by exploiting physical proximity as well as by using expression quantitative trait loci (eQTLs) that capture information about both cis- and trans-acting regulatory effects. We control for known bias-inducing aspects of enrichment based analyses, such as: 1) gene length, 2) gene set size, 3) presence of biologically related genes within the same linkage disequilibrium (LD) region, and, 4) genes shared among multiple gene sets. We applied this approach to publicly available SJS/TEN genome-wide genotype data and identified the ABC transporter and Proteasome pathways as potentially implicated in the genetic susceptibility of non-drug-specific SJS/TEN. We demonstrated that the innovative SNP-to-gene mapping phase of the method was essential in detecting the significant enrichment for those pathways. Analysis of an independent gene expression dataset provides supportive functional evidence for the involvement of Proteasome pathways in SJS/TEN cutaneous lesions. These results suggest that Pointer provides a useful framework for the integrative analysis of pharmacogenetic GWAS data, by increasing the power to detect aggregate effects of multiple low risk variants. The software is available for download at https://sourceforge.net/projects/pointergsa/.     

Structural modeling of HLA-B*1502/peptide/carbamazepine/T-cell receptor complex architecture: implication for the molecular mechanism of carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis

Drug-induced adverse reactions are a significant problem in healthcare worldwide and are estimated to cost billions of dollars annually in the United States. A portion of such reactions is observed to strongly associate with certain human leukocyte antigen (HLA) alleles; one of the strongest associations is the HLA-B*1502 protein with carbamazepine (CBZ)-induced Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) – the odds ratio value can even be higher than one thousand. The particularly strong association in CBZ-induced SJS/TEN suggests that the HLA-B*1502 is not only a genetic marker but also a participant in the pathogenesis of the disease. In the current study, we attempt to computationally model the atomic-level structure of the complete HLA-B*1502/peptide/CBZ/T-cell receptor (TCR) complex architecture based on prior knowledge obtained from epidemiological investigations as well as in vitro and in vivo assays. The model tells a different story about the molecular mechanism of CBZ-induced SJS/TEN from that previously reported for abacavir (ABC)-induced hypersensitivity (HSR); the CBZ molecule is located at the interface between HLA-B*1502/peptide and TCR, directly contacts the P3–P6 residues of antigen peptide, and bound within a pocket region encompassed by two TCR CDR3 fingers. Molecular dynamics simulation and binding energy analysis further reveal that the CBZ shows considerably high affinity to TCR over HLA-B*1502/peptide, which can tightly interact with the former rather than the latter. From the model, two hypotheses are proposed that can well explain most previous observations and are expected to guide next wet-lab experiments. This study could help to promote our understanding of the molecular mechanism and pathological implication underlying CBZ-induced SJS/TEN.     

Recovered Patients with Stevens–Johson Syndrome and Toxic Epidermal Necrolysis Maintain Long-Lived IFN-γ and sFasL Memory Response

There is evidence that drug-specific T cells are involved in inducing keratinocyte apoptosis in acute stage of Steven-Johson syndrome (SJS) and Toxic epidermal necrolysis (TEN). However, there are few studies that have attempted to examine T cell memory responses over time. We sought to determine the duration of IFN-γ and sFasL memory response to causal drugs in patients with SJS and TEN after remission. Eight patients with previous SJS and TEN were enrolled. Memory T cells were measured by 10-day cultured IFN-γ enzyme-linked immunosorbent spot-forming cell (ELISpot) assay. Effector T-cell responses were measured by ex vivo IFN-γ ELISpot assay and sFasL ELISA. The sFasL-mediated toxicities of drug-stimulated PBMC supernatants against keratinocyte line were further investigated by MTT proliferation assay and Annexin-V staining. We observed significant cultured and ex vivo IFN-γ ELISpot responses against causal drugs in all 8 patients. In addition, the sFasL levels were specifically increased in the supernatant of PBMCs cultured with causal drugs from 6 of 8 patients. Drug-stimulated PBMC supernatants were cytotoxic against keratinocyte line, which was inhibited by anti-FasL mAb in a dose-dependent manner. Our findings confirmed that drug-specific IFN-γ and sFasL memory response against causal drugs could be sustained over several years and further suggest that patients should avoid causal drug re-exposure after the recovery of TEN and SJS.     

