Curr Rheumatol Rep (2017) 19: 3 DOI 10.1007/s11926-017-0626-z
ORPHAN DISEASES (B MANGER, SECTION EDITOR)
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome and the Rheumatologist Marwan H. Adwan 1
Published online: 30 January 2017 # Springer Science+Business Media New York 2017
Abstract Purpose of the Review The purpose of the review is to summarise the various drugs used in rheumatology practice implicated in the causation of DRESS syndrome. Recent Findings The most commonly reported drugs are allopurinol, sulfasalazine and minocycline, which pose a very high risk for DRESS syndrome development, followed by strontium ranelate and dapsone. Other, less commonly reported, drugs include leflunomide, hydroxychloroquine, non-steroidal anti-inflammatory drugs, febuxostat, bosentan and solcitinib. Reaction to some drugs is strongly associated with certain HLA alleles, which may be used to screen patients at risk of serious toxicity. Summary DRESS syndrome is a serious reaction to many drugs used in rheumatic diseases, with a potentially fatal outcome and needs to be considered in any patient started on these medications who presents with a rash, fever and eosinophilia, sometimes with internal organ involvement.
Keywords DRESS syndrome . Eosinophilia . Hypersensitivity . Toxicity . Idiosynchratic . Allopurinol . Minocycline . Sulfasalazine
This article is part of the Topical Collection on Orphan Diseases * Marwan H. Adwan [email protected] 1
Division of Rheumatology, Department of Medicine, The University of Jordan, Queen Rania Street, Amman 11942, Jordan
Introduction Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare idiosyncratic hypersensitivity reaction to many drugs. It was first reported with anticonvulsant drugs and was therefore denoted “anticonvulsant hypersensitivity syndrome” [1], but was subsequently reported to result from many other medications. The acronym DRESS syndrome was coined by Bocquet et al. in 1996 to distinguish between the acute drug-induced hypersensitivity reaction and the more insidious pseudolymphoma, which may produce similar histological features [2]. The syndrome is characterised by the appearance of a fever, rash, lymphadenopathy, internal organ involvement and haematologic manifestations, such as eosinophilia and lymphocytosis with or without the appearance of atypical lymphocytes on peripheral blood film. Visceral manifestations include eosinophil infiltration of internal organs, principally the liver, kidney, heart and lung, which may result in failure of these organs. Cutaneous manifestations (Figs. 1 and 2) include maculopapular rash, erythroderma and, less commonly, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme or a purpuric rash [3]. DRESS syndrome generally develops 2–6 weeks following exposure to the offending drug [4], and symptoms resolve in the majority of cases after drug withdrawal [2]. Fortunately, this rather unpredictable complication is quite rare and occurs in only 1 to 10 per 10,000 exposures [5]. But it is, nonetheless, serious with an estimated mortality rate of around 10% [2]. A 7-year prospective study reported an estimated incidence of 0.9/100,000 in a West Indian population of African ancestry [6]. As far as rheumatology practice is concerned, this syndrome has been classically associated with allopurinol under the name “allopurinol hypersensitivity syndrome”. However,
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Curr Rheumatol Rep (2017) 19: 3 Table 1
Drugs causing DRESS syndrome in rheumatic diseases
Immunomodulatory antibiotics Sulfasalazine, Minocycline, Dapsone Non-antibiotic DMARDs Leflunomide, Hydroxychloroquine Hypouricemic drugs Allopurinol, Febuxostat Anti-osteoporotic drugs Fig. 1 Palmar skin eruptions in a patient after 4 weeks of allopurinol therapy. Courtesy of Dr. Bernhard Manger
an increasing number of other medications prescribed by rheumatologists have been reported to cause this clinical entity. This review addresses these medications, the frequency of this complication, the extent of organ involvement, the possible pathogenetic mechanisms responsible and treatment.
Strontium ranelate NSAIDs Celecoxib, Ibuprofen, Phenylbutazone Diclofenac ET-1 antagonists Bosentan JAK1 inhibitors Solcitinib DMARDs disease-modifying dugs, DRESS drug rash with eosinophilia and systemic symptoms, ET-1 endothelin-1, JAK1 janus kinase 1, NSAIDs non-steroidal anti-inflammatory drugs
Causative Drugs A Pubmed and Google Scholar search for case reports on DRESS syndrome, caused by the various drugs used in rheumatology, uncovered 14 different drugs that belonged to seven main categories (Table 1). Allopurinol and sulfasalazine together accounted for almost two thirds of cases. These drugs will be presented in descending order in terms of the frequency of DRESS syndrome. Frequency of Various Clinical Manifestations Table 2 lists the frequencies of various manifestations reported in the two largest studies (Kardoun and Cacoub et al.) [4, 7••]. As can be seen from the table, the most common
manifestations are rash and eosinophilia followed by fever, liver involvement, lymphadenopathy and facial oedema in descending order. Renal, cardiac and pulmonary manifestations occurred only in a small number of patients. In the largest retrospective study of DRESS syndrome due to various drugs, the two drugs relevant to this review were allopurinol and minocycline [3]. Allopurinol-realted DRESS was associated with fever in 23%, rash in 95%, lymphadenopathy in 10%, eiosinophilia in 62%, liver involvement in 62%, renal involvement in 43% while pulmonary involvement was not reported in any cases. Minocycline-induced DRESS, on the other hand, was associated with fever and/or in 94%, lymphadenopathy in 78%, eiosinophilia in 72%, liver
Table 2 Percentages of clinical features of DRESS syndrome reported in two large studies
Fig. 2 Generalised skin eruption 3 weeks after allopurinol therapy
Reference Manifestation
Kardaun et al. Ref 7 %
Cacoub et al. Ref 4 %
Fever Rash Facial oedema Lymphadenopathy Liver kidney Lung heart CNS Eosinophilia Atypical lymphocytes
90 100 76 54 75 37 32 13 4.3 95 67
64. 97. 39. 56. 59. 8 5 2 2 66. 27
LFT liver function test, CNS central nervous system
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involvement in 72%, renal involvement in 17% and pulmonary involvemet in 11%. Allopurinol Allopurinol is a purine analogue inhibitor of xanthine oxidase, the enzyme involved in uric acid generation from xanthine and hypoxanthine. It is the most commonly reported drug to cause the syndrome among the medications used in rheumatic diseases and is considered to pose a very high risk for its development [8]. The incidence of allopurinol hypersensitivity has been quoted as reaching 0.1% [9]. In a review of reported cases, allopurinol accounted for 19 of the 172 cases reported (11%) and was found to be the second most common cause after carbamazepine [4]. The RegiSCAR is a multinational registry of serious cutaneous adverse reactions (SCAR). Analysis of 117 cases of DRESS syndrome recorded in this registry revealed that allopurinol was second only to carbamazepine; accounting for 21 cases (18%) [7••]. In several retrospective studies, it is reported to be the most common cause, surpassing individual anticonvulsants [8, 10–14]. Risk factors associated with allopurinol hypersensitivity include recent initiation of allopurinol, co-prescription of diuretics, impaired renal function [15, 16] and the presence of the HLA-B*5801 allele [15]. The latter is particularly important in Asian populations. Association with this allele was confirmed in several studies. Firstly, in a case-control study involving a Han Chinese population, the allele was identified in 100% of patients who developed severe SCAR, but in only 15% of patients who had less severe reactions, yielding an odd’s ratio of 580.3 [17]. Secondly, in a recent systematic review