1. Part II: Contact Dermatitis & Drug Eruptions
Andrew’s 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 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

5. 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

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
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

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
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

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 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)

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 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

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 TEN’s 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 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

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 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

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 “ 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

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 rxn’s 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
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

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 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

28. 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

29. Photoallergic Reactions

30. 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

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

34. 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

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. 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

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 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

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 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

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 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

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 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

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
> 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

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 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

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 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

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 hrs

64. 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

65. Adverse Reactions to Chemotherapeutic Agents

66. 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

67. 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

68. 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

69. 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

70. NEH

71. Histology-NEH
Infiltrate of inflammatory cells surrounding eccrine coils

72. 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

73. 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

74. 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

78. Etiology Broken thermometers Teething powders Poisoned fish
Broken phosphorescent bulbs
?Gas heaters

79. Treatment
Chelating agents
-dimercaprol

80. 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

81. 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

82. Bromoderma

83. Bromoderma
Bromide eruption on shin; bullae and granulomas

84. 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

85. Iododerma
Only brief duration distinguishes it clinically from basal cell carcinoma

86. Iododerma

87. 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

88. 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

89. 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

90. 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

91. Side effects…
Atrophy and purpura caused by prolonged applications of corticosteroid preparations

92. Atrophy and fragility caused by chronic corticosteroid applications

93. 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

94. Side effects corticosteriods:
Lipoatrophy of the buttock resulting from a corticosteroid injection

95. 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

96. 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

97. THE END- Thank you