Urticaria, Erythemas & Drug Reactions PDF

1/27/25 Urticaria, Erythemas & Drug Reactions D R E W M I T C H E L L , M D P G Y- 4 D E PA R T M E N T O F D E R M AT O L O G Y 1 2 Urticaria Vascular reaction of skin and/or mucous membranes ± angioedema...

1/27/25 Urticaria, Erythemas & Drug Reactions D R E W M I T C H E L L , M D P G Y- 4 D E PA R T M E N T O F D E R M AT O L O G Y 1 2 Urticaria Vascular reaction of skin and/or mucous membranes ± angioedema Common Lifetime prevalence = 10-25% Wheals are pruritic, pale pink edematous plaques w erythematous flare Individual lesions last < 24 hours, entire rash often lasts much longer Acute vs Chronic urticaria Acute: < 6 weeks Chronic: ≥ 6 weeks (urticaria occurring at least 2x/week off treatment) Spontaneous vs inducible Should not have constitutional symptoms, fever, myalgias/arthralgias 3 1  1/27/25 Angioedema Swellings which occur deeper in the dermis and subcutaneous/submucosal tissue Tend to be normal to faint pink in color, painful and less well-defined than wheals Often last for 2-3 days Can affect mouth, respiratory tract and/or GI tract as well as skin Urticaria-associated vs angioedema w/o wheals Common to have angioedema with urticaria If only angioedema present, then need to pursue additional workup 4 Spontaneous Urticaria Acute spontaneous urticaria most common in children Idiopathic 50%, infection 40%, drug 10% Chronic spontaneous urticaria peaks in 4th decade Idiopathic 50%, autoimmune 40-50%, chronic infection ≤ 5% ~2:1 female predominance Associated w autoimmune thyroid disease (strongest) as well as other autoimmune disorders (vitiligo, IDDM, RA) Association w intestinal strongyloidiasis in endemic areas ?association w Helicobacter pylori gastritis 5 Inducible Urticaria Urticaria that is induced by exogenous stimulus Usually chronic Multiple forms can co-exist in the same patient 6 2  1/27/25 Dermographism Simple vs Symptomatic Simple: occurs in 5% of normal population, exaggerated physiologic response to moderate stroking of skin Symptomatic: most common type of physical urticaria, linear wheals at sites of scratching or friction (collars, cuffs of shirts) O ften note pruritus even prior to appearance of w heals Often worse in the evening Lesions resolve within an hour Course is unpredictable but tendency toward improvement over several years No association with systemic disease, atopy, food allergy or autoimmunity 7 Delayed Pressure Urticaria Characterized by delayed development (30m- 12h) of deep, pink/red, edematous plaques at site of sustained skin pressure Waistline, ankles, feet d/t tight clothing; palms & soles after manual labor/walking/climbing; genitalia after intercourse Can be pruritic, painful or both Lesions can persist for several days Can have malaise/flu-like symptoms and joint pains Prognosis is variable Mean duration 6-9 years 8 Cold Urticaria H eterogeneous group of conditions characterized by w healing occurring w ithin m inutes of rew arm ing after cold exposure P rim ary ≥ 95% of cases Most commonly idiopathic C a n fo llo w U R I, a rth ro p o d a s s a u lt, H IV in fe c tio n Often relate onset relative to changes in temperature, not absolute temperature Can develop flushing, HA, syncope, abdominal pain if large body areas involved Must avoid cold baths/swimming as they can induce anaphylaxis Mean duration 6-9 years Diagnosis w ice-cube test S econdary Due to cryoproteinemia (cryoglobulins, cryofibrinogens) Rare, associated w Raynaud phenomenon or purpura R eflex Generalized cooling of the body induces widespread whealing Negative ice-cube test Fam ilial Familial cold autoinflammatory syndrome 9 3  1/27/25 Cholinergic Urticaria Characterized by symmetric, multiple, transient, papular (2-3 mm) wheals w obvious flare occurring within 15 minutes of sweat-inducing stimuli More common in young adults