Part II: Contact Dermatitis

1
Part II Contact Dermatitis Drug Eruptions

• Andrews Chapter 6
• JoAnne M.LaRow, D.O.

2
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

3
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?

4
Additional testing?

• Skin testing is most useful in evaluating type I
  (immediate) hypersensitivity
• Skin testing is most frequently used in
  evaluating adverse rxns 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

5
Pathogenesis

• The pts metabolism of medication may determine
  the likelihood of a rxn occurring
• As in anticonvulsant and sulfonamide rxns, 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 rxns are often nonimmunologic
• May result from normal pharmacologic effects of
  drug- ie urticaria worsening from aspirin
  ingestion
• Rxns may be immunologic, based on an immune
  response by the pt to the drug or its matabolite

6
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

• 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 rxns to amoxicillin are likely
  mediated by helper T cells similar to ACD and
  tuberculin rxns

7
Exanthems

• Morbilliform drug eruption caused by sulfonamide

8
Exanthems
9
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

• 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

10
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

11
Anticonvulsant HypersensitivitySyndrome

• 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)

12
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

13
Sulfonamide HypersensitivitySyndrome

• 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

14
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 TENs may occur(25)
  may occur

15

• Exfoliative dermatitis caused by allopurinol

16
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 responsibleanticonvulsants, sulfa
  drugs, dapsone, and antidepressants

• True pseudolymphoma rxns 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 rxns
  from true lymphoma

17
Urticaria
18
Urticaria
19
Urticaria

• Secondary to amoxicillin

20
Urticaria

• Aspirin and nonsteroidal anti inflammatory drugs
  are the most common cause of nonimmunologic
  urticarial rxns
• 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

21

• 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
  allergyare 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
  rxns occur in pts with a history of pcn allergy

22

• 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 rxns and angioedema
• Although dose dependent, ACE inhibitor users with
  one episode of angioedema have a ten-fold risk of
  a second

23
Angioedema
24
Angioedema
25
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
• Rxns 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

26

• 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

27

• Desquamation, as seen following sunburn, is NOT
  observed following amiodarone photosensitivity
  rxns
• 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 rxns seen on
  initial exposure to the med may be related to
  prior sensitization during thimerosal exposure

28

• Photodistributed kichenoid rxns have been
  reported with thiazide diuretics, quinide, and
  NSAIDs
• They present with erythematous patches and
  plaques
• Sometimes, typical Wickhams stria are observed
  in the lesions
• Histologically, photodistributed lichenoid rxns
  are often indistinquishable fron idiopathic
  lichen planus

• Sulfonamide antibiotics, related hypoglycemic
  agents, and the sulfonylurea diuretics may all be
  associated with photoallergic rxns
• 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

29
Photoallergic Reactions
30

• Other meds causing similar bullous rxns 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 rxns 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

31
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

32

• Warfarin-induced necrosis

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34
Vitamin K Reactions

• 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 PPTs
• 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

• Generalized eczematous small papules may occur on
  other skin sites in severe rxns
• Rxns 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

35

• Allergic reaction at site of vitamin K injection

36
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

37

• 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

38

• Cutaneous reaction to IV infusion and
  extravasation of chemotherapeutic agent

39
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

40

• 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

41
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

42
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,

43

• 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 Hansens
  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

44

• Purple pigmentation in patient who had been on
  high doses of chlorpromazine
• There is sparing of deep creases of the face

45

• 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

46
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 STDs

• 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

47
Fixed Drug Eruption
48

• Unknown pathogenesis
• Persons with fixed drug eruptions to pyrazole
  derivatives are much more likely to be HLA-B22
  pos
• Occasionally fixed drug rxns 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

49

• 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

50
Bullous Drug Reactions

• Skin blistering may complicate drug rxns in
  numerous ways
• The term bullous drug reaction most commonly
  refers to a drug rxn in the EM group
• Uncommon-0.4- 1.2 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 lt 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

51
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

• gt 100 meds have been reported as a cause
• Most commontrimethoprim/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

52

• 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

53
Histology

• A lymphocytic infiltrate at the D-E junction
• Necrosis of keratinocytes that may be full
  thickness
• Infiltrate may be marked or very scant

54
Histology

• Subepidermal separation
• Full thickness epidermal necrosis

55
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 rxns 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 gt 30- 50 loss of
  epidermis should be transferred to burn unit

56

• 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 hosts 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

57
EM
58

• Erythema multiforme bullosum
• Note predilection for arms, sparing the trunk
  unlike

59
EM/TEN/SJS
60
TEN

• Desquamation in sheets-leaving raw, red surface

61
SJS
62
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

63
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 48-72 hrs

64
HIV Disease and Drug Reactions

• If dermatitis is tx limiting, but eruption is not
  life threatening, low-dose rechallenge/desensitiza
  tion may be attempted
• It is successful in 65-85 of pts short term,
  and gt50 long term
• Most rxns occur in first few days of
  rechallenge, adverse rxns may appear months
  after restatring drug
• MOA?? Many AIDS pts are slow acetylators
• Severe bullous rxns-SJS, TEN are 100-1000 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 rxns
  to meds
• Morbilliform rxns to Bactrim occurs in 45of
  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 txs 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
  bxs 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

• 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 individuals 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 Cushings 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(1.0-1.5 g calcium and 400-800 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