of case reports of allopurinol hypersensitivity, HLAB*5801 was identified in 166 of the 167 patients who were tested for this allele. Interestingly, 89% of those who tested positive were of Asian origin [15]. Thirdly, a fairly recent study reported association of HLA-B*5801 in a Portuguese population, particularly females, indicating that its effect may not be merely restricted to Asians [18]. Thus far, there is no evidence that high-dose allopurinol poses a risk factor for the syndrome development [15]. Allopurinol-related DRESS syndrome is more likely to be associated with renal impairment than that caused by other drugs. In a retrospective review of cases notified to the French pharmacovigilance centres between 1985 and 2000 combined with a literature review of case reports until 2001, Pyeriere et al. reported that allopurinol was more likely to be associated with renal dysfunction than other medications [3]. Among the various drugs, allopurinol and minocycline seem to be associated with a particularly higher risk of severe DRESS syndrome [19]. A retrospective review of cases of severe DRESS syndrome resulting in either intensive care unit (ICU) admission or death, for instance, uncovered that allopurinol and minocycline were responsible for 4 and 3 (27 and
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20%) of the 15 cases reported, respectively [19]. Furthermore, allopurinol was reported to be responsible for 3 of the 9 cases of severe DRESS syndrome included in a systematic review [4]. Mortality among allopurinol-induced cases also seems to be higher than that reported with other drugs and has been quoted as high as 12–27% [9, 15]. Allopurinol is metabolised to oxipurinol. The former has a half life 1.2 h whereas the latter’s half life is much longer (23 h) [20]. The half life of oxipurinol is prolonged even further in renal impairment, resulting in drug accumulation [21]. This accounts, in part, for the increased incidence of adverse reactions to allopurinol in patients with renal impairment. Increased plasma oxypurinol and granulysin level is associated with poor prognosis and more severe DRESS syndrome [16]. In vitro studies showed that oxypurinol increases the expression of granulysin, a protein produced by cytotoxic T lymphocytes and natural killer (NK) cells. Furthermore, oxypurinol stimulates clonotype-specific T cells that express granulysin [22]. In our literature search, more than half of the cases reported were given allopurinol for asymptomatic hyperuricaemia. This is in agreement with a recent systematic review, which revealed that allopurinol was given for asymptomatic hyperuricaemia to more than 45% of the cases reported as having allopurinol hypersensitivity [15]. As asymptomatic hyperuricaemia is common in the general population, this almost certainly explains the high incidence of DRESS syndrome due to allopurinol. Taking into account the high incidence, considerable risk and significant mortality of allopurinol-induced DRESS syndrome, it is absolutely important not to prescribe this drug merely for asymptomatic hyperuricaemia. Sulfasalazine Sulfasalazine is the second most common cause of DRESS syndrome among the drugs used in rheumatic diseases. It is also considered to pose a very high risk [8]. A review involving 172 cases of DRESS syndrome reported that sulfasalazine accounted for 10 cases (6%) and was the third most common cause (together with Phenobarbital and lamotrigine) after carbamazepine and allopurinol [4]. In the prospective RegiSCAR study mentioned under allopurinol, 8 of the 117 cases identified were caused by sulfasalazine, which was also found to be the third most common individual drug after carbamazepine and allopurinol. A recent review of published case reports of sulfasalazine-inducd DRESS syndrome uncovered 48 cases [23]. The most common internal organ to be involved was the liver (72%), followed by the kidney (35%). The lung was involved in only one case. Mortality was lower than is generally reported for DRESS syndrome and occurred in only two cases (4.1%) [23].
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The sulphapyridine component of sulfasalazine undergoes acetylation prior to excretion in the urine. Sulfasalazine toxicity in general is related to acetylator status and is more common in slow acetylators [24]. The HLA-B*13: 01 was demonstrated to pose a risk for sulfasalazine toxicity in Han Chinese population in one study [25], but this has not so far been replicated or demonstrated in other populations. Minocycline Minocycline is the next most important anti-rheumatic drug to cause this syndrome. This antibiotic is occasionally used as a disease-modifying drug (DMARD) in rheumatoid arthritis (RA). Minocycline-induced DRESS syndrome is particularly likely to be associated with lung involvement in the form of eosinophilic pneumonitis. This complication occurred in one third of reported cases [3]. As stated under allopurinol, 3 of the 15 patients with severe DRESS resulting in either death or ICU admission were caused by minocycline, all of whom had pneumonitis [19]. Cardiac involvement and lymphadenopathy also seem to be reported more commonly than with other drugs [3]. Another characteristic of minocycline cases is the development of autoimmune phenomena such as autoimmune thyroiditis [26–28], diabetes mellitus and ANA antibodies [26], which may sometimes develop long after DRESS has resolved. Similar to allopurinol and sulfasalazine, minocycline poses a very high risk for DRESS syndrome [8]. Patients with minocycline-related DRESS syndrome are usually younger than cases due to other causes, reflecting the age group for which this drug is mostly given, namely, patients with acne. Strontium Ranelate Strontium is an alkaline earth metal that belongs to group 2A of the periodic table of elements, which also contains beryllium, magnesium, calcium, barium and radium. Its atomic weight is just over twice that of calcium. It is used in the form of strontium ranelate (SR) salt for the treatment of severe osteoporosis in patients who cannot tolerate other agents, provided there are no contraindications, particularly cardiovascular co-morbidity [29]. SR poses a moderate risk for DRESS syndrome [8]. A review of the UK General Practice Research Database (GPRD) in 2008 identified 1574 patients exposed to SR but no cases of DRESS syndrome were detected [30]. Cacoub et al., however, studied the reported reactions from the SR pharmacovigilance database between 2004 and 2011 and uncovered 47 cases of DRESS syndrome related to SR reported from 16 different countries (mostly Europe) of whom 4 patients (8.5%) died [31]. The authors estimated the incidence of SR-related DRESS syndrome to be 1/24,112. Thus, failure to detect any cases in the GPRD study may be explained by the
