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Drug reactions can present with almost every clinical and histologic variant of skin disease including lymphomas. Some drugs elicit very specific tissue reactions such as erythema multiforme or a fixed drug reaction. In other cases, one or more patterned inflammatory tissue reactions are elicited. It is difficult to estimate the true prevalence of drug reactions though studies of hospital inpatients have estimated 2%. Given the wide variety of tissue reactions, the pathologist is often left with the daunting task of discerning whether a rash is a primary skin dermatoses or a secondary drug reaction. In some cases, it is impossible to know for certain and a trial of discontinuing the possible offending drug is sometimes recommended. The timing is critical as most drug reactions occur within 10 days after receiving the agent, although there is wide variability. In addition, discontinuing the drug may still leave lingering effects for weeks to months.


Gross Appearance and Clinical Variants Antiretroviral
Imatinib (Gleevec, STI571)
Histopathological Features and Variants  
Commonly Used Terms  
Internet Links  


Drug interactions: Proteins, pumps, and P-450s.

Shapiro LE, Shear NH.

Division of Clinical Pharmacology, Department of Medicine, Sunnybrook and Women's College Health Science Centre and the University of Toronto, Ontario, Canada.

J Am Acad Dermatol 2002 Oct;47(4):467-84 Abstract quote

The two major concerns in drug safety are adverse drug reactions and drug interactions. When multiple drug therapies are prescribed, drug interactions become an important consideration for patients and physicians.

The life of a drug is reviewed with emphasis on absorption, distribution, metabolism, and excretion. Pharmacokinetic and pharmacodynamic mechanisms for drug interactions are reviewed. The contributions of P-glycoprotein, pharmacogenetic variation, and genetic polymorphisms to drug interactions are highlighted. Prediction of drug interactions is possible with knowledge of which agents are likely to cause alterations in drug metabolism. (J Am Acad Dermatol 2002;47:467-84.)

Learning objective: At the conclusion of this learning activity, participants should have an understanding of the life of a drug. This knowledge should help predict important potential drug interactions.


Antibiotics Sulfonamides, penicillin, ampicillin Exanthem
Corticosteroids   Acne
Alterations of fat distribution (Cushingnoid appearance)
Facial erythema
Lanugo hair
Cytotoxic drugs   Alopecia, neutrophilic eccrine hidradenitis, eccrine squamous syringometaplasia, sclerodermoid reaction, urticaria, porphyria

May occur up to 2 yrs following start of therapy

Eczematous or maculopapular, exfoliative, lichenoid

Non-steroidal anti-inflammatory drugs (NSAIDS) Aspirin, indomethacin, ibuprofen Urticaria, vasculitis, erythema nodosum, fixed drug eruption
Phenytoin (Dilantin)   Exanthems, TEN, EM, gingival hyperplasia, fetal hydantoin syndrome, pseudolymphoma syndrome, generalized pustules
Psychotropic drugs Tricyclic antidepressants, lithium, antipsychotics Porphyria, pigmentation, acneiform eruption
Recombinant cytokines GMCSF, GCS, interferon, interleukin-2 Neutrophilic dermatosis, widespread folliculitis, bullous pyoderma gangrenosum, alopecia, erythema nodosum

Cutaneous manifestations of antiretroviral therapy

Holly A. Ward, MD
Glenn G. Russo, MD
Joseph Shrum, MD

New Orleans, Louisiana

J Am Acad Dermatol 2002;46:284-93 Abstract quote

The pandemic created by HIV, a retrovirus, has stimulated increased research in viral diseases and has generated greater interest in the development of antiretroviral medications.

These new medications are presently divided into 3 categories: protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and nucleoside reverse transcriptase inhibitors (NRTIs). These antiretroviral agents carry their own risk for causing adverse reactions, as well as drug interactions. The most recently approved class of antiretrovirals, PIs have been associated with lipodystrophy syndrome, hypersensitivity reactions, urticaria, morbilliform eruptions, and a large number of drug interactions. NNRTIs have resulted in various cutaneous eruptions, as well as a hypersensitivity syndrome. NRTIs have resulted in alterations of the nails, nail and mucocutaneous pigmentation, hair changes, vasculitis, and morbilliform eruptions.