w atopic diathesis; rare in elderly Pruritus often precedes development of wheals Most prominent on upper half of body Can have angioedema and/or systemic symptoms (faintness, HA, palpitations, abd pain, wheezing) Gradual tendency toward improvement over years 10 Cholinergic Urticaria - DDx Exercise-induced anaphylaxis Same appearance as clinical urticaria but only appears after exercise (not after other increases in temperature, i.e. hot bath) Food- and Exercise-induced anaphylaxis: rare subtype where ingestion of certain foods prior to exercise induce skin eruption Adrenergic urticaria Blanched vasoconstricted skin surrounding pink wheals induced by sudden stress P ale w heals w pink halo seen in typical urticaria/cholinergic urticaria 11 Solar Urticaria Pruritus and whealing within 5-10 minutes of sun exposure, limited to sun-exposed areas, that resolves over 1-2 hours Upper chest and extensor arms commonly affected Triggers: visible light > UVA, (rarely UVB) Often have accompanying burning sensation “Hardening” occurs in some Phototesting to diagnosis Resolution in 15% at 5 years, 25% at 10 years 12 4  1/27/25 13 14 15 5  1/27/25 Erythema Multiforme Mucocutaneous immune reaction in the Typical target lesions: regular round shape setting of an infection in a predisposed w well-defined border and three distinct individual zones—central dusky zone, edematous pale ring and surrounding macular Usually seen in young adults erythema Precipitating factors: Favor face and distal extremities Infection (~90%): HSV 1/2 (most common), ± atypical papular “targetoid” lesions mycoplasma pneumoniae, etc. Pruritus and/or burning often described Rarely drugs or systemic diseases Lesions appear within 24 hours of onset Triggers: and full development by 72 hours Trauma, cold, UV exposure Remain fixed for ≥ 7 days then heal w/o sequelae Minor vs Major Typical episodes last ~2 weeks Recurrence is common 16 17 Erythema Multiforme - Minor Herpes-associated EM most common cause Herpes labialis outbreak typically precedes EM by 1-3 weeks Absent or mild mucosal involvement No systemic symptoms 18 6  1/27/25 Erythema Multiforme - Major Mycoplasma pneumoniae most common cause HSV also common cause Significant mucosal involvement Vesiculobullous lesions on buccal mucosa and lips à rapidly evolve to painful erosions w crusting Ocular and genital mucosa less commonly involved Almost always have concurrent fevers, fatigue Sometimes have joint pains 19 Reactive Infectious Mucocutaneous Eruption (RIME) Associated w mycoplasma pneumoniae infection Usually children/adolescents Severe mucositis w minimal to no skin involvement Mucositis usually affects ≥ 2 locations Mucosal lesions are vesiculobullous à quickly rupture to lead to erosions/ulcerations w crusting Hemorrhagic crusting on lips characteristic Cutaneous lesions sparse and usually acrally distributed No target lesions as seen in EM 20 Erythema Multiforme - Treatment Treat precipitating factor, if identified (i.e. HSV, mycoplasma) Antiviral therapy has minimal impact if given after appearance of acute episode of EM Symptomatic treatment is mainstay Topical steroids or cutaneous and mucosal lesions PO steroids (~5 days) for more severe/symptomatic involvement Recurrent disease Valacyclovir 500-1000 mg/day --> decreases frequency and duration of outbreaks in 90% of HSV-associated cases 21 7  1/27/25 Drug Reactions 22 Drug Reactions Adverse drug eruptions (ADE) occur in 2-3% of hospitalized patients 55% able to definitely identify medication Simple exanthem (92%) > urticaria (6%) > vasculitis (2%) Severe cutaneous adverse reactions (SCARs) account for 2% Highest risk drugs (% that have drug eruption): Aminopenicillins 8% Anticonvulsants 5% Bactrim 4% NSAIDs 0.5% Risk factors: Immune dysregulation (HIV [esp. CD4 < 200], SLE, BMT) Concurrent viral illness Certain HLA