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rare number of events reflected by the size of the sample reviewed, which is far below that of this incidence. A recent study reported a significant association between the closely related SR-induced conditions Stevens Johnsons syndrome/toxic epidermal necrolysis and the class I alleles HLA-A*33:03 and HLA-B*58:01 in Han Chinese [32], but no alleles have yet been identified in association with DRESS syndrome. This association has so far not been replicated or demonstrated in other populations. Leflunomide Leflunomide inhibits pyrimidine synthesis by inhibiting the enzyme dihydroorotate dehydrogenase. With the exception of one case in an Italian case series [14], all leflunomiderelated cases are reported from India. This may either reflect a genetic susceptibility or widespread use of the drug in India, as it is manufactured by Indian companies and costs a fraction of its cost in other countries. Or it may indeed reflect underutilization of leflunomide in other parts of the world, as most guidelines now recommend the use of biologic agents after methotrexate failure in RA. Besides, the drug is not available in some countries. A large proportion of patients with leflunomide-induced DRESS syndrome reported in the literature had diarrhoea [33]. Interestingly, five of the 14 reported cases died [33–37] indicating that this condition may be more serious than is currently appreciated. Studies have shown that patients with the CYP1A2*1F allele of cytochrome P450 [38] and the dihydroorotate dehydrogenase polymorphism DHODH A40C [39] are at higher risk of leflunomide toxicity. Possession of the two alleles may pose an even higher risk of toxicity [39]. Another study showed association with CYP 2C19, but did not detect any association with CYP1A2*1F or DHODH A40C [40]. A recent study showed association with CYP1A2 C163A allele [41]. Although no cases of DRESS syndrome were reported among these studies. Dapsone Dapsone is a sulfone derivative which was initially used for treatment of leprosy, but is now used to treat various conditions including Pneumocystis jirovecii, vasculitis and several dermatological conditions, including some lupus rashes. Dapsone-related serious drug reactions have long been reported under the name “dapsone hypersensitivity syndrome” (DHS), which is a variant of DRESS syndrome, although DHS may sometimes be associated with haemolytic anaemia, which is not found in DRESS. In addition, some cases do not fulfil the criteria of true DRESS syndrome. DHS develops in 0.5–3.6% of people treated with dapsone [42] and has similar clinical features and mortality to DRESS
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syndrome [43]. A systematic review of case reports and observational studies retrieved 336 cases of DHS, most of whom (72%) were given dapsone for leprosy [44]. Furthermore, a retrospective review of patients treated with dapsone for leprosy in the whole of China between 2006 and 2009 identified 63 DHS cases among 6243 leprosy patents. Among these, 7 patients (11.1%) died [45]. Of note, delay in initiation of treatment after the onset of DHS was a significant contributing factor to mortality. On the other hand, a retrospective study involving 361 non-leprosy patients in Taiwan revealed a more favourable outcome and no deaths were reported [46]. Genetics may play a role in susceptibility to dapsone hypersensitivity, as the HLA-B*13:01 poses a strong risk factor in Chinese patients with leprosy [42]. This is the same allele that increases the risk of DRESS syndrome due to sulfasalazine, another sulfa-related compound. Bosentan Bosentan is an endothelin-1 antagonist used for the treatment of pulmonary hypertension. There are 3 cases of DRESS syndrome induced by this drug reported in the literature [47–49]. They all subsided after discontinuation of the drug and, in 2 cases, initiation of corticosteroid therapy [48, 49]. Although one case relapsed when steroids were tapered [48]. Hydroxychloroquine HCQ is generally safe and is not a common cause of DRESS syndrome. There are only 2 case reports in the English literature. Both cases involved men 58 and 62 years old and symptoms occurred in both within 2 weeks of starting the drug and settled with drug cessation and corticosteroid therapy without any sequelae [50, 51]. Non-steroidal Anti-inflammatory Drugs Non-steroidal anti-inflammatory drugs (NSAIDs) are a large and heterogeneous group of drugs which are used frequently in most rheumatic diseases for their anti-inflammatory and analgesic effects. In a review of reported cases of DRESS syndrome, 4 of the 172 cases were caused by NSAIDs (Celecoxib, ibuprofen and phenylbutazone) [4]. Another retrospective review of 45 cases of DRESS syndrome reported NSIADs to also be responsible for 4 cases (diclofenac and celecoxib) (8.9%) [52]. In another retrospective review, NSIADs accounted for 5 of 38 cases (ibuprofen and diclofenac) (13.2%) [53]. Febuxostat Febuxostat is a non-purine competitive inhibitor of xanthine oxidase. Unlike allopurinol, it does not require dose
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adjustment in mild to moderate renal impairment (creatinine clearance 30–80 ml/min) [54]. Therefore, it is particularly useful and safe in this patient group [55]. A multicentre double-blind randomized controlled trial (RCT) involving 760 patients receiving febuxostat 80 or 120 mg versus allopurinol 300 mg reported significantly more patients in the febuxostat groups than in the allopurinol group achieving a target serum uric acid of 6 mg/dl. No cases of DRESS syndrome, however, were reported [56]. There is only one case report in the literature implicating febuxostat [57]. Although this patient was commenced on sulindac 2 weeks before and febuxostat 2 days before developing symptoms. The time lapse perhaps suggests that sulindac may have been the cause rather than febuxostat. Furthermore, a large multicentre open-label prospective observational study including 5948 patients with gout, of whom 5592 were treated with febuxostat, did not report any DRESS cases after 4 weeks of observation [58]. Therefore, unless more cases are reported in the future, it can be presumed that febuxostat does not cause DRESS syndrome. What is more, there is no cross-reactivity between febuxostat and allopurinol hypersensitivity [22]. Thus, it is a safe alternative in patients with a history of allopurinol hypersensitivity and/or renal impairment. It is worth noting that the duration of the RCT mentioned above is long enough for DRESS syndrome to develop. However, the observational study’s duration may not have been long enough. Solcitinib (GSK2586184) There are 2 cases reported by the same author of patients with systemic lupus erythematosus (SLE) developing reactions following the JAK1 inhibitor GSK2586184 [59]. The cases do not, however, fulfil the criteria for DRESS syndrome; the first case had fever, rash and liver function abnormality and the second had fever, hand and facial oedema and abnormal liver function. A recent RCT employing this drug in SLE was declared futile and subsequently terminated because 6 of the recruited 50 patients developed abnormal liver functions and 2 patients developed DRESS syndrome [60]. It is worth mentioning that both patients were also taking HCQ, although the duration of treatment with this drug is not clear. Furthermore, this complication was not observed in an RCT of this drug in psoriasis [61]. Thus, whether this effect is limited to patients with SLE remains to be seen. DRESS Syndrome and Vasculitis Another way DRESS syndrome may present to the rheumatologist is by mimicking or being associated with vasculitis. Its clinical presentation (fever, rash and internal organ involvement) may be misdiagnosed as vasculitis. The rash
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may sometimes be purpuric and look like vasculitis [62]. Additionally, the presence of eosinophilia may initially cause misinterpretation as eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss). Vasculitic change has been reported in some cases. For instance, a retrospective study of the cutaneous histological findings of 32 patients with DRESS syndrome noted vasculitis in 6% [62]. In fact, some cases in the literature have been reported to be associated with clinical, histological and radiological features of vasculitis. There is, for instance, a case of DRESS syndrome caused by leflunomide that showed vasculitis on renal histology [33]. Vahid et al. reported a case of allopurinol-induced DRESS syndrome associated with diffuse alveolar haemorrhage [63], and Wi et al. reported a DRESS case with leukocytoclastic vasculitis demonstrated on skin biopsy [64]. Finally, there are several cases of DRESS syndrome associated with neurological features and cerebral vasculitis-like lesions on brain imaging [65, 66]. One must remember though that these are isolated cases and may simply be just a coincidence.
