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Journal of Immunology (Baltimore, Md. :... Apr 2023Previous studies have shown that cysteine-reactive drug metabolites bind covalently with protein to activate patient T cells. However, the nature of the antigenic...
Previous studies have shown that cysteine-reactive drug metabolites bind covalently with protein to activate patient T cells. However, the nature of the antigenic determinants that interact with HLA and whether T cell stimulatory peptides contain the bound drug metabolite has not been defined. Because susceptibility to dapsone hypersensitivity is associated with the expression of HLA-B*13:01, we have designed and synthesized nitroso dapsone-modified, HLA-B*13:01 binding peptides and explored their immunogenicity using T cells from hypersensitive human patients. Cysteine-containing 9-mer peptides with high binding affinity to HLA-B*13:01 were designed (AQDCEAAAL [Pep1], AQDACEAAL [Pep2], and AQDAEACAL [Pep3]), and the cysteine residue was modified with nitroso dapsone. CD8+ T cell clones were generated and characterized in terms of phenotype, function, and cross-reactivity. Autologous APCs and C1R cells expressing HLA-B*13:01 were used to determine HLA restriction. Mass spectrometry confirmed that nitroso dapsone-peptides were modified at the appropriate site and were free of soluble dapsone and nitroso dapsone. APC HLA-B*13:01-restricted nitroso dapsone-modified Pep1- (n = 124) and Pep3-responsive (n = 48) CD8+ clones were generated. Clones proliferated and secreted effector molecules with graded concentrations of nitroso dapsone-modified Pep1 or Pep3. They also displayed reactivity against soluble nitroso dapsone, which forms adducts in situ, but not with the unmodified peptide or dapsone. Cross-reactivity was observed between nitroso dapsone-modified peptides with cysteine residues in different positions in the peptide sequence. These data characterize a drug metabolite hapten CD8+ T cell response in an HLA risk allele-restricted form of drug hypersensitivity and provide a framework for structural analysis of hapten HLA binding interactions.
Topics: Humans; Dapsone; Cysteine; CD8-Positive T-Lymphocytes; HLA-B Antigens; Drug Hypersensitivity; Peptides; Haptens
PubMed: 36881872
DOI: 10.4049/jimmunol.2200531 -
International Journal of Trichology 2023Folliculitis decalvans (FD) represents a chronic and recurrent pustulofollicular scalp inflammation resulting in scarring alopecia. The presence of a bacterial bioflilm...
Folliculitis decalvans (FD) represents a chronic and recurrent pustulofollicular scalp inflammation resulting in scarring alopecia. The presence of a bacterial bioflilm at the interface of the hair shaft may provide an explanation for the chronicity and high relapse rate of FD, even after prolonged systemic antibiotic treatments. We originally read with enthusiasm Melián-Olivera .'s retrospective study of patients with FD treated with topical dapsone published in the . However, we experienced an unsuccessful trial of 5% dapsone gel in a patient with FD resulting in worsening of the disease with a pustular flareup and questioned why positive study reports with novel therapeutic options in dermatology often fail in practice. The authors admitted the limitations of their study: small sample size, retrospective, uncontrolled nature of the study, and concomitant use of other treatments. Clinical research ultimately aims at improving the patient outcome. For this purpose, trials must evaluate the outcomes that genuinely reflect the clinical utility of drugs. Therefore, we postulate stricter criteria for treatment trials and statistics in dermatology before publication in peer-reviewed scientific journals to avoid frustrations of physicians and patients alike.
PubMed: 38179006
DOI: 10.4103/ijt.ijt_39_22 -
JAMA Dermatology Apr 2018Dapsone-induced hypersensitivity syndrome (DHS) is a life-threatening adverse drug reaction. Based on available epidemiologic studies, HLA genotypes may play an... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Dapsone-induced hypersensitivity syndrome (DHS) is a life-threatening adverse drug reaction. Based on available epidemiologic studies, HLA genotypes may play an important role in DHS.
OBJECTIVE
To assess the association between HLA-B*1301 and dapsone-induced cutaneous adverse drug reactions (cADRs).
DATA SOURCES
Human studies investigating associations between HLA-B*1301 and dapsone-induced cADRs were systematically searched without language restriction from the inception of each database until September 12, 2017, in PubMed, the Human Genome Epidemiology Network), and the Cochrane Library. Combinations of HLA genotypes, dapsone, and synonymous terms were used; reference lists were searched in selected articles.
STUDY SELECTION
Two reviewers identified studies investigating the associations between HLA-B*1301 and dapsone-induced cADRs that reported sufficient data for calculating the frequency of HLA-B*1301 carriers among case and control patients, in which all patients received dapsone before HLA-B*1301 screening. An initial search of the databases identified 391 articles, of which 3 studies (2 in Chinese populations and 1 in a Thai population) met the inclusion criteria.
