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Part II: Contact Dermatitis & Drug Eruptions
Andrew’s Chapter 6 JoAnne M.LaRow, D.O.
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Drug Reactions Adverse reactions occurs at low rate- 1/1000 exposures
Except for commonly used meds-semisynthetic penicillins and sulfamethoxazole/trimethoprim – 30-50/1000 Presence of HIV disease or EBV infection increases rate One of the most common reasons pts visit dermatologist
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Pt evaluation Three rules: 1.) stop all unnecessary meds
2.) ask about nonprescription meds and meds delivered by other means-suppositories,eye drops, implants, patches, etc 3.) no matter how atypical the presentation always consider pts meds as a possible cause Diagnose cutaneous eruption by clinical pattern(ie urticaria, exanthem, vasculitis, erythema multiforme, etc) Ask two questions: 1.) which med can cause this pattern of rxn? 2.) how commonly does this med cause this rxn pattern?
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Additional testing? Skin testing is most useful in evaluating type I (immediate) hypersensitivity Skin testing is most frequently used in evaluating adverse rxn’s to penicillin, local anesthetics, insulin, and vaccines Radioallergosorbent (RAST) tests have 20% false-neg rate in penicillin type I allergy Therefore RAST must be followed by skin testing RAST test cannot replace skin testing
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Pathogenesis The pts metabolism of medication may determine the likelihood of a rxn occurring As in anticonvulsant and sulfonamide rxn’s, the P-450 system of individuals generates toxic metabolites of the med that binds to proteins and stimulates an immunologic rxn This defect can be found in family members and is linked to HLA subtypes Immune status and clinical condition may be a factor- AIDS pts-may be related to glutathione deficiency In most patterns pathogenesis is UNKOWN!! Drug rxn’s are often nonimmunologic May result from normal pharmacologic effects of drug- ie urticaria worsening from aspirin ingestion Rxn’s may be immunologic, based on an immune response by the pt to the drug or its matabolite
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Exanthems Commonest form of adverse cutaneous eruption
Characterized by erythema, often with papules throughout Tend to occur within the first two weeks of tx, but may occur later, even up to 10 days after tx Lesions first appear proximally-especially groin and axilla, generalizing within 1-2 days Pruritus is usually prominent-a distinguishing factor from a viral exanthem Exanthems Most common cause of this rxn pattern-antibiotics, especially semi-synthetic penicillins & sulfamethoxazole/trimethopirm Ampicillin given during infectious mononucleosis and Bactrim given to AIDS pts cause exanthems in a large # of pts treated Morbilliform rxn’s to amoxicillin are likely mediated by helper T cells similar to ACD and tuberculin rxn’s
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Exanthems Morbilliform drug eruption caused by sulfonamide
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Exanthems
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Treatment Simple exanthems-supportive tx
Eruption may resolve even if offending med is continued Topical steroidal medications and antihistamines may allow course of tx to be completed Rechallenge may or may not result in reappearance of eruption In HIV infection and rarely, in persons with normal immune status rechallenge may result in a more severe blistering rxn Treatment Complex exanthems or hypersensitivity syndromes are seen mostly with anticonvulsants, and long-acting sulfonamides; less commonly with allopurinol, gold, dapsone, and sorbinil These present with fever, rash, and variably , with eosinophilia, lymphadenopathy, hepatitis, nephritis, and rarely heart, lung & brain
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Anticonvulsant Hypersensitivity Syndrome
Can be seen with-diphenylhydantoin, phenobarbital, carbamazepine, and other anticonvulsants Eruption may occur in as many as 1 of 5000 pts tx with these meds Skin eruption is typically initially morbilliform, but may have various morphologies in different pts at different times Histologic picture is compatible with clinical morphology Syndrome begins with fever between 2 and 6 weeks after agent is started Eruption begins with prominent facial swelling
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Anticonvulsant Hypersensitivity Syndrome
Associated findings: pharyngitis, lymphadenopathy, hepatosplenomegaly Lab abnormalities: eosinophilia, atypical lymphocytosis, elevated liver function tests, and occasionally nephritis Untreated pts can lead to death from hepatitis Pathogenesis is an inability to detoxify arene oxide metabolites of these meds Metabolites bind to proteins and elicit an immune response leading to an adverse drug rxn Cross-rxn with different anticonvulsants are common (because meds are metabolized by same pathway)
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Management Ruling other infectious etiologies
