Stevens–Johnson syndrome

Stevens–Johnson syndrome
Synonyms Erythema multiforme major[1]
Man with Stevens–Johnson syndrome
Specialty Dermatology
Symptoms Fever, skin blisters, skin peeling, painful skin, red eyes[2]
Complications Dehydration, sepsis, pneumonia, multiple organ failure.[2]
Usual onset Age < 30[1]
Causes Certain medications, certain infections, unknown[2][1]
Risk factors HIV/AIDS, systemic lupus erythematosus, genetics[2]
Diagnostic method <10% of the skin involved, skin biopsy[1]
Similar conditions Chickenpox, staphylococcal epidermolysis, staphylococcal scalded skin syndrome, autoimmune bullous disease[3]
Treatment Hospitalization, stopping the cause[1]
Medication Pain medication, antihistamines, antibiotics, corticosteroids, intravenous immunoglobulins[1]
Prognosis Mortality 10%[2]
Frequency 1–2 per million per year (together with TEN)[2]

Stevens–Johnson syndrome (SJS) is a type of severe skin reaction. Together with toxic epidermal necrolysis (TEN) it forms a spectrum of disease, with SJS being less severe. Early symptoms include fever and flu-like symptoms. A few days later the skin begins to blister and peel forming painful raw areas. Mucous membranes, such as the mouth, are also typically involved. Complications include dehydration, sepsis, pneumonia, and multiple organ failure.[2]

The most common cause is certain medications such as lamotrigine, carbamazepine, allopurinol, sulfonamide antibiotics, and nevirapine.[2] Other causes can include infections such as Mycoplasma pneumoniae and cytomegalovirus or the cause may remain unknown.[1][2] Risk factors include HIV/AIDS and systemic lupus erythematosus. The diagnosis is based on involvement of less than 10% of the skin.[1] It is known as TEN when more than 30% of the skin is involved and an intermediate form with 10 to 30% involvement.[3] Erythema multiforme (EM) is generally considered a separate condition.[4]

Treatment typically takes place in hospital such as in a burn unit or intensive care unit. Efforts may include stopping the cause, pain medication, antihistamines, antibiotics, intravenous immunoglobulins, or corticosteroids.[1] Together with TEN it affects 1 to 2 people per million per year.[2] It is twice as common in males as females. Typical onset is under the age of 30. Skin usually regrows over two to three weeks; however, complete recovery can take months.[1]

Signs and symptoms

Mucosal desquamation in a person with Stevens–Johnson syndrome
Conjunctivitis (inflammation of eye and eyelid) in SJS

SJS usually begins with fever, sore throat, and fatigue, which is commonly misdiagnosed and therefore treated with antibiotics. SJS and TEN are often heralded by fever, sore throat, cough, and burning eyes for 1 to 3 days.[5] Patients with SJS and TEN frequently experience burning pain of their skin at the start of disease.[5] Ulcers and other lesions begin to appear in the mucous membranes, almost always in the mouth and lips, but also in the genital and anal regions. Those in the mouth are usually extremely painful and reduce the patient's ability to eat or drink. Conjunctivitis of the eyes occurs in about 30% of children who develop SJS. A rash of round lesions about an inch across arises on the face, trunk, arms and legs, and soles of the feet, but usually not the scalp.[6]

Causes

SJS is thought to arise from a disorder of the immune system.[6] The immune reaction can be triggered by drugs or infections.[7] Genetic factors are associated with a predisposition to SJS.[8] The cause of SJS is unknown in one-quarter to one-half of cases.[8] SJS and TEN are considered a single disease with common causes and mechanisms.[5]

Medication

Although SJS can be caused by viral infections and malignancies, the main cause is medications.[9] A leading cause appears to be the use of antibiotics, particularly sulfa drugs.[8][10] Between 100 and 200 different drugs may be associated with SJS.[11] No reliable test exists to establish a link between a particular drug and SJS for an individual case.[9] Determining what drug is the cause is based on the time interval between first use of the drug and the beginning of the skin reaction. Drugs discontinued more than 1 month prior to onset of mucocutaneous physical findings are highly unlikely to cause SJS and TEN.[5] SJS and TEN most often begin between 4 and 28 days after culprit drug administration.[5] A published algorithm (ALDEN) to assess drug causality gives structured assistance in identifying the responsible medication.[9][12]