Intraocular and intraorbital compartment pressure changes following orbital bone grafting: a clinical and laboratory study

Visual loss is an uncommon but catastrophic complication after intraorbital bone grafting for the reconstruction of acute traumatic defects or long-standing enophthalmos. Increased intraocular or intraorbital compartment pressure may be pathogenic in this setting. A two-part study was designed to test the null hypothesis that intraocular and intraorbital compartment pressure values remain constant despite orbital volume reduction with graft material. Laboratory study: Intraocular and intraorbital compartment pressures were measured during sequential orbital volume reduction in New Zealand White rabbits that had been randomized to one of three groups: intact orbits (n = 10), acute orbital wall defects (n = 8), and chronic (3 months) orbital wall defects (n = 11). Intraocular pressure was significantly (p<0.05) elevated in all three groups of orbits undergoing orbital volume reduction compared with control, nonoperated orbits. Intraorbital compartment pressure values did not change significantly from control levels throughout the grafting sequence. Although no significant differences existed between groups in the maximum levels of intraocular pressure attained, the chronic group demonstrated a greater rate of rise and slower rate of decline. Clinical study: Using applanation tonometry, intraocular pressure was measured before and serially after orbital floor exploration and intraorbital placement of split calvarial bone grafts in 19 patients who presented with orbital-zygomatic complex fractures that required surgery. A separate group of 16 patients with orbital-zygomatic complex fractures that required exploration of the orbital floor but not bone grafting was used for comparison. A significant (p<0.05) elevation of intraocular pressure was observed immediately after bone grafting compared with nongrafted orbits, but values returned to normal within 30 minutes and remained stable through the third postoperative day. There were no cases of visual impairment in any patients in either group as the result of surgical treatment. These data indicate that orbital volume reduction with graft material results in significant, temporary elevation of intraocular pressure. No significant elevations of intraorbital compartment pressure were detected in the rabbit orbits. Data from this study may have direct relevance in defining guidelines for "tolerable" changes in orbital tissue and globe pressures after surgery.     

Toxic epidermal necrolysis in two rhesus macaques (Macaca mulatta) after administration of rituximab

A 2- and a 7-year-old rhesus macaque developed toxic epidermal necrolysis (TEN) after administration of ritux imab. Rituximab, a chimeric monoclonal antibody (mAb) directed against the CD20 antigen on B lymphocytes, is used to treat certain B cell neoplasias. The macaques were part of a gene therapy study that involved administering an adeno-associated viral vector encoding human factor IX (hFIX) to the animals. Both animals developed antibody against hFIX, which eliminated expression of the protein. Rituximab was administered to deplete the population of B cells producing antibodies against the protein. Two days after treatment, the 7-year-old animal developed erythemic skin lesions that rapidly progressed in severity, resulting in epidermal sloughing and ulceration. Despite aggressive treatment with analgesics, antibiotics, and corticosteroids, the animal had to be euthanized 5 days later. The 2-year-old macaque had no reaction to the initial dose of rituximab and received a second infusion 2 weeks later. Two days after drug administration, skin lesions developed; aggressive analgesic, antibiotic, and corticosteroid treatment was initiated, and the lesions resolved. A third rituximab dose was given approximately 2 months after the second. Skin lesions developed and were treated. The animal made a full recovery. In both cases, skin biopsies were taken and histopathologic findings were consistent with TEN. A severe, life-threatening condition, TEN manifests as an intolerance reaction in the skin. The most common cause of TEN is a response to previous drug administration. To our knowledge, this condition has not been reported in association with rituximab administration in macaques.     

Drug induced exfoliative dermatitis: state of the art

Drug induced exfoliative dermatitis (ED) are a group of rare and severe drug hypersensitivity reactions (DHR) involving skin and usually occurring from days to several weeks after drug exposure. Erythema multiforme (EM), Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are the main clinical presentations of drug induced ED. Overall, T cells are the central player of these immune-mediated drug reactions. Here we provide a systematic review on frequency, risk factors, pathogenesis, clinical features and management of patients with drug induced ED.     

Sleep and rest activity measured by wrist actigraphy in an HIV-infected patient with Steven–Johnson syndrome

The Steven–Johnson syndrome (SJS) is characterized by a sudden onset of mucous membrane erosion (predominantly oral mucosa, lips, and conjunctivae) with widespread blistering of the skin involving up to 10% of the body surface area. It is almost always a drug-related reaction, although it can be caused by infections and immunizations. A 33-year-old man with recent diagnosis of HIV infection developed antiretroviral treatment (ART)-associated SJS. Physical activity and sleep parameters were recorded by wrist actigraphy in four different consecutive scenarios: baseline assessment, first ART regimen, hospitalization, and second ART regimen. Significant differences were observed in physical activity patterns between the four phases. No differences in sleep parameters were found. To our knowledge, this is the first study recording physical activity changes and sleep during a SJS reaction.     