This article focuses on the cutaneous manifestations of antiretroviral therapy to help dermatologists recognize them.

Histologic patterns of polyethylene glycol-liposomal doxorubicin-related cutaneous eruptions.

Cady FM, Kneuper-Hall R, Metcalf JS.

Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.

Am J Dermatopathol. 2006 Apr;28(2):168-72. Abstract quote  

Polyethylene glycol (PEG)-liposomal doxorubicin (Stealth R, Doxil) is a formulation of doxorubicin, which is encapsulated in liposomes formulated with PEG. It is favored in the palliative setting over doxorubicin because of its generally favorable side effect profile. Adverse reactions are predominantly skin eruptions.

We report 3 cases of women with breast cancer undergoing treatment with liposomal doxorubicin who developed palmar-plantar erythrodysesthesia and diffuse morbilliform eruptions. Biopsies in the 2 cases demonstrated vacuolar interface dermatitis with epidermal dysmaturation and the third case suggested a drug eruption. Additionally, we report a woman with metastatic breast cancer who developed a similar morbilliform eruption soon after completing a regimen of liposomal doxorubicin.

The biopsy revealed an atypical squamous proliferation showing epidermal dysmaturation with focal evidence of interface damage. Both clinician and pathologist alike should be cognizant of this cutaneous eruption, as well as the histologic patterns.

Cutaneous hyperpigmentation induced by doxycycline: histochemical and ultrastructural examination, laser microprobe mass analysis, and cathodoluminescence.

Bohm M, Schmidt PF, Lodding B, Uphoff H, Westermann G, Luger TA, Bonsmann G, Metze D.

Departments of Dermatology (M.B., T.A.L., G.B., D.M.), Medical Physics.

Am J Dermatopathol 2002 Aug;24(4):345-50 Abstract quote

Skin hyperpigmentation induced by minocycline is a well-recognized side effect of minocycline but has rarely been reported for other tetracyclines. Based on a previously reported unusual case of chronic doxycycline abuse in a psychotic patient, we have investigated the nature of the observed pigment changes in the same patient.

Histopathologic investigation of lesional skin by light microscopy disclosed hyperpigmentation of the basal keratinocytes and pigment-laden histiocytes in the dermis and subcutaneous fat. Only the pigment in the histiocytes of the upper dermis was reactive for Fontana Masson stain and could be bleached by hydrogen peroxide. The other histiocytes contained iron and calcium deposits as shown by von Kossa and Perls staining as well as by laser microprobe mass analysis. Ultrastructurally, these histiocytes contained amorphous material within the cytoplasm and stored in lysosomal structures. Comparative cathodoluminescence disclosed the presence of doxycycline in affected skin by means of overlapping emission spectra between the patient's skin and pure doxycycline. Taken together, the histomorphologic and ultrastructural changes induced by doxycycline shared several features with cutaneous hyperpigmentation caused by minocycline.

Our biophysical findings further suggest a direct deposition of doxycycline, probably chelated with iron and/or calcium, within the lesional skin. Based on the presented unique case and the reviewed literature, only suprapharmacologic doses of doxycycline may be sufficient to cause such pigment changes.


Cutaneous Adverse Reactions to Hydroxyurea in Patients With Sickle Cell Disease

Bénédicte Chaine, etal.

Arch Dermatol. 2001;137:467-470 Abstract quote

Treatment with hydroxyurea may alleviate the symptoms of sickle cell disease (SCD). Because treatment with hydroxyurea may be responsible for several cutaneous side effects and is often lifelong in patients with SCD, we conducted this study to evaluate the risk of cutaneous adverse reactions in SCD patients treated with hydroxyurea.

Seventeen adult patients with SCD treated with hydroxyurea at one institution were examined by a dermatologist. Hydroxyurea was given for a mean of 3.04 years (range, 0.42-6.5 years). None of the patients had skin cancer, but 5 (29%) had disabling hydroxyurea-induced leg ulcers. Four of these 5 patients had a previous history of SCD ulcer, compared with none of the 12 patients without hydroxyurea-induced leg ulcers (P<.05). The mean age of patients with induced ulcers was 35.8 years and for those without ulcers was 23.5 years (P<.01).

