Case 1A -

Toxic Epidermal Necrolysis/Stevens Johnson Overlap Syndrome Triggered by Exotic Wood Exposure Cynthia M. Magro Weill Medical College of Cornell University New York, New York

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Key Words: Reactive Cytotoxic CD8 Interface Dermatitis Introductory Comments: I have selected three cases of reactive interface dermatitis whereby the antigenic triggers and clinical circumstances resulting in these striking presentations are varied. I would like to first of all consider in brief a broad overview of the morphologic pattern that more or less defines these three cases namely a relatively cell poor vacuolar pattern of interface dermatitis. The varied pathogenetic mechanisms that lie behind this form of interface dermatitis are explored. The definition of cell-poor vacuolar interface dermatitis is a morphologic one and it is characterized by basilar keratinocyte and subepithelial vacuolopathy unaccompanied by a significant inflammatory cell infiltrate. Usually, there is a component of lymphocyte tagging along the dermal-epidermal junction pointing to the immunopathogenetic basis, namely, one of type IV cellular cytotoxicity. In a dermatosis that falls under the general rubric of a cell poor interface dermatitis it is not uncommon to see areas of interface dermatitis that have a more lichenoid morphology. This may be either in the context of a type 4 immune reaction or reflective of antibody dependent cellular cytotoxicity. Traditionally a true type IV cytotoxic immune response is a cutaneous reaction pattern e that one associates with an exogenous trigger such as drug while antibody dependent cellular immunity would indicate a connective tissue disease diathesis. It is very difficult at a light microscopic level to distinguish between a true type IV cytotoxic immune response and one initiated by antibodies. Although we traditionally consider cutaneous manifestations of collagen vascular disease in the context of being antibody mediated a role for true cellular immunity may also be operational . The differential diagnoses of a cell-poor interface dermatitis is broad and includes: erythema multiforme and related conditions specifically in the context of Stevens Johnson syndrome, toxic epidermal necrolysis and fixed drug eruption. graft-versus-host disease a morbilliform viral exanthum a morbilliform drug reaction collagen vascular disease specifically in the context of lupus erythematosus, dermatomyositis, and mixed connective tissue disease While the aforesaid diagnostic considerations are specific clinical and pathological entities, in general type IV immunologic response to circulating exogenous antigen and or antibody dependent cellular immunity can be associated with vacuolar interface change along the dermal epidermal junction. Although the morphologic end point of both type IV hypersensitivity and antibody dependent cellular immunity is remarkably similar, namely one of lymphocyte apposition to keratinocytes with the subsequent induction of keratinocyte injury the pathogenetic mechanisms are different. The three cases I have chosen are varied in their clinical presentation and the etiologic trigger although the way in which epithelial injury occurs is the same namely in the context of a cytotoxic CD8 T cell. In other forms of interface dermatitis including certain forms of collagen vascular disease such as subacute cutaneous lupus erythematosus and dermatomyositis and the early phase of lichen planus and graft versus host disease, the main cell infiltrating the epidermis may be the CD4 lymphocyte. The contribution of the CD4 lymphocyte to frank epithelial injury is less defined. Case 1A Diagnosis: Toxic Epidermal Necrolysis/Stevens Johnson Overlap Syndrome Triggered by Exotic Wood Exposure Case 1a - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 1a - Figure 1a Case 1a - Figure 1b Case 1a - Figure 2a Case 1a - Figure 2b Case 1a - Figure 3a Case 1a - Figure 3b Case 1a - Figure 4 Case 1a - Figure 5a Case 1a - Figure 5b Case 1a - Figure 6a Case 1a - Figure 6b Case 1a - Figure 7a CD8 Case 1a - Figure 7b Granzyme Discussion: This patient's case presentation serves as a prototypic example of a rare but severe form of type IV hypersensitivity falling under the designation of Stevens Johnson Syndrome(SJS). In the vast majority of cases the inciting trigger is of drug based etiology although in this case the apparent antigen was of unquestionable contactant based etiology. There has been confusion in the literature regarding the differences if any existing between erythema multiforme and SJS/Toxic epidermal necrolysis(TEN). The distinction of TEN from SJS is based on the extent of cutaneous involvement with greater than 30% skin necrosis being characteristic for TEN. In SJS the extent of mucosal involvement is marked and cutaneous necrosis is usually less than 10% of the total body surface area. There are cases which exhibit an overlap between SJS and TEN whereby the cutaneous necrosis is between 10 and 30%. In the past, SJS and TEN were considered under the designation of erythema multiforme major while other forms of erythema multiforme fell under the appellation of erythema