Drug reaction fixe L27.1

Bourns in 1899; Brocq in 1894;

Localized, patchy or plaque-like, also bullous or exfoliative drug reaction,

• which occurs in a temporal connection with the intake of drugs (for triggering drugs, see table) in therapeutic doses
• is limited to a solitary focus or to a few foci
• tends to recur on the spot (recurrence in loco).

Fixed drug exanthema (FDE) may be solitary, scattered, or generalized; the majority of patients have five or fewer lesions (Pai V et al. 2014). The interval between drug exposure and onset of FDE can be up to two weeks, but in most patients, especially those with previous drug exposure, onset occurs within 48 hours. At the time of presentation, most patients state that similar lesions have occurred in the past. With each recurrence, lesions typically occur at the same sites as in previous outbreaks, and with repeated exposure to the causative drug, the disease may spread to additional sites that were not previously affected. Local symptoms such as itching and/or burning associated with the outbreak occur in approximately one-quarter of patients .

The immunopathogenetic mechanism of the fixed drug response is as yet unclear (see also under erythema multiforme).

An important role is played by CD8+ memory T cells, which are located in the basal layer of the epidermis of dormant FDE lesions. CD8+ positive cells persist for years in old, already clinically healed lesions (tissue-resident memory cells) and can be expressed and activated on keratinocytes after re-exposure to the agent via a probably TNF-alpha induced upregulation of ICAM-1 (see below adhesion molecules) (see also UV reactivation reaction). Within 24 hours of ingestion of a causative drug, these CD8+ T cells migrate up the epidermis, produce cytokines such as interferon-gamma and TNF-alpha, and take on the phenotype of a natural killer cell expressing the cell surface molecule CD56 and the cytotoxic molecules granzyme B and perforin. This activity leads to the epidermal necrosis observed in FDE [15]. At the same time, CD4+ Foxp3+ regulatory T cells migrate into the epidermis and dampen the damage caused by CD8+ T cells. The action of CD4+ regulatory T cells, which includes the production of the anti-inflammatory cytokine IL-10, explains the self-limiting nature of the fixed drug response. After the acute phase of FDE has subsided, CD8+ cells lose the natural killer phenotype they acquired during an acute onset of FDE, and they remain dormant in the basal layer of the epidermis at the site of the earlier onset for many years (Mizukawa Y et al. 2008).

FDEs to the same drug have been reported in immediate family members, suggesting that there may be a genetic component in the pathogenesis of FDE. Drugs implicated in familial cases of FDE include tetracycline/demeclocycline , feprazone , trimethoprim/sulfamethoxazole , diphenhydramine , and aspirin and ibuprofen . Specific associations have been found between human leukocyte antigen (HLA) genes and FDE by certain drugs. For example, the HLA-A30 B13 Cw6 haplotype was found to be significantly more prevalent in patients with FDE after trimethoprim/sulfamethoxazole than in healthy control patients (Özkaya-Bayazit E e al 2001), whereas the HLA-B22 allele was associated with feprazone-induced FDE.

Apoptosis of keratinocytes (clearly evident histologically) seems to be induced by a FAS-FAS ligand interaction (see below CD classification - CD95, or CD95L).

Of note is the role of viral infections (e.g., herpes simplex infections) as cofactors for the "recurrence" of the fixed drug response. For the recurrent "in-loco occurrence" a so-called recall reactivation reaction can be assumed, although the immunological processes are also still unclear (see also under UV reactivation reaction).

FDE can occur in all age groups, including children and the elderly. However, it is most common in young to middle-aged adults, with the average age ranging from 35 to 60 years. The mean age of patients with nongeneralized bullous FDE was significantly younger than that of GBFDE patients (47.2 versus 69.1), and the median age was similarly different (46 versus 74) [12]. FDE occurs essentially equally in men and women (Zaouak A et al. 2019)

Ubiquitous occurrence is generally possible. However, there are clear priorities as shown in review studies (Jhaj R et al. 2018). The preference for the upper extremity is recognizable (around 50%), followed by the lower extremity and lips, face, penis, vulva; involvement of the oral mucosa can be very prominent (buccal mucosa, gingiva, hard and soft palate) (Ben Fadhel N et al. 2019). The mucosa of the glans penis and vulva are also typical (often unrecognized) sites of manifestation.

One study reported a gender-dependent distribution of lesions, with 89% of women showing involvement of the limbs (particularly the hands and feet), while 90% of men had lesions on the genitals (Brahimi N et al. 2010).