DATA EXTRACTION AND SYNTHESIS
Overall odds ratios (ORs) with 95% CIs were calculated using a random-effects model to determine the association between HLA-B*1301 and dapsone-induced cADRs. Subgroup analyses by type of cADR were also performed. PRISMA guidelines were used to abstract and assess data.
MAIN OUTCOMES AND MEASURES
Primary outcomes were associations between HLA-B*1301 and dapsone-induced cADRs in dapsone-tolerant controls. The outcomes are reported as overall OR. Statistical heterogeneity was assessed using the Q statistic and I2 tests.
RESULTS
From the 3 included studies, there were 111 unique patients with dapsone-induced cADRs (subsequently used in the meta-analysis), 1165 dapsone-tolerant patients, and 3026 healthy controls. The cases included 64 men and 49 women (2 patients were missing from the meta-analysis; 1 each from 2 of the 3 studies); mean age was 39.7 years. An association between HLA-B*1301 and dapsone-induced cADRs was identified (summary OR, 43.0; 95% CI, 24.0-77.2). Subgroup analyses among types of cADRs produced similar findings in DHS (OR, 51.7; 95% CI, 16.9-158.5), dapsone-induced severe cADRs (Stevens-Johnson syndrome and toxic epidermal necrolysis [SJS/TEN] plus drug rash [adverse skin reaction to a drug] along with eosinophilia and systemic symptoms [DRESS]) (OR, 54.0; 95% Cl, 8.0-366.2), dapsone-induced SJS/TEN (OR, 40.5; 95% CI, 2.8-591.0), and dapsone-induced DRESS (OR, 60.8; 95% CI, 7.4-496.2). There was no heterogeneity (I2 = 0%, P = .38).
CONCLUSIONS AND RELEVANCE
Associations between HLA-B*1301 and dapsone-induced cADRs were found in dapsone-tolerant and healthy control groups. For patient safety, genetic screening for HLA-B*1301 in Asian populations before dapsone therapy is warranted.
Topics: Anti-Infective Agents; Dapsone; Drug Eruptions; Drug Hypersensitivity Syndrome; Genotype; HLA-B13 Antigen; Humans
PubMed: 29541744
DOI: 10.1001/jamadermatol.2017.6484 -
Naunyn-Schmiedeberg's Archives of... Jul 2023Viral respiratory diseases (VRDs) cause lung inflammation and inflammatory cytokine production. We study whether dapsone is responsible for its observed preventive... (Randomized Controlled Trial)
Randomized Controlled Trial
Viral respiratory diseases (VRDs) cause lung inflammation and inflammatory cytokine production. We study whether dapsone is responsible for its observed preventive treatment effects of the sustained viral RNA interferon response. Around 2008 and 2012, Korea's Dementia Management Act stipulated drastic changes in the administration of dementia medication by medical staff. Participants were randomized and we compared leprosy patients with VRDs after prescribing dapsone as a standard treatment from 2005 to 2019. Significance was evaluated based on the dapsone-prescribed (+) subgroup and the dapsone-unprescribed (-) subgroup of the VRD diagnosed (+) and VRD undiagnosed (-) subgroup. We analyzed VRD ( +)/(- with dapsone (+)/(-) group and used a T-test, and designed the equation of acetylation with dapsone and acetylcholine (AA) equation. The 6394 VRD participants who received the dapsone intervention compared to the 3255 VRD participants in the control group demonstrated at T2 VRD (+) dapsone (-) (mean (M) = 224.80, SD = 97.50): T3 VRD (-) dapsone (+) (M = 110.87, SD = 103.80), proving that VRD is low when dapsone is taken and high when it is not taken. The t value is 3.10, and the p value is 0.004395 (significant at p < 0.05). After an increase in VRDs peaked in 2009, bronchitis, COPD, and pneumonia surged in 2013. The AA equation was strongly negatively correlated with the prevalence of bronchitis and chronic obstructive pulmonary disease (COPD): with bronchitis, r(15) = -0.823189, p = 0.005519, and with COPD, r(15) = -0.8161, p = 0.000207 (significant at p < 0.05). Dapsone treated both bronchitis and COPD. This study provides theoretical clinical data to limit acetylcholine excess during the VRD pandemic for bronchitis, COPD, and pneumonia.
Topics: Humans; Acetylcholine; Pulmonary Disease, Chronic Obstructive; Bronchitis; Pneumonia; Dapsone; Leprosy; Dementia
PubMed: 36773052
DOI: 10.1007/s00210-023-02407-7 -
The Journal of Investigative Dermatology May 2023Dapsone hypersensitivity syndrome (DHS) is restricted to HLA-B∗13:01. However, the positive predictive value for HLA-B∗13:01 is only 7.8%. To explore the potential...