multiforme minor. This arbitrary designation of EM minor versus major is no longer the preferred nomenclature as there is enough pathophysiologic evidence to suggest certain differences although in each the inciting trigger is an immunologic response to an exogenous antigen. The antigen is varied and whether one is dealing with EM, TEN or SJS the immune response to the antigen is considered idiosyncratic. Specifically only a small subset of people develops an immune response to a specific antigen that will manifest as EM, SJS, and or TEN. Erythema multiforme represents the most common form of cytotoxic epidermal hypersensivity encountered from both a clinical and morphologic perspective and hence we will consider in detail its distinctive features followed by a brief review of SJS and TEN with a consideration regarding their pathogenesis. I. Classic Erythema Multiforme Introduction/Clinical Features Erythema multiforme is a distinctive clinical and pathological entity whereby the trigger leading to its development is varied. From a clinical perspective, the classic lesion has a targetoid morphology with a peripheral rim of erythema and a central zone of pallor. Some lesions may manifest a dusky or violaceous appearance with no true central clearing. Blisters may be observed. As the pathogenetic basis of erythema multiforme is one of cellular cytotoxicity, the morphologic sites of predilection are those where antigenic processing is maximal, which includes the palms and soles, however, the lesions can become widespread. The disease is typically self-limited but it may recur. There are rare reports of erythema multiforme following allergic contact dermatitis with nickel and poison ivy (i.e.Rhus dermatitis). The concept of a contactant in the induction of erythema multiforme is not well known but it clearly occurs. Histopathology In those cases of erythema multiforme which are mediated by infection, one typically observes a fairly brisk angiocentric superficial and deep lymphocytic infiltrate along with a cell-poor interface dermatitis with minimal epidermal injury. In contrast, drug-based erythema multiforme show a less intense dermal-based inflammatory cell infiltrate with more pronounced epithelial necrosis. Focal small areas of basilar vacuolopathy accompanied by lymphocyte tagging along the dermal-epidermal junction are the hallmarks; suprabasilar lymphocytosis around degenerating keratinocytes may also be seen. In drug-based erythema multiforme, acrosyringeal accentuation of these interface inflammatory and degenerative epithelial changes is typical and streak dyskeratosis is demonstrated. The latter refers to the acquisition of a distinctive keratinocyte morphology whereby keratinocytes demonstrate an elongate cigar-shaped morphology with a hypereosinophilic condensed cytoplasm and pyknotic elongated nuclei. Such cells may or may not be accompanied by lymphocyte satellitosis. Lesions of active herpes show areas of interface dermatitis resembling erythema multiforme. Characteristic viral cytopathic changes of herpes however are observed. Differential Diagnosis The main consideration is that of acute collagen vascular disease and acute graft verus shost disease. In our experience, in lesions of systemic lupus erythematosus or dermatomyositis, the presence of striking dermal mucin deposition is a critical distinguishing clue that is present in most cases. As well, the degree of epithelial injury in such cases is usually less than that observed in erythema multiforme. Acrosyringeal accentuation, as seen in drug associated erythema multiforme, is not a typical feature of acute systemic collagen vascular disease. While sparse tissue eosinophilia may be observed in drug associated erythema multiforme, tissue eosinophilia in the setting of systemic collagen vascular disease is uncommon. In erythema multiforme there usually is no alteration of the stratum corneum and or the epidermal thickness, pointing to the transient and acute nature of the eruption. In contrast, in the interface dermatitis of collagen vascular disease, hyper- and parakeratosis is frequent. Also in lesions of collagen vascular disease one observes an atrophying interface dermatitis with retiform effacement. The distinction of erythema multiforme from acute graft versus host disease may be difficult. A recent study demonstrated that intraepidermal bile pigment deposition can be seen in biopsies of graft versus host disease and correlates with hyperbilirubinemia and or liver involvement. While this finding is only observed in a minority of cases of graft versus host disease (i.e. 6% of biopsies) it is a highly specific finding; it is not observed in erythema multiforme unless, of course, there is unrelated liver disease. Autoimmune progesterone dermatitis is temporally associated with the menstrual period and may also have its onset during pregnancy. The manifestations are polymorphous and include urticaria, erythema multiforme, and eczema. Histologically the cases show a variable histomorphology dependent on the clinical presentation. Cases resembling erythema multiforme show a vacuolar interface dermatitis with varying degrees of keratinocyte necrosis. During