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(MHC) (e.g. allopurinol, dapsone, SR, anti-epileptic and anti-retroviral drugs), although a few are class II-mediated (e.g. lapatinib, co-amoxyclav) [75]. These drug-specific HLA haplotypes may provide tools to identify patients at risk of drug toxicity, just like thiopurine methyltranserase (TPMT) is employed in identifying patients at risk of azathioprine toxicity. A test with high sensitivity and specificity has been developed to screen for HLA-B*58:01/*57:01 alleles and thus predict patients at risk of allopurinol and abacavir toxicity [76]. Several alleles are reported to be associated with hypersensitivity to other drugs including anticonvulsants, antibiotics and anti-retroviral drugs [77]. Another recently identified mechanism contributing to the pathogenesis is the so-called the pharmacological reaction with immune receptor (p-i) concept, where a drug interacts non-covalently with the HLA molecule or T cell receptor (TCR) directly, bypassing antigen processing [67]. This has been shown for the interaction of allopurinol and its metabolite oxipurinol with HLA-B*58:01 [78]. Treatment
Pathogenesis The exact pathogenesis of DRESS syndrome is not fully known. Detailed aspects of the immunopathogenesis of the syndrome are beyond the scope of this review and are discussed in detail elsewhere [67, 68]. Human herpes virus-6 (HHV-6) immunoglobulin G (IgG) is increased in the majority of patients, indicating that HHV-6 reactivation may be involved in the pathogenesis [4]. Furthermore, HHV-6 reactivation is associated with more severe DRESS syndrome [69]. Reactivation of other viruses including Epstein-Barr virus (EBV) and HHV-7 has also been reported [70]. DRESS syndrome is a type IVb delayed hypersensitivity reaction [67], which involves type 2 helper (Th2) lymphocytes that produce interleukin-4 (IL-4) and IL-5. The latter plays an important role in eosinophil differentiation and activation [71], the hallmark of the disease. A small study demonstrated that serum level of the C-C Motif Chemokine Ligand 17 (CCL17) (a mediator of Th2 inflammatory response) is increased in DRESS syndrome and correlated with IL-5 level and eosinophil count [72]. The DRESS reaction exclusively complicates drugs with an aromatic benzene-like ring in their structure [14], as do all the drugs discussed in this review. Aromatic compounds form reactive epoxide intermediate structures, which may result in an immune response [14]. Many drugs possess aromatic structure and yet do not cause DRESS syndrome. Thus, there must be something more to these drugs than merely processing a benzene ring that renders them immunogenic. The hypersensitivity reaction involves anti-drug specific CD4+ and CD8+ T cells [73, 74]. Most drug reactions are associated with class I major histocompatibility complex
Treatment of DRESS syndrome, as reported in the literature, is by stopping the offending drug and the initiation of corticosteroid therapy [4, 11, 19, 79–83]. Although there is no consensus on the dose, route of administration or duration of steroid therapy. Symptoms may recur after steroid tapering or discontinuation. Other treatments reported in the literature include, antihistamines [52, 82, 84], pentoxyphylline [84] and intravenous immunoglobulin [4, 19, 85]. There is a report of a paediatric case of life-threatening DRESS syndrome showing a dramatic response to plasma exchange after failing to respond to corticosteroids [86]. Other immunosuppressive drugs are not reported extensively, there is a single report of successful and sustained treatment of 2 cases with ciclosporin (one induced by minocycline) [87].
Conclusion In this review, we have discussed the important drugs used in rheumatic diseases that may potentially cause DRESS syndrome. Allopurinol, sulfasalazine and minocycline are the most important medications and pose a very high risk, followed by SR, dapsone and NSAIDs. Other drugs such as HCQ, bosentan and febuxostat are not extensively reported in the literature and are limited to few case reports. Allopurinol and minocycline are also more likely to be associated with severe DRESS syndrome. Interestingly, no cases involving any of the biologic DMARDs have been reported. This may not come as a surprise, since all drugs that cause DRESS syndrome generally possesses an aromatic ring and are not protein-based.
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Susceptibility to the syndrome due to some medications (allopurinol, sulfasalazine and dapsone) may be predicted by the presence of certain HLA alleles, but for many other drugs, no such alleles have been identified. Thus, predicting which patients may be susceptible remains an enigma. Apart from allopurinol-related DRESS syndrome, which may be expected, and hopefully, avoided in the presence of some predisposing factors, such as renal impairment and diuretic co-prescription, there are no obvious such non-genetic factors that are known to increase the risk and, therefore, prediction of DRESS syndrome due to other drugs. Compliance with Ethical Standards Conflict of Interest The author declares no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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Lee H, et al. Increased risk of strontium ranelate-related SJS/TEN is associated with HLA. Osteoporos Int. 2016;1–7. Pinto B et al. Leflunomide-induced DRESS syndrome with renal involvement and vasculitis. Clin Rheumatol. 2013;32(5):689–93. Parajuli S et al. Leflunomide induced DRESS syndrome: a case report. Nepal J Dermatol, Venereol Leprol. 2012;10(1):46–8. Shastri V et al. Severe cutaneous adverse drug reaction to leflunomide: a report of five cases. Indian Journal of Dermatology. Venereol Leprol. 2006;72(4):286. Uppal M, Rai R, Srinivas C. Leflunomide induced drug rash and hepatotoxicity. Indian J Dermatol. 2004;49(03):154. Do‐Pham G et al. Drug reaction with eosinophilia and systemic symptoms and severe involvement of digestive tract: description of two cases. Br J Dermatol. 2011;165(1):207–9. Grabar PB et al. Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients. Eur J Clin Pharmacol. 2008;64(9):871–6. Grabar PB et al. Dihydroorotate dehydrogenase polymorphism influences the toxicity of leflunomide treatment in patients with rheumatoid arthritis. Ann Rheum Dis. 2009;68(8):1367–8. Wiese MD et al. Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis. Arthritis Res Ther. 2012;14(4):1. Hopkins AM et al. Genetic polymorphism of CYP1A2 but not total or free teriflunomide concentrations is associated with leflunomide cessation in rheumatoid arthritis. Br J Clin Pharmacol. 2016;81(1): 113–23. Zhang F-R et al. HLA-B* 13: 01 and the dapsone hypersensitivity syndrome. N Engl J Med. 2013;369(17):1620–8. Zhu YI, Stiller MJ. Dapsone and sulfones in dermatology: overview and update. J Am Acad Dermatol. 2001;45(3):420–34. Lorenz M, Wozel G, Schmitt J. Hypersensitivity reactions to dapsone: a systematic review. Acta Derm Venereol. 2012;92(2):194– 199III. Tian W et al. Dapsone hypersensitivity syndrome among leprosy patients in China. Lepr Rev. 2012;83(4):370–7. Sheen Y-S et al. Dapsone hypersensitivity syndrome in non-leprosy patients: a retrospective study of its incidence in a tertiary referral center in Taiwan. J Dermatol Treat. 2009;20(6):340–3. Allanore Y et al. Bosentan-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. J Rheumatol. 2010;37(5):1077–8. Nagai Y et al. Drug eruption due to bosentan in a patient with systemic sclerosis. Mod Rheumatol. 2006;16(3):188–90. Romano A et al. Delayed hypersensitivity to bosentan. Allergy. 2009;64(3):499–501. Kretzmann BR, Fang MA. Hydroxychloroquine-induced DRESS Syndrome. Proc UCLA Healthcare. 2011;15. Volpe A et al. Hydroxychloroquine-induced DRESS syndrome. Clin Rheumatol. 2008;27(4):537–9. Nam YH et al. Drug reaction with eosinophilia and systemic symptoms syndrome is not uncommon and shows better clinical outcome than generally recognised. Allergol Immunopathol (Madr). 2015;43(1):19–24. Um SJ et al. Clinical features of drug-induced hypersensitivity syndrome in 38 patients. J Investig Allergol Clin Immunol. 2010;20(7): 556–62. Mayer MD et al. Pharmacokinetics and pharmacodynamics of febuxostat, a new non-purine selective inhibitor of xanthine oxidase in subjects with renal impairment. Am J Ther. 2005;12(1):22–34. Schumacher HR et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallelgroup trial. Arthritis Care Res. 2008;59(11):1540–8.