Discontinue offending med Supportive tx If liver or renal involvement or pt is ill requires hospitalization, systemic steroids may be used
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Sulfonamide Hypersensitivity Syndrome
Clinical syndrome similar to anticonvulsants Pts develop severe bullous rxn like Stevens-Johnson syndrome or TEN Pts with this are almost always slow acetylators who produce toxic hydroxylamine metabolites during metabolism of the sulfonamide
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Allopurinol Hypersensitivity Syndrome
Associated with the dermatitis is fever, eosinophilia, sometimes hepatitis, and typically worsening renal failure Syndrome may be steroid responsive, but is slow to resolve Frequently lasts months after allopurinol has been stopped About 25% of pts die as a consequence Dialysis does not accelerate resolution of this syndrome- Typically occurs in pts with preexisting renal failure, whose dose is not adjusted for their renal function Weeks to months (average 7 weeks) after allopurinol is begun, a morbilliform eruption (50%) that often evolves to an exfoliative erythroderma(20%) Bullous eruptions including TEN’s may occur(25%) may occur
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Exfoliative dermatitis caused by allopurinol
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Drug-Induced Pseudolymphoma
T-cell receptor gene rearrangements in skin and blood may be positive in these drug-induced cases More rarely, meds may induce plaques or nodules, usually in elderly white men after months of tx Lymphadenopathy and circulating Szary cells may also be present Pseodolymphoma resolves with discontinuation of the med Primary meds responsible:anticonvulsants, sulfa drugs, dapsone, and antidepressants Drug-Induced Pseudolymphoma True pseudolymphoma rxn’s are rare Histology must be consistent with the diagnosis of lymphoma Exposure to a med will result in cutaneous inflammatory infiltrates that resemble lymphoma Most frequently MF Usually other features like keratinocyte necrosis and dermal edema help to distinguish these rxn’s from true lymphoma
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Urticaria
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Urticaria
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Urticaria Secondary to amoxicillin
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Urticaria Aspirin and nonsteroidal anti inflammatory drugs are the most common cause of nonimmunologic urticarial rxn’s They alter prostaglandin metabolism, enhancing degranulation of mast cells They may also exacerbate chronic urticaria of other causes Nonacetylated salicylates(Trisisate and salsalate) do not cross- react with aspirin in pts experiencing bronchospasm and may be safe alternatives Meds may induce urticaria by immunologic and nonimmunologic mechanisms Clinically lesions are wheals or angioedema Urticaria may be part of a more severe anaphylactic rxn with bronchospasm, laryngospasm, or hypotension Immediate hypersensitivity skin testing and sometimes RAST tests are useful in evaluating risk for these patterns of rxn
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Immunologic urticaria is most commonly associated with penicillin and related beta-lactam antibioics
It is associated with IgE antibodies to penicillin or its metabolite Skin testing is useful in evaluating pts with a history of urticaria associated with penicillin exposure If pt is positive , an alternative antibiotic must be considered , or pt may be given a desensitization protocol Most pts with a history of penicillin “ allergy”are skin test neg These pts ca be tx with a low liklihood of a severe adverse event Pts with pen allergy have an increased rate of rxn to cephalosporins Third-generation cephalosporins are much less likely to induce a rxn in a pcn allergic pt than the first- or second generation ones In the case of Cefaclor, half of ana phylactic rxn’s occur in pts with a history of pcn allergy
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Angioedema is a known complication of the use of ACE inhibitors
Blacks are nearly five times greater risk than whites Lisinopril and enalapril produce angioedema more commonly than captopril Episodes may reqire hospitalization 45% of the time, ICU 27% of the time, and intubation 18% of the time One quarter of pts give a history of previous angioedema Captopril enhances the flare rxn around wheals Angioedema is dose dependent, as it may resolve with decreased dose These factors suggest that the angioedema may represent a consequence of a normal pharmacologic effect of the ACE inhibitors Blocking of kininase II by ACE inhibitors may increase tissue kinin levels, enhancing urticarial rxn’s and angioedema Although dose dependent, ACE inhibitor users with one episode of angioedema have a ten-fold risk of a second
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Angioedema
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Angioedema
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Photosensivity Reactions