each cycle, the eruptions may appear at previously affected sites, hence mimicking the clinical features of a fixed drug eruption. This rare phenomenon is attributed to an autoimmune reaction to female sex hormones. The condition can improve with tamoxifen which suppresses ovulation and the post-ovulation rise in endogenous progesterone levels. In extreme cases an oophorectomy is performed Pathogenesis Erythema multiforme is a type 4 cellular cytotoxic reaction provoked by antigenic triggers which include drugs and infectious agents including Mycoplasma pneumoniae, and herpes simplex virus infection including in the context of recurrent herpes labialis. Typical target lesions are more common in patients whose erythema multiforme is triggered by herpes simplex. Herpes-associated erythema multiforme occurs in association with recurrent herpes simplex infection. A recent study has shown herpes DNA polymerase gene(Pol) and pol gene expression, the latter through immunohistochemistry using antibody directed against pol in lesional skin of patients with herpes associated erythema multiforme. In addition the T cell receptor variable chain repertoire in such patients is composed primarily of v beta 2 chain positive cells, suggesting a selective homing of lymphocytes to sites of viral antigen Recently antibodies directed against desmosomal plaque proteins desmoplakin I and II have been described in a subset of patients with erythema multiforme. Such studies suggest a humoral based etiology in the propagation of lesions of erythema multiforme in these patients. The epitope is localized at the carboxy terminal domain of desmoplakin and is responsible for the assembly of keratin filaments with desmosomes. Purified human antibody directed against the carboxy terminus of desmoplakin 1 and II when injected into newborn mice produces a constellation of changes that resembles erythema multiforme, suggesting a role for these antibodies in a subset of patients with erythema multiforme. II. Stevens Johnson Syndrome/toxic Epidermal Necrolysis As a point of reiteration SJS/TEN represents an idiosyncratic type IV immune response to a drug whereby the main implicated drugs are sulfasalzine, allopourinol, and nonsteroidal anti-inflammatory drugs with the commonest class of drugs however are the sulfonamides. The main distinguishing features which separate both SJS and TEN from EM is the severity of epithelial damage. In SJS the mucosal involvement is striking and may extend to involve the respiratory tract and conjunctiva. Severe mucosal involvement can also occur in TEN although in general the extent of mucosal involvement is greater in SJS than in TEN. The difference between SJS and TEN is reflected by the extent of cutaneous involvement. In SJS despite the massive epithelial injury the extent of cutaneous involvement is less than 10%. In TEN the extent of skin involvement is more than 30%. Cases that exhibit between 10 to 30% body surface involvement are designated as an SJS/TEN overlap. This patient(case 1) had a degree of skin involvement along with severe mucosal disease to warrant the categorization as an SJS/TEN overlap. An exceptional aspect of this case is the nature of the trigger which appeared to be an exotic wood. To add further to the rarity of this extraordinary case is the fact that his coworker who came from the same town developed a virtually eruption suggesting that he too was an idiosyncratic responder reflecting a common genotypic predisposition in both of these individuals as will be alluded to presently. His coworker's eruption was also compatible with an SJS/TEN overlap although in his case the administration of oral prednisone was sufficient to eradicate his skin rash and prevent further progression. The goal of this case is to review the known pathophysiology of SJS/TEN and the role of contactants in the evolution of SJS/TEN. I: Decreased Ability to Metabolize the Active Allergen/Drug Metabolite It has been shown that in patients with SJS and TEN, the drug reactive metabolites are produced in excess due to the inability to adequately detoxify and or metabolize the drugs. Such patients are said to be slow acetylators. II. Haplotype Predisposition In addition to this inability to adequately metabolize the drug hapten a certain HLA B genotype:HLA B12,HLA B5801 and HLA B1502(Hans Chinese) selectively expressed on keratinocytes bind to the drug. The HLA is divided into three basic groups : HLA-A, HLA-B, and HLA,C and represents class I major histocompatibility antigens. These genes make proteins that are expressed on the surface of the cell and bind foreign peptides that are extruded from the interior of the cell to the surface. This complex is recognized as foreign and is then destroyed by the immune system. There are many normal variations of the HLA B gene. Depending on the specific alleles will determine whether or not that particular HA-B associated protein is recognized by a certain foreign peptide processed by the host cell. Hence there are specific HLA alleles that are associated with severe drug reactions. For example the HLA-B*1502 is at greater risk for developing TEN in response to carbamazepine while the