Our rate of hydroxyurea-induced leg ulcers (29%) is higher than that reported for patients with myeloproliferative syndromes (9%). In addition, use of hydroxyurea has induced ulcers mainly in patients with previous SCD ulcers, suggesting that hydroxyurea could act in conjunction with other vascular abnormalities. Careful attention should be required when giving hydroxyurea to patients with SCD with previous ulcers as well as in older patients with SCD.


Adverse cutaneous reactions to imatinib (STI571) in Philadelphia chromosome-positive leukemias: A prospective study of 54 patients.

Valeyrie L, Bastuji-Garin S, Revuz J, Bachot N, Wechsler J, Berthaud P, Tulliez M, Giraudier S.

Departments of Dermatology, Public Health, Pathology, and Hematology, Henri-Mondor Hospital (Assistance Publique Hopitaux de Paris), Paris XII University; and Novartis Laboratory, Basel.

J Am Acad Dermatol 2003 Feb;48(2):201-6 Abstract quote

BACKGROUND: Imatinib is a new major treatment in chronic myeloid leukemia.

OBJECTIVE: To study the cutaneous reactions induced by imatinib.

METHODS: All inpatients and outpatients with Philadelphia chromosome-positive leukemia treated by imatinib were included in this prospective study. Clinical features, pathologic findings, evolution of each case, and analysis of potential risk factors were recorded.

RESULTS: A total of 54 patients were included, 48 of whom experienced at least 1 cutaneous reaction. These reactions consisted of 36 rashes, 35 edemas, and 22 pruritus. The rash was severe in 5 patients, resulting in temporary interruption of treatment in 3. Highly significant relationships were observed between the daily dose of imatinib and both rashes and edema. In a multivariate analysis, female sex and the daily dose of imatinib were independent risk factors for the development of rashes.

CONCLUSION: Adverse cutaneous reactions induced by imatinib are frequent, generally moderate, and dose-dependent.


An analysis of reports of depression and suicide in patients treated with isotretinoin

Diane K. Wysowski, PhD
Marilyn Pitts, PharmD
Julie Beitz, MD

Rockville, Maryland

J Am Acad Dermatol 2001;45:515-9 Abstract quote

Background: The Food and Drug Administration (FDA) has received reports of depression and suicide in patients treated with isotretinoin.

Objective: Our purpose was to provide the number and describe the cases of depression and suicide reported to the FDA in US patients treated with isotretinoin and to consider the nature of a possible association between isotretinoin and depression.

Methods: An analysis was made of reports of depression, suicidal ideation, suicide attempt, and suicide in US isotretinoin users voluntarily submitted to the manufacturer and the FDA from 1982 to May 2000 and entered in the FDA's Adverse Event Reporting System database.

Results: From marketing of isotretinoin in 1982 to May 2000, the FDA received reports of 37 US patients treated with isotretinoin who committed suicide; 110 who were hospitalized for depression, suicidal ideation, or suicide attempt; and 284 with nonhospitalized depression, for a total of 431 patients. Factors suggesting a possible association between isotretinoin and depression include a temporal association between use of the drug and depression, positive dechallenges (often with psychiatric treatment), positive rechallenges, and possible biologic plausibility. Compared with all drugs in the FDA's Adverse Event Reporting System database to June 2000, isotretinoin ranked within the top 10 for number of reports of depression and suicide attempt.

Conclusion: The FDA has received reports of depression, suicidal ideation, suicide attempt, and suicide in patients treated with isotretinoin. Additional studies are needed to determine whether isotretinoin causes depression and to identify susceptible persons. In the meantime, physicians are advised to inform patients prescribed isotretinoin (and parents, if appropriate) of the possibility of development or worsening of depression. They should advise patients (and parents) to immediately report mood swings and symptoms suggestive of depression such as sadness, crying, loss of appetite, unusual fatigue, withdrawal, and inability to concentrate so that patients can be promptly evaluated for appropriate treatment, including consideration of drug discontinuation and referral for psychiatric care.

Use of isotretinoin (Accutane) in the United States: Rapid increase from 1992 through 2000.

Wysowski DK, Swann J, Vega A.

Office of Post-Marketing Drug Risk Assessment, Food and Drug Administration.