SJS may be caused by adverse effects of the drugs vancomycin, allopurinol, valproate, levofloxacin, diclofenac, etravirine, isotretinoin, fluconazole,[13] valdecoxib, sitagliptin, oseltamivir, penicillins, barbiturates, sulfonamides, phenytoin, azithromycin, oxcarbazepine, zonisamide, modafinil,[14] lamotrigine, nevirapine,[5] pyrimethamine, ibuprofen,[15] ethosuximide, carbamazepine, bupropion, telaprevir,[16][17] and nystatin.[18][19]

Medications that have traditionally been known to lead to SJS, erythema multiforme, and toxic epidermal necrolysis include sulfonamide antibiotics,[5] penicillin antibiotics, cefixime (antibiotic), barbiturates (sedatives), lamotrigine, phenytoin (e.g., Dilantin) (anticonvulsants) and trimethoprim. Combining lamotrigine with sodium valproate increases the risk of SJS.[20]

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a rare cause of SJS in adults; the risk is higher for older patients, women, and those initiating treatment.[21] Typically, the symptoms of drug-induced SJS arise within a week of starting the medication. Similar to NSAIDs, paracetamol (acetaminophen) has also caused rare cases[22][23] of SJS. People with systemic lupus erythematosus or HIV infections are more susceptible to drug-induced SJS.[6]

Infections

The second most common cause of SJS and TEN is infection, particularly in children. This includes upper respiratory infections, otitis media, pharyngitis, and Epstein-Barr virus, Mycoplasma pneumoniae and cytomegalovirus infections. The routine use of medicines such as antibiotics, antipyretics and analgesics to manage infections can make it difficult to identify if cases were caused by the infection or medicines taken.[24]

Viral diseases reported to cause SJS include: herpes simplex virus (debated), AIDS, coxsackievirus, influenza, hepatitis, and mumps.[8]

In pediatric cases, Epstein-Barr virus and enteroviruses have been associated with SJS.[8]

Recent upper respiratory tract infections have been reported by more than half of patients with SJS.[8]

Bacterial infections linked to SJS include group A beta-hemolytic streptococci, diphtheria, brucellosis, lymphogranuloma venereum, mycobacteria, Mycoplasma pneumoniae, rickettsial infections, tularemia, and typhoid.[8]

Fungal infections with coccidioidomycosis, dermatophytosis, and histoplasmosis are also considered possible causes.[8] Malaria and trichomoniasis, protozoal infections, have also been reported as causes.[8]

Genetics

In some East Asian populations studied (Han Chinese and Thai), carbamazepine- and phenytoin-induced SJS is strongly associated with HLA-B*1502 (HLA-B75), an HLA-B serotype of the broader serotype HLA-B15.[25][26][27] A study in Europe suggested the gene marker is only relevant for East Asians.[28][29] This has clinical relevance as it is agreed upon that prior to starting a medication such as allopurinol in a patient of Chinese descent, HLA-B*58:01 testing should be considered.[5]

Based on the Asian findings, similar studies in Europe showed 61% of allopurinol-induced SJS/TEN patients carried the HLA-B58 (phenotype frequency of the B*5801 allele in Europeans is typically 3%). One study concluded: "Even when HLA-B alleles behave as strong risk factors, as for allopurinol, they are neither sufficient nor necessary to explain the disease."[30]

Pathology

Micrograph showing full-thickness epidermal necrosis with a basket weave-like stratum corneum and separation of the dermis and epidermis, skin biopsy, H&E stain

SJS, like TEN and erythema multiforme, is characterized by confluent epidermal necrosis with minimal associated inflammation. The acuity is apparent from the (normal) basket weave-like pattern of the stratum corneum.

