Amino Acid Variants of HLA-DRB1 Confer Susceptibility to Dapsone Hypersensitivity Syndrome in Addition to HLA-B*13:01.

Dapsone hypersensitivity syndrome is a rare yet severe adverse drug reaction caused by dapsone, a principal drug in multidrug therapy for leprosy. HLA-B*13:01 has been identified as a strong risk factor of dapsone hypersensitivity syndrome; however, its low positive predictive value indicated that additional genetic variants may be involved in the disease development. To discover contributing genetic variants within HLA loci in addition to HLA-B*13:01, we performed a high-coverage next-generation sequencing (NGS)-based HLA typing analysis in 103 dapsone-hypersensitive and 857 dapsone-tolerant HLA-B*13:01-positive leprosy patients in a Chinese population. Five amino acid variants in high linkage disequilibrium of HLA-DRB1 were significantly associated with dapsone hypersensitivity syndrome (positions 133, 142, -17, 11, and 13). DRB1*16:02 and DRB1*15:01 tagged by these risk-conferring amino acid residues were associated at a nominal significance level. This study identifies five amino acid variants within HLA-DRB1 that are in high linkage disequilibrium and significantly associated with dapsone hypersensitivity syndrome in a Chinese population.

A Review on Dapsone Hypersensitivity Syndrome Among Chinese Patients with an Emphasis on Preventing Adverse Drug Reactions with Genetic Testing.

AbstractDapsone is a bactericidal and bacteriostatic against Mycobacterium leprae, a causative agent of leprosy. Dapsone is also applied in a range of medical fields because of its anti-inflammatory and immunomodulatory effects. Dapsone hypersensitivity syndrome (DHS) is a rare yet serious adverse drug reaction (ADR) caused by dapsone involving multiple organs. We performed a systematic review of published articles describing dapsone-induced hypersensitivity syndrome, including all Chinese articles and the latest literature available in online databases published between October 2009 and October 2015. We determined the prevalence, clinical characteristics, and mortality rate of DHS. Importantly, we also summarized the recent advances in genetic testing allowing prediction of ADRs. In an initial systematic electronic search, we retrieved 191 articles. Subsequently, these articles were further filtered and ultimately 84 articles (60 Chinese case reports, 21 non-Chinese articles, and three epidemiological studies) were selected, which included 877 patients. The prevalence of DHS among Chinese patients was 1.5% with a fatality rate of 9.6%. Early withdrawal of dapsone and appropriate treatment reduced the fatality rate. Most importantly, genetic screening for the HLA-B*13:01 allele among high-risk populations showed a significant utility as a useful genetic marker to DHS. In conclusion, this review discusses the epidemiological and clinical characteristics of DHS among Chinese patients, which may help physicians to understand this syndrome.

A lethal case of the dapsone hypersensitivity syndrome involving the myocardium.

In the Netherlands dapsone is used for the treatment of dermatitis herpetiformis, leprosy and Pneumocystis jiroveci pneumonia and prophylaxis in case of cotrimoxazole allergy. An idiosyncratic drug reaction, known as the dapsone hypersensitivity syndrome (DHS), appears in about 0.5-3.6% of persons treated with dapsone. DHS can be associated with fever, rash and systemic involvement. We present a 35-year-old woman who developed severe DHS seven weeks after starting dapsone. Six weeks after being discharged in a good clinical condition she died from fulminant myocarditis, 11 weeks after the first DHS symptoms and the discontinuation of dapsone.

Fulminant hepatitis linked to dapsone hypersensitivity syndrome requiring urgent living donor liver transplantation: a case report.

Dapsone is a sulfone-type drug used widely for different infectious, immune, and hypersensitivity disorders as an antibacterial treatment alone or in combination for leprosy and sometimes for infected skin lesions. DHS is a severe idiosyncratic adverse reaction with multi-organ involvement. However, acute necrotic hepatitis requiring an emergent LT is rare. Herein, we report a case of 12-yr-old girl who suffered from fulminant hepatitis and multi-organ failure due to DHS for PPD. She was saved by emergent LDLT. A high index of suspicion and rapid diagnosis are necessary not to miss this potentially lethal but rare disease.