HLA-B*5801, is associated with an increased risk of severe skin reactions in people treated with allopurinol. Among people with human immunodeficiency virus (HIV) infection, a version of HLA-B designated HLA-B*5701 is associated with an extreme sensitivity to abacavir. III. Dysregulated Progressive Apoptosis Another unique aspect of TEN/ SJS is one of massive keratinocyte necrosis which far exceeds the extent of lymphocyte infiltration. There are likely both in situ mechanisms operational in the induction of keratinocyte injury as well as the role of soluble pro-apoptotic factors in the evolution of the epithelial injury. A. In situ factors promoting epithelial injury The drug induces a clonal proliferation of cytotoxic CD8 T cells which express granzyme, a cytotoxic protein which will induce keratinocyte injury. These antigenically responsive T cells are found both in the peripheral blood and in an situ location with the target organ, namely the skin. These activated CD8 cells localized in the skin may also express Fas ligand which can bind to Fas normally expressed by keratinocytes. If the extent of epithelial injury was to a large extent determined by the number of CD8 T cells localized to the skin the degree of epithelial injury which characterized TEN and SJS would not occur however. There is a relatively disparity between the extent of T cell infiltration which can be minimal and the degree of massive keratinocyte and epithelial injury. Hence there are likely additional soluble distant factors which contribute to epithelial injury. B. Soluble factors in the evolution of the epithelial injury Soluble factors are likely operational in the evolution of SJS/TEN and may define a very important mechanism of epithelial injury. These soluble factors include TNF, interleukin 6 and soluble CD40 Ligand. The actual soluble levels of Fas Ligand are significantly higher in patients with SJS/TEN. Peripheral blood mononuclear cells from patients with SJS/TEN elaborate more Fas ligand. The basis of using IVIG to treat SJS/TEN relates to potential neutralization of soluble Fas ligand and the blockage of intracellular Fas signaling. Activation of FAS through FASL leads to diffuse apoptotic cell death. Fas mediates death of epidermal cells in TEN. Fas L mediates apoptotic cell death by binding to FAS inducing the activation of caspase enzymes. Fas is expressed in many cells including keratinocytes, hepatocytes and peripheral blood mononuclear cells. Fas L is normally expressed by activated T cells and natural killer cells. SJS derived peripheral blood mononuclear cells produce large quantities of soluble Fas after stimulation with the implicated drug. All of these studies indicate that sensitized T cells produce large quantities of Soluble Fas Ligand, an apparent major factor pathogenetically in the evolution of SJS/TEN. The question arises as to why the peripheral blood mononuclear cells produce such large quantities of Fas ligand. This anomaly may reflect a Fas ligand gene polymorphism. The result of the Fas ligand gene polymorphism is enhanced elaboration of Fas ligand by activated peripheral blood mononuclear cells. Localization of injury is organ specific reflecting high sensitivity end organ target cells to Fas Ligand. If for example the end organ cell with high sensitivity to Fas ligand is the hepatocyte the drug will evoke massive hepatic necrosis. C. Other single nucleotide gene polymorphisms in the pathogenesis of TEN and SJS It has been demonstrated that genetic alterations in the Il 13/Il-4R signaling pathway may regulate Th1 or Th2 cytokine driven inflammatory mechanisms. In one study Japanese patients with SJS/TEN had polymorphisms in the allergy related Il-4R gene and that the ratio of each allele in the polymorphisms was the opposite of the ratio reported in atopy and asthma. IV. Contactants as the Trigger to TEN/SJS In regards to the literature precedent addressing contactants as a cause of TEN/SJS it is in the context of small series and anecdotal case reports. What are the known contactants that can evoke TEN/ SJS ? Dendrimers have been implicated. There is one case report describing a student who handled dendrimers in a chemistry lab and then developed targetoid plaques on the arms. The biopsy showed typical changes of erythema multiforme. His rash progressed to diffuse exudative erythema and bullae In addition he had coalescing bullae and a positive Nikolsky sign. The latter is demonstrated by applying pressure on the skin resulting in the induction of lateral epidermal separation following light pressure in an apparently normal appearing area of skin. There were some relevant lab findings which included a low titer of serum complement and C3. The rash improved on methylprednisolone IV 1000mg/day for 3 days followed by a gradual taper of prednisone from 40/day. His rash relapsed whenever he reentered the laboratory. There are multiple reports (case series of 15) reporting SJS/TEN-like reactions to dormex (hydrogen cyanamide), a growth promoter of grapes including in the context of cleaning utensils which had been in contact with the chemical developing a rash in 5 to 7 days. The rash had a specific prodrome of