Drug reactions Flashcards
Difference between EM minor and major
- 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)
EM epidemiology
- Young adults
- Very uncommon in childhood
- Slight male predominance
Pathogenesis of EM
- 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
M pneumoniae EM
- 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
HSV pathomechanism in EM
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
Describe the target lesion in EM
- 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
Distribution of EM
- 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
Mucosal lesions in EM
- 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
Systemic features of EM
- 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
Natural history of EM
- 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
EM histology
- 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
EM Ddx
- 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
EM Rx
- 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
Who is at risk of SJS/TEN
- 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
Epi of SJS/TEN
- Women:men 2:1
- SJS more common than TEN
- Incidence: ~1-2 per million per year
HLA types associated with Sulfonamides
HLA-A29, HLA-B12, HLA-DR7
HLA types associated with Oxicam NSAIDs
HLA-A2, HLA-B12
HLA types associated with carbamazepine
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
HLA types associated with allopurinol
HLA-B*58:01 (should check for all Han Chinese)
Medications that causer SJS/TEN
CABANAS RAH Checkpoint inhibitors - nivolumab/ipilimumab Aromatic anticonvulsants Barbituates Antibiotics NSAIDs Allopurinol Sulphonamide antibiotics and sulfasalazine Rituximab Anti-retroviral HIV drugs (nevirapine)
Cross-reactivity of medications that cause SJS/TEN
- Anticonvulsants carbamazepine, phenytoin, lamotrigine, phenobarbital
- Beta lactam antibiotics penicillin, cephalosporins and carbapenam
- NSAIDs
- Sulfonamides sulfamethoxazole, sulfadiazine, sulfapyridine
Which drugs are more fatal in SJS/TEN
Drugs with longer half lives are more likely to cause drug reactions and a fatal outcome than those with short half-lives
Causes of SJS/TEN that aren’t medications
- Infections - M pneumoniae
- particularly in children
- more severe involvement of mucosal sites with sparse involvement of skin –> is this just M pneumoniae mucositis
- Immunizations
- Contrast medium
- Herbal medicines? Foods?
- Post-BM transplant as manifestation of acute GVHD
Pathogenesis of SJS/TEN
- This results in clonal expansion of a population of drug-specific cytotoxic T cells that kill keratinocytes directly and indirectly through recruiment of mediators
- Drug binding to the HLA is recognised as a forein antigen and subsequently causes severity of reaction
- The cytotoxic reaction is drug specific, HLA-class 1 restricted, and directed against the native form of the drug rather than against a reactive metabolite
- Mediators of keratinocyte apoptosis
- CD8 cytotoxic and NK cells
- Granulysin:
- Cytolytic protein secreted by cytotoxic T lymphocytes, NK cells and NK/T cells
- Levels of this in blister fluid correlates with severity
- Unsure why it is released so much
- IL-15
- Correlates with disease severity
- Widely expressed - produced by immune cells and keratinocytes
- Has been shown to increase secretion of granulysin
- Other factors:
- Soluble Fas-ligand
- Used to be thought that this was very important
- Member of the TNF family of cytokines –> ability to induce apoptosis by binding to its specific cell surface receptor - Fas death receptor
- Perforin
- TNF-alpha
- TRAIL
- Granzyme B
- Soluble Fas-ligand
- All the above results in cytotoxic destruction of keratinocytes
- Period of onset: 1-3 weeks –> suggests a period of sensitization, and happens quicker if re-exposure
- Early SJS/TEN:
- Individual apoptosis
- Becomes necrosis if not phagocytosed quick enough
- Later SJS/TEN
- Overwhelming apoptosis results in necrosis, loss of cohesion to adjacent keratinocytes and eventual full-thickness epidermal necrolysis
SJS/TEN prodrome
Fever >39 degrees
Ocular: stinging, photophobia, conjunctival itching, burning
Pain on swallowing
Malaise, myalgia, arthralgia
Systems involved in SJS/TEN
Cutaneous, mucosal, urogenital, respiratory, GIT, ocular, haematologic
SJS/TEN cutaneous
First appear on trunk and face, then spread to neck, face, proximal extremtiies
Distal portions of limbs and scalp spared
Palms and soles can be involved