In a retrospective study, it was found that in 68.8% of cases of genital FDE, lesions of the oral mucosa were associated with genital lesions (Özkaya E 2013). Lesions of the oral mucosa were bullous and erosive in most cases; however, aphthous or erythematous morphology was observed in a minority of patients. This can lead to the misdiagnosis of Behçet's disease (Özkaya E 2013). In about five percent of patients with FDE, only the mucous membranes are affected without accompanying skin lesions.

Solitary or limited to a few foci, 2.0-5.0 cm in size (rarely up to 10 cm in size), round or oval (rarely also anular), initially saturated red, later blue- to brown-red, after healing brown (postinflammatory hyperpigmentation), sharply demarcated, succulent, itchy or also slightly painful spots or plaques. Vesicular transformation in the center is possible. Diagnosis may be complicated in intertriginous involvement because the characteristic clinical morphology there is obscured by acting local factors. Clinically, a (large-) area erosion may appear at these sites due to the detachment of the surface epithelium.

The maximum variant described is the generalized and possibly multilocular bullous fixed drug reaction (GBFDE), which can occur in adults as well as in children. A variant, which is highlighted by its intertriginous localization, is the so-called"Baboon syndrome".

Upon re-exposure, the lesions reappear in exactly the same location within 24 hr. However, a refractory period may occur immediately after healing of the lesion.

To be distinguished are:

• Classic fixed drug reaction: Most common form that heals over a long persistent postinflammatory hyperpigmentation.
• Non-pigmented variant of fixed drug reaction: rarer form; usually occurring over a larger area (up to 10 cm in size) and healing without postinflammatory hyperpigmentation.
• Urticular fixed drug reaction: Rare variant that again becomes urticarial and recurs in loco when provoked
• Multilocular bullous fixed drug reaction: common variant with multiple lesions
• Neutrophilic fixed drug reaction: Extremely rare variant presenting histologically as neutrophilic dermatitis. Only a few case reports have been published to date

Clinical picture with recurrence in loco.

Note: Eye drops should also be considered in the history!

The results of prick scratch tests are evaluated differently. They are performed in healed lesions in loco. In individual studies (e.g., for nonsteroidal anti-inflammatory drugs), reliable positive results of 40% are reported (Andrade 2011) .

Patch testing is considered a safer, albeit less sensitive, method for identifying the causative agent in FDE. Patch tests are performed at the site of a previous lesion of FDE at least two weeks after a previous eruption has resolved. The drug is diluted in petroleum jelly or in water at a concentration of 10 to 20 percent. The patch is applied for 24 to 48 hours, and infiltrated erythema or an intense local reaction represents a positive test result. A retrospective study of 52 patients with a clinical diagnosis of FDE who underwent patch testing showed a positive reaction in the lesional skin in 40.4% of patients. Positive reactivity in this study was almost exclusively for NSAIDs, whereas other drug classes, particularly antibiotics, consistently yielded negative test results, even when clinical suspicion was high. In the same study, patch testing on non-lesional skin was negative in all but one patient. The fact that diagnostic utility depends on the drug class involved implies a detrimental limitation of epicutaneous testing.

Ultimately, an oral provocation with the drug in question is conclusive. It is not recommended to perform this test procedure on an outpatient basis!

In case of corresponding severity of the clinical picture: systemic glucocorticoids in medium dosages, e.g. 60-80 mg prednisolone equivalent per day p.o. (e.g. Decortin ®).

Later gradual dose reduction, stomach protection. For severe pruritus antihistamines such as Dimetinden, e.g. Fenistil® 2 times/day 1 amp. i.v. or Desloratadin (Aerius®) 1 time / day 1 tbl. p.o.

In larger collectives an average of 2.6 recurrences (1-10 recurrences) were anamnestized.

Medical history: A 67-year-old patient reported a treatment with Terbinafine because of a therapy-resistant onychomycosis. 2 hours after taking the 1st tablet he had noticed strongly itchy wheals on the inner side of the right upper arm. The treatment was then discontinued. The symptoms had receded.

Diagnosis: Epicutaneous and prick tests with Terbinafine o.B. When provoking the drug orally (125 mg Terbinafine) the patient developed an itchy wheal field of 6x6 cm on the inner side of the right upper arm within 3 hours. Testing was discontinued; the patient received symptomatic therapy with prednisolone and clemastine. Below this the symptoms improved within a few hours.