Dapsone hypersensitivity syndrome with myocarditis.

Drug hypersensitivity with myocarditis is known to occur with many drugs especially with antiepileptics, sulpha-compounds and daposne. Dapsone (4, 4 diaminodiphenyl sulphone) induced hypersensitivity is known to occur in about 2% of leprosy patients on treatment and an incidence of 1.66% in non-leprosy patients. We report this rare case of dapsone hypersensitivity syndrome in a girl on dapsone who presented with fever, anaemia, jaundice, skin rash, lymphadenopathy, and hepatomegaly and later developed myocarditis. The drug was withdrawn and the patient was treated with steroids. She improved and was discharged. She relapsed after the corticosteroids were discontinued at home.

Tumor necrosis factor-α antagonists: Side effects and their management.

As elevated levels of tumor necrosis factor-alpha (TNF-α) are associated with disease severity in psoriasis and psoriatic arthritis, TNF-α antagonists are being used to treat moderate to severe disease in patients who have contraindications, fail to respond or develop side effects to conventional systemic therapies. It is of utmost importance to be well versed with the possible adverse effects and contraindications of TNF-α antagonists so that they can be used effectively and safely. Many of their adverse effects have been well studied in patients of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) and may not be completely applicable in psoriasis. This is because patients with RA and IBD are on multiple immunosuppressants while those with psoriasis are mostly receiving single systemic therapy and often have comorbidities that distinguish them from those with RA or IBD. Also, some of the side effects are still controversial and debated. Long-term prospective randomized controlled studies are needed to better understand the associated risk in patients of psoriasis. Baseline screening and periodic monitoring during treatment can reduce and help in early identification and appropriate management of the adverse outcomes. This article reviews the side effects known to be associated with TNF-α antagonists, their pathomechanisms and management guidelines. Some of the common side effects include infusion and injection site reactions, infections particularly reactivation of tuberculosis, autoantibody formation and drug induced lupus erythematosus, liver function abnormalities, hematological, and solid organ malignancies.

Dapsone in the management of autoimmune bullous diseases.

Dapsone is used in the treatment of autoimmune bullous diseases (AIBD), a group of disorders resulting from autoimmunity directed against basement membrane and/or intercellular adhesion molecules on cutaneous and mucosal surfaces. This review summarizes the limited published data evaluating dapsone as a therapy for AIBD.

Dapsone hypersensitivity syndrome among leprosy patients in China.

OBJECTIVE: To Study the incidence and clinical characteristics of dapsone hypersensitivity syndrome (DHS) among MDT-treated leprosy patients from 2006 to 2009 in China. METHODS: A retrospective survey was carried out throughout China using a specially designed questionnaire. RESULTS: From 2006 to 2009, there were 63 new patients reported to have DHS with an incidence of 1.0%. Among these patients, 13 were complete types of DHS, the others were incomplete ones. The average age of patients with DHS was 38 years and the male to female ratio was 2.15. The average incubation period from taking dapsone to DHS onset was 32.8 days (2-6 weeks). There were 60 (95.2%) patients who presented with various skin lesions, 56 (88.9%) with fever, 40 (63.5%) with hepatic damage and 22 (34.9%) with lymphopathy. Seven patients died with a death rate of 11.1% among all patients with DHS. CONCLUSIONS: DHS is a serious adverse event resulted from dapsone. It can occur in a small number of new leprosy patients treated with dapsone containing regimen. Some patients may die of DHS if not taking timely and adequate management. Therefore local doctors should pay an attention to DHS among leprosy patients newly treated with the dapsone-containing MDT regimen.

Drug hypersensitivity syndrome.