Diagnosis

The diagnosis is based on involvement of less than 10% of the skin.[1] It is known as TEN when more than 30% of the skin is involved and an intermediate form with 10 to 30% involvement.[3] A positive Nikolsky's sign is helpful in the diagnosis of SJS and TEN.[5] A skin biopsy is helpful, but not required, to establish a diagnosis of SJS and TEN.[5] 

Classification

Stevens–Johnson syndrome (SJS) is a milder form of toxic epidermal necrolysis (TEN).[31] These conditions were first recognised in 1922.[21] A classification first published in 1993, that has been adopted as a consensus definition, identifies Stevens–Johnson syndrome, toxic epidermal necrolysis, and SJS/TEN overlap. All three are part of a spectrum of severe cutaneous reactions (SCAR) which affect skin and mucous membranes.[9] The distinction between SJS, SJS/TEN overlap, and TEN is based on the type of lesions and the amount of the body surface area with blisters and erosions.[9] It is agreed that the most reliable method to classify EM, SJS, and TEN is based on lesion morphology and extent of epidermal detachment.[5] Blisters and erosions cover between 3% and 10% of the body in SJS, 11–30% in SJS/TEN overlap, and over 30% in TEN.[9] The skin pattern most commonly associated with SJS is widespread, often joined or touching (confluent), papuric spots (macules) or flat small blisters or large blisters which may also join together.[9] These occur primarily on the torso.[9]

SJS, TEN, and SJS/TEN overlap can be mistaken for erythema multiforme.[32] Erythema multiforme, which is also within the SCAR spectrum, differs in clinical pattern and etiology.[9] Although both SJS and TEN can also be caused by infections, they are most often adverse effects of medications.[9]

Treatment

SJS constitutes a dermatological emergency. Patients with documented Mycoplasma infections can be treated with oral macrolide or oral doxycycline.[6]

Initially, treatment is similar to that for patients with thermal burns, and continued care can only be supportive (e.g. intravenous fluids and nasogastric or parenteral feeding) and symptomatic (e.g., analgesic mouth rinse for mouth ulcer). Dermatologists and surgeons tend to disagree about whether the skin should be debrided.[6]

Beyond this kind of supportive care, no treatment for SJS is accepted. Treatment with corticosteroids is controversial. Early retrospective studies suggested corticosteroids increased hospital stays and complication rates. No randomized trials of corticosteroids were conducted for SJS, and it can be managed successfully without them.[6]

Other agents have been used, including cyclophosphamide and cyclosporin, but none has exhibited much therapeutic success. Intravenous immunoglobulin treatment has shown some promise in reducing the length of the reaction and improving symptoms. Other common supportive measures include the use of topical pain anesthetics and antiseptics, maintaining a warm environment, and intravenous analgesics.

An ophthalmologist should be consulted immediately, as SJS frequently causes the formation of scar tissue inside the eyelids, leading to corneal vascularization, impaired vision, and a host of other ocular problems. Those with chronic ocular surface disease caused by SJS may find some improvement with PROSE treatment (prosthetic replacement of the ocular surface ecosystem treatment).[33]

Prognosis

SJS (with less than 10% of body surface area involved) has a mortality rate of around 5%. The mortality for toxic epidermal necrolysis (TEN) is 30–40%. The risk for death can be estimated using the SCORTEN scale, which takes a number of prognostic indicators into account.[34] It is helpful to calculate a SCORTEN within the first 3 days of hospitalization.[5] Other outcomes include organ damage/failure, cornea scratching, and blindness.. Restrictive lung disease may develop in patients with SJS and TEN after initial acute pulmonary involvement.[5] Patients with SJS or TEN caused by a drug have a better prognosis the earlier the causative drug is withdrawn.[5] 

Epidemiology

SJS is a rare condition, with a reported incidence of around 2.6[6] to 6.1[21] cases per million people per year. In the United States, about 300 new diagnoses are made each year. The condition is more common in adults than in children.