Meds may cause phototoxic (sunburn-like) reactions, lichenoid reactions, pseudoporphyria Most drug-induced photosensitivity is triggered by radiation in the UVA range Most common drugs implicated are: NSAIDs, sulfamethoxazole/trimethoprin, thiazide diuretics and related sulfonylureas, quinine and quinidine, and certain tetracyclines Phototoxic reactions are related to dose of both med and UV irradiation Does not require prior exposure or participation by the immune system Rxn’s can appear from hrs to days after to exposure Tetracyclines(especially demeclocyline), amiodarone, and the NSAIDs are common culprits Ts may include dose reduction and photoprotection
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Amiodarone photosensitivity develops in 75% of tx pts, and occurs after a cummulative dose of 40g
A reduced MED to UVA, but not UVB occurs, and gradually returns to normal between 12 and 24 months after stopping the med Stinging and burning may occur as soon as a half hr after sun exposure Clinically a dusky, blue-red erythema of face and dorsa of the hands is most common, but a papular rxn has been seen Photoallergic reactions are typically eczematous, pruritic, and occur after some period of drug exposure They involve the immune system, and are confirmed by positive photopatch testing In general, they are not as drug dose dependent as phototoxic reactions Photosensivity both of the phototoxic and photoallergic types may persist for some time after the med has been d/cd
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Desquamation, as seen following sunburn, is NOT observed following amiodarone photosensitivity rxn’s
NSAIDs, especially piroxicam are frequently associated with phototsensitivity Characteristic rxn is a vesicular eruption of dorsa of hands, sometimes associated with dyshidrosiform pattern on the lateral aspects of hands and fingers Pts with photosensitivity to piroxicam react on initial exposure to the med These pts also react to thiosalicylic acid, a common sensitizer in thimerosal Half of pts having a positive patch test result to thimerosal with no prior exposure to piroxicam are photopatch test positive to piroxicam This suggests that piroxicam rxn’s seen on initial exposure to the med may be related to prior sensitization during thimerosal exposure
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Photodistributed kichenoid rxn’s have been reported with thiazide diuretics, quinide, and NSAIDs
They present with erythematous patches and plaques Sometimes, typical Wickham’s stria are observed in the lesions Histologically, photodistributed lichenoid rxn’s are often indistinquishable fron idiopathic lichen planus Sulfonamide antibiotics, related hypoglycemic agents, and the sulfonylurea diuretics may all be associated with photoallergic rxn’s These agents may all cross-react Also, pts may tolerate one of these meds, but when another member is added, clinical photosensitivity occurs Typical pattern is: erythema, scale, and in chronic cases, lichenification and hyperpigmentation
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Photoallergic Reactions
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Other meds causing similar bullous rxn’s are: tetracycline, furosemide, nalidixic acid, dapsone, nabumetone, and pyridoxine Histologically, a pauci-inflammatory subepidermal vesicle is sen DIF may show IgG and complement deposition at the d-e junction and perivascularly, as seen in PCT The histo picture resembling “cell poor” pemphigoid has resulted in these rxn’s being reported as drug induced pemphigoid Pseudoporphyria is a photodistributed bullous rxn clinically and histologically resembling porphyria cutanea tarda Hypertrichosis, skin fragility, dyspigmentation, and sclerodermoid changes are not seen Porphyrin studies are normal and the rxn resolves on discontinuation of provoking med Naproxen is most commonly reported cause
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Anticoagulant-Induced Skin Necrosis
Both warfarin and heparin induce lesions of cutaneous necrosis, but by different mechanisms Obese, postmenopausal women are predispoded secondary to the fact that lesions tend to occur in areas with abundant subcutaneous fat(breast, abdomen, or buttocks) Warfarin necrosis occurs 3 –5 days after therapy is begun(the higher the initial dose, the higher the risk) Lesions begin as red, painful plaques that become necrotic Hereditary or acquired deficiency of protein C and less commonly protein S is associated Persons are usually aysmptomatic heterozygotes with protein C deficiency
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Warfarin-induced necrosis
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1-2 weeks after injection of vitamin K, an allergic reaction at the injection site may occur
Most affected pts have liver disease & are being tx for elevated PPT’s Lesions are pruritic, red plaques-deep-seated involving the dermis and subcutaneous tissue Occur most frequently on posterior arm and over hip or buttocks Plaques on hip tend to progress around the waist and down thigh, forming a “cowboy gunbelt & holster” pattern Vitamin K Reactions Generalized eczematous small papules may occur on other skin sites in severe rxn’s Rxn’s usually persist for 1-3 weeks or may be longer, they may resolve and reoccur On testing, pts are positive on intradermal testing to vit K, not to components of the material In Europe, another pattern of vit K has been reported-subcutaneous sclerosis with or without fasciitis appears at the site many months later