Drug hypersensitivity syndrome (DHS) is an adverse drug reaction commonly associated with the aromatic antiepileptic drugs (AEDs), viz., phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), lamotrigine, primidone, etc. It can also be caused by other drugs, such as sulfonamides, dapsone, minocycline, gold derivatives, cyclosporine, captopril, diltiazem, terbinafine, azathioprine and allopurinol. Diagnosis of DHS may be difficult because of the variety of clinical and laboratory abnormalities and manifestations and because the syndrome may mimic infectious, neoplastic or collagen vascular disorders. The risk for developing hypersensitivity within 60 days of the first or second prescription in new users of PHT or CBZ was estimated to be 2.3-4.5 per 10,000 and 1-4.1 per 10,000, respectively. The syndrome is defined by the fever, skin rash, lymphadenopathy and internal organ involvement within the first 2-8 weeks after initiation of therapy. Internal manifestations include, among others, agranulocytosis, hepatitis, nephritis and myositis. Insufficient detoxification may lead to cell death or contribute to the formation of antigen that triggers an immune reaction. Cross-reactivity among PHT, CBZ and PB is as high as 70%-80%. Management mainly includes immediate withdrawal of the culprit drug, symptomatic treatment and systemic steroids or immunoglobulins.

Dapsone hypersensitivity syndrome in non-leprosy patients: a retrospective study of its incidence in a tertiary referral center in Taiwan.

BACKGROUND: Dapsone hypersensitivity syndrome (DHS) is a potentially life-threatening adverse drug reaction consisting of fever, hepatitis, exfoliative dermatitis, lymphadenopathy and hemolytic anemia. The incidence of DHS is estimated to be 2% in leprosy patients. Because the incidence of this drug eruption may be different in different ethnicities and diseases, we thought to investigate the incidence of DHS in non-leprosy patients. METHODS: This is a retrospective study to examine the incidence, clinical manifestations and prognosis of DHS in non-leprosy patients who were given dapsone at the National Taiwan University Hospital between June 2001 and December 2005. RESULTS: The incidence of DHS among non-leprosy patients was 1.66%. These patients ran a relatively benign course as compared with leprosy patients. CONCLUSION: The incidence of DHS among non-leprosy patients was compatible to that observed among leprosy patients. DHS in non-leprosy patients runs a favorable course with low morbidity in our study.

Leprosy: not always an easy diagnosis and often a management challenge.

Leprosy is rare in Australia, particularly in the southern states. We report two cases of leprosy in southern Australia that presented to the dermatology outpatients' department within a 4-month period. The presentation of the first case was complex, making the correct diagnosis difficult. Both cases involved immigrants from South-East Asia, were classified as multi-bacillary leprosy as defined by the World Health Organization, and were commenced on the recommended multiple drug therapy. The ensuing clinical course was complicated, with both cases developing Type 1 leprosy reactions. The first case also developed the rare but serious dapsone-induced delayed hypersensitivity reaction.

Mortality due to dapsone hypersensitivity syndrome complicating multi-drug therapy for leprosy in Nepal.

Dapsone is a component of multi-drug therapy (MDT) for the treatment of all types of leprosy. It is known that dapsone hypersensitivity syndrome (DHS) complicates the treatment in a proportion of patients. We performed a retrospective study of patients commenced on MDT between 1990 and 2006; 2% developed DHS and 0.25% died due to DHS.

Severe dapsone hypersensitivity syndrome.

Dapsone, a potent antiparasitic and anti-inflammatory compound, is mainly used in the treatment of leprosy and a variety of blistering skin diseases. It may cause a severe adverse drug reaction with multiorgan involvement known as dapsone hypersensitivity syndrome. We report the case of a 21-year-old female patient with dapsone hypersensitivity syndrome. The clinical presentation mimicked a viral exanthema.

Renal hypersensitivity vasculitis associated with dapsone.