Diagnosis: Fixed (urticarial) drug reaction.

1. Agnew KL, Oliver GF (2001) Neutrophilic fixed drug eruption. Australas J Dermatol 42: 200-202
2. Al Aboud K et al. (2003) Fixed drug eruption to ibuprofen in daughter and father. J Drugs Dermatol 2: 658-659
3. Anderson HJ et al. (2021) A Review of Fixed Drug Eruption with a Special Focus on Generalized Bullous Fixed Drug Eruption. Medicina (Kaunas) 57:925.
4. Andrade P et al. (2011) Patch testing in fixed drug eruptions--a20-year review. Contact Dermatitis 65:195-201.
5. Ben Fadhel N et al. (2019) Clinical features, culprit drugs, and allergology workup in 41 cases of fixed drug eruption. Contact Dermat81, 336-340.
6. Bourns DCG (1889) Unusual effects of antipyrine. Br Med J 2: 218-220
7. Brahimi N et al. (2010) A three-year-analysis of fixed drug eruptions in hospital settings in France. Eur J Dermatol 20, 461-464.
8. Brocq L (1894) Eruption érythémateuse fixe a l`antipyrine. Ann Dermatol Vénéréol 5: 308-313
9. Flowers H et al (2014) Fixed drug eruptions: presentation, diagnosis, and management. South Med J 107:724-727.
10. Gilmore E et al. (2004) Extensive fixed drug eruption secondary to vancomycin. Pediatric Dermatology 21: 600-602
11. Hayashi H et al. (2003) Multiple fixed drug eruption caused by acetaminophen. Clin Exp Dermatol 28: 455-456
12. Handisuraya A et al (2011) Fixed drug eruption due to mefenamic acid: a case series and diagnostic algorithms. JDDG 9: 374 - 378
13. Hoetzenecker W et al.m(2016) Adverse cutaneous drug eruptions: current understanding. Semin Immunopathol 38:75-86.

14. Jhaj R et al. (2018) Fixed-drug Eruptions: What can we Learn from a Case Series? Indian J Dermatol 63:332-337.

15. Jung JW et al. (2014) Clinical features of fixed drug eruption at a tertiary hospital in Korea. Allergy Asthma Immunol Res 6:415-420
16. Kleinhans M et al. (2004) Fixed drug eruption caused by articaine. Allergy 59: 117
17. Kornmehl H et al. (2018) Generalized fixed drug eruption to piperacillin/tazobactam and review of literature.
18. literature.Dermatol Online J 24. pii: 13030/qt8cr714g5.
19. Lee SS et al. (2011) Maximum Points of Head's Zone in Fixed Drug Eruption. Ann Dermatol 23(Suppl 3):S383-386.
20. Mizukawa Y et al. (2008) In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption. Br. J. Dermatol 158, 1230-1238.
21. Özkaya E (2013) Oral mucosal fixed drug eruption: Characteristics and differential diagnosis. J Am Acad Dermatol 69: e51-e58.
22. Pai V et al. (2014) Retrospective analysis of fixed drug eruptions among patients attending a tertiary care center in Southern India. Indian J Dermatol Venereol Leprol 80: 194.
23. Pionetti CH et al. (2003) Fixed drug eruption due to loratadine. Allergol Immunopathol (Madr) 31: 291-293
24. Rödiger C et al. (2011) Fixed urticarial drug eruption? Abstract-CD 46 DDG-Conference: P02/07
25. Sehgal VN et al. (2003) Bullous fixed drug eruption (BFDE) following per-oral metronidazole. J Eur Acad Dermatol Venereol 17: 607-609
26. Shiohara T et al.(2015) Crucial Role of Viral Reactivation in the Development of Severe Drug Eruptions: a Comprehensive Review. Clin Rev Allergy Immunol 49:192-202.
27. Sidhu-Malik NK et al. (2003) Multiple fixed drug eruption with interferon/ribavirin combination therapy for hepatitis C virus infection. J Drugs Dermatol 2: 570-573
28. Tan C et al. (2010) Annular fixed drug reaction. JDDG 8: 823-825
29. Vester K et al (2011) Fixed drug exanthema due to flupirtine. Abstract-CD 46th DDG conference:P02/21.
30. Zaouak A et al. (2019) Bullous fixed drug eruption: A potential diagnostic pitfall: A study of 18 cases. Therapies 74, 527-530.