types Treatment: withdrawal of medication 23 24 8  1/27/25 Morbilliform/Exanthematous Most common ADE Onset: 7-14 days after initiating medication Appears earlier if rechallenge Symmetric erythema w small papules Starts in intertriginous areas (groin/axilla) and generalizes over 1-2 days No mucosal involvement; no facial edema Prominent pruritus, ± low-grade fever Most common culprits: Penicillin & Bactrim (#1) AIDS patients receiving Bactrim – 40% develop morbilliform eruption Ampicillin/amoxicillin in EBV Anticonvulsants & allopurinol also common Treatment: supportive Can treat through if medication is needed 25 26 Urticaria & Angioedema Second most common ADE Angioedema due to ACEi (lisinopril, enalapril > captopril) Usually starts within 1 week of initiating medication, but can appear after months Appears to be dose-dependent IMMUNOLOGIC NON-IMMUNOLOGIC Penicillin and related beta-lactam Aspirin, NSAIDs most common antibiotics Increased rate of reaction to cephalosporins 27 9  1/27/25 28 Fixed Drug Eruption Onset: 1-2 weeks after first drug exposure 30m-8h in previously exposed Red round/oval patches à develop dusky, intensely inflamed central portion ± bulla or erosion à prolonged post-inflammatory hyperpigmentation Usually ≤ 6 lesions, often just one Half of lesions occur on the genital mucosa Refractory period (weeks/months) where lesion will not recur Continued exposure à development of more lesions Can result in generalized (bullous) fixed drug eruption à similar mortality to SCARs Most common causes: NSAIDs (naproxen), Bactrim, tetracyclines, aspirin, OCPs 29 FDE – Non-Pigmenting Variants Large, tender, erythematous plaques Can mimic cellulitis Pseudoephedrine common cause Symmetric drug-related intertriginous and flexural exanthem (SDRIFE) AKA “Baboon syndrome” Buttocks, groin, axilla w symmetric erythematous, fixed plaques Antibiotics most common cause, esp. penicillin 30 10  1/27/25 Vancomycin Infusion Reaction AKA “Red Man Syndrome” IV vancomycin à direct toxic effect on mast cells à rapid degranulation Macular erythema on back of neck à spreads to upper trunk, face and arms ++Pruritus ±hypotension Treatment: Antihistamines, topical steroids for symptomatic relief Slow down infusion rate and premedicate w antihistamine to prevent recurrence 31 32 Photosensitivity Reactions Usually due to UVA exposure Phototoxic vs photoallergic Phototoxic: no sensitization needed; occurs immediately after exposure to UV radiation Dose-dependent (increase drug levels and/or increased UVR exposure) Looks like exaggerated sunburn in exposed areas à prolonged post- inflammatory hyperpigmentation Common culprits: doxy/minocycline, NSAIDs, HCTZ, voriconazole, quinoles, amiodarone Treatment: supportive and improved photoprotection Photoallergic: prior sensitization required (involves immune system); reaction occurs weeks to months after drug exposure Idiosyncratic reaction Resemble eczematous dermatitis and/or lichen planus in sun-exposed areas More chronic than phototoxic reactions; can persist for months even after culprit drug is stopped Common culprits: drugs that contain a sulfur moiety (thiazide diuretics, sulfonamide antibiotics, sulfonylureas) Treatment: discontinue medication (due to risk of chronicity of rash and flare w low-dose UVR exposure) 33 11  1/27/25 34 Toxic Erythema of Chemotherapy Constellation of diseases caused by toxic effect of chemo on eccrine glands Develops 2-4 weeks after chemo à dysesthesias/tingling followed by painful, symmetric erythema and edema à can become dusky and desquamate Common causes: cytarabine, anthracyclines, taxanes, 5FU 35 36 12  1/27/25 Drug-Induced Hyperpigmentation Can be due to induction of melanin production or deposition of drug complexes in dermis Localized or generalized Can involve the skin, mucous membranes, teeth, hair and/or nails Numerous