Practice Essentials
Adverse cutaneous reactions to medications are a common reason for consultations with dermatologists. Drug-induced skin disorders may manifest in a variety of ways. Drugs may cause exanthems, urticaria, hypersensitivity syndromes, pustular eruptions, erythema multiforme, toxic epidermal necrolysis, cutaneous necrosis, and abnormal pigmentation of the skin and mucosa. Although pigmentary changes caused by drugs usually result in a limited degree of morbidity, these changes may be very disturbing to the patient.
The image below depicts a patient with amiodarone pigmentation.
Drug-induced pigmentary abnormalities may be classified into 3 groups, which are (1) hyperpigmentation/melanosis, (2) hypopigmentation/leukoderma, and (3) dyspigmentation or occurrence of unusual skin color.
A related article is Fixed Drug Eruptions.
Signs and symptoms
See Presentation.
For information on specific drug reactions, see Etiology.
Diagnostics
Many metabolic and endocrine diseases induce pigmentary changes that appear identical to those seen with drug-related etiologies; these alternative etiologies require exclusion, often best achieved through laboratory investigation for genetic mutations or hormonal/electrolyte disturbances. Several situations in which laboratory examination assists in obtaining a patient's diagnosis are discussed below.
Addison disease is the syndrome of adrenal insufficiency, and its cutaneous manifestations can include diffuse, gray dyspigmentation of the skin, mucosa, skin folds, and scar tissue. This skin discoloration is distinguished from drug-related causes by a constellation of abnormal serum laboratory test results, including hyponatremia, hyperkalemia, low serum cortisol levels, and an inappropriate response to a corticotrophin stimulation test.
Alternatively, hemochromatosis and Wilson disease induce a generalized, blue-gray metallic skin dyspigmentation; when the family history and other systemic involvement is unknown, findings that include elevated ferritin and trans -ferritin saturation levels or low serum copper or ceruloplasmin levels can help confirm these diagnoses.
Jaundice occurs when serum bilirubin levels are greater than 3 mg/dL; abnormally elevated serum bilirubin levels can help distinguish yellow dyspigmentation of the skin, conjunctiva, sclera, and oral mucosa from the discoloration sometimes induced by the antimalarial drugs mepacrine and quinacrine.
Normal thyroid function test results help eliminate hypothyroidism as a potential etiology of generalized yellow dyschromia.
Also see Procedures and Histologic Findings.
Management
The most important factor in the management of drug-induced dyspigmentation involves the identification and discontinuation of the offending drug. Most mucocutaneous pigmentation is reversible and spontaneously resolves with avoidance of the inciting drug.
In a scenario in which several drugs may be implicated as the cause of dyspigmentation, a decision must be made between the physician and patient to stop all nonessential medications. Decreasing the dose of any essential, life-saving treatment is often sufficient to diminish drug-related dyschromia. Additionally, merely explaining the benign nature of the cutaneous reaction may alleviate patient anxiety and allow time to determine the offending medication.
In addition, exposure to sun or UV light may increase pigmentation, especially after sensitization with a photosensitizing medication. Sunscreen use and vigilant avoidance of the sun are helpful to prevent progression or recurrence of pigmentary changes.
Finally, topical depigmenting agents and laser treatments (eg, Q-switched alexandrite laser, Q-switched ruby laser) have been reported to improve cases of permanent dyspigmentation. The use of these therapies is controversial because they have shown inconsistent results; further evaluation is needed.
For patients whose dyspigmentation may be the result of a systemic illness such as Addison disease, consultation with an internist and/or endocrinologist may be indicated.
Pathophysiology
Multiple pathologic mechanisms are responsible for drug-induced pigmentation disorders. Compared with the immunological etiology underlying many drug allergies, most cases of pharmacologic pigmentation are not immunologically mediated.
The pathogenesis underlying drug-related dyspigmentation can also be categorized into 3 mechanisms, which are (1) drug or drug metabolite deposition in the dermis and epidermis, (2) enhanced melanin production with or without an increase in the number of active melanocytes, and (3) drug-induced postinflammatory changes to skin. Similarly, chemical hypopigmentation is also thought to occur through a variety of pathologic mechanisms, including a reduced number of skin melanocytes, enzymatic blockade of melanogenesis, and inhibition of melanosome transfer.
Etiology
A large number of drug groups are well known for their tendency to induce mucocutaneous dyspigmentation. These medications tend to be associated with distinct clinical and histological patterns largely dependent on their underlying pathogenesis. Antimalarials, chemotherapeutic agents, heavy metals, miscellaneous medications (eg, amiodarone, zidovudine, minocycline, clofazimine, psoralens), and psychotropic drugs are among the most commonly implicated medications in acquired dyschromia.