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Becker MA et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353(23):2450– 61. 57. Chou HY et al. Febuxostat-associated drug reaction with eosinophilia and systemic symptoms (DRESS). J Clin Pharm Ther. 2015;40(6):689–92. 58. Tausche A-K, Reuss-Borst M, Koch U. Urate lowering therapy with febuxostat in daily practice—a multicentre, open-label, prospective observational study. Int J Rheumatol. 2014;2014. 59. van Vollenhoven R et al. DRESS syndrome and reversible liver function abnormalities in patients with systemic lupus erythematosus treated with the highly selective JAK-1 inhibitor GSK2586184. Lupus. 2015;0961203315573347. 60. Kahl L, et al. Safety, tolerability, efficacy and pharmacodynamics of the selective JAK1 inhibitor GSK2586184 in patients with systemic lupus erythematosus. Lupus. 2016;0961203316640910. 61. Ludbrook V et al. Investigation of selective JAK1 inhibitor GSK2586184 for the treatment of psoriasis in a randomized placebo-controlled phase IIa study. Br J Dermatol. 2016;174(5): 985–95. 62. Chi MH et al. Histopathological analysis and clinical correlation of drug reaction with eosinophilia and systemic symptoms (DRESS). Br J Dermatol. 2014;170(4):866–73. 63. Vahid B. What caused diffuse alveolar hemorrhage in a patient with gout? J Respir Dis. 2006;27(10):441. 64. Wi JO et al. A case of DRESS syndrome accompanied by leukocytoclastic vasculitis. Korean J Asthma Allergy Clin Immunol. 2010;30(4):320–4. 65. Gaha M et al. DRESS syndrome: cerebral vasculitic-like presentation. Neuroradiology. 2015;57(10):1015–21. 66. Sola D et al. DRESS syndrome with cerebral vasculitis. Intern Med. 2013;52(12):1403–5. 67. Schrijvers R et al. Pathogenesis and diagnosis of delayed-type drug hypersensitivity reactions, from bedside to bench and back. Clin Translat Allergy. 2015;5(1):1. 68. Pichler WJ et al. Drug hypersensitivity: how drugs stimulate T cells via pharmacological interaction with immune receptors. Int Arch Allergy Immunol. 2015;168(1):13–24. 69. Tohyama M et al. Association of human herpesvirus 6 reactivation with the flaring and severity of drug-induced hypersensitivity syndrome. Br J Dermatol. 2007;157(5):934–40. 70. Picard D et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): a multiorgan antiviral T cell response. Sci Transl Med. 2010;2(46):46ra62-46ra62. 71. Torres M, Mayorga C, Blanca M. Nonimmediate allergic reactions induced by drugs: pathogenesis and diagnostic tests. J Investig Allergol Clin Immunol. 2009;19(2):80–90. 72. Ogawa K et al. Identification of thymus and activation-regulated chemokine (TARC/CCL17) as a potential marker for early indication of disease and prediction of disease activity in drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS). J Dermatol Sci. 2013;69(1):38–43. 73. Hari Y et al. T cell involvement in cutaneous drug eruptions. Clin Exp Allergy: J Br Soc Allergy Clin Immunol. 2001;31(9):1398– 408. 74. Ye YM, et al. Drug-specific CD4+ T-cell immune responses are responsible for antituberculosis drug-induced maculopapular exanthema and DRESS. Br J Dermatol. 2016. 75. Pavlos R et al. T cell-mediated hypersensitivity reactions to drugs. Annu Rev Med. 2015;66:439. 76. Nguyen DV et al. Validation of a rapid test for HLA-B* 58: 01/57: 01 allele screening to detect individuals at risk for drug-induced hypersensitivity. Pharmacogenomics. 2016;17(5):473–80. 77. Su S-C, Chung W-H, Hung S-I. Digging up the human genome: current progress in deciphering adverse drug reactions. BioMed Res Int. 2014;2014.
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ORPHAN DISEASES (B MANGER, SECTION EDITOR)
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome and the Rheumatologist Marwan H. Adwan 1
Published online: 30 January 2017 # Springer Science+Business Media New York 2017
Abstract Purpose of the Review The purpose of the review is to summarise the various drugs used in rheumatology practice implicated in the causation of DRESS syndrome. Recent Findings The most commonly reported drugs are allopurinol, sulfasalazine and minocycline, which pose a very high risk for DRESS syndrome development, followed by strontium ranelate and dapsone. Other, less commonly reported, drugs include leflunomide, hydroxychloroquine, non-steroidal anti-inflammatory drugs, febuxostat, bosentan and solcitinib. Reaction to some drugs is strongly associated with certain HLA alleles, which may be used to screen patients at risk of serious toxicity. Summary DRESS syndrome is a serious reaction to many drugs used in rheumatic diseases, with a potentially fatal outcome and needs to be considered in any patient started on these medications who presents with a rash, fever and eosinophilia, sometimes with internal organ involvement.
Keywords DRESS syndrome . Eosinophilia . Hypersensitivity . Toxicity . Idiosynchratic . Allopurinol . Minocycline . Sulfasalazine
This article is part of the Topical Collection on Orphan Diseases * Marwan H. Adwan [email protected] 1
Division of Rheumatology, Department of Medicine, The University of Jordan, Queen Rania Street, Amman 11942, Jordan
Introduction Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare idiosyncratic hypersensitivity reaction to many drugs. It was first reported with anticonvulsant drugs and was therefore denoted “anticonvulsant hypersensitivity syndrome” [1], but was subsequently reported to result from many other medications. The acronym DRESS syndrome was coined by Bocquet et al. in 1996 to distinguish between the acute drug-induced hypersensitivity reaction and the more insidious pseudolymphoma, which may produce similar histological features [2]. The syndrome is characterised by the appearance of a fever, rash, lymphadenopathy, internal organ involvement and haematologic manifestations, such as eosinophilia and lymphocytosis with or without the appearance of atypical lymphocytes on peripheral blood film. Visceral manifestations include eosinophil infiltration of internal organs, principally the liver, kidney, heart and lung, which may result in failure of these organs. Cutaneous manifestations (Figs. 1 and 2) include maculopapular rash, erythroderma and, less commonly, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme or a purpuric rash [3]. DRESS syndrome generally develops 2–6 weeks following exposure to the offending drug [4], and symptoms resolve in the majority of cases after drug withdrawal [2]. Fortunately, this rather unpredictable complication is quite rare and occurs in only 1 to 10 per 10,000 exposures [5]. But it is, nonetheless, serious with an estimated mortality rate of around 10% [2]. A 7-year prospective study reported an estimated incidence of 0.9/100,000 in a West Indian population of African ancestry [6]. As far as rheumatology practice is concerned, this syndrome has been classically associated with allopurinol under the name “allopurinol hypersensitivity syndrome”. However,
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Curr Rheumatol Rep (2017) 19: 3 Table 1
Drugs causing DRESS syndrome in rheumatic diseases
Immunomodulatory antibiotics Sulfasalazine, Minocycline, Dapsone Non-antibiotic DMARDs Leflunomide, Hydroxychloroquine Hypouricemic drugs Allopurinol, Febuxostat Anti-osteoporotic drugs Fig. 1 Palmar skin eruptions in a patient after 4 weeks of allopurinol therapy. Courtesy of Dr. Bernhard Manger
an increasing number of other medications prescribed by rheumatologists have been reported to cause this clinical entity. This review addresses these medications, the frequency of this complication, the extent of organ involvement, the possible pathogenetic mechanisms responsible and treatment.
