Drug reactions Flashcards
1
Q
Difference between EM minor and major
A
- EM minor –> targets, absent or mild mucosal involvement, no systemic symptoms, especially elbows, knees, wrists
- EM major –> targets, can be bullous, extremities and face, severe mucosal invovlement, systemic features present (fever, arthralgias)
2
Q
EM epidemiology
A
- Young adults
- Very uncommon in childhood
- Slight male predominance
3
Q
Pathogenesis of EM
A
- Infection in predisposed individual results in a mucocutaneous immune reaction
- Causative agents:
- Infections:
- Viral: HSV most common, Orf, VZV, Vaccinia, Adenovirus, EBV, CMV, Hepatitis, Coxsackie virus, PB19, HIV
- Bacterial: Mycoplasma pneumonia, chlamydophila psittaci, Salmonella, M TB
- Fungal: Histoplasma capsulatum, dermatophytes
- Drugs:
- NSAIDs
- Sulfonamides
- Anticonvulsants
- Allopurinol
- Antibiotics
- Exposures
- Poison Ivy
- Systemic disease (rare)
- IBD
- Behcets
- Lupus
- Infections:
- Reported triggers: trauma, cold, UV, orthovoltage irradiation
- ?Genetics: HLA-DQw3, DRw53 and Aw33 –> different to SJS/TEN
4
Q
M pneumoniae EM
A
- M pneumoniae: severe acro-mucosal –> mucositis, conjunctivitis and targetoid/bullous skin eruptions, primarily CAP –> occurs in young boys
- You can culture M pneumoniae from the bullae suggesting an aetiologic role as opposed to immune-mediated
- Association could also be explained by autoimmune molecular mimicry
5
Q
HSV pathomechanism in EM
A
Theorized that patients have normal immunity to HSV, but aren’t that good at clearing the virus from infected cells –> HSV DNA is in the skin –> Th1 cells produce interferon-gamma in response to viral antigens within the skin –> autoantigens released by lysed/apoptotic viral antigen-containing cells
6
Q
Describe the target lesion in EM
A
- Typical target lesion:< 3 cm in diameter, regular round shape, well-defined border, consists of at least 3 distinct zones –> central zone has dusky appearance over time ‘bulls eye’
- each concentric ring likely represents one of a sequence of events of the same, ongoing pathologic process
- explains why some are monomorphic in appearance (cells all in same stage)
- Atypical papular target lesions - can accompany or be the primary cutaneous lesion
- round, oedematous, palpable and reminiscent of EM
- 2 zones, and poorly defined border
- Must distinguish from flat atypical targets that are seen in SJS or TEN, but not EM
7
Q
Distribution of EM
A
- Numerous lesions usually present
- Preferential on the extremities and the face - particularly favouring the upper extremities
- Most frequent: dorsal aspects of the hands and the forearms, but palms, neck, face and trunk are common locations as well
- Involvement of the legs is less frequently seen
- Can also appear within areas of sunburn
- Lesions tend to be grouped, especially on the elbows or knees
- Koebner phenomenon: may be observed, target lesions appearing within areas of cutaneous injury such as scratches, or as erythema and swelling of the proximal nail folds at sites of chronic self-trauma
- Injury must precede onset of EM eruption
8
Q
Mucosal lesions in EM
A
- Severe mucosal involvement characteristic of EM Major, not seen in EM minor
- Primary mucosal lesions of EM are vesiculobullous, rapidly develop into painful erosions that involve the buccal mucosa and lips
- Less commonly ocular and genital involvement
- Lips: erosions rapidly become covered by painful crusts
- Anogenital mucosa: often large and polycyclic with a moist base
Can involve eyes –> need to speak to ophthal
9
Q
Systemic features of EM
A
- Always present in EM major, absent or limited in EM minor
- Fever, weakness/lack of energy
- Rarely: arthralgias, atypical pneumonia (?M pneumonia thoug)
- Very rare: renal, hepatic and haematologic abnormalities
10
Q
Natural history of EM
A
- Almost all lesions appear within 24 hours, and fully develop by 72
- Pruritic or burning sensations within the lesions may be described
- Individual lesions remain fixed for >7 days
- For most, lasts ~ 2 weeks and heals without sequelae
- Occasionally PIH, and if not instituted ocular care then ocular A/E
- Recurrences in HSV-associated are common –> some recur every spring
- Can also recur in the immunosuppressed, and can be associated with longer periods of having EM –> can have 5-6 episodes a year, and can be associated with prolonged steroid use