Antimalarials [1]
Hyperpigmentation is considered one of the most notorious and frequent adverse cutaneous effects of this drug group.
These drugs exhibit powerful antimalarial, as well as anti-inflammatory and immunomodulating, efficacy and thus are used to treat various autoimmune disorders such as systemic lupus and rheumatoid arthritis in addition to malaria. The antimalarials most widely known to trigger dyschromia are chloroquine, hydroxychloroquine, amodiaquine, and quinacrine.
These medications have a well-established association with epidermal pigmentation, and an estimated 25% of all patients receiving one of the aforementioned antimalarials for at least 4 months will develop bluish-gray or purple pigmentation. See image below.
Discoloration appears most frequently in the pretibial areas of the lower extremities but can also involve the entire nail bed, nose, cheeks, forehead, ears, and oral mucosa (specifically the hard palate).
Initial lesions manifest as discrete, oval macules before eventually coalescing into large patches; histologic examination of the discolored areas reveals increased epidermal melanin and hemosiderin deposition in the dermis.
The pigmentary effects of this drug tend to be reversible, with slow reversal of skin color back to baseline within several months after stopping the inciting agent.
Another distinct type of dyspigmentation commonly mistaken for jaundice occurs in patients who ingest quinacrine; with regular use of this drug, a large percentage of patients develop a characteristic lemon-yellow skin discoloration that can extend to the conjunctiva and the oral mucosa. The drug's acridine dye qualities appear to induce this adverse effect via direct staining of tissues. The yellow discoloration does not manifest clinically in darker-skinned individuals, although their sclerae may be involved. Laboratory investigation of serum bilirubin levels can help distinguish between jaundice and this drug-induced skin discoloration. This adverse effect normally resolves within 1-4 months of drug discontinuation.
Chemotherapeutics [2]
Cancer chemotherapeutic agents can cause various adverse cutaneous effects, including photosensitivity and diffuse or localized hyperpigmentation of the skin, nails, and mucous membranes. Individual medications within this group induce a variety of distinctive patterns and colors of dyspigmentation.
The pathogenesis underlying chemotherapy-related dyspigmentation is not completely known, but some proposed mechanisms for this hyperpigmentation include direct stimulation of melanin production and postinflammatory hyperpigmentation after drug-induced toxicity to the keratinocytes.
Agents known to cause skin dyspigmentation include bleomycin, busulfan, doxorubicin, daunorubicin, fluorouracil, cyclophosphamide, carmustine, and docetaxel.
Bleomycin is a cytotoxic antibiotic used to treat malignancies such as testicular carcinoma and Hodgkin lymphoma; it is associated with a wide variety of adverse cutaneous effects, including hyperpigmentation in up to 20% of patients.
Hyperpigmentation typically appears within 1-9 weeks following drug administration at doses as low as 15-30 mg and can be accompanied by pruritus, pigmented banding of the patient's nails, or both. Skin discoloration varies from generalized hypermelanosis to focal pigmentation of pressure points, skin overlying joints, or linear or flagellated bands on the trunk. The flagellated pigmented bands, a distinct clinical picture associated with this drug, are thought to be associated with minor trauma caused by scratching or irritation from clothing (see image below); however, some patients deny they have pruritus. [3] A similar phenomenon has been reported with the ingestion of shiitake mushrooms. [4]
Histologic examination demonstrates increased epidermal melanin without an increase in epidermal melanocytes and little dermal pigment incontinence.
5-Fluorouracil is an antimetabolite chemotherapy agent used for cutaneous premalignant lesions and in the treatment of gastrointestinal and breast cancers. When used systemically, up to 5% of individuals develop a photosensitivity reaction in sun-exposed skin, followed by hyperpigmentation in those areas. Additionally, hypermelanosis may also develop in skin near infusion or portal irradiation sites or on the dorsal aspects of the hands, palms, soles, and trunk. [5] 5-FU has also been reported to cause hyperpigmentation overlying the vein into which it was infused. This has been labeled "serpentine supravenous hyperpigmentation" and may also be associated with alkylating agents, antibiotics, antimetabolites, proteasome inhibitors, and anti-mitotics. [6] It is seen most commonly in men treated for solid tumors. [7]
Adriamycin may cause pigmented patches in the oral mucosa, particularly the lateral aspect of the tongue. See image below.