burning and stinging followed by itchy, erythematous papules which subsequently progressed in targetoid and bullous lesions and finally broad zones of epidermal denudement. A biopsy was typical for erythema multiforme. Rapid resolution occurred within 7 days of treatment. There is another reported case of 32 year old female who developed EM which quickly progressed to TEN following double exposure to an applied perfume. The rash initially remained limited to the area sprayed, neck, and appeared as blotchy erythema. Upon second exposure to the abdomen diffuse targetoid lesions with bulla developed over her trunk and arms within a day. The biopsy was confirmatory of SJS/TEN. Unfortunately the patient became infected and died of toxic shock in the setting of prednisone and antibiotic therapy. Another reported case involved a 36 year old carpenter admitted for 5 days of blisters and target lesions on the hands and forearms., much more on the left. Within three days the rash spread to the neck, thighs and penis, with mucosal ulceration and conjunctivitis. Vesicles and bullae were most conspicuous around the neck line and on the forearms. The patient was taking no medications but mentioned that as a hobby he worked as a wood turner and had been in contact with rosewood. He did remember that as he sanded the wood with his right hand the saw dust was sprayed on the left arm. A patch test to saw dust was strongly positive with a blistering reaction at 96 hours. The final case concerned a 25 year old Japanese woman, a luthier, developed intensely pruritic, red-bean sized papulovesicles and erythema that started on palms and arms and then progressed to cover upper arms, trunk, and ankles and coalescing into targetoid lesions which blistered with a positive Nikolsky skin. The patient had handled Pao ferro. A biopsy was confirmatory of SJS. A patch test to Pao Ferro was positive and continued for two weeks. There are 4 other reports of Pao Ferro EM/SJS like reactions and in all cases biopsies were not consistent with a contact dermatitis and were indistinguishable from EM/SJS from drug or infection. In summation then contactants are a potential cause of SJS/TEN. The implicated contactants that can induce this severe reaction are few in number and there may be pathophysioloogic basis. Dendrimers are able to mimic biological molecules. Dormex is hydrogen cyanamide. Rosewood/Dalbergia latifolia or East Indian rosewood have as active agents quinonoids of which 3,4-dimethoxydalbergione is the most potent Pao ferro is also a quinonoid and essentially similar to rosewood Macassar ebony and epoxy resins have effective compounds similar to those implicated in rosewood. Cutaneous absorption or inhalation of an immunogenic chemical may provide some basis for contactants as a potential trigger to SJS/TEN. Concluding Remarks Regarding Contactant Triggered SJS/TEN In summary then SJS/TEN is distinctive clinically and pathophysiologically. The differential diagnosis would comprise erythema multiforme, generalized fixed drug eruption, severe acute graft versus host disease, and a TEN - like presentation of paraneoplastic pemphigus and linear IgA disease. The clinical history and light microscopic findings should allow distinction between these various entities. While one always must consider a drug based etiology there is the potential for other triggers including contactant and infection. The distribution of the lesions and patient history might provide clues. Some of these contactants are fairly common in certain professions. The basis of the potentially life threatening epithelial injury an idiosyncratic allergic response to drug/contactant generating a clonally responsive CD8 T cell population found in both the skin and peripheral blood responding to antigen, large quantities of soluble Fas ligand released by sensitized C8 T cells reflecting a potential gene polymorphism and a high sensitivity of the end organ cell expressing Fas to Fas ligand. Treatment at the initial phases to bind soluble Fas ligand could emerge as an important tool in reducing injury. References: Toxic Epidermal Necrolysis Stevens Johnson Syndrome Ferrell PB Jr, McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics. 2008 Oct;9(10):1543-6. Abe R. Toxic epidermal necrolysis and Stevens-Johnson syndrome: soluble Fas ligand involvement in the pathomechanisms of these diseases. J Dermatol Sci. 2008 Dec;52(3):151-9. Epub 2008 Jul 26. Borchers AT, Lee JL, Naguwa SM, Cheema GS, Gershwin ME. Stevens-Johnson syndrome and toxic epidermal necrolysis. Autoimmun Rev. 2008 Sep;7(8):598-605. Epub 2008 Jul 9. Review. Michael D, Grando SA. Novel mechanism for therapeutic action of IVIg in autoimmune blistering dermatoses. Curr Dir Autoimmun. 2008;10:333-43. Review. Parrillo SJ. Stevens-Johnson syndrome and toxic epidermal necrolysis. Curr Allergy Asthma Rep. 2007 Jul;7(4):243-7. Review. Murata J, Abe R. Soluble Fas ligand: is it a critical mediator of toxic epidermal necrolysis and Stevens-Johnson syndrome? J Invest Dermatol. 2007 Apr;127(4):744-5. Review. French LE. Toxic epidermal necrolysis and Stevens Johnson syndrome: our current understanding.Allergol Int. 2006 Mar;55(1):9-16. Review.