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Drug-induced subacute cutaneous lupus erythematosus related to doxycycline

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Drug-induced subacute cutaneous lupus erythematosus related to doxycycline
Kristen K Miller MD, Julie Chu MD, Rishi Patel MD, Hideko Kamino MD
Dermatology Online Journal 17 (10): 3

Department of Dermatology, New York University, New York, New York


An 84-year-old woman presented with a three-month history of scaly, erythematous, annular papules and plaques on her chest, back, arms, and legs, which developed after a short course of doxycycline. Histopathologic examination of skin biopsy specimens was consistent with subacute cutaneous lupus erythematosus (SCLE). A presumptive diagnosis of drug-induced SCLE secondary to doxycycline was made. Although minocycline-induced SCLE is widely reported in the literature, there are no known previous case reports of doxycycline-induced SCLE.


Figure 1Figure 2

Figure 3

An 84-year-old woman presented to the Charles C. Harris Skin and Cancer Pavilion in August, 2010, for evaluation of asymptomatic, erythematous papules and plaques on her chest, back, abdomen, and extremities. She developed the lesions three months prior, after completing a three-day course of doxycycline for a routine dental procedure. On review of systems, she noted generalized fatigue but otherwise denied fevers, chills, arthralgias, gastrointestinal symptoms, or recent illness. She reported judicious sun avoidance. She takes levothyroxine and occasional aspirin but denied the use of additional medications. She had not had the lesions evaluated in the past and had not received any treatment.

The patient experienced a lichenoid drug eruption related to anesthesia during a routine colonoscopy one year prior to this presentation, which was confirmed on biopsy by an outside dermatologist and resolved with no sequelae. Medical history included hypothyroidism. She has no known drug allergies. She denies a family history of autoimmune diseases.

A punch biopsy and a shave biopsy were performed. Triamcinolone 0.05 percent cream has been applied twice daily.

Physical examination

Multiple, scaly, erythematous papules and scaly, erythematous, annular, 5 to 10 cm plaques with central blanching were present on the chest, back, abdomen, arms, and legs.

Laboratory data

An anti-nuclear antibody titer was positive at 1:160 with a speckled pattern. An anti-Ro/SS-A titer was positive at 5184 (normal less than 20). Anti-ds DNA, anti-La/SS-B antibodies, erythrocyte sedimentation rate, C-reactive protein, a complete blood count, and a comprehensive metabolic panel were normal or negative.


Figure 4

There is a superficial, mid perivascular, focal band-like inflammatory infiltrate predominantly of lymphocytes. Lymphocytes extend to the dermoepidermal junction where there is vacuolar alteration, effacement of the rete ridge pattern, necrotic keratinocytes, ortho- and parakeratosis, and follicular plugs. A colloidal iron stain highlights abundant deposits of connective-tissue mucin. A periodic acid-Schiff and diastase stain demonstrates a focally thick basement membrane.


Subacute cutaneous lupus erythematosus (SCLE) was first defined as a distinct clinical entity in 1979. It represents a subset of lupus erythematosus (LE) that is characterized by photosensitivity, a non-scarring papulosquamous eruption, and an association with anti-Ro/SS-A antibodies [1].

The possibility that a proportion of SCLE may be drug-induced was first recognized in a series of five patients, who developed the condition after exposure to hydrochlorothiazide [2]. Drug-induced SCLE (DI-SCLE) remains difficult to definitively diagnose because there are currently no standard diagnostic criteria. A temporal association between onset of disease and initiation of the drug, with drug withdrawal resulting in resolution of symptoms, remains the best evidence for this diagnosis [3].

Subacute cutaneous lupus erythematosus typically presents with either scaly, erythematous, annular plaques or with papulosquamous lesions that resemble psoriasis. However, more uncommon morphologies, such as exanthematous, pityriasiform, erythrodermic, bullous, poikilodermatous, and erythema-multiforme-like, have been described. Lesions usually are restricted to a photosensitive distribution on the anterior chest, upper back, shoulders, and extensor aspects of the arms. Lesions are longer-lasting than those observed in acute cutaneous lupus erythematosus (LE) and are non-scarring in contrast to those in discoid LE. Drug-induced SCLE and idiopathic SCLE display almost identical morphologic features, although idiopathic SCLE tends to spare the lower extremities in contrast to DI-SCLE [4, 5].