J Am Acad Dermatol 2002 Apr;46(4):505-9 Abstract quote

BACKGROUND: Isotretinoin, a drug approved to treat severe recalcitrant nodular acne, has been marketed in the United States since 1982. The drug is an effective treatment for acne that is refractory to other therapies, but it is a teratogen and can cause serious side effects.

OBJECTIVE: Our purpose was to describe trends in the use of isotretinoin in the United States from marketing through year 2000 and summarize characteristics of patients and prescribers.

METHODS: Data from 2 pharmaceutical marketing research databases, the National Prescription Audit Plus and the National Disease and Therapeutic Index, and from 2 health plan networks were obtained and analyzed.

RESULTS: Retail pharmacies dispensed 19.8 million outpatient prescriptions for isotretinoin from marketing in 1982 through 2000. From 1983 through 1993, the median annual number of prescriptions was just over 800,000; between 1992 and 2000, the number of prescriptions increased 2.5-fold (250%) to nearly 2 million in year 2000. The increases registered in the health plans were somewhat larger: about 275% increases from 1995 through 1999. There is no ICD-9 code for nodulocystic acne; consequently, the type of acne treated with isotretinoin is not determinable from these data. However, between 1993 and 2000, the proportion of isotretinoin treatment for severe acne declined from 63% to 46%, whereas the proportion of treatment for mild and moderate acne increased from 31% to 49%. Data also indicated that the sex distribution of patients was nearly even, and that 63% of male patients prescribed isotretinoin were 15 to 19 years old, whereas 51% of female patients were 15 to 24 years old.

CONCLUSION: In the last 8 years, there has been a 2.5-fold (250%) increase in the number of dispensed prescriptions for isotretinoin in the United States. Data also reveal an increasing proportion of isotretinoin use for mild and moderate acne

Degradation and migration of facial foundations

Zoe Diana Draelos, MD

Winston-Salem, North Carolina

J Am Acad Dermatol 2001;45:542-3 Abstract quote

The surface characteristics of a facial foundation on the skin affect not only photoprotection, but also aesthetic appearance. A 400× video microscope was used to study the movement of facial foundation on the face of 12 female subjects with oily, dry, and normal skin in a controlled environment over 8 hours.

This evaluation revealed gradual degradation of the cosmetic film and accumulation of facial foundation pigment particles in the follicular ostia. This cosmetic migration decreases photoprotection and may explain the perifollicular nature of some cutaneous reactions to facial foundations.

The histopathology of subcutaneous minocycline pigmentation.

Department of Dermatology, University of Utah, Salt Lake City, Utah, USA.

J Am Acad Dermatol. 2007 Nov;57(5):836-9. Abstract quote

Hyperpigmentation associated with prolonged minocycline use is well documented. The histopathology of cutaneous minocycline pigment is characterized by deposition of brown/black, Fontana-Masson, and Perls' positive granules deposited along elastic fibers in the papillary dermis and occurring within macrophages along vessels and eccrine units in the dermis. The subcutis may also be involved; however, the specific subcutaneous findings associated with minocycline hyperpigmentation have not been well established.

We present the histopathologic findings of 4 cases of minocycline hyperpigmentation with subcutaneous involvement. Green-gray, flocculent, nonrefractile globules within macrophages were found in the subcutis of all patients. Two of 4 cases exhibited lipomembraneous changes that were also associated with pigment.

These distinctive findings may provide additional clues to enable a diagnosis of drug-induced hyperpigmentation to be offered, even in the absence of a clear clinical history.

Autoimmune progesterone dermatitis: treatment with oophorectomy.

Rodenas JM, Herranz MT, Tercedor J.

Department of Dermatology, Hospital General Universitario Morales Meseguer, Av. Marques de los Velez, 30008 Murcia, Spain.

Br J Dermatol 1998 Sep;139(3):508-11 Abstract quote

Autoimmune progesterone dermatitis is a rare manifestation of hypersensitivity to endogenous hormones with polymorphic clinical manifestations.

We report a 28-year-old woman with a 5-year history of mucocutaneous erythema multiforme occurring cyclically in the premenstrual period. Progesterone sensitivity was demonstrated by challenge test with medroxyprogesterone acetate.

Treatments with oestrogens, tamoxifen and triptorelin had to be withdrawn because of intolerable adverse effects. Oophorectomy finally cured the disease.