Hydroxyurea and zidovudine may cause similar pigmentary changes, including nail bed and/or lunula hyperpigmentation and tongue pigmentation.
Pemetrexed (Alimta) has been reported to cause hyperpigmentation of the palms and soles. [8]
Epidermal growth factor receptor inhibitors have been associated with telangiectasias, which upon resolution have been associated with hyperpigmentation. Facial involvement of this process may resemble acne and/or rosacea. [9, 10]
Heavy metals
The heavy metals gold, silver, bismuth, and mercury are well known for their ability to cause pigmentary disturbances. The prevalence of this occurrence is decreasing as the use of these metals declines in current clinical practice.
Today, silver sulfadiazine is still considered the standard of care in the treatment of extensive burns; occupational exposure or alternative medical therapies account for the other major sources of silver salt exposure. Systemic absorption of silver results in generalized slate-gray pigmentation, otherwise known as argyria. [11]
Skin discoloration is most accentuated in sun-exposed areas and often involves a patient's nails, sclera, and mucous membranes, while sparing the skin folds. Dyspigmentation may also be more intense at localized sites of application and has occurred with local exposure from silver earrings and acupuncture needles. [12, 13]
Histologically, silver granules are found deposited in the basement membrane, on the membrane propria of the eccrine glands, and in elastic fibers of the upper dermis; these granules are thought to stimulate melanin production in adjacent melanocytes. Discontinuation of the medication results in slow resolution of the dyspigmentation, although residual pigmentation is often observed.
Gold is another heavy metal that is now rarely used as an alternative therapy for patients with pemphigus vulgaris or rheumatoid or psoriatic arthritis. Prolonged parenteral use with a minimum cumulative dose of 20 mg/kg can result in a blue-gray hyperpigmentation of sun-exposed skin, known as chrysiasis, which may be most prominent around the eyes. Localized pigmentary changes induced by gold jewelry have also been reported [14] ; however, gold typically does not cause nail or mucosal dyspigmentation like that seen with silver. Biopsies demonstrate gold particles within dermal macrophage lysosomes and surrounding blood vessels. Strict avoidance of the sun along with cessation of gold intake allows for slow resolution of the dyspigmentation.
Injection of iron salts into the dermis can also cause focal, permanent blue-gray discoloration; this scenario occasionally occurs in patients with iron-deficiency anemia or after the use of ferric subsulfate (Monsel solution) as a hemostatic agent. Histologically, deposition of iron particles into the macrophages or along collagen fibers in the dermis is seen.
Tetracyclines
Pigmentary disturbances are disconcerting adverse events associated with the tetracycline drug group, particularly with minocycline ingestion. [15, 16, 17, 18] Tetracyclines, including minocycline, have been associated with brown discoloration of the teeth in children. Use of these medications in children younger than 9 years is discouraged.
Minocycline is a lipid-soluble antibiotic with anti-inflammatory properties that is frequently used in the treatment of acne or other inflammatory conditions; adverse cutaneous effects from its use are common, with hyperpigmentation occurring in roughly 3-5% of all patients who report using it long term.
In addition to a prolonged period of ingestion, other risk factors such as higher cumulative dose, excessive sun exposure, and prior inflammatory skin changes have been shown to increase the risk of minocycline-related hyperpigmentation.
Minocycline has the following three classic and distinct patterns of dyspigmentation (also see the images below):
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Type I is blue-black discoloration localized to scars and postinflammatory sites; this discoloration is proposed to be the result of hemosiderin and/or iron chelate dermal deposition.
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Type 2 is blue-gray pigmentation of normal skin on the extremities, especially the anterior shins (which may mimic antimalarial pigmentation). These changes are derived from deposition of melanin and iron-containing granules in the dermis and subcutis.
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Type 3 is generalized "muddy" brown hyperpigmentation seen most prominently in sun-exposed skin, thought to result from increased basal layer melanin (without evidence of iron deposition).
In addition to these clinical patterns, other tissues such as the sclera, [19] oral mucosa, thyroid, breast, aorta, bones, and lymph nodes may exhibit dyspigmentation.
Histopathologic findings are largely dependent on the clinical type of discoloration.
Cessation of minocycline therapy typically results in a gradual fading of dyspigmentation, although in some cases symptoms never completely resolve.