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Allergic reaction at site of vitamin K injection
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Injection Site Reactions
IM injection may produce a syndrome called-embolia cutis medicamentosa or Nicolau syndrome Immediately after injection there is a local intense pain, and ischemic palor Within mins-hrs site develops an erythematous macule that evolves into a livedoid violaceous patch with dendrites This becomes hemorrhagic, then ulcerates, and eventually heals with an atrophic scar Cutaneous necrosis may occur at sites of med injections Two types: 1.) those associated with IV infusions 2.) those related to IM injections
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Rarely surgical intervention is needed
Muscle and liver enzymes may be elevated, and neurologic symptoms and sequela occur in a third of pts Circulation of the limb may be affected, rarely leading to amputation Syndrome appears to be related to periarterial injection leading to arterial thrombosis Tx-conservative-dressing changes, debridement, bed rest, and pain control Rarely surgical intervention is needed
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Cutaneous reaction to IV infusion and extravasation of chemotherapeutic agent
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Acute Generalized Exanthematous Pustulosis
90% of time is related to medication Not uncommon Sudden onset on eruption an average of 5 days after med is started- about 50% of cases occur within the first 24 hrs Mercury is sole cause in 13% of cases in France, beta-lactams in 44%, and macrolides in 17% Sulfonamides have NOT been reported to cause this rxn 17% of pts have a h/o psoriasis Course and evolution are different from true pustular psoriasis, although pts with psoriasis may be at increased risk for this form of drug rxn
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Initially there is a scarlatiniform erythema
Eruption evolves and disseminates rapidly, consisting of usually more than 100 nonfollicular pustules less than 5 mm in diameter Widespread desquamation occurs after a few days Edema of face, purpura, and target lesions may appear in the background Mucous membranes are involved in 22% Fever is universal Neutrophilia in 90%, and eosinophilia in 30% Once inciting agent is discontinued or removed, eruption usually resolves within 15 days without sequelae Patch tesing with the suspected agent may reproduce a pustular eruption on an erythematous base at 48 hrs
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Histology Early lesions show marked papillary edema, neutrophil clusters in dermal papillae, and perivascular eosinophils May be an associated leukocytoclastic vasculitis Well developed lesions show intraepidermal or subcorneal spongiform pustules If there is a background of EM clinically, the histology of EM may be superimposed Presence of eosinophils, and marked papillary edema help to distinguish this eruption from pustular psoriasis
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Drug-Induced Pigmentation
Chloroquine, hydroxychloroquine, and quinacrine all may cause a blue-black pigmentation of face, extremities,ear cartilage, oral mucosa, and nails Pretibial hyperpigmentation is most common Quinidine may also rarely cause this pattern Quinacrine is yellow and is concentrated in epidermis Generalized yellow discoloration of skin and sclera Postinflammatory hyperpigmentation or actual deposition of drug in skin Minocycline causes three types of pigmentation: 1.) blue-black discoloration in areas of prior inflammation(not rel ated total or daily dose exposure) 2.)appearance of a similar-colored pigmentation on normal skin of anterior shims(is dose dependent) 3.) least common-total generalized, muddy brown hyperpigmentation,
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Amiodarone after 3-6 months causes photosensitivity in 30-57% of pts tx
1-10% of pts a slate-gray hyperpigmentation develops in areas of photosensitivity Pigmentation fades after med is discontinued Clofazimine tx reproducibly causes a pink discoloration that gradually becomes reddish blue or brown concentrated in lesions of Hansen’s disease This pigmentation is disfiguring and a major cause of noncompliance Zidovudine causes a blue or brown hyperpigmentation most frequently in nails Lunula may be blue, or whole nail plate may be dark brown Diffuse hyperpigmentation of skin, pigmentation lateral tongue, and increased tanning are less common Occurs in darkly pigmented pts, is dose dependent, clears after med discontinued
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Purple pigmentation in patient who had been on high doses of chlorpromazine
There is sparing of deep creases of the face