Prospective evaluation of risk factors of cutaneous drug reactions to sulfonamides in patients with AIDS.

Eliaszewicz M, Flahault A, Roujeau JC, Fillet AM, Challine D, Mansouri S, Wolkenstein P, Aractingi S, Penso-Assathiany D, Maslo C, Bourgault-Villada I, Chosidow O, Caumes E; Epitox Study Group.

Department of Infectious Diseases, Hopital de l'Institut Pasteur, Paris, France.

J Am Acad Dermatol 2002 Jul;47(1):40-6 Abstract quote

BACKGROUND: Persons with HIV infection have increased rates of drug eruptions.

OBJECTIVE: Our aim was to evaluate the risk factors of drug eruptions in response to sulfonamides in patients with AIDS, using a case-control analysis.

METHODS: One hundred thirty-six patients who were hospitalized for pneumocystosis or toxoplasmosis were evaluated at the onset of treatment for various risk factors, which were then compared among patients with (48, 36%) and without (88, 64%) a drug eruption.

RESULTS: In multivariate analysis, high CD8(+) cell count and age less than 36 years indicated a risk of drug eruption (respective odds ratios: 3.5 [95% CI 1.6-7.8], P =.002, and 2.1 [95% CI 1-4.6], P =.06). Markers of viral replication for HIV, Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, and parvovirus B19, slow acetylation phenotype or genotype, and glutathione level were not associated with a risk. Administration of corticosteroids had no preventive effect.

CONCLUSIONS: Our results challenge several current concepts regarding drug eruptions by discarding a strong association with glutathione deficiency, slow acetylation, or active viral infections and by showing no preventive effect of corticosteroids.


Dermatologic side effects of thalidomide in patients with multiple myeloma.

Hall VC, El-Azhary RA, Bouwhuis S, Rajkumar SV.

Department of Dermatology, Mayo Clinic, Jacksonville; and the Department of Dermatology, and Division of Hematology and Internal Medicine, Mayo Clinic, Rochester.


J Am Acad Dermatol 2003 Apr;48(4):548-52 Abstract quote

BACKGROUND: Thalidomide, an antiangiogenic agent, was approved by the Food and Drug Administration in 1998 for the treatment of erythema nodosum leprosum. Although its teratogenic and neurologic side effects are well known, its dermatologic side effects continue to be defined.

OBJECTIVE: We report the dermatologic side effects in 87 patients with multiple myeloma enrolled in a comparative, open-label, clinical trial treated with thalidomide alone (50 patients) or thalidomide and dexamethasone (37 patients).

METHOD: We reviewed the records of all patients enrolled in the clinical trial. The frequency, type, severity, and time of onset of all skin eruptions that were temporally related to thalidomide treatment were recorded.

RESULTS: Minor to moderate skin eruptions were noted in 46% of patients taking thalidomide alone and in 43% of those taking thalidomide and dexamethasone. These included morbilliform, seborrheic, maculopapular, or nonspecific dermatitis. Severe skin reactions (exfoliative erythroderma, erythema multiforme, and toxic epidermal necrolysis) that required hospitalization and withdrawal of thalidomide developed in 3 patients receiving thalidomide and dexamethasone.

CONCLUSION: The prevalence of dermatologic side effects of thalidomide appear to be higher than previously reported. Although in most patients they were minor, in a few patients they were quite severe, particularly when given in conjunction with dexamethasone for newly diagnosed myeloma. Further studies are needed to verify the extent of the interaction between thalidomide and dexamethasone in this group of patients.


Tissue Reaction Associated Drugs and Chemical Agents
Gold, methyldopa, beta adrenergic blockers, penicillamine, quinine, anti-malarials, ethambutol, ACE inhibitors, NSAIDs

Lichenoid drug eruption to salsalate Mindy L. Powell, MD
Alison Ehrlich, MD
Donald V. Belsito, MD

Kansas City, Kansas

J Am Acad Dermatol 2001;45:616-9 Abstract quote

Cutaneous lichenoid eruptions can arise as a result of exogenous compound exposures. Pharmaceutical drugs, industrial compounds, and inhaled particles have been implicated as causative agents. To date, there have been no recorded cases of lichenoid drug eruptions (LDEs) caused by clinical use of the nonsteroidal anti-inflammatory drug salsalate.