Subacute cutaneous lupus erythematosus occurs most frequently in women in the third and fourth decades of life, although the drug-induced form occurs in both genders and typically at an older age. Approximately one-half of patients meet the American College of Rheumatology criteria for systemic LE, but this form usually manifests with milder symptoms and the activity does not necessarily parallel cutaneous flares. Up to 70 percent of patients with idiopathic SCLE and DI-SCLE have anti-Ro/SS-A antibodies, whereas 30 to 40 percent have anti-La/SS-B antibodies [4, 6]. Although anti-histone IgG autoantibodies are traditionally associated with drug-induced LE, a recent study showed that an equal percent (75%) of patients with idiopathic and drug-induced LE are positive and that this test is uncommonly positive in SCLE. In contrast, 50 to 70 percent of patients with idiopathic systemic LE are positive for anti-double stranded DNA antibodies, whereas less than 5 percent of patients with drug-induced systemic LE and SCLE are positive [7, 8, 9].

The pathogenesis of SCLE is unknown although it has been documented that certain genetic backgrounds favor development. The HLA haplotype HLA1, B8, DR3 has been associated with SCLE. A predisposition for SCLE also has been associated with the TNF-alpha-308 polymorphism and deficiencies in C1q, C2, and C4. It is likely that the appropriate environmental insult in the setting of a favorable genetic background leads to disease development by triggering an inflammatory response that is mediated by a direct autoantibody effect, direct T-cell cytotoxicity, and antibody-dependent cell-mediated cytotoxicity. The most important triggers are ultraviolet light and drugs [5, 6].

The pathogenesis of DI-SCLE also is poorly understood. On average, development of disease occurs after four to 20 weeks but ranges from days to years. It remains unknown if autoantibodies develop in response to drug exposure or if autoantibodies predate drug exposure and exacerbate an underlying predisposition [9, 10]. Most patients experience improvement within eight weeks of discontinuing the offending medication, with anti-Ro titers becoming normal within eight months. Drugs classically associated with the development of DI-SCLE are calcium channel blockers, angiotenin-converting enzyme inhibitors, thiazide diuretics, and terbafine, although there have been case reports of more than 80 other medications, which include bupropion, beta-blockers, proton pump inhibitors, NSAIDs, and TNF-alpha antagonists [4, 5, 6, 11].

An association between minocycline and drug-induced systemic and cutaneous LE has been extensively documented. Minocycline exposure results in a three-fold increased risk of developing either the systemic or cutaneous form, with longer duration of exposure correlated with increased incidence. Although initial studies implicated other tetracyclines, the most recent literature found no association between other tetracyclines and systemic LE or SCLE. A search of the literature showed no documented association between doxycycline and DI-SCLE [12, 13, 14].

In our case, we suggest that the previous lichenoid drug eruption in fact may have been a manifestation of SCLE. The patient likely had a preexisting diagnosis of SCLE unknown to her, which existed at a sublinical level prior to her exposure to doxycycline. Doxycycline is a known photosensitizer and may have precipitated a flare of SCLE, which can be triggered by UV light. In this case, doxycycline acted as an exacerbating factor of an underlying condition, but did not directly lead to the development of SCLE as would be expected in DI-SCLE.

The mainstays of treatment for SCLE are antimalarials and glucocorticoids. Up to 75 percent of patients respond to hydroxychloroquine (an initial dose of 200 mg twice daily) within two to three months. If the response is inadequate, a second antimalarial such as quinacrine can be added (100 mg daily). Although topical glucocorticoids can provide relief, they are typically inadequate as monotherapy. Two-to-four week pulses of oral prednisone (1 mg/kg) may be helpful for flares. There are limited data available on other immunomodulators, mostly in the form of small patient series and case reports. Clinical experience has been most extensive with methotrexate and thalidomide, with positive response rates of 98 percent and 97 percent, respectively, in small retrospective cohort studies. Dapsone also has shown a positive clinical response in 48 percent of patients treated with this medication. Azathioprine, oral retinoids, and mycophenolate mofetil have been associated with promising responses in small case series and case reports [4].


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