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Chlorpromazine, thioridazine, imipramine, and clomipramine may cause a slate-gray hyperpigmentation in sun-exposed areas after long periods of ingestion Frequently, corneal and lens opacities are present Therefore all pts with hyperpigmentation from these meds should have ophthalmologic exam Pigmentation from phenothiazines fades gradually over yrs Corneal, but not lenticular changes resolve Heavy metals gold, silver, and bismuth produce blue to slate-gray hyperpigmentation Pigmentation occurs after yrs of exposure, mainly in sun-exposed areas It is permanent Bismuth also pigments gingival margin Arsenical melanosis is characterized by black, generalized pigmentation or by pronounced truncal hyperpigmentation that spares the face
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Fixed Drug Reactions Common
Named such because they recur at same site with each exposure to med Six or less lesions occur; frequently only one Present anywhere on body(50% occur on oral and genital mucosa) Represent 2% of all genital ulcers evaluated at clinics for STD’s Clinically begin as a red patch that soon evolves to an iris or target lesion identical to EM Eventually may even blister and erode Lesions of oral mucosa and genitalia usually present as erosions Characteristically, prolonged or permanent postinflammatory hyperpigmentation results
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Fixed Drug Eruption
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Unknown pathogenesis Persons with fixed drug eruptions to pyrazole derivatives are much more likely to be HLA-B22 pos Occasionally fixed drug rxn’s do not result in long-lasting hyperpigmentation The so-called nonpigmented fixed drug eruption is distinctive It is characterized by large, tender, often symmetrical erythematous plaques that resolve completely within weeks, only to recur on reingestion of offending drug Meds inducing fixed drug eruptions are usually those taken intermittently Many NSAIDs, especially pyrazolone derivatives, naproxen, mefenamic acid; sulfonamides, trimethoprim, or combination are responsible mainly Barbiturates, tetracyclines, phenolphthalein(in laxatives), and erythromycin
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Pseudoephedrine hydrochloride is by far most common culprit of nonpigmented fixed drug eruption
There is the so-called “baboon syndrome” where the buttocks, groin, and axilla are preferentially involved in this category
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Bullous Drug Reactions
Skin blistering may complicate drug rxn’s in numerous ways The term bullous drug reaction most commonly refers to a drug rxn in the EM group Uncommon per million person for TEN a & 1.2 to 6.0 per million person yrs for Stevens-Johnson syndrome drug-induced EM is usually more extensive than that induced by infectious agents Exact definitions of SJS and TEN remain arbitrary as a result of overlap in some cases SJS < 10% of body surface area involved, cases with 10-30% are overlap cases, and 30% involvement is TEN Others classify: SJS as cases that begin with skin pain and simple erythema rapidly followed by skin loss
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EM & SJS &TEN Although definitions remain controversial, SJS and TEN are probably a disease spectrum based on the following: most commonly induced by the same meds; pts initially presenting with SJS may progress to extensive skin loss resembling TEN; histology is indistinguishable; both are increased by same magnitude in HIV infection; identical metabolic abnormalities are identified in cases induced by sulfonamides or anticonvulants > 100 meds have been reported as a cause Most common:trimethoprim/sulfamethoxazole(1-3/100,000), Fansidar-R, sulfadoxine pluspyrimethamine(10/100,000), and carbamazepine(14/100,000) Antibiotics(especially long-acting sulfa drugs and penicillins), other anticonvulsants, antiinflammatories, and allopurinol are also causes
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Fever and influenza-like symptoms often procede the eruption
Skin lesions appear on face and trunk and spread rapidly (within 4 days) to their maximum extent Initial lesions are macular and remain so, followed by desquamation, or may form atypical targets with purpuric centers that coalesce, form bullae, the slough Virtually always more than two mucosal surfaces are also eroded, the oral and conjunctiva being most frequently affected There may be difficulty with swallowing, photophobia, painful urination, and extensive respiratory and alimentary tract involvement Skin bx usually performed to exclude other diseases Independent of extent of slough, clinical morphology or the clinical diagnosis the histology is alike Paraneoplastic pemphigus also shows changes of EM and must be excluded with DIF Pts with graft-versus host disease may also be alike
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Histology A lymphocytic infiltrate at the D-E junction
Necrosis of keratinocytes that may be full thickness Infiltrate may be marked or very scant
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Histology Subepidermal separation Full thickness epidermal necrosis