We describe a patient who experienced a lichenoid eruption after the initiation of salsalate for relief of arthritic pain. This eruption emerged after 1 month of therapy with salsalate, persisted for as long as salsalate was administered, and cleared within 3 weeks of discontinuing the medication.

LDEs can clinically and histologically resemble idiopathic or classic lichen planus. Integrating drug history, clinical morphology, clinical distribution, and histopathology can aid in the differentiation. As in our patient's case, curative treatment for LDE requires discontinuation of the drug.

Tetracycline, thiazides
Contact dermatitis
Color film developers

Linear IgA bullous dermatosis in one of two piroxicam-induced eruptions: A distinct direct immunofluorescence trend revealed by the literature

Richard W. Plunkett, PhD
Stephen E. Chiarello, MD
Ernst H. Beutner, PhD

Buffalo, New York, and Port Charlotte, Florida

J Am Acad Dermatol 2001;45:691-6. Abstract quote

Background: The report focuses first on two patients with piroxicam-induced bullous eruption, one whose disease was diagnosed as linear IgA bullous dermatosis (LABD) and the other with no disease-specific immunologic findings using immunofluorescence methods. A review of the literature points to a distinctive direct immunofluorescence feature of drug-induced LABD cases.

Objective: Our purposes were to focus on divergent piroxicam reactions and to compare immunofluorescence findings in our and other reported drug-induced LABD cases to randomly occurring LABD cases.

Methods: Direct and indirect immunofluorescence methods were used to study biopsy and serum samples from both cases and biopsy specimens of 40 other LABD cases.

Results: Tense blisters developed in two patients medicated with piroxicam. Immunofluorescence studies demonstrated deposits of IgA at the basement membrane zone (BMZ) in case 1 and only non-disease-specific fibrin deposits at the BMZ in case 2. Within 1 month of discontinuation of piroxicam, all lesions were gone in both patients.

Conclusion: In LABD cases proven by direct immunofluorescence, (1) the index of suspicion of drug induction should be higher in cases with only IgA and no IgG in the BMZ; (2) possibly up to two thirds of all LABD cases may be drug induced; and (3) the negative immunofluorescence findings in case 2 and other cases reported in the literature suggest that LABD is one of several host responses in drug-induced blistering diseases.

Linear IgA bullous dermatosis induced by atorvastatin.

Konig C, Eickert A, Scharfetter-Kochanek K, Krieg T, Hunzelmann N.

Department of Dermatology, University of Cologne, Germany.

J Am Acad Dermatol 2001 Apr;44(4):689-92 Abstract quote

Linear IgA bullous dermatosis (LABD) is an autoimmune blistering skin disease characterized by circulating IgA antibodies binding the basement membrane zone. In most cases the origin is not clear, but in a minority of cases LABD is drug induced. We describe a patient in whom linear IgA disease developed shortly after beginning therapy with atorvastatin. In Western blotting analysis we detected IgA and IgG class antibodies targeting a 97-kd protein. To our knowledge this is the first reported case of atorvastatin-induced LABD.

Pseudoepitheliomatous hyperplasia
Halogenodermas (Iodine, bromide, fluoride)
Acanthosis nigricans
Hormone and steroids
Cosmetics, drugs, industrial chemicals
Anti-mitotic chemotherapy
Elastosis perforans serpiginosa
Sulfonamides, allopurinol, injection of toxoids containing aluminum salts
Minoxodil, oral contraceptives
Warfarin (coumadin)
Adverse Antibiotic-Induced Eruptions Associated With Epstein Barr Virus Infection and Showing Kikuchi-Fujimoto Disease-Like Histology.

Carlson JA, Perlmutter A, Tobin E, Richardson D, Rohwedder A.

From the *Divisions of Dermatology and Dermatopathology, Department of Pathology, Albany Medical College, Albany, New York; daggerUpstate Infectious Disease, Albany, New York; double daggerFour Irongate Center, Glens Falls, New York; and section signBio-Med-Mol-Service, Kalkar, Germany.