In recent years, Q-switched lasers such as the Q-switched ruby, alexandrite, and Nd-Yag have had success in reducing or clearing minocycline induced dyspigmentation [20, 21, 22, 23, 24]
Doxycycline has also been documented in at least 18 cases as the culprit in hyperpigmentation. The most commonly affected sites are the hands, face, and old scars. Discontinuation of doxycycline usually leads to resolution. [25]
Amiodarone, a coronary vasodilator used in the treatment of cardiac arrhythmias, can induce blue-gray or violaceous pigmentation of sun-exposed skin and yellow-brown stippling of the cornea. See image below.
Pigmentary changes usually develop after long-term therapy (≥6 mo); the risk of such adverse cutaneous effects increases with a longer duration of use and at doses greater than 400 mg/d.
Many times, dyspigmentation is preceded by a photoallergic reaction.
Histopathologic examination reveals focal deposition of yellow-brown granules and lipofuscin within dermal macrophages; electron microscopy further demonstrates the granules contained within intralysosomal laminated inclusion bodies.
Pigmentation has been shown to slowly resolve months to years after withdrawal of therapy, although the dyspigmentation can be permanent.
Antiretrovirals
Azidothymidine, otherwise known as AZT or zidovudine, is commonly used in highly active antiretroviral therapy (HAART) for patients with HIV disease. It causes a reversible dyspigmentation of the nails and occasionally brown mucocutaneous hyperpigmentation. [28]
Reported nail changes associated with this drug include diffuse blue pigmentation and longitudinal or transverse banding that begins in the proximal nail bed.
Histologically, pigmented skin lesions demonstrate increased melanin deposition along the epidermal basal layer and within dermal histiocytes.
Skin and nail discoloration have been shown to gradually resolve with drug discontinuation.
Emtricitabine (FTC) is known to cause skin pigmentation in African Americans at an incidence of 8% and in Asians at an incidence of 4%. The pigmentation was asymptomatic and often located on the distal extremities. [29]
Clofazimine [30]
Clofazimine is a phenazine dye used to treat rhinoscleroma, discoid lupus, leprosy, and other mycobacterial infections; it regularly induces a diffuse, reddish cutaneous and conjunctival discoloration within the first few weeks of use.
With prolonged ingestion, affected patients typically develop violet-brown or bluish cutaneous pigmentation most apparent in lesional skin.
Histological findings that correlate with these progressive skin changes include initial drug deposition within macrophages and subcutaneous and visceral fat; enhanced epidermal melanin deposition with ceroid lipofuscinosis is seen with continued medication use.
Gradual fading of pigmentary changes is seen with withdrawal of the drug.
Psychotropic drugs [31]
Antipsychotic medications produce adverse cutaneous effects in approximately 5% of patients; patients taking phenothiazines, imipramine, or desipramine most frequently develop a progressive slate or blue-gray pigmentation in sun-exposed areas of the skin.
Among the phenothiazines, the low-potency antipsychotic chlorpromazine is the most commonly implicated drug. [32] It is known to induce a purple discoloration of the face and extremities, with marked sparing of the facial wrinkles. Pigmentation may involve the nail beds and exposed portions of the eye. Dyspigmentation tends to develop after a prolonged course of high doses of the drug and has been shown to slowly resolve if switched out for another neuroleptic, such as levomepromazine. [33, 34] Histologically, pigmented granules are visible in dermal macrophages around the superficial capillaries, and ultrastructural analysis has found that the electron-dense granules are composed of melanin and complexes of melanin and drug metabolite.
Tricyclic antidepressants, particularly imipramine [35] and desipramine, [36] may also induce blue or slate-gray pigmentation in sun-exposed skin. [37] Pathologic investigations reveal brown granules composed of drug-melanin complexes free in the dermis (along the basement membrane) and deposited within dermal macrophages. Replacement of the inciting drugs with alternative antidepressants has been successful in resolving the patient's skin discoloration. Additionally, the Q-switched alexandrite laser has shown promising reductions of pigmented granules caused by prior imipramine use. [38]
In general, antiepileptic drugs are not known to induce pigmentary changes. However, recently a drug used to treat partial seizures in adults, ezogabine (retigabine), has been documented to cause blue-gray mucocutaneous discoloration that affected the face, lips, hard palate, conjunctivae, and nails. [39]
Miscellaneous
Other drugs associated with mucocutaneous dyspigmentation include oral contraceptives, [40] psoralens, and topical hydroquinone. Approximately 30% of all women using oral estrogen therapy report the development of melasmalike facial pigmentation. Discontinuation of the hormonal therapy in conjunction with strict sun avoidance allows for resolution of the hyperpigmentation.