Mucosal involvement in >90% of patients
Tender
Morphology:
Initially erythematous, dursky red or purpuric macules that coalesce, can be target like but lack 3 concentric rings
As full thickness necrosis occurs –> grey hue, Nikolsky positive, Asboe-Hansen positive, development of blisters
‘Wet cigarette paper’ or ‘scalded’
Tense blisters on palmoplantar surfaces
SJS/TEN urogenital mucosal
Urethritis in 2/3 of patients –> urinary tension
Genital erosions
Can lead to long-term adhesions, stenosis, obstructed urinary stream, urinary retention, recurrent cystitis, haemtocolpos (menstruation staying in the vagina)
? risk of malignancy –> vulvovaginal adenosis (metaplasia)
SJS/TEN ocular involvement
Commonly severe conjunctivitis with purulent discharge
Can get corneal ulceration, anterior uveitis, panophthalmitis
Pain, photophobia
Graded assessment:
1. No involvement
2. Mild (1) - conjunctival hyperaemia
3. Severe (2): Either ocular surface epithelial defect or pseudomembrane formation
4. Very severe (3): ocular surface epithelial defect and pseudomembrane formation
Eye changes may regress completely, but 50% have late eye sequelae: pain, dryness, scarring, synechiae development between eyelids and conjunctiva
Respiratory involvement SJS/TEN
Pharyngeal mucosa always affected
Trachea, bronchial less frequently
25% resp tract involvement in TEN
Gastrointestinal involvement SJS/TEN
Cholestasis due to vanishing bile duct syndrome
Can have involvement of intestines and small bowel
Hepatitis
SJS/TEN complications
- Infections
- Staph aureus and pseudomonas
- Overwhelming sepsis
- Pulmonary
- pneumonia
- interstitial pneumonitis
- GI
- epithelial necrosis of oesophagus, small bowel, colon
- diarrhoea, melena, small bowel ulcerations, colonic perforation, small bowel intussusception
Diagnosis of SJS vs TEN
- Classify skin detachment:
- <10% BSA –> SJS
- 10-30% BA –> SJS/TEN
- > 30% BSA –> TEN
SCORTEN
Age>40 HR.120 Malignancy BA on day 1 >10% Serum urea >10 mmol Serum bicarb level <20 Serum glucose >14
Scorten: 0-1: 3.2% 2: 12.1% 3: 35.8% 5: 58.3% >5: 90%
SJS/TEN long term sequelae
- Re-epithelialisation starts within days, complete by 2-4 weeks
- Proliferation and migration of keratinocytes from reservoir sites (healthy areas around denuded ones)
- Ocular complications: 35%
- Erosion of the lower lateral eyelid margin
- Conjunctival adhesions
- Entropion
- Blindness
- Sicca
- Cutaneous
- Scarring
- Dyspigmentation
- Eruptive melanocytic naevi
- Nail dystrophy
- Hair loss
- Mucosal/genital
- Persistent erosions of the mucous membranes
- Urethral stenosis
- Phimosis
- Dyspareunia and haematocolpos
- Psych
- Long-term psych complications
- can get recurrence with infection - M pneumoniae and HSV
SJS/TEN Ix
- haematologic abnormalities: anaemia and lymphopaenia
- neutropenia 1/3 and associated with poor prognosis
- hypoalbuminaemia, electrolyte imbalance and increased urea and glucose
- serum urea nitrogen >10 mmol/L and glucose >14 bad markers
- mild elevation in ALT and AST
Histology
- Early: apoptotic keratinocytes in basal and immediate suprabasal layer of the epidermis –> dusky gray colour clinically
- Later: subepidermal blister with overlying confluent necrosis of the entire epidermis, and sparse perivascular infiltrate of lymphocytes –> lymphocytes are CD4
SJS/TEN Ddx
- Infectious
- staph scalded skin
- staph/strep toxic shock
- EM
- Invasive fungal dermatitis - see in low birth weight newborns
- Chikungunya fever - fever, generalized, vesicobullous eruption
- Drug
- other SCAR - AGEP, TEN
- Generalised fixed drug eruption - isn’t that really what it is anyway
- Toxic erythema of chemotherapy
- Physical
- severe burns
- Immunobullous
- paraneoplastic pemphigus
- pemphigus
- Drug induced linear IgA bulloud dermatosis
- Immune
- TEN like SLE
- Kawasaki disease
- DIC/ purpura fulminans
- Neoplastic
- CTCL
SJS/TEN hospital admission management
SCORTEN 0 or 1 –> ward
>2 –> ICU/burn unit. BJD had an article that outlined importance for prognosis
Epidermal detachment 10-20% –> ICU
Controlled pressure
Room temp 30-32 degrees to prevent excessive caloric expenditures due to epidermal loss/body warmers
Fluidized air beds when patient’s back is denuded
SJS/TEN wound care
Manipulate as little as possible
Aseptic technique - isotonic sterile sodium chloride
Focus on face, eyes, anogenital region, axillary, interdigital spaces
Nonadherent nanocrystalline gauze containing silver seem to be replacing petrolatum impregnated gauze - you can leave this for up to 7 days