Strontium ranelate NSAIDs Celecoxib, Ibuprofen, Phenylbutazone Diclofenac ET-1 antagonists Bosentan JAK1 inhibitors Solcitinib DMARDs disease-modifying dugs, DRESS drug rash with eosinophilia and systemic symptoms, ET-1 endothelin-1, JAK1 janus kinase 1, NSAIDs non-steroidal anti-inflammatory drugs
Causative Drugs A Pubmed and Google Scholar search for case reports on DRESS syndrome, caused by the various drugs used in rheumatology, uncovered 14 different drugs that belonged to seven main categories (Table 1). Allopurinol and sulfasalazine together accounted for almost two thirds of cases. These drugs will be presented in descending order in terms of the frequency of DRESS syndrome. Frequency of Various Clinical Manifestations Table 2 lists the frequencies of various manifestations reported in the two largest studies (Kardoun and Cacoub et al.) [4, 7••]. As can be seen from the table, the most common
manifestations are rash and eosinophilia followed by fever, liver involvement, lymphadenopathy and facial oedema in descending order. Renal, cardiac and pulmonary manifestations occurred only in a small number of patients. In the largest retrospective study of DRESS syndrome due to various drugs, the two drugs relevant to this review were allopurinol and minocycline [3]. Allopurinol-realted DRESS was associated with fever in 23%, rash in 95%, lymphadenopathy in 10%, eiosinophilia in 62%, liver involvement in 62%, renal involvement in 43% while pulmonary involvement was not reported in any cases. Minocycline-induced DRESS, on the other hand, was associated with fever and/or in 94%, lymphadenopathy in 78%, eiosinophilia in 72%, liver
Table 2 Percentages of clinical features of DRESS syndrome reported in two large studies
Fig. 2 Generalised skin eruption 3 weeks after allopurinol therapy
Reference Manifestation
Kardaun et al. Ref 7 %
Cacoub et al. Ref 4 %
Fever Rash Facial oedema Lymphadenopathy Liver kidney Lung heart CNS Eosinophilia Atypical lymphocytes
90 100 76 54 75 37 32 13 4.3 95 67
64. 97. 39. 56. 59. 8 5 2 2 66. 27
LFT liver function test, CNS central nervous system
Curr Rheumatol Rep (2017) 19: 3
involvement in 72%, renal involvement in 17% and pulmonary involvemet in 11%. Allopurinol Allopurinol is a purine analogue inhibitor of xanthine oxidase, the enzyme involved in uric acid generation from xanthine and hypoxanthine. It is the most commonly reported drug to cause the syndrome among the medications used in rheumatic diseases and is considered to pose a very high risk for its development [8]. The incidence of allopurinol hypersensitivity has been quoted as reaching 0.1% [9]. In a review of reported cases, allopurinol accounted for 19 of the 172 cases reported (11%) and was found to be the second most common cause after carbamazepine [4]. The RegiSCAR is a multinational registry of serious cutaneous adverse reactions (SCAR). Analysis of 117 cases of DRESS syndrome recorded in this registry revealed that allopurinol was second only to carbamazepine; accounting for 21 cases (18%) [7••]. In several retrospective studies, it is reported to be the most common cause, surpassing individual anticonvulsants [8, 10–14]. Risk factors associated with allopurinol hypersensitivity include recent initiation of allopurinol, co-prescription of diuretics, impaired renal function [15, 16] and the presence of the HLA-B*5801 allele [15]. The latter is particularly important in Asian populations. Association with this allele was confirmed in several studies. Firstly, in a case-control study involving a Han Chinese population, the allele was identified in 100% of patients who developed severe SCAR, but in only 15% of patients who had less severe reactions, yielding an odd’s ratio of 580.3 [17]. Secondly, in a recent systematic review of case reports of allopurinol hypersensitivity, HLAB*5801 was identified in 166 of the 167 patients who were tested for this allele. Interestingly, 89% of those who tested positive were of Asian origin [15]. Thirdly, a fairly recent study reported association of HLA-B*5801 in a Portuguese population, particularly females, indicating that its effect may not be merely restricted to Asians [18]. Thus far, there is no evidence that high-dose allopurinol poses a risk factor for the syndrome development [15]. Allopurinol-related DRESS syndrome is more likely to be associated with renal impairment than that caused by other drugs. In a retrospective review of cases notified to the French pharmacovigilance centres between 1985 and 2000 combined with a literature review of case reports until 2001, Pyeriere et al. reported that allopurinol was more likely to be associated with renal dysfunction than other medications [3]. Among the various drugs, allopurinol and minocycline seem to be associated with a particularly higher risk of severe DRESS syndrome [19]. A retrospective review of cases of severe DRESS syndrome resulting in either intensive care unit (ICU) admission or death, for instance, uncovered that allopurinol and minocycline were responsible for 4 and 3 (27 and
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20%) of the 15 cases reported, respectively [19]. Furthermore, allopurinol was reported to be responsible for 3 of the 9 cases of severe DRESS syndrome included in a systematic review [4]. Mortality among allopurinol-induced cases also seems to be higher than that reported with other drugs and has been quoted as high as 12–27% [9, 15]. Allopurinol is metabolised to oxipurinol. The former has a half life 1.2 h whereas the latter’s half life is much longer (23 h) [20]. The half life of oxipurinol is prolonged even further in renal impairment, resulting in drug accumulation [21]. This accounts, in part, for the increased incidence of adverse reactions to allopurinol in patients with renal impairment. Increased plasma oxypurinol and granulysin level is associated with poor prognosis and more severe DRESS syndrome [16]. In vitro studies showed that oxypurinol increases the expression of granulysin, a protein produced by cytotoxic T lymphocytes and natural killer (NK) cells. Furthermore, oxypurinol stimulates clonotype-specific T cells that express granulysin [22]. In our literature search, more than half of the cases reported were given allopurinol for asymptomatic hyperuricaemia. This is in agreement with a recent systematic review, which revealed that allopurinol was given for asymptomatic hyperuricaemia to more than 45% of the cases reported as having allopurinol hypersensitivity [15]. As asymptomatic hyperuricaemia is common in the general population, this almost certainly explains the high incidence of DRESS syndrome due to allopurinol. Taking into account the high incidence, considerable risk and significant mortality of allopurinol-induced DRESS syndrome, it is absolutely important not to prescribe this drug merely for asymptomatic hyperuricaemia. Sulfasalazine Sulfasalazine is the second most common cause of DRESS syndrome among the drugs used in rheumatic diseases. It is also considered to pose a very high risk [8]. A review involving 172 cases of DRESS syndrome reported that sulfasalazine accounted for 10 cases (6%) and was the third most common cause (together with Phenobarbital and lamotrigine) after carbamazepine and allopurinol [4]. In the prospective RegiSCAR study mentioned under allopurinol, 8 of the 117 cases identified were caused by sulfasalazine, which was also found to be the third most common individual drug after carbamazepine and allopurinol. A recent review of published case reports of sulfasalazine-inducd DRESS syndrome uncovered 48 cases [23]. The most common internal organ to be involved was the liver (72%), followed by the kidney (35%). The lung was involved in only one case. Mortality was lower than is generally reported for DRESS syndrome and occurred in only two cases (4.1%) [23].