Pulmonary vasodilation by acetazolamide during hypoxia is unrelated to carbonic anhydrase inhibition

Acute hypoxic pulmonary vasoconstriction can be inhibited by high doses of the carbonic anhydrase inhibitor acetazolamide. This study aimed to determine whether acetazolamide is effective at dosing relevant to human use at high altitude and to investigate whether its efficacy against hypoxic pulmonary vasoconstriction is dependent on carbonic anhydrase inhibition by testing other potent heterocyclic sulfonamide carbonic anhydrase inhibitors. Six conscious dogs were studied in five protocols: 1) controls, 2) low-dose intravenous acetazolamide (2 mg.kg(-1).h(-1)), 3) oral acetazolamide (5 mg/kg), 4) benzolamide, a membrane-impermeant inhibitor, and 5) ethoxzolamide, a membrane-permeant inhibitor. In all protocols, unanesthetized dogs breathed spontaneously during the first hour (normoxia) and then breathed 9-10% O(2) for the next 2 h. Arterial oxygen tension ranged between 35 and 39 mmHg during hypoxia in all protocols. In controls, mean pulmonary artery pressure increased by 8 mmHg and pulmonary vascular resistance by 200 dyn.s.cm(-5) (P <0.05). With intravenous acetazolamide, mean pulmonary artery pressure and pulmonary vascular resistance remained unchanged during hypoxia. With oral acetazolamide, mean pulmonary artery pressure increased by 5 mmHg (P < 0.05), but pulmonary vascular resistance did not change during hypoxia. With benzolamide and ethoxzolamide, mean pulmonary artery pressure increased by 6-7 mmHg and pulmonary vascular resistance by 150-200 dyn.s.cm(-5) during hypoxia (P < 0.05). Low-dose acetazolamide is effective against acute hypoxic pulmonary vasoconstriction in vivo. The lack of effect with two other potent carbonic anhydrase inhibitors suggests that carbonic anhydrase is not involved in the mediation of hypoxic pulmonary vasoconstriction and that acetazolamide acts on a different receptor or channel.     

Study of the damaging effects of acetazolamide on gastric mucosa in rats

The present study demonstrated that acetazolamide (100 and 200 mg/kg, s.c.) induced severe gastric hemorrhagic ulceration in rats. The ulceration was aggravated by oral administration of HCl, but was inhibited by NaHCO3. Furthermore, the severity of ulceration was also decreased by pretreatment with methysergide, chlorpheniramine, or cimetidine. These protective effects were accompanied by an increase in serotonin and histamine released from the stomach. Acetazolamide injection also increased the protein level but reduced the sialic acid content in the gastric secretion, indicating that the gastric mucosal barrier may have been damaged. Prostaglandin E2 content of the gastric mucosa was not affected by the drug; however, carbonic anhydrase activity was markedly reduced in a dose-dependent manner. Thus, it is suggested that the ulceration induced by acetazolamide is mainly due to the inhibition of carbonic anhydrase activity and mucus secretion. The increase in serotonin and histamine release also may have been the contributing factors for gastric ulcer formation.     

Phacoemulsification, vitrectomy and the implantation of an intraocular lens in diabetic patients

The purpose of this study was to evaluate results of combined phacoemulsification, intraocular lens implantation and pars plana vitrectomy in patients with advanced diabetic retinopathy. We retrospectively evaluated postoperative outcomes and complications in 102 eyes of 102 patients who underwent a combined procedure. All patients had a visually significant cataract. Forty two patients had vitreous hemorrhage and mild proliferative diabetic retinopathy. Sixty patients had a mild tractional retinal detachment. The median follow up was 14 months (range 6-36 months). 80% of patients had an increase of visual acuity of at least 2 Snellen lines. The most frequent early postoperative complication was elevated intraocular pressure, followed by mild fibrinous reaction. The most frequent late postoperative complication was the presence of posterior synechia, followed by glaucoma. Eleven patients required a repeated pars plana vitrectomy. Combined phacoemulsification, posterior chamber intraocular lens implantation and pars plana vitrectomy can be successfully performed in selected diabetic patients with favorable postoperative outcome.     

Endogenous interleukin-11 (IL-11) levels in newly diagnosed children with acquired severe aplastic anemia (SAA)

BACKGROUND: Impaired hematopoietic growth factor production is a hypothetical contributing factor to the development of acquired severe aplastic anemia (SAA). The serum levels of most hematopoietic cytokines in SAA patients are elevated. OBJECTIVE: To measure interleukin-11 levels in newly diagnosed SAA children and attempt to correlate levels with disease severity and response to therapy. DESIGN/METHODS: Following enrollment into a clinical study but prior to treatment, serum samples were obtained from 11 newly diagnosed children with acquired SAA. These samples were collected between May 2000 and September 2002. IL-11 levels were quantified utilizing an ELISA technique. RESULTS: Ten of the 11 patients had low or normal levels of IL-11 (<85 pg/mL) and one had an elevated level of 409 pg/mL (normal range 15-200 pg/mL). CONCLUSIONS: The production of IL-11 does not increase in response to thrombocytopenia in most children with SAA. The significance of this laboratory observation is not clear at this time. Further studies are warranted to determine what, if any, role this plays in the development of this disorder and if the administration of recombinant human IL-11 might be beneficial in the treatment of acquired SAA.     