History

SJS is named for Albert Mason Stevens and Frank Chambliss Johnson, American pediatricians who jointly published a description of the disorder in the American Journal of Diseases of Children in 1922.[35][36]

Notable cases

Research

In 2015, the NIH and the Food and Drug Administration (FDA) organized a workshop entitled “Research Directions in Genetically-Mediated Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis”.[5]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 "Stevens-Johnson syndrome". GARD. Retrieved 26 August 2016.
  2. 1 2 3 4 5 6 7 8 9 10 "Stevens-Johnson syndrome/toxic epidermal necrolysis". Genetics Home Reference. July 2015. Retrieved 26 April 2017.
  3. 1 2 3 "Orphanet: Toxic epidermal necrolysis". Orphanet. November 2008. Retrieved 26 April 2017.
  4. ↑ Schwartz, RA; McDonough, PH; Lee, BW (August 2013). "Toxic epidermal necrolysis: Part I. Introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis.". Journal of the American Academy of Dermatology. 69 (2): 173.e1–13; quiz 185–6. PMID 23866878. doi:10.1016/j.jaad.2013.05.003.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Maverakis, Emanual; Wang, Elizabeth A.; Shinkai, Kanade; Mahasirimongkol, Surakameth; Margolis, David J.; Avigan, Mark; Chung, Wen-Hung; Goldman, Jennifer; Grenade, Lois La. "Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Standard Reporting and Evaluation Guidelines". JAMA Dermatology. doi:10.1001/jamadermatol.2017.0160.
  6. 1 2 3 4 5 6 7 Tigchelaar, H.; Kannikeswaran, N.; Kamat, D. (December 2008). "Stevens–Johnson Syndrome: An intriguing diagnosis". pediatricsconsultantlive.com. UBM Medica. (Registration required (help)).
  7. ↑ Tan SK, Tay YK; Tay (2012). "Profile and pattern of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in a general hospital in Singapore: Treatment outcomes". Acta Dermato-Venereologica. 92 (1): 62–6. PMID 21710108. doi:10.2340/00015555-1169.
  8. 1 2 3 4 5 6 7 8 9 Foster, C. Stephen; Ba-Abbad, Rola; Letko, Erik; Parrillo, Steven J.; et al. (12 August 2013). "Stevens-Johnson Syndrome". Medscape Reference. Roy, Sr., Hampton (article editor). Etiology.
  9. 1 2 3 4 5 6 7 8 9 10 Mockenhaupt M (2011). "The current understanding of Stevens–Johnson syndrome and toxic epidermal necrolysis". Expert Review of Clinical Immunology. 7 (6): 803–15. PMID 22014021. doi:10.1586/eci.11.66.
  10. ↑ Teraki Y, Shibuya M, Izaki S; Shibuya; Izaki (2010). "Stevens-Johnson syndrome and toxic epidermal necrolysis due to anticonvulsants share certain clinical and laboratory features with drug-induced hypersensitivity syndrome, despite differences in cutaneous presentations". Clin. Exp. Dermatol. 35 (7): 723–8. PMID 19874350. doi:10.1111/j.1365-2230.2009.03718.x.
  11. ↑ Cooper KL (2012). "Drug reaction, skin care, skin loss". Crit Care Nurse. 32 (4): 52–9. PMID 22855079. doi:10.4037/ccn2012340.
  12. ↑ Sassolas B, Haddad C, Mockenhaupt M, Dunant A, Liss Y, Bork K, Haustein UF, Vieluf D, Roujeau JC, Le Louet H; Haddad; Mockenhaupt; Dunant; Liss; Bork; Haustein; Vieluf; Roujeau; Le Louet (2010). "ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis: Comparison with case-control analysis". Clinical Pharmacology & Therapeutics. 88 (1): 60–8. PMID 20375998. doi:10.1038/clpt.2009.252.