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The sulphapyridine component of sulfasalazine undergoes acetylation prior to excretion in the urine. Sulfasalazine toxicity in general is related to acetylator status and is more common in slow acetylators [24]. The HLA-B*13: 01 was demonstrated to pose a risk for sulfasalazine toxicity in Han Chinese population in one study [25], but this has not so far been replicated or demonstrated in other populations. Minocycline Minocycline is the next most important anti-rheumatic drug to cause this syndrome. This antibiotic is occasionally used as a disease-modifying drug (DMARD) in rheumatoid arthritis (RA). Minocycline-induced DRESS syndrome is particularly likely to be associated with lung involvement in the form of eosinophilic pneumonitis. This complication occurred in one third of reported cases [3]. As stated under allopurinol, 3 of the 15 patients with severe DRESS resulting in either death or ICU admission were caused by minocycline, all of whom had pneumonitis [19]. Cardiac involvement and lymphadenopathy also seem to be reported more commonly than with other drugs [3]. Another characteristic of minocycline cases is the development of autoimmune phenomena such as autoimmune thyroiditis [26–28], diabetes mellitus and ANA antibodies [26], which may sometimes develop long after DRESS has resolved. Similar to allopurinol and sulfasalazine, minocycline poses a very high risk for DRESS syndrome [8]. Patients with minocycline-related DRESS syndrome are usually younger than cases due to other causes, reflecting the age group for which this drug is mostly given, namely, patients with acne. Strontium Ranelate Strontium is an alkaline earth metal that belongs to group 2A of the periodic table of elements, which also contains beryllium, magnesium, calcium, barium and radium. Its atomic weight is just over twice that of calcium. It is used in the form of strontium ranelate (SR) salt for the treatment of severe osteoporosis in patients who cannot tolerate other agents, provided there are no contraindications, particularly cardiovascular co-morbidity [29]. SR poses a moderate risk for DRESS syndrome [8]. A review of the UK General Practice Research Database (GPRD) in 2008 identified 1574 patients exposed to SR but no cases of DRESS syndrome were detected [30]. Cacoub et al., however, studied the reported reactions from the SR pharmacovigilance database between 2004 and 2011 and uncovered 47 cases of DRESS syndrome related to SR reported from 16 different countries (mostly Europe) of whom 4 patients (8.5%) died [31]. The authors estimated the incidence of SR-related DRESS syndrome to be 1/24,112. Thus, failure to detect any cases in the GPRD study may be explained by the
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rare number of events reflected by the size of the sample reviewed, which is far below that of this incidence. A recent study reported a significant association between the closely related SR-induced conditions Stevens Johnsons syndrome/toxic epidermal necrolysis and the class I alleles HLA-A*33:03 and HLA-B*58:01 in Han Chinese [32], but no alleles have yet been identified in association with DRESS syndrome. This association has so far not been replicated or demonstrated in other populations. Leflunomide Leflunomide inhibits pyrimidine synthesis by inhibiting the enzyme dihydroorotate dehydrogenase. With the exception of one case in an Italian case series [14], all leflunomiderelated cases are reported from India. This may either reflect a genetic susceptibility or widespread use of the drug in India, as it is manufactured by Indian companies and costs a fraction of its cost in other countries. Or it may indeed reflect underutilization of leflunomide in other parts of the world, as most guidelines now recommend the use of biologic agents after methotrexate failure in RA. Besides, the drug is not available in some countries. A large proportion of patients with leflunomide-induced DRESS syndrome reported in the literature had diarrhoea [33]. Interestingly, five of the 14 reported cases died [33–37] indicating that this condition may be more serious than is currently appreciated. Studies have shown that patients with the CYP1A2*1F allele of cytochrome P450 [38] and the dihydroorotate dehydrogenase polymorphism DHODH A40C [39] are at higher risk of leflunomide toxicity. Possession of the two alleles may pose an even higher risk of toxicity [39]. Another study showed association with CYP 2C19, but did not detect any association with CYP1A2*1F or DHODH A40C [40]. A recent study showed association with CYP1A2 C163A allele [41]. Although no cases of DRESS syndrome were reported among these studies. Dapsone Dapsone is a sulfone derivative which was initially used for treatment of leprosy, but is now used to treat various conditions including Pneumocystis jirovecii, vasculitis and several dermatological conditions, including some lupus rashes. Dapsone-related serious drug reactions have long been reported under the name “dapsone hypersensitivity syndrome” (DHS), which is a variant of DRESS syndrome, although DHS may sometimes be associated with haemolytic anaemia, which is not found in DRESS. In addition, some cases do not fulfil the criteria of true DRESS syndrome. DHS develops in 0.5–3.6% of people treated with dapsone [42] and has similar clinical features and mortality to DRESS
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syndrome [43]. A systematic review of case reports and observational studies retrieved 336 cases of DHS, most of whom (72%) were given dapsone for leprosy [44]. Furthermore, a retrospective review of patients treated with dapsone for leprosy in the whole of China between 2006 and 2009 identified 63 DHS cases among 6243 leprosy patents. Among these, 7 patients (11.1%) died [45]. Of note, delay in initiation of treatment after the onset of DHS was a significant contributing factor to mortality. On the other hand, a retrospective study involving 361 non-leprosy patients in Taiwan revealed a more favourable outcome and no deaths were reported [46]. Genetics may play a role in susceptibility to dapsone hypersensitivity, as the HLA-B*13:01 poses a strong risk factor in Chinese patients with leprosy [42]. This is the same allele that increases the risk of DRESS syndrome due to sulfasalazine, another sulfa-related compound. Bosentan Bosentan is an endothelin-1 antagonist used for the treatment of pulmonary hypertension. There are 3 cases of DRESS syndrome induced by this drug reported in the literature [47–49]. They all subsided after discontinuation of the drug and, in 2 cases, initiation of corticosteroid therapy [48, 49]. Although one case relapsed when steroids were tapered [48]. Hydroxychloroquine HCQ is generally safe and is not a common cause of DRESS syndrome. There are only 2 case reports in the English literature. Both cases involved men 58 and 62 years old and symptoms occurred in both within 2 weeks of starting the drug and settled with drug cessation and corticosteroid therapy without any sequelae [50, 51]. Non-steroidal Anti-inflammatory Drugs Non-steroidal anti-inflammatory drugs (NSAIDs) are a large and heterogeneous group of drugs which are used frequently in most rheumatic diseases for their anti-inflammatory and analgesic effects. In a review of reported cases of DRESS syndrome, 4 of the 172 cases were caused by NSAIDs (Celecoxib, ibuprofen and phenylbutazone) [4]. Another retrospective review of 45 cases of DRESS syndrome reported NSIADs to also be responsible for 4 cases (diclofenac and celecoxib) (8.9%) [52]. In another retrospective review, NSIADs accounted for 5 of 38 cases (ibuprofen and diclofenac) (13.2%) [53]. Febuxostat Febuxostat is a non-purine competitive inhibitor of xanthine oxidase. Unlike allopurinol, it does not require dose