Dapsone hypersensitivity syndrome (DHS) is restricted to HLA-B∗13:01. However, the positive predictive value for HLA-B∗13:01 is only 7.8%. To explore the potential coexisting factors involved in the occurrence of DHS, we carried out a GWAS and a genome-wide DNA methylation profile analysis comparing patients with DHS with dapsone-tolerant control subjects (all carrying HLA-B∗13:01). No non-HLA SNPs associated with DHS were identified at the genome-wide level. However, the pathway of antigen processing and presentation was enriched in patients with DHS, and the gene TAP2 was identified. Expression of TAP2 and its molecular chaperone, TAP1, were validated by quantitative PCR, and in vitro functional experiments were performed. The results showed that patients with DHS have higher mRNA levels of TAP1 and TAP2 and an enhanced capacity for antigen-presenting cells activating dapsone-specific T cells compared with dapsone-tolerant controls. Activation of dapsone-specific T cells was inhibited when TAP function of antigen-presenting cells was impaired. This study shows that epigenetic regulation of TAP1 and TAP2 affects the function of antigen-presenting cells and is a critical factor that mediates the development of DHS.
Topics: Humans; Epigenesis, Genetic; Drug Hypersensitivity Syndrome; Hypersensitivity; Dapsone; HLA-B Antigens; ATP Binding Cassette Transporter, Subfamily B, Member 3
PubMed: 37306379
DOI: 10.1016/j.jid.2022.10.009 -
The Pan African Medical Journal 2022Sneddon-Wilkinson disease is a benign amicrobial pustulosis belonging to the spectrum of neutrophilic dermatoses. It is characterized by evident stereotypic clinical...
Sneddon-Wilkinson disease is a benign amicrobial pustulosis belonging to the spectrum of neutrophilic dermatoses. It is characterized by evident stereotypic clinical features, including, in most cases, pustular lesions of the trunk and prominent skin folds. This pustulosis may be associated with other diseases (IgA monoclonal gammopathy, rheumatoid arthritis, neoplasms or other neutrophilic dermatoses) and therefore requires regular follow-up. This disease has a relapsing-remitting course. First line therapy is dapsone. We here report the case of a 49-year-old patient with amicrobial pustulosis (Sneddon-Wilkinson disease).
Topics: Humans; Middle Aged; Skin Diseases, Vesiculobullous; Blister; Arthritis, Rheumatoid; Dapsone; Dermatitis
PubMed: 36721471
DOI: 10.11604/pamj.2022.43.115.33116 -
Indian Journal of Dermatology 2017Autoimmune bullous disorders (AIBDs) are a heterogeneous group of diseases which are rarely seen in children. Studies concerning the immunobullous diseases in pediatric...
BACKGROUND
Autoimmune bullous disorders (AIBDs) are a heterogeneous group of diseases which are rarely seen in children. Studies concerning the immunobullous diseases in pediatric patients are scarce.
AIMS AND OBJECTIVES
In this study, we aimed to investigate the clinical features and treatment outcomes of AIBDs in children.
MATERIALS AND METHODS
The electronic records of the patients in our AIBDs outpatient clinic were retrospectively reviewed. All cases diagnosed before the age of 16 years were included in the analysis of clinical features, treatment outcomes, and follow-up data.
RESULTS
Of the 196 patients with immunobullous diseases, 9 (4.6%) were diagnosed before the age of 16 years. Mean age of the patients at the time of diagnosis was 7.72 ± 5.66 years. Among nine patients, linear immunoglobulin A disease (LAD), pemphigus vulgaris (PV), and bullous pemphigoid (BP) were seen in 5, 2, and 2 children, respectively. All patients were treated with at least two systemic agents (including methylprednisolone, dapsone, methotrexate, salazopyrine, intravenous Ig [IVIg], and rituximab) leading to clinical remission in all of them after a mean period of 31.77 ± 27.99 months.
CONCLUSION
In line with earlier studies, LAD was the most common immunobullous disease and in general, associated with a favorable response to dapsone. This study was noteworthy in that the patients with PV and BP demonstrated a relatively more recalcitrant course, requiring rituximab and IVIg for remission, respectively. Overall, patients had a good prognosis.
PubMed: 28794567
DOI: 10.4103/ijd.IJD_366_16 -
Dermatology Online Journal Jul 2021Dermatitis herpetiformis (DH) is a rare autoimmune blistering disorder in which patients with celiac disease, a gluten-sensitive enteropathy, present with a severely...