Am J Dermatopathol. 2006 Feb;28(1):48-55. Abstract quote  

The antibiotic-induced eruption of infectious mononucleosis is a well-known clinical phenomenon. Latent viral infection with herpesviridae (eg, human herpes virus 6 (HHV-6) and Epstein-Barr virus (EBV)) is suspected to play a role in the drug hypersensitivity syndrome. The cutaneous pathologic findings have not been reported in the former, and are infrequently reported in the latter entity.

Herein, we describe the biopsy findings of a cefprozil-induced rash in infectious mononucleosis and a minocycline-associated drug hypersensitivity syndrome. Biopsy of these exanthematous eruptions revealed an acute vacuolar interface superficial and deep perivascular and interstitial lymphocytic dermatitis. CD8+ lymphocytes predominated and were associated with non-neutrophilic nuclear (karyorrhectic) debris and numerous small CD68+ and CD123+ monocytes.

These aforementioned features have been described in cutaneous lesions of Kikuchi-Fujimoto disease, an entity whose clinicopathologic findings overlap with both infectious mononucleosis and lupus erythematosus. Serologic evidence of active and chronic active EBV infection was found in both patients, respectively. No evidence of EBV or HHV6 was found in the cutaneous lesions. Plasmacytoid monocytes (CD68+/CD123+ cells), which produce type I interferon, are believed to play a role in viral immunity by protecting other cells from viral infections and promoting survival of antigen-activated T cells.

Their presence in these two putative examples of viral-drug immune dysregulation could be a clue to pathogenesis and represent a common cellular component of some adverse cutaneous drug eruptions
Calcium channel blockers

Drug-induced reversible lymphoid dyscrasia: a clonal lymphomatoid dermatitis of memory and activated T cells.

Magro CM, Crowson AN, Kovatich AJ, Burns F.

Department of Pathology, Division of Dermatopathology, Ohio State University, Columbus, USA.

Hum Pathol 2003 Feb;34(2):119-29 Abstract quote

Certain systemic conditions predispose patients to excessive lymphocyte responses to immune-perturbing drugs, which may progress to malignant lymphoma. Many pathologists and clinicians believe that differentiation of pseudolymphoma from cutaneous T cell lymphoma (CTCL) can be reliably made through phenotypic and molecular analysis.

We encountered 15 cases of atypical cutaneous T-cell lymphoid hyperplasia in the setting of drug therapy. We explored phenotypic anomalies using antibodies to CD2, 3, 4, 7, 8, 20, 30 and CD62 K and sought T-cell receptor gene rearrangements by a polymerase chain reaction methodology. The lymphoid infiltrates showed reproducible CD7 and/or CD62 K deletion in concert with T cell clonality and variable CD30 positivity-findings similar to those of CTCL-but the rashes resolved or improved substantially after drug modulation.

We hypothesize that the infiltrates represent an unrepressed expansion of CD7- and CD62 K-negative activated memory T lymphocytes in response to antigenic triggers. We propose the term "drug-induced reversible lymphoid dyscrasia" to describe this entity.

Neutrophilic eccrine hidradenitis
Cytarabine, other chemotherapy
Corticosteroid withdrawal, thiazides, sulfonamides, oral contraceptives, sulindac
Antimalarials, phenothiazines, tetracycline, amiodarone, clofazimine
Minocycline hyperpigmentation isolated to the subcutaneous fat.

Rahman Z, Lazova R, Antaya RJ.

Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.

J Cutan Pathol. 2005 Aug;32(7):516-9. Abstract quote  

We present a 15-year-old girl with bilateral lower extremity discoloration of one-year duration while taking minocycline for acne vulgaris.

The clinical characteristics best supported type II minocycline hyperpigmentation, but the histology revealed that the pigmentation was solely limited to the subcutaneous adipose tissue, completely sparing the dermis. Special stain for iron was negative.