  13. ↑ "Diflucan One" (data sheet). Medsafe; New Zealand Ministry of Health. 29 April 2008. Archived from the original on 2010-06-03.
  14. ↑ "Provigil (modafinil) Tablets". MedWatch. US Food and Drug Administration. 24 October 2007.
  15. ↑ Raksha MP, Marfatia YS; Marfatia (2008). "Clinical study of cutaneous drug eruptions in 200 patients". Indian Journal of Dermatology, Venereology and Leprology. 74 (1): 80. PMID 18193504. doi:10.4103/0378-6323.38431.
  16. ↑ "Incivek prescribing information" (PDF) (package insert). Vertex Pharmaceuticals. December 2012.
  17. ↑ Surovik J, Riddel C, Chon SY; Riddel; Chon (2010). "A case of bupropion-induced Stevens-Johnson syndrome with acute psoriatic exacerbation". Journal of Drugs in Dermatology: JDD. 9 (8): 1010–2. PMID 20684153.
  18. ↑ Fagot JP, Mockenhaupt M, Bouwes-Bavinck JN, Naldi L, Viboud C, Roujeau JC; Mockenhaupt; Bouwes-Bavinck; Naldi; Viboud; Roujeau; Euroscar Study (2001). "Nevirapine and the risk of Stevens–Johnson syndrome or toxic epidermal necrolysis". AIDS. 15 (14): 1843–8. PMID 11579247. doi:10.1097/00002030-200109280-00014.
  19. ↑ Devi K, George S, Criton S, Suja V, Sridevi PK; George; Criton; Suja; Sridevi (2005). "Carbamazepine – The commonest cause of toxic epidermal necrolysis and Stevens–Johnson syndrome: A study of 7 years". Indian Journal of Dermatology, Venereology and Leprology. 71 (5): 325–8. PMID 16394456. doi:10.4103/0378-6323.16782.
  20. ↑ Kocak S, Girisgin SA, Gul M, Cander B, Kaya H, Kaya E (2007). "Stevens-Johnson syndrome due to concomitant use of lamotrigine and valproic acid". Am J Clin Dermatol. 8: 107–11. PMID 17428116. doi:10.2165/00128071-200708020-00007.
  21. 1 2 3 Ward KE, Archambault R, Mersfelder TL; Archambault; Mersfelder (2010). "Severe adverse skin reactions to nonsteroidal antiinflammatory drugs: A review of the literature". American Journal of Health-System Pharmacy. 67 (3): 206–213. PMID 20101062. doi:10.2146/ajhp080603.
  22. ↑ Khawaja A, Shahab A, Hussain SA; Shahab; Hussain (2012). "Acetaminophen induced Steven Johnson syndrome-Toxic Epidermal Necrolysis overlap". Journal of Pakistan Medical Association. 62 (5): 524–7. PMID 22755330.
  23. ↑ Trujillo C, Gago C, Ramos S; Gago; Ramos (2010). "Stevens-Jonhson syndrome after acetaminophen ingestion, confirmed by challenge test in an eleven-year-old patient". Allergol Immunopathol (Madr). 38 (2): 99–100. PMID 19875224. doi:10.1016/j.aller.2009.06.009.
  24. ↑ Bentley, John; Sie, David (8 October 2014). "Stevens-Johnson syndrome and toxic epidermal necrolysis". The Pharmaceutical Journal. 293 (7832). Retrieved 8 October 2014.
  25. ↑ Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, Wu JY, Chen YT; Hung; Hong; Hsih; Yang; Ho; Wu; Chen (2004). "Medical genetics: A marker for Stevens–Johnson syndrome". Brief Communications. Nature. 428 (6982): 486. PMID 15057820. doi:10.1038/428486a.
  26. ↑ Locharernkul C, Loplumlert J, Limotai C, Korkij W, Desudchit T, Tongkobpetch S, Kangwanshiratada O, Hirankarn N, Suphapeetiporn K, Shotelersuk V; Loplumlert; Limotai; Korkij; Desudchit; Tongkobpetch; Kangwanshiratada; Hirankarn; Suphapeetiporn; Shotelersuk (2008). "Carbamazepine and phenytoin induced Stevens–Johnson syndrome is associated with HLA-B*1502 allele in Thai population". Epilepsia. 49 (12): 2087–91. PMID 18637831. doi:10.1111/j.1528-1167.2008.01719.x.