One case of diffuse facial hyperpigmentation was noted after the administration of adalimumab. [41]
Psoralens are plant extracts currently used in the treatment of psoriasis and vitiligo. When used with UV light, these chemicals cause a predictable pigmentation of the skin via a proliferation of follicular melanocytes and increased production and transfer of melanin.
Hydroquinone is a hydroxyphenolic bleaching chemical normally used in the treatment of skin hyperpigmentation. Blue-black pigmentation similar to that seen in inherited ochronosis has been shown to develop with topical application in darker-skinned individuals. [42]
Topical ophthalmic medications (latanoprost and bimatoprost) used to treat glaucoma have been reported to cause periocular and diffuse facial hyperpigmentation as well as darkening of the iris. [43, 44]
Imatinib (Gleevec), a tyrosine kinase inhibitor, has been reported on several occasions to cause mucosal pigmentation that stains positively with both Fontana-Masson and Prussian blue stains, similar to minocycline. [45] It has also been associated with both hypopigmentation and hyperpigmentation, [46, 47] and it has been suggested that cases of hyperpigmentation may be due to imatinib mediated increases in c-Kit signaling resulting in melanogenesis. [48] Five patients developed melasmalike pigmentation of the face due to imatinib. [49]
Diffuse cutaneous hyperpigmentation has occurred as a result of intravenous administration of polymyxin B. [50] The patient had been treated with polymyxin B for a life-threatening infection with multiple-drug resistant Klebsiella pneumonia.
A diffuse yellowish discoloration of the skin and mucosa is known to result from overconsumption of beta-carotene (carotenemia) found in certain vegetables and dietary supplements. [51]
Miscellaneous chemical agents
Loss of pigmentation, hypopigmentation, or leukoderma may be caused by a variety of chemical agents. Phenolic compounds, hydroquinones, monobenzyl ether of hydroquinone, sulfhydryl compounds (eg, sulfanilic acid, azelaic acid, kojic acid), and corticosteroids are all known to cause loss of pigmentation. [52] Amyl nitrate that was spilled on the lower portion of the face was reported to cause vitiliginous areas in a 37-year-old African American. [53]
Hydroquinones and azelaic acid may cause inhibition of tyrosinase, an enzyme required for the production of melanin. Phenols and monobenzyl ether of hydroquinone are lethal to melanocytes and may cause permanent depigmentation.
Corticosteroids, administered either topically or intralesionally, may induce a loss of pigmentation. This loss of pigment results from the suppression of melanocytes in the production of melanin and normally is reversible over time. Intralesional corticosteroids may cause linear or stellate hypopigmentation that extends out from the original injection site as the steroid is taken up by lymphatics. This type of hypopigmentation may also resolve over a period of months to years.
There is a report of a substance used in Traditional Chinese Medicine, citri reticulatae pericarpium (sun-dried Mandarin orange peel) caused dyspigmentation in the form of toenail melanonychia after topical exposure in a foot soak. [54]
Epidemiology
Frequency
United States
The rate of drug-induced dyspigmentation varies depending on the drug and cumulative dose. Some drugs, such as amiodarone, have been reported to have a rate of blue-gray dyspigmentation as high as 24% when the cumulative dose is greater than 200 mg.
International
Drug-induced skin pigmentation is estimated to account for approximately 20% of all cases of acquired dyspigmentation worldwide. [55]
Race-, sex-, and age-related information
Drug-induced pigmentary changes can occur in persons of any race, but hypomelanosis is seen more frequently and appears more dramatically in patients with darker-pigmented skin. Additionally, people with darker skin often exhibit more intense hyperpigmentation than individuals with fair skin. [56]
No differences are reported in the prevalence of drug-related pigmentation among males versus females.
Drug-related dyspigmentation is seen in persons of all ages.
Prognosis
Drug-induced pigmentation is not generally associated with any systemic toxicity and thus has an excellent prognosis. With some exceptions, pigmentation is usually reversible and slowly fades with discontinuation of the drug. Drug-induced pigmentation is not generally associated with increased mortality or morbidity, although it may result in considerable psychological and social impairment.
Patient Education
For patient education resources, see Drug Allergy and DermNet NZ's article Drug-induced skin pigmentation.
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Perioral chloroquine pigmentation.
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Bleomycin flagellate pigmentation.
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Adriamycin pigmented macule (arrow) on the tongue.
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Minocycline pigmentation of the sclera.
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Minocycline pigmentation of the forearms.
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Minocycline pigmentation of the lower leg.
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Minocycline "muddy" pigmentation of the face in photodistribution.
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Amiodarone pigmentation.