Real-World Efficiency of Pharmacogenetic Screening for Carbamazepine-Induced Severe Cutaneous Adverse Reactions

Objectives

We evaluated the cost and efficiency of routine HLA-B*15∶02 screening to prevent carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (CBZ-SJS/TEN) in Hong Kong.

Methods

Data were extracted from patients who commenced CBZ as the first-ever AED treatment or tested for HLA-B*15∶02 allele in three years before policy implementation (pre-policy: 16 September 2005 to 15 September 2008) and three years after (post-policy: 16 September 2008 to 15 September 2011). Using published unit costs, we estimated the cost of screening by comparing the costs to prevent and treat CBZ-SJS/TEN. We compared the number of person-tests needed and the cost to prevent resultant death with cancer screening programs.

Results

The number of screening tests needed to prevent one case of CBZ-SJS/TEN was 442, and to prevent one resultant death was 1,474 to 8,840. The screening cost was $332 per person, of which 42% was attributed to an additional consultation to review result and prescribe appropriate medication. HLA-B*15∶02 screening expended $146,749 to prevent a case of CBZ-SJS/TEN, and $489,386– $2,934,986 to prevent a resultant death. The corresponding numbers of tests and costs for mammography and Pap smear to prevent death due to breast and cervical cancers were 7,150 and 7,000, and $614,900 and $273,000, respectively. Comparing to the SJS/TEN treatment cost, HLA-B*15∶02 screening would become cost saving if a point-of-care test of less than $37 was available.

Conclusions

HLA-B*15∶02 screening is as efficient as mammography and Pap smear in preventing death. Development of point-of-care testing will vastly improve efficiency.     

Structural and functional mutations of the perlecan gene cause Schwartz-Jampel syndrome, with myotonic myopathy and chondrodysplasia

Perlecan, a large heparan sulfate proteoglycan, is a component of the basement membrane and other extracellular matrices and has been implicated in multiple biological functions. Mutations in the perlecan gene (HSPG2) cause two classes of skeletal disorders: the relatively mild Schwartz-Jampel syndrome (SJS) and severe neonatal lethal dyssegmental dysplasia, Silverman-Handmaker type (DDSH). SJS is an autosomal recessive skeletal dysplasia characterized by varying degrees of myotonia and chondrodysplasia, and patients with SJS survive. The molecular mechanism underlying the chondrodystrophic myotonia phenotype of SJS is unknown. In the present report, we identify five different mutations that resulted in various forms of perlecan in three unrelated patients with SJS. Heterozygous mutations in two patients with SJS either produced truncated perlecan that lacked domain V or significantly reduced levels of wild-type perlecan. The third patient had a homozygous 7-kb deletion that resulted in reduced amounts of nearly full-length perlecan. Unlike DDSH, the SJS mutations result in different forms of perlecan in reduced levels that are secreted to the extracellular matrix and are likely partially functional. These findings suggest that perlecan has an important role in neuromuscular function and cartilage formation, and they define the molecular basis involved in the difference in the phenotypic severity between DDSH and SJS.     

Liposomes as an ocular delivery system for acetazolamide: In vitro and in vivo studies

The purpose of this study was to formulate topically effective controlled release ophthalmic acetazolamide liposomal formulations. Reverse-phase evaporation and lipid film hydration methods were used for the preparation of reversephase evaporation (REVs) and multilamellar (MLVs) acetazolamide liposomes consisting of egg phosphatidylcholine (PC) and cholesterol (CH) in the molar ratios of (7∶2), (7∶4), (7∶6), and (7∶7) with or without stearylamine (SA) or dicetyl phosphate (DP) as positive and negative charge inducers, respectively. The prepared liposomes were evaluated for their entrapment efficiency and in vitro release. Multilamellar liposomes entrapped greater amounts of drug than REVs liposomes. Drug loading was increased by increasing CH content as well as by inclusion of SA. Drug release rate showed an order of negatively charged > neutral > positively charged liposomes, which is the reverse of the data of drug loading efficiency. Physical stability study indicated that approximately 89%, 77%, and 69% of acetazolamide was retained in positive, negative, and neutral MLVs liposomal formulations up to a period of 3 months at 4°C. The intraocular pressure (IOP)-lowering activity of selected acetazolamide liposomal formulations was determined and compared with that of plain liposomes and acetazolamide solution. Multilamellar acetazolamide liposomes revealed more prolonged effect than REVs liposomes. The positively charged and neutral liposomes exhibited greater lowering in IOP and a more prolonged effect than the negatively charged ones. The positive multilamellar liposomes composed of PC:CH:SA (7:4:1) molar ratio showed the maximal response, which reached a value of −7.8±1.04 mmHg after 3 hours of topical administration. Published: January 5, 2007