medications/drug classes are known to cause hyperpigmentation Notably: minocycline, antimalarials, chemotherapeutic agents, zidovudine 37 Severe Cutaneous Adverse Reactions (SCARs) 38 39 13  1/27/25 Anticoagulant-Induced Skin Necrosis Warfarin Develops 3-5 days after starting à antithrombotic protein C levels fall before clotting factors Red, painful plaques à large hemorrhagic bulla w necrosis Treatment: stop warfarin, give vitamin K, start LMW H Heparin-induced thrombocytopenia Antibody to platelet factor 4 à thrombocytopenia & platelet clotting Local reactions at injection site most common: tender red plaques that undergo necrosis C an lead to diffuse/system ic clotting and be life-threatening Treatment: stop heparin, given direct thrombin inhibitor 40 41 Acute Generalized Exanthematous Pustulosis (AGEP) Onset ≤ 4 days after drug initiation High fever and pinpoint non-follicular pustules on background erythematous skin starting on face/intertriginous sites à generalizes within hours à pustules coalesce to form “lakes of pus” à resolves of ~2 weeks w desquamation Edema of face/hands common +leukocytosis w neutrophilia (90%), eosinophilia (30%) Common culprits: beta-lactams, macrolides, diltiazem, antimalarials Potential complications: high-output cardiac failure, AKI, hypocalcemia Treatment: topical steroids 42 14  1/27/25 43 Drug Reaction with Eosinophilia & Systemic Symptoms (DRESS) A K A drug-induced hypersensitivity syndrom e (D IH S ) O nset 2-6 w eeks after initiating drug D iffuse m orbilliform rash (75% ) w follicular accentuation, fever (85% ) and m ultiorgan involvem ent Rash starts on face/upper trunk and disseminates; facial edema Liver most commonly involved (primary cause of mortality) followed by kidney Peripheral eosinophilia, lymphocytosis/atypical lymphocytes C om m on culprits: arom atic anticonvulsants (phenytoin, carbam azepine, phenobarbital), sulfonam ides, m inocycline, dapsone, allopurinol, abacavir, nevirapine C an use R egiS C A R to help diagnosis C om plications: Acute: hepatitis, interstitial nephritis, pneumonitis, myocarditis Delayed: thyroiditis/Graves’ syndrome, SIADH, myocarditis, DM P rognosis: m ortality 5-10% Poor prognosis: tachycardia, leukocytosis, tachypnea, coagulopathy, thrombocytopenia, GI bleeding Treatm ent: high-dose P O steroids tapered over m onths to prevent relapse 44 45 15  1/27/25 46 Stevens-Johnson Syndrome (SJS) – Toxic Epidermal Necrolysis (TEN) Spectrum of disease SJS: < 10% BSA; SJS/TEN overlap: 10-30% BSA; TEN: > 30% Occurs 7-21 days after drug initiation Prodrome of fever/malaise à atypical targetoid macules, mucocutaneous erythema & skin pain à dusky plaques w skin and mucosal sloughing Mucosal involvement always present (usually ≥ 2 sites) Skin lesions usually appear on trunk first then generalize End-organ damage common Common culprits: allopurinol, anticonvulsants (lamotrigine, carbamazepine, phenytoin, phenobarbital), sulfonamides, abacavir, nevirapine 47 Stevens-Johnson Syndrome (SJS) – Toxic Epidermal Necrolysis (TEN) Complications: Mostly due to scarring in cutaneous and mucosal sites Ocular sequelae most common (up to 80%) Dry eye syndrome (most common), scarring, entropion, blindness Phimosis, vaginal synechiae, nail dystrophy/loss, alopecia Prognosis: Correlated w rapidity of drug discontinuation Mortality: SJS: < 5%; TEN: 30% SCORTEN system can help predict mortality (must be done on hospital day 1 & 3) Death is most commonly due to infection (staph aureus & pseudomonas) Treatment: Rapid withdrawal of causative medication can decrease risk of death by 30% per day Cyclosporine, etanercept, IVIG, systemic steroids Admit to burn unit for intensive supportive skin regimen, nutritional/electrolyte management and secondary infection monitoring Urgent consult to ophthalmology, urology/gynecology 48 16  1/27/25 49 17