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Management One recent report of IVIG in 10 pts in doses up to 0.75 g/kg/day for 4 days led to response in 48 hrs and skin healing within 1 week No adverse rxn’s where observed MOA of IVIG in this condition was blocking apoptosis through blockade of the death receptor FAS(CD 95) Immunsuppressive therapy is very controversial Similar to an extensive burn They suffer fluid and electolyte imbalances, bacteremia from loss of protective skin barrier, hypercatabolism, and sometimes ARDS Survival is improved if tx in a burn unit Pts who are very ill or have > 30%- 50% loss of epidermis should be transferred to burn unit
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Benefit of immunosuppresives is to stop the process very quickly to reduce the ultimate amount of skin lost Once most of skin loss has occurred, immunosuppresives only add to morbidity and perhaps mortality If considering immunosuppressive therapy it should be done quickly, in adequate doses, given a short trial to see if the process can be arrested, and then tapered rapidly As with burns, the host’s age, severity of underlying disease, and extent of skin loss are the most important factors determining the outcome rather than the use of immunosuppressive agents In pts who survive, the average time for epidermal regrowth is 3 weeks Most common sequelae are ocular scarring and vision loss A sicca like syndrome may also result
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EM
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Erythema multiforme bullosum
Note predilection for arms, sparing the trunk unlike
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EM/TEN/SJS
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TEN Desquamation in sheets-leaving raw, red surface
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SJS
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Radiation-Induced EM Erythema and edema initally on the head in the radiation ports, as dose of steroids is being reduced Evolves over 1-2 days to lesions clinically and histologically similar to EM Eruption spreads caudad and mucosal involvemant may occur Can rarely be seen with radiation therapy alone, but is more common if phenytoin is administered Occurs if phenytoin is given prophylactically in neurosurgical pts who are receiving whole-brain radiation therapy and systemic steroids
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Urticarial EM Unusual rxn virtually always associated with antibiotic ingestion Skin lesions consist of urticarial papules and plaques, some of which clear centrally forming annular lesions,but no true iris lesions Lesions can be distinguished from true urticaia in that they are fixed for days Pruritis is common Bullae are absent, and mucous membranes are uninvolved Rarely, hypotension may occur Histologically, there is a superficial and deep dermal infiltrate containing eosinophils with dermal edema Epidermis is not involved Response to systemic steroids is dramatic, with clearing in hrs
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HIV Disease and Drug Reactions
If dermatitis is tx limiting, but eruption is not life threatening, low-dose rechallenge/desensitization may be attempted It is successful in 65%-85% of pts short term, and >50% long term Most rxn’s occur in first few days of rechallenge, adverse rxn’s may appear months after restatring drug MOA?? Many AIDS pts are slow acetylators Severe bullous rxn’s-SJS, TEN are times more common HIV-infected pts, especially those with helper T-cell counts between 25 and 200, are at increased risk for development of adverse rxn’s to meds Morbilliform rxn’s to Bactrim occurs in 45%of AIDS pts Associated hepatitis or neutropenia may require discontinuation of drug A similar increased risk is seen in HIV pts receiving Augmentin
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Adverse Reactions to Chemotherapeutic Agents
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Radiation Enhancement &Recall Reactions
Radiation dermatitis in form of intense erythema and vesiculation may be observed in radiation ports Administration of many chemotherapeutic agents, during or in close proximity to time of radiation therapy, may enhance this rxn It is termed “radiation recall” because it may occur a week or more after radiation therapy A similar rxn of reactivation of a sunburn after methotrexate therapy also occurs This probably represents synergistic toxicity reactions
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Chemo-induced acral erythema
Common syndrome induced most frequently by 5-florouracil, doxorubicin, cystosine arabinoside Rxn may occur in as many as 40% of tx pts Rxn is dose dependent May appear with bolus short-term infusions or low-dose, long-term infusions May present weeks to months after tx’s are started May present days to months after treatments are started Likely a direct toxic effect of chemotherapeutic agents on the skin Large number of sweat glands on the palms and soles that may concentrate the chemotherapeutic agent explaining the localization of the toxicity
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Blisters developing over pressure areas is a variant
