Drug-Induced Pigmentation Clinical Presentation

A thorough history is essential to determine the cause of a pigmentary disorder. Very important information to gather during the evaluation of the patient includes the temporal relationship of medications taken and the development of the pigmentation, the presence of accentuation from exposure to sunlight, a list of medications taken, and a personal and family history of disorders such as alkaptonuria.

• A patient should be questioned on the timing of initial symptom appearance; drug-induced pigmentation is an acquired disease that tends to progress insidiously over time as the patient has further exposure to the chemical.
• A review of associated symptoms and comorbid illnesses should be elicited to rule out potential alternative etiologies; additionally, a patient should report any other recent skin changes because lichenoid or bullous eruptions often accompany drug-induced dyschromia.
• A thorough review of the patient's medication list is also essential, taking care to include any herbal drugs or over-the-counter medications. Any medications taken in the 6 months preceding the dyspigmentation should be documented.
• Any prior history of adverse reactions to drugs often provides supportive evidence for a medication-related etiology. Recent exposure to sunlight or artificial UV light is also important because sun exposure can lead to an exacerbation of drug-related cutaneous dyspigmentation.
• Finally, a patient's pigmentary changes should fade with time after the causative agent is discontinued. A patient should be asked about prior resolution of symptoms with withdrawal of therapy.

Specific clues in the physical examination of a dyschromic patient may indicate a drug-specific etiology. The particular distribution of the pigmentation and whether cartilage or mucosae are involved are important clues from the physical examination of the patient.

• Most importantly, drug-related pigmentation usually has a characteristic topographic distribution (eg, confined to pretibial areas or scars) and may cause prominent discoloration in sun-distributed areas, mucous membranes, sclerae, cartilage, and/or nails.

  • Patchy dyspigmentation is commonly enhanced by sun exposure and thus tends to occur in sun-distributed areas on the face, neck, V of the chest, upper back, and distal upper extremities. Specific drugs such as amiodarone, daunorubicin, gold, methotrexate, psoralens, and 5-fluorouracil induce hyperpigmented changes in this topographic distribution.
  • Generalized dyspigmentation, in contrast, usually appears uniform and along the entire length of the body. Changes such as these are commonly seen with minocycline use and can resemble those incited by other metabolic or endocrinologic diseases such as Addison disease or hypothyroidism.
  • Other medications primarily affect certain areas of the body, such as the palms and soles, mucous membranes, or teeth; often, pigmentary changes are greatest at the site of drug-administration, as is seen with iron, silver, or topical hydroquinone, or in previous scars, as with hydroxyurea.
  • Various inciting medications can also cause uncommon but predictable patterns of pigmentation, as in the case of flagellate pigmentation caused by bleomycin.
• Skin dyschromia induced by medications is also distinctive by the array of unusual colors of the lesions; drugs such as amiodarone, clofazimine, or heavy metals routinely induce slate-gray, blue, yellow, or red skin discoloration.
• Acanthosis nigricans may be mistaken for hyperpigmentation because it appears as dark velvety patches and plaques in the axillae, inguinal creases, neck, and upper back. The dark color is caused by marked folding of the epidermis and hyperkeratosis. Certain drugs, such as somatotrophin, testosterone, nicotinic acid, oral contraceptives, and insulin, have been associated with the development of acanthosis nigricans.
• Finally, drug-related pigmentation may also exhibit a more sharply defined outline than hyperpigmentation or leukoderma from other etiologies.

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^[2]

  • 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. Perioral chloroquine pigmentation.
  • 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^[3]

  • 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, and carmustine.
    • 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.^[4] A similar phenomenon has been reported with the ingestion of shiitake mushrooms.^[5] Bleomycin flagellate pigmentation.
    • 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.^[6] 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. 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.Adriamycin pigmented macule (arrow) on the tongue.
    • Hydroxyurea and zidovudine may cause similar pigmentary changes, including nail bed and/or lunula hyperpigmentation and tongue pigmentation.
• 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.^[8]
    • 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.^{[9, 10]}
    • 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 still used today 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^[11] ; 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.^{[12, 13, 14, 15]} 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 3 classic and distinct patterns of dyspigmentation. See images below.Minocycline pigmentation of the sclera. Minocycline pigmentation of the forearms. Minocycline pigmentation of the lower leg. Minocycline "muddy" pigmentation of the face in photodistribution.
    • 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.
    • 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.
    • 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,^[16] 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, tattoo removal lasers such as the Q-switched ruby laser have been shown to be partially effective in reducing residual pigmentation present after an extended minocycline-free period.^[17]
• Amiodarone^{[18, 19]}

  • 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. Amiodarone pigmentation.
  • 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.
• Azidothymidine

  • 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.^[20]
  • 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.
• Clofazimine^[21]

  • 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^[22]

  • 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.^[23] 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.^{[24, 25]} 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^[26] and desipramine,^[27] may also induce blue or slate-gray pigmentation in sun-exposed skin.^[28] 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.^[29]
• Miscellaneous

  • Other drugs associated with mucocutaneous dyspigmentation include oral contraceptives,^[30] 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.^[31]
  • 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.^[32]
  • 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.^{[33, 34]}
• 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.^[35]
  • 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.