This is the first case to our knowledge with pigment exclusively located in the subcutaneous fat and with the unusual finding of a negative stain for iron.
Polyarteritis nodosa

J Am Acad Dermatol 2001;44:198-206

Two young women receiving long-term minocycline therapy (>3 years) in whom P-ANCA-positive cutaneous polyarteritis nodosa developed

Both patients presented with a violaceous reticulated pattern on the lower extremities

Histologic examination of biopsy specimens from a reticulated area and a subcutaneous nodule showed necrotizing vasculitis of medium-sized arteries in the deep dermis, consistent with the diagnosis of polyarteritis nodosa

The cutaneous lesions rapidly resolved on discontinuation of minocycline and initiation of prednisone therapy

Steroid withdrawal
Beta blockers
Icodextrin Cutaneous Hypersensitivity Report of 3 Psoriasiform Cases

Arch Dermatol. 2001;137:309-310

Icodextrin is proposed as a new osmotic agent for use in peritoneal dialysis. Because of its recent use, adverse reactions are not well known. Cutaneous adverse effects have been described. We report 3 cases of cutaneous hypersensitivity to icodextrin and discuss the pathogenesis of this reaction.

The cutaneous adverse reaction was psoriasiform in our 3 cases. The eruption was generalized with acute generalized exanthematous pustulosis in 1 case, and limited to the palms and soles in 1 case. It occurred 10 to 15 days after icodextrin therapy was initiated. In patient 1, the results of a rechallenge with icodextrin were positive. Icodextrin therapy was discontinued in all patients.

Some cases of cutaneous reactions to icodextrin have been reported in the literature, but they are rare. As in our cases, most eruptions are psoriasiform, limited to the palms and soles, or extensive. Although the etiology is unclear, a hypersensitivity reaction, with the formation of immunocomplexes, is probable.

Diltiazem, isoniazid, cephalosporins

Mesalazine-induced pustular drug eruption

Karen L. Gibbon, MRCP
Anthony P. Bewley, MRCP
Kathleen Thomas, FRCPath

London, United Kingdom

J Am Acad Dermatol 2001;45:S220-1 Abstract quote

We describe a patient with acute generalized eosinophilic pustuloderma induced by mesalazine therapy. The patient responded to cessation of mesalazine and treatment with systemic corticosteroids.

This type of unusual pustuloderma to mesalazine has not to our knowledge been described before.

Polyvinyl chloride, bleomycine, injection of phyotmenadione or pentazocine

Interstitial Granulomatous Drug Reaction with a Histological Pattern of Interstitial Granulomatous Dermatitis

Christophe Perrin, M.D.; Jean-Philippe Lacour, M.D.; Jérome Castanet, M.D.; Jean-Francois Michiels, M.D.

From the Department of Pathology (C.P.,J.F.M.) and Dermatology (J.P.L.,J.C.), University of Nice, France.

Am J Dermatopathol 2001;23:295-298 Abstract quote

The interstitial granulomatous drug reaction (IGDR) is a novel drug-associated entity, characterized by violaceous plaques with a predilection for skin fold areas. Light microscopically, it resembles the incipient diffuse interstitial phase of granuloma annulare. Differentiating light microscopic features include the absence of complete collagen necrobiosis, the presence of interface dermatitis, and variable lymphoid atypia. The lack of vasculitis rules out the extravascular necrotizing granuloma (Winkelmann granuloma) associated with systemic disease. The differential diagnosis with interstitial granulomatous dermatitis with arthritis as defined by Ackerman et al. has not been studied until now. Our aim was to determine the histologic criteria allowing us to differentiate IGDR without interface dermatitis and lymphoid atypia from interstitial granulomatous dermatitis.

We report three patients with IGDR triggered, in two cases by respectively angiotensin convertin enzyme (ACE) inhibitors and furosemide, and in one case by the association of an ACE inhibitor, furosemide, and fluindione.

Histologic examination showed a histological pattern of interstitial granulomatous dermatitis. We found a dense, diffuse histiocytic infiltrate distributed interstitially and in palisaded array within the reticular dermis. Eosinophils and some neutrophils were scattered throughout the infiltrate. In some tiny foci, enveloped by histiocytes, thick collagen bundles associated with basophilic nuclear debris or ``flame figures'' were seen. Vasculitis, interface dermatitis, or lymphoid atypia were absent. Our study allowed us to expand the histological spectrum of IGDR including a histological pattern similar to interstitial granulomatous dermatitis. The lack of degenerated collagen could be a subtle clue in favor of interstitial granulomatous dermatitis triggered by a drug.

Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Commonly Used Terms

Acute Generalized Exanthematous Pustulosis (AGEP)

Erythema multiforme

Fixed Drug Eruption

Lichenoid dermatoses


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