Pts usually recover without complications Although rarely, full thickness ischemic necrosis occurs in areas of blistering Histology is nonspecific Most cases require only local supportive care Cold compresses and elevation are helpful; cooling of hands during tx may reduce severity of rxn Modification of dose decreases the pain of fluorouracil induced syndrome Initial manifestation is often dysesthesia or tingling of the palms and soles This is followed by painful, symmetric erythema and edema most pronounced over the distal pads of the digits Rxn may spread to dorsal hands and feet & may be accompanied by a morbilliform eruption Erythema becomes dusky develops areas of pallor, blisters, desquamates, then reepithelializes Dequamation is often prominent
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Neutrophilic Eccrine Hidradenitis
Clinical lesions are nonspecific Bx performed to exclude infection Histology-a neutrophilic infiltrate involving glandular and ductal portions of the eccrine gland May be necrosis of eccrine unit, and in later bx’s syringometaplasia Skin lesions resolve in 10 days, but in severe cases may be tx with corticosteroids Most cases occur in neutropenic pts with malignancies, usually AML Occurs in children and adults-most commonly associated with chemo, especially cytoarabine Appears about after 7-10 days of tx Pts usually febrile Erythematous papules, plaques, or nodules localized to trunk, extremities, axillae, or pubic area, but may be generalized
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NEH
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Histology-NEH Infiltrate of inflammatory cells surrounding eccrine coils
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Chemotherapy-Induced Hyperpigmentation
Bleomycin and 5FU causes similar transverse bands Busulfan and 5FU in duiffuse hyperpigmentation that may be photoaccentuated Bleomycin induces characteristic flagellate erythmatous urticarial wheals associated with pruritis within hrs-days of infusion Fluorouracil causes a serpentine hyperpigmentation overlying veins of infusion Adriamycin causes marked hyperpigmentation of nails, skin ,tongue Most commonly seen in black pts Very similar to Zidovudine-associated pigmentation seen in pigmented persons Cyclophosphamide causes transverse banding of nails or diffuse nail hyperpigmentation
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Acrodynia Caused by mercury poisoning, usually in infancy
Skin changes are characteristic-almost pathognomonic Painful swelling of hands and feet Sometimes with pruritis Hands & feet are dusky red, pink, cold & clammy Erythema is usually blotchy but may be diffuse
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Acrodynia May be hypertension, hypertonia, anorexia, and insomnia
Erythema is blotchy but may be diffuse Hemorrrhagic puncta are sometimes evident Over trunk, a blotchy macular or papular erythema is usually present Stomatitis and loss of teeth may occur Constitutional symptoms consist of fever, irritability, photophobia, increased perspiration Always moderate upper respiratory inflammation and sore throat May be hypertension, hypertonia, anorexia, and insomnia Albuminuria and hematuria are usually present Diagnosis is made by finding mercury in the urine
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Etiology Broken thermometers Teething powders Poisoned fish
Broken phosphorescent bulbs ?Gas heaters
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Treatment Chelating agents -dimercaprol
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Bromoderma A thick inflammatory plaque, with pustules in its border, resembling blastomycosis, may also occur There is rapid resolution of lesions when bromide is stopped It may occur after a small dose or after protracted use of bromides A small child suffered fatal bromoderma as a result of one 50-mg dose of methacholine bromide by injection Bromides commonly produce distinctive follicular eruptions Most common is acneform-with inflammatory pustules in hairy parts of body and butterfly area of face(must be differentiated from rosacea) Vesicular lesions and bullae are common Nodular lesions with a violaceous color are mistaken for malignant lymphoma of skin
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Bromoderma Bromides are excreted in breast milk
No correlation seems to exist between plasma levels and the severity of cutaneous lesions Tx of bromoderma is simply cessation of bromide ingestion In acute intoxication 2 to 4 g of sodium chloride by mouth, taken daily, rapidly replaces the bromide in body fluids Ammonium chloride is also helpful In severe cases of intoxication in which the pt is badly confused, ethacrynic acid rapidly decreases the bromide level, with clearing of lesions
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Bromoderma
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Bromoderma Bromide eruption on shin; bullae and granulomas
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Iododerma Causes a wide variety of skin eruptions
Most common-acneiform eruption with numerous acutely inflammed follicular pustules, surrounded by a ring of hyperemia Bullous lesions are also common and may become ulcerated and crusted Pruitus and urticaria may be only manifestations of mild iodism Purpura, furnuncles, erythema multiforme, erythema nodosum, polyarteritis nodosa may also occur Swelling, redness, and scaling of eyelids occur Acne vulgaris and rosacea are worsened by iodine Treatment is same as bromoderma