  27. ↑ Man CB, Kwan P, Baum L, Yu E, Lau KM, Cheng AS, Ng MH; Kwan; Baum; Yu; Lau; Cheng; Ng (2007). "Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese". Epilepsia. 48 (5): 1015–8. PMID 17509004. doi:10.1111/j.1528-1167.2007.01022.x.
  28. ↑ Alfirevic A, Jorgensen AL, Williamson PR, Chadwick DW, Park BK, Pirmohamed M; Jorgensen; Williamson; Chadwick; Park; Pirmohamed (2006). "HLA-B locus in Caucasian patients with carbamazepine hypersensitivity". Pharmacogenomics. 7 (6): 813–8. PMID 16981842. doi:10.2217/14622416.7.6.813.
  29. ↑ Lonjou C, Thomas L, Borot N, Ledger N, de Toma C, LeLouet H, Graf E, Schumacher M, Hovnanian A, Mockenhaupt M, Roujeau JC; Thomas; Borot; Ledger; De Toma; Lelouet; Graf; Schumacher; Hovnanian; Mockenhaupt; Roujeau; Regiscar (2006). "A marker for Stevens–Johnson syndrome ...: Ethnicity matters" (PDF). The Pharmacogenomics Journal. 6 (4): 265–8. PMID 16415921. doi:10.1038/sj.tpj.6500356.
  30. ↑ Lonjou C, Borot N, Sekula P, Ledger N, Thomas L, Halevy S, Naldi L, Bouwes-Bavinck JN, Sidoroff A, de Toma C, Schumacher M, Roujeau JC, Hovnanian A, Mockenhaupt M; Borot; Sekula; Ledger; Thomas; Halevy; Naldi; Bouwes-Bavinck; Sidoroff; De Toma; Schumacher; Roujeau; Hovnanian; Mockenhaupt; Regiscar Study (2008). "A European study of HLA-B in Stevens–Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs". Pharmacogenetics and Genomics. 18 (2): 99–107. PMID 18192896. doi:10.1097/FPC.0b013e3282f3ef9c.
  31. ↑ Rehmus, W. E. (November 2013). "Stevens–Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)". In Porter, R. S. The Merck Manual ((online version) 19th ed.). Whitehouse Station, NJ: Merck & Co.
  32. ↑ Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O, Schröder W, Roujeau JC; Mockenhaupt; Naldi; Correia; Schröder; Roujeau; SCAR Study Group. Severe Cutaneous Adverse Reactions (2002). "Correlations between clinical patterns and causes of Erythema Multiforme Majus, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis results of an international prospective study". Archives of Dermatology. 138 (8): 1019–24. PMID 12164739. doi:10.1001/archderm.138.8.1019.
  33. ↑ Ciralsky, JB; Sippel, KC; Gregory, DG (July 2013). "Current ophthalmologic treatment strategies for acute and chronic Stevens-Johnson syndrome and toxic epidermal necrolysis.". Current Opinion in Ophthalmology. 24 (4): 321–8. PMID 23680755. doi:10.1097/icu.0b013e3283622718.
  34. ↑ Foster et al. 2013, Prognosis.
  35. ↑ Enerson, Ole Daniel (ed.), "Stevens-Johnson syndrome", Whonamedit?.
  36. ↑ Stevens, A.M.; Johnson, F.C. (1922). "A new eruptive fever associated with stomatitis and ophthalmia; Report of two cases in children". American Journal of Diseases of Children. 24 (6): 526–33. doi:10.1001/archpedi.1922.04120120077005.
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  40. ↑ Graff, Chad (31 July 2013). "3M golf: Gene Sauers thriving after torturous battle with skin disease". St. Paul Pioneer Press.
  41. ↑ "Family awarded $63 million in Motrin case". Boston Globe. 2013-02-13.
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  43. ↑ Morton, Karen. "Karen Morton Biography". imdb.com.
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