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adjustment in mild to moderate renal impairment (creatinine clearance 30–80 ml/min) [54]. Therefore, it is particularly useful and safe in this patient group [55]. A multicentre double-blind randomized controlled trial (RCT) involving 760 patients receiving febuxostat 80 or 120 mg versus allopurinol 300 mg reported significantly more patients in the febuxostat groups than in the allopurinol group achieving a target serum uric acid of 6 mg/dl. No cases of DRESS syndrome, however, were reported [56]. There is only one case report in the literature implicating febuxostat [57]. Although this patient was commenced on sulindac 2 weeks before and febuxostat 2 days before developing symptoms. The time lapse perhaps suggests that sulindac may have been the cause rather than febuxostat. Furthermore, a large multicentre open-label prospective observational study including 5948 patients with gout, of whom 5592 were treated with febuxostat, did not report any DRESS cases after 4 weeks of observation [58]. Therefore, unless more cases are reported in the future, it can be presumed that febuxostat does not cause DRESS syndrome. What is more, there is no cross-reactivity between febuxostat and allopurinol hypersensitivity [22]. Thus, it is a safe alternative in patients with a history of allopurinol hypersensitivity and/or renal impairment. It is worth noting that the duration of the RCT mentioned above is long enough for DRESS syndrome to develop. However, the observational study’s duration may not have been long enough. Solcitinib (GSK2586184) There are 2 cases reported by the same author of patients with systemic lupus erythematosus (SLE) developing reactions following the JAK1 inhibitor GSK2586184 [59]. The cases do not, however, fulfil the criteria for DRESS syndrome; the first case had fever, rash and liver function abnormality and the second had fever, hand and facial oedema and abnormal liver function. A recent RCT employing this drug in SLE was declared futile and subsequently terminated because 6 of the recruited 50 patients developed abnormal liver functions and 2 patients developed DRESS syndrome [60]. It is worth mentioning that both patients were also taking HCQ, although the duration of treatment with this drug is not clear. Furthermore, this complication was not observed in an RCT of this drug in psoriasis [61]. Thus, whether this effect is limited to patients with SLE remains to be seen. DRESS Syndrome and Vasculitis Another way DRESS syndrome may present to the rheumatologist is by mimicking or being associated with vasculitis. Its clinical presentation (fever, rash and internal organ involvement) may be misdiagnosed as vasculitis. The rash
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may sometimes be purpuric and look like vasculitis [62]. Additionally, the presence of eosinophilia may initially cause misinterpretation as eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss). Vasculitic change has been reported in some cases. For instance, a retrospective study of the cutaneous histological findings of 32 patients with DRESS syndrome noted vasculitis in 6% [62]. In fact, some cases in the literature have been reported to be associated with clinical, histological and radiological features of vasculitis. There is, for instance, a case of DRESS syndrome caused by leflunomide that showed vasculitis on renal histology [33]. Vahid et al. reported a case of allopurinol-induced DRESS syndrome associated with diffuse alveolar haemorrhage [63], and Wi et al. reported a DRESS case with leukocytoclastic vasculitis demonstrated on skin biopsy [64]. Finally, there are several cases of DRESS syndrome associated with neurological features and cerebral vasculitis-like lesions on brain imaging [65, 66]. One must remember though that these are isolated cases and may simply be just a coincidence.
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(MHC) (e.g. allopurinol, dapsone, SR, anti-epileptic and anti-retroviral drugs), although a few are class II-mediated (e.g. lapatinib, co-amoxyclav) [75]. These drug-specific HLA haplotypes may provide tools to identify patients at risk of drug toxicity, just like thiopurine methyltranserase (TPMT) is employed in identifying patients at risk of azathioprine toxicity. A test with high sensitivity and specificity has been developed to screen for HLA-B*58:01/*57:01 alleles and thus predict patients at risk of allopurinol and abacavir toxicity [76]. Several alleles are reported to be associated with hypersensitivity to other drugs including anticonvulsants, antibiotics and anti-retroviral drugs [77]. Another recently identified mechanism contributing to the pathogenesis is the so-called the pharmacological reaction with immune receptor (p-i) concept, where a drug interacts non-covalently with the HLA molecule or T cell receptor (TCR) directly, bypassing antigen processing [67]. This has been shown for the interaction of allopurinol and its metabolite oxipurinol with HLA-B*58:01 [78]. Treatment
Pathogenesis The exact pathogenesis of DRESS syndrome is not fully known. Detailed aspects of the immunopathogenesis of the syndrome are beyond the scope of this review and are discussed in detail elsewhere [67, 68]. Human herpes virus-6 (HHV-6) immunoglobulin G (IgG) is increased in the majority of patients, indicating that HHV-6 reactivation may be involved in the pathogenesis [4]. Furthermore, HHV-6 reactivation is associated with more severe DRESS syndrome [69]. Reactivation of other viruses including Epstein-Barr virus (EBV) and HHV-7 has also been reported [70]. DRESS syndrome is a type IVb delayed hypersensitivity reaction [67], which involves type 2 helper (Th2) lymphocytes that produce interleukin-4 (IL-4) and IL-5. The latter plays an important role in eosinophil differentiation and activation [71], the hallmark of the disease. A small study demonstrated that serum level of the C-C Motif Chemokine Ligand 17 (CCL17) (a mediator of Th2 inflammatory response) is increased in DRESS syndrome and correlated with IL-5 level and eosinophil count [72]. The DRESS reaction exclusively complicates drugs with an aromatic benzene-like ring in their structure [14], as do all the drugs discussed in this review. Aromatic compounds form reactive epoxide intermediate structures, which may result in an immune response [14]. Many drugs possess aromatic structure and yet do not cause DRESS syndrome. Thus, there must be something more to these drugs than merely processing a benzene ring that renders them immunogenic. The hypersensitivity reaction involves anti-drug specific CD4+ and CD8+ T cells [73, 74]. Most drug reactions are associated with class I major histocompatibility complex
Treatment of DRESS syndrome, as reported in the literature, is by stopping the offending drug and the initiation of corticosteroid therapy [4, 11, 19, 79–83]. Although there is no consensus on the dose, route of administration or duration of steroid therapy. Symptoms may recur after steroid tapering or discontinuation. Other treatments reported in the literature include, antihistamines [52, 82, 84], pentoxyphylline [84] and intravenous immunoglobulin [4, 19, 85]. There is a report of a paediatric case of life-threatening DRESS syndrome showing a dramatic response to plasma exchange after failing to respond to corticosteroids [86]. Other immunosuppressive drugs are not reported extensively, there is a single report of successful and sustained treatment of 2 cases with ciclosporin (one induced by minocycline) [87].
Conclusion In this review, we have discussed the important drugs used in rheumatic diseases that may potentially cause DRESS syndrome. Allopurinol, sulfasalazine and minocycline are the most important medications and pose a very high risk, followed by SR, dapsone and NSAIDs. Other drugs such as HCQ, bosentan and febuxostat are not extensively reported in the literature and are limited to few case reports. Allopurinol and minocycline are also more likely to be associated with severe DRESS syndrome. Interestingly, no cases involving any of the biologic DMARDs have been reported. This may not come as a surprise, since all drugs that cause DRESS syndrome generally possesses an aromatic ring and are not protein-based.
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Susceptibility to the syndrome due to some medications (allopurinol, sulfasalazine and dapsone) may be predicted by the presence of certain HLA alleles, but for many other drugs, no such alleles have been identified. Thus, predicting which patients may be susceptible remains an enigma. Apart from allopurinol-related DRESS syndrome, which may be expected, and hopefully, avoided in the presence of some predisposing factors, such as renal impairment and diuretic co-prescription, there are no obvious such non-genetic factors that are known to increase the risk and, therefore, prediction of DRESS syndrome due to other drugs. Compliance with Ethical Standards Conflict of Interest The author declares no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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