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Iododerma Only brief duration distinguishes it clinically from basal cell carcinoma
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Iododerma
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Topical Corticosteroids
Prolonged exposure produces distinctive changes Appearance of these side effects depends on three factors: 1.) strength of steroid 2.) area to which it is applied 3.) the individual’s predisposition to certain side effects Atrophy, striae, telangiectasia, skin fragility, and purpura most frequent changes seen Most striking telangiectasias in fair-skinned individuals using fluorinated corticosteroids on the face Changes in skin are enhanced with occlusion
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When these side effects occur, reduce strength of steroid and add topicals like doxepin, pramoxine, or menthol and camphor Telangiectasiases usually disappear in a few months after corticosteroid applications are stopped When corticosteroid preparations are applied to face over a period of weeks to months, persist erythema with telangiectases may occur Perioral dermatitis and rocacea may occur Steroid rosacea has been reported from long-term use of 1% hydrocortisone cream
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Repeated application of corticosteroids to the face, scrotum or vulva may lead to marked atrophy of these tissues Tissue becomes “addicted” to the topical steroid, so that withdrawing it results in severe itching or burning Difficult to manage Best to apply judicious use of topical steroid preparations in these areas Topical applications can produce epidermal atrophy with hypopigmentation If used over a large area, sufficient topical steroids may be absorbed to suppress the hypothalamic pituitary axis May affect growth of children with atopic dermatitis and has led to Addisonian steroid dependency and also Cushing’s syndrome
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Paradoxically, topical corticosteroids may induce allergic contact dermatitis
Consider this complication in any pt with an eczematous dermatitis who becomes worse or is refractory to topical steroid tx Systemic corticosteroid administration may be tolerated, but in some pts there is a cross reaction manifested by whole-body allergic dermatitis Atopic children with more than 50% body surface area involvement have short stature This may be related to their increased use of potent topical steroids Bone mineral density is reduced in adults with chronic atopic dermatitis severs enough to require steroids stronger than hydrocortisone
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Side effects… Atrophy and purpura caused by prolonged applications of corticosteroid preparations
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Atrophy and fragility caused by chronic corticosteroid applications
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Injected Corticosteroids
Intralesional injection may produce subcutaneous atrophy at site of injection Injected steroid may migrate along lymphatics causing not only local side effects but linear atrophic hypopigmented hairless streaks These may take years to resolve To avoid these complications-inject directly into the lesion, not into the fat, and use only minimal concentration and volume Intramuscular steroid injections should always be given in the buttocks with a long needle (at least 1.5 inches in adults) Injection into deltoid muscle sometimes causes subcutaneous atrophy Pt becomes aware of rxn by noticing depression and depigmentation at injection site Pt can be assured that this will fill in but it may take several yrs
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Side effects corticosteriods:
Lipoatrophy of the buttock resulting from a corticosteroid injection
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Systemic Corticosteroids
Prolonged use may produce numerous changes of skin Have a profound effect on metabolism of many tissues, leading to preditable, and preventable complications Intramuscular injections are not a safer delivery method than oral administration Purpura or ecchymoses Cushingoid changes Steroid acne Striae Hair loss in 50% of pts Increased hair growth on bearded areas and arms, back(vellus hairs) HTN,aseptic necrosis of hip, osteoporosis
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How to combat side effects…
Bone loss can occur early in course of tx-so manage preemptively-supplement with calcium & vitamin D( g calcium and U of cholecalciferol daily) Stop smoking Decrease alcohol consumption Obtain bone mineral density at baseline (via DEXA scan) & throughout tx period (yrly?) Hypogonadism which contributes to osteoporosis can be treated in men and women with testosterone and estrogen respectively Calcitonin and bisphosphonates may be added to mangement as needed
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THE END- Thank you
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