Dermatitis herpetiformis (DH) is a rare autoimmune blistering disorder in which patients with celiac disease, a gluten-sensitive enteropathy, present with a severely pruritic papulovesicular eruption over extensor surfaces such as the knees, elbows, lower back, buttocks, and neck. Patients are instructed to adhere to a gluten-free diet for purposes of improving their skin disease and gluten-sensitive enteropathy; this is the only treatment that lowers risk of enteropathy-associated T cell lymphoma. Patients who adhere to a strict gluten-free diet often have remission of their skin disease over months to years. Dapsone is a rapid and extremely effective first-line treatment option and often used while transitioning to a gluten-free diet. Aside from gluten-free diet and dapsone, second-line treatment options include sulfapyridine, sulfasalazine, and colchicine. Some patients have difficulty adhering to a gluten-free diet or develop intolerable side effects to systemic therapies. Furthermore, there is limited data on the use of the second-line treatments. Recent studies have shed light on the role of JAK-STAT-dependent pathways in the pathogenesis of dermatitis herpetiformis. We present a patient treated with tofacitinib, 5mg twice daily, an oral JAK1/3 inhibitor, who demonstrated clinical improvement of DH and control of new lesion development.
Topics: Aged; Celiac Disease; Dapsone; Dermatitis Herpetiformis; Diet, Gluten-Free; Drug Administration Schedule; Humans; Janus Kinase 1; Janus Kinase 3; Male; Patient Compliance; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Remission Induction; Treatment Outcome
PubMed: 34391330
DOI: 10.5070/D327754365 -
Pharmaceuticals (Basel, Switzerland) Sep 2021Dermatologic pathologies are the fourth most common cause of non-fatal disease worldwide; however, they produce a psychosocial, economic, and occupational impact equal... (Review)
Review
Dermatologic pathologies are the fourth most common cause of non-fatal disease worldwide; however, they produce a psychosocial, economic, and occupational impact equal to or greater than other chronic conditions. The most prevalent are actinic keratosis, followed by basal-cell carcinoma, in a lesser proportion acne vulgaris, psoriasis, and hidradenitis suppurativa, among others, and more rarely dermatitis herpetiformis. To treat actinic keratosis and basal-cell carcinoma, 5-fluorouracil (5-FU) 0.5% is administered topically with good results, although in certain patients it produces severe toxicity. On the other hand, dapsone is a drug commonly used in inflammatory skin conditions such as dermatitis herpetiformis; however, it occasionally causes hemolytic anemia. Additionally, biologic drugs indicated for the treatment of moderate-to-severe psoriasis and hidradenitis suppurativa have proved to be effective and safe; nevertheless, a small percentage of patients do not respond to treatment with biologics in the long term or they are ineffective. This interindividual variability in response may be due to alterations in genes that encode proteins involved in the pathologic environment of the disease or the mechanism of action of the medication. Pharmacogenetics studies the relationship between genetic variations and drug response, which is useful for the early identification of non-responsive patients and those with a higher risk of developing toxicity upon treatment. This review describes the pharmacogenetic recommendations with the strongest evidence at present for the treatments used in dermatology, highlighting those included in clinical practice guides. Currently, we could only find pharmacogenetic clinical guidelines for 5-FU. However, the summary of product characteristics for dapsone contains a pharmacogenetic recommendation from the United States Food and Drug Administration. Finally, there is an enormous amount of information from pharmacogenetic studies in patients with dermatologic pathologies (mainly psoriasis) treated with biologic therapies, but they need to be validated in order to be included in clinical practice guides.
PubMed: 34577605
DOI: 10.3390/ph14090905 -
Boletin Medico Del Hospital Infantil de... 2023Acquired epidermolysis bullosa is a rare and chronic autoimmune subepidermal bullous disease characterized by the formation of autoantibodies against type VII collagen....
BACKGROUND
Acquired epidermolysis bullosa is a rare and chronic autoimmune subepidermal bullous disease characterized by the formation of autoantibodies against type VII collagen. Presentation in childhood is rare and with several manifestations.
CASE REPORT
We report the case of a 12-year-old female patient who presented bullous and polymorphic lesions on the chest and extremities of several months of evolution. Due to the characteristics of the skin lesions, a histopathological and direct immunofluorescence study was conducted, confirming the diagnosis of acquired epidermolysis bullosa. Subsequently, corticosteroid and dapsone treatment was administered, with favorable clinical response during follow-up.
CONCLUSIONS
Acquired epidermolysis bullosa is unusual in pediatric age, so it should be considered in the differential diagnosis of other congenital and acquired bullous diseases of childhood. The definitive diagnosis is performed through an immunofluorescence, study, which allows for rapid and effective treatment to control the disease and avoid permanent sequelae.
Topics: Humans; Female; Child; Epidermolysis Bullosa Acquisita; Diagnosis, Differential; Dapsone
PubMed: 37490686
DOI: 10.24875/BMHIM.22000118