We describe clinical and pathological features of kidney and skin involvement in a patient with hypersensitivity vasculitis associated with dapsone. Although visceral damage occurs rarely, similar skin and kidney histopathologic and immunohistochemical findings indicate that this organ is a target for type IV cell-mediated dapsone reaction. To our knowledge, this is the first reported case of renal hypersensitivity vasculitis associated with dapsone.

Eosinophilic leukemoid reaction associated with carbamazepine hypersensitivity.

Carbamazepine is widely used in the treatment of epilepsy, neuralgic pain, and bipolar affective disorders. Several adverse drug reactions have been described during the course of carbamazepine administration, including exanthemata and hematological reactions. Carbamazepine is one of the common drugs that have been implicated in the etiology of drug hypersensitivity syndrome. A 50-year-old male presented with generalized erythroderma following 10 weeks of ingestion of carbamazepine 200 mg daily for idiopathic epilepsy. His systemic examination was within normal limits. Blood counts revealed marked eosinophilia of 52% (absolute eosinophil count of 10,400 per mm3). Bone marrow aspiration revealed a moderate increase in the eosinophilic series with cells showing normal morphology. The eosinophil counts returned to normal after 2 weeks of oral prednisolone therapy. This case is reported because of its rarity in the Indian medical literature.

Dapsone hypersensitivity syndrome in an adolescent during treatment during of leprosy.

A 12 y old girl was admitted 24 days after start a WHO multidrug therapy scheme for multibacillary leprosy (dapsone, clofazimine and rifampicin) with intense jaundice, generalized lymphadenopathy, hepatoesplenomegaly, oral erosions, conjunctivitis, morbiliform rash and edema of face, ankles and hands. The main laboratory data on admission included: hemoglobin, 8.4 g/dL; WBC, 15,710 cells/mm3; platelet count, 100,000 cells/mm3; INR = 1.49; increased serum levels of aspartate and alanine aminotransferases, gamma-glutamyl transpeptidase, alkaline phosphatase, direct and indirect bilirubin. Following, the clinical conditions had deteriorated, developing exfoliative dermatitis, shock, generalized edema, acute renal and hepatic failure, pancytopenia, intestinal bleeding, pneumonia, urinary tract infection and bacteremia, needing adrenergic drugs, replacement of fluids and blood product components, and antibiotics. Ten days after admission she started to improve, and was discharged to home at day 39th, after start new supervised treatment for leprosy with clofazimine and rifampicin, without adverse effects. This presentation fulfils the criteria for the diagnosis of dapsone hypersensitivity syndrome (fever, generalized lymphadenopathy, exfoliative rash, anemia and liver involvement with mixed hepatocellular and cholestatic features). Physicians, mainly in geographical areas with high prevalence rates of leprosy, should be aware to this severe, and probably not so rare, hypersensitivity reaction to dapsone.

Dapsone induced cholangitis as a part of dapsone syndrome: a case report.

BACKGROUND: Dapsone can rarely cause a hypersensitivity reaction called dapsone syndrome, consisting of fever, hepatitis, exfoliative dermatitis, lymphadenopathy and hemolytic anemia. Dapsone syndrome is a manifestation of the DRESS (drug rash with eosinophilia and systemic symptoms) syndrome which is a serious condition that has been reported in association with various drugs. Cholangitis in dapsone syndrome has not been reported so far in the world literature. CASE PRESENTATION: We report a patient who presented with fever, exfoliative dermatitis, jaundice and anemia within three weeks of starting of dapsone therapy. These features are typical of dapsone syndrome, which is due to dapsone hypersensitivity and is potentially fatal. Unlike previous reports of hepatitic or cholestatic injury in dapsone syndrome we report here a case that had cholangitic liver injury. It responded to corticosteroids. CONCLUSION: We conclude that cholangitis, though unusual, can also form a part of dapsone syndrome. Physicians should be aware of this unusual picture of potentially fatal dapsone syndrome.