Other option: large, non-adherent layered dressing (Exu-dry) over the patient and on the bed
Infection prevention: around orifices mupirocin
Some centres are surgically debriding wounds and using whirlpool therapy to remove necrotic epidermis
Others are using antishear wound care –> detached skin left as biologic dressing
Observational study –> same outcomes
SJS/TEn Ocular care
Examine with fluorescein staining
Cleanse: isotonic sterile sodium chloride solution
Ophthalmic antibiotic
Eyedrops TDS - reduce bacterial colonization
Conjunctival hyperaemia: topical steroids and broad spectrum antibiotics 4-6 times a day
Grade 2-3: antibiotics, steroids, lubricants, amniotic membrane transplantation (has good evidence for it ? is it available in Australia)
No evidence for systemic therapy with eyes
SJS/TEN mouth care
Rinse several times a day with isotonic sterile sodium chloride solution
Aspiration
JAAD Jan 2020: 5% tranexamic acid in gauze and then apply –> 500 mg of 5mL IV with 5 mL of sterile water –> no increased risk of VTE
NG tube
Lignocaine washes
SJS/TEN anogenital and interdigital care
Short applications of silver nitrate solution in case of maceration
SJS/TEN pain management
Implement pain scale
Mild pain –> non-opioid analgesics
>4. –> opioids
Severe –> IV
SJS/TEN vulvovaginal management
Gynaecology team Intra-vaginal steroids - ointments over creams Soft vaginal molds Menstrual suppression Topical anti-fungal with steroids
SJS/TEN infection prophylaxis
Antibiotics are not recommended and cannot be advised
Instead sterile handling
Antiseptic solutions: chlorhex, silver nitrate
If suspected to be sulfonamide cause then don’t use silver sulfadiazine
Repeat cultures at 48 hour intervals and monitor neutrophils and CRP
What is there evidence for for systemic treatment of SJS/TEN
Cyclosporin:
MOA: inhibition of T cell activation, preventing the production and release by cytotoxic T cells and NK cells of cytokines
There is some evidence to support its use
Retrospective review of 71 patients - administered 3-5 mg/kg/day for an average of 7 days –> reduced mortality of 0.43 compared to IVIG of 1.43
Large case series in Spain and 2 systematic reviews: evidence may slow progression of SJS/TEN in absence of toxicitiy
Other study of 71: 10% mortality rate with cycloiporin, as opposed to 32% in other therapies
Case series in kids was good –> celared within 15 days, treated at 3 mg/kg/day
Meta-analysiis: CsA had 70% reduction in mortality risk
SJS/TEN give them steroids?
Remains controversial
Study indicates acute pulse therapy with IV dex over 3 days at 1.5 mg/kd
No confirmation of survival benefit with RegiSCAR
SJS/TEN give them tnf-alpha?
Series of 10 patients who received stat dose of etanercept 50 mg –> median healing time of 8.5 days
Randomized unblinded etanercept versus pred –> etanercept had shorter healing and less mortality (8.3% versus 16.3%)
SJS/TEN give them IVIG?
Contains antibodies that can block the binding of FaL to Fas –> however now acknowledged that granulysin is the most important mediator, making IVIG a little redundant
Meta-analyses: cumulative dose >2 g/kg is associated with an increased survival rate, but <2 g doesn’t show that, but only 12 patients received less than 2 g
Large European cohort study could not demonstrate a survival advantage that was significant
Overall there is little evidence
A/E include renal, haematologic and thrombotic
There is also too limited data to draw conclusions on combined therapy with steroids and IVIG
List treatments for SJS/TEN reported
Steroids TNF alpha Cyclosporin IVIG Plasmapharaesis Cyclophosphamide` N-acetylcystine
HLA type for lamotrigine
HLA-B*1502
HLA type for dapsone induced DRESS
HLA-B*13:01
More commonly seen in Thai population
CYP450 inducers
CRAP GPS
- Carbemazepines
- Rifampicin
- Alcohol
- Phenytoin
- Griseofulvin
- Phenobarbitone
- Sulphonylureas
CYP450 inhibitors
SICKFACES.COM
- Sodium valproate
- Isoniazid
- Cimetidine
- Ketoconazole
- Fluconazole
- Alcohol & Grapefruit juice
- Chloramphenicol
- Erythromycin
- Sulfonamides
- Ciprofloxacin
- Omeprazole
- Metronidazole
Drugs that cause generalised hypertrichosis
- ACADEMISM
- Anti-inflammatory: steroids
- Chelators: penicillin
- Anti-convulsants: phenytoin
- Diuretics
- EGFR inhibitors
- Minoxidil, other vasodilateors
- Streptomycin
- Methoxypsoralen
Drugs that cause ANCA associated vasculitis
Pimps and hoes, margaritas and cocaine Propylthiouracil Hydralazine Minocycline Levamisole tainted cocaine