11
Q
EM histology
A
- The keratinocyte is the target of the inflammatory insult with apoptotic keratinocytes the earliest finding
- Large areas of full thickness epidermal necrosis are not seen
- As evolves –> mild spongiosis and focal vacuolar degeneration of basal keratinocytes
- Superficial dermal oedema and perivascular infiltrate of lymphocytes with exocytosis into the epidermis is also seen
- IF: non-specific, granular deposits of IgM and C3 around superficial BV and focally at the DEJ have been described
- HSV antigens have been detected within keratinocytes by IF, and HSV genomic DNA detected in skin biopsy specimens
12
Q
EM Ddx
A
- External:
- Infectious
- Mycoplasma mucositis
- Drugs
- Fixed drug
- SJS/TEN
- Physical –> DA
- Infectious
- Internal
- Inflammatory
- Neoplasms
- Immune mediated:
- Urticaria
- Urticarial vasculitis
- EAC
- Other vasculitides
- Rowell syndrome
- Systemic
- Metabolic
- Endocrine
- Infiltrates
13
Q
EM Rx
A
- Admit if concern of SJS/TEN as differential
- General skin care measures
- Education
- Topicals
- Antiseptics for eroded skin lesions
- Antiseptic/antihistamine rinses
- Local anaesthetics for oral lesions
- Ophthal: speak to ophthal, if ocular involvement need topical drops to prevent complications
- Treat underlying cause if there is one
- Oral systemic
- No double blind or open trials of systemic therapies for the acute episode of EM
- Treat specific precipitating factor if identified
- HSV –> antivirals –> minimal impact if given after the appearance of the acute episode of EM
- Oral antihistamines –> 3-4 days, may reduce stinging and burning
- Severe EM with functional impairment:
- early therapy with steroids - 0.5-1 mg/kg/day for 3-5 days or pulse methylpred 20 mg/kg/day for 3 days
- Recurrences:
- For HSV-associated: 6 months oral acyclovir: 10 mg/kg/day in divided doses or valacyclovir 500-1000 mg/day or famciclovir 250 mg BD
- There is a double-blind, placebo-controlled study in young adults with EM that demonstrated efficacy of acyclovir prophylaxis
- beneficial effect may continue even after the antiviral drug is discontinued
- in non-responsive patients, you can double the dose of the medication or trial a different antiviral
- When recalcitrant, other things tried are (although no evidence): azathioprine, prednisone, thalidomide, dapsone, cyclosporin, MMF, PUVA
14
Q
Who is at risk of SJS/TEN
A
- Immunocompromised
- AIDS: 1000-fold higher risk, HIV 100-fol
- Malignancy: haematologic in particular
- Drug metabolism
- Slow acetylator genotypes
- metabolise drugs at a decreased rate
- CYP2C19 gene –> codes for CYP450, increased risk with phenobarbital, phenytoin or carbamazepine
- CYP2C variants
- HLA alleles
- All Asians who commence carbamazepine should be screened for HLA-B*15:02
- Should consider HLA-B*58:01 in Han Chine when starting allopurinol
- Another consensus panel says do HLA-A*31:01 screen for anyone starting carbamazepine
- Slow acetylator genotypes
- Excessive drug
- Physical stimuli
- UV
- Radiation - those on aromatic anticonvulsant + radiation have higher risk –> localized to site of radiation
- SLE - could just be TEN-like lupus
15
Q
Epi of SJS/TEN
A
- Women:men 2:1
- SJS more common than TEN
- Incidence: ~1-2 per million per year
16
Q
HLA types associated with Sulfonamides
A
HLA-A29, HLA-B12, HLA-DR7
17
Q
HLA types associated with Oxicam NSAIDs
A
HLA-A2, HLA-B12
18
Q
HLA types associated with carbamazepine
A
HLA-B*15:02 (all asians who start should have this tested)
HLA 31:01 as well –> some think everyone should be tested for this, more common in Europeans
19
Q
HLA types associated with allopurinol
A
HLA-B*58:01 (should check for all Han Chinese)
20
Q
Medications that causer SJS/TEN
A
CABANAS RAH Checkpoint inhibitors - nivolumab/ipilimumab Aromatic anticonvulsants Barbituates Antibiotics NSAIDs Allopurinol Sulphonamide antibiotics and sulfasalazine Rituximab Anti-retroviral HIV drugs (nevirapine)
21
Q
Cross-reactivity of medications that cause SJS/TEN
A
- Anticonvulsants carbamazepine, phenytoin, lamotrigine, phenobarbital
- Beta lactam antibiotics penicillin, cephalosporins and carbapenam
- NSAIDs
- Sulfonamides sulfamethoxazole, sulfadiazine, sulfapyridine
22
Q
Which drugs are more fatal in SJS/TEN
A
Drugs with longer half lives are more likely to cause drug reactions and a fatal outcome than those with short half-lives
