Skin, Heart Meds Join List Of Lupus-Inducing Drugs

NEW YORK — The contemporary use of minocycline for acne and hydralazine for heart failure is expanding the spectrum of drug-induced lupus, and physicians need to heighten their index of suspicion for these as well as for other types of drug-induced lupus.

Minocycline-induced lupus was first reported in the early 1990s, and more than 250 cases have now been reported to the World Health Organization. There is a 5:1 female- to-male predominance. The clinical features include fever, morning stiffness, myalgias, polyarthralgias, and symmetric arthritis.

It is also characterized by large vessel vasculitis, and in more than 60% of patients, antineutrophil cytoplasmic antibodies are present and antihistone antibodies are not. This is in contrast to “classic” drug-induced lupus, in which antihistone antibodies are prominent.

Other autoantibodies also can be seen in minocycline-induced lupus, including antinuclear antibody (ANA) and anti-double-stranded DNA, said Dr. Andrew G. Franks Jr., of the department of dermatology at New York University Medical Center, New York.

“The likelihood of developing a lupus-like syndrome is elevated 8.5-fold with minocycline, so many clinicians are moving away from using minocycline for acne and rosacea and switching to doxycycline, which doesn't have this effect. I haven't used minocycline for 5 years,” he said.

Hydralazine, which had fallen out of favor as an antihypertensive, has regained popularity as part of combination therapy for heart failure in African Americans following the benefits seen in the African-American Heart Failure Trial (N. Engl. J. Med. 2004;351:2049-57).

Younger physicians might not be familiar with the association of hydralazine with drug-induced lupus, Dr. Franks said. The drug is one of the “big five” causes of classic drug-induced lupus, along with procainamide, isoniazid, quinidine, and phenytoin, but more than 100 drugs have been implicated in the 15,000-20,000 cases reported in the United States annually.

Classic drug-induced lupus is characterized by flulike symptoms and significant musculoskeletal involvement, with most patients being ANA and antihistone antibody positive. “Patients starting hydralazine or any drug in the big five should have a baseline test for ANA, although that is somewhat controversial,” Dr. Franks said.

The third main type of drug-induced lupus is subacute cutaneous lupus erythematosus (SCLE), which also is associated with an ever-widening variety of agents, including the thiazide diuretics, antifungals, calcium channel blockers, and ACE inhibitors. There also have been reports involving statins, leflunomide, and tumor necrosis factor inhibitors.

Clinically, SCLE can be difficult to sort out, he said, with targetoid lesions mixed with papulosquamous or annular lesions. The presentation can also resemble erythema multiforme or toxic epidermal necrolysis, with disadhesion of the epidermal layer and sloughing of the skin. “Patients with this subtype have very high morbidity and mortality.”

An audience member asked what happens when the offending drug is withdrawn. Dr. Franks explained that the situation is different from that with an allergic reaction, where the process should resolve in a week or two. “It can sometimes take months for this to remit, and some patients require additional therapy, but 95% of patients ultimately do remit,” he said at a rheumatology meeting sponsored by New York University.

Another audience member asked what to do if a patient's baseline ANA is positive, and whether that represents a contraindication to hydralazine therapy, for example. “That is why I said doing a baseline ANA is controversial,” Dr. Franks replied. “A number of groups do not suggest doing this, but clearly autoantibodies and a loss of tolerance precede the development of lupus, so one could be prudent and repeat the ANA yearly and see if it turns positive and the titer starts rising.”

No single mechanism has been identified to explain the variety of drugs associated with drug-induced lupus or the varied clinical and laboratory manifestations. Hypotheses include the possibility that the drugs can act as haptens or antigens that drive an immune response, or as immune system modulators that permit development of self-directed responses (Semin. Arthritis Rheum. 2007 Dec. 31 [doi:10.1016/j.sem arthrit.2007. 10.001]).

Dr. Franks reported having no financial relationships to disclose.

The likelihood of developing a lupus-like syndrome is elevated 8.5-fold with minocycline. DR. FRANKS

NEW YORK — The contemporary use of minocycline for acne and hydralazine for heart failure is expanding the spectrum of drug-induced lupus, and physicians need to heighten their index of suspicion for these as well as for other types of drug-induced lupus.

Minocycline-induced lupus was first reported in the early 1990s, and more than 250 cases have now been reported to the World Health Organization. There is a 5:1 female- to-male predominance. The clinical features include fever, morning stiffness, myalgias, polyarthralgias, and symmetric arthritis.

It is also characterized by large vessel vasculitis, and in more than 60% of patients, antineutrophil cytoplasmic antibodies are present and antihistone antibodies are not. This is in contrast to “classic” drug-induced lupus, in which antihistone antibodies are prominent.

Other autoantibodies also can be seen in minocycline-induced lupus, including antinuclear antibody (ANA) and anti-double-stranded DNA, said Dr. Andrew G. Franks Jr., of the department of dermatology at New York University Medical Center, New York.

“The likelihood of developing a lupus-like syndrome is elevated 8.5-fold with minocycline, so many clinicians are moving away from using minocycline for acne and rosacea and switching to doxycycline, which doesn't have this effect. I haven't used minocycline for 5 years,” he said.

Hydralazine, which had fallen out of favor as an antihypertensive, has regained popularity as part of combination therapy for heart failure in African Americans following the benefits seen in the African-American Heart Failure Trial (N. Engl. J. Med. 2004;351:2049-57).

Younger physicians might not be familiar with the association of hydralazine with drug-induced lupus, Dr. Franks said. The drug is one of the “big five” causes of classic drug-induced lupus, along with procainamide, isoniazid, quinidine, and phenytoin, but more than 100 drugs have been implicated in the 15,000-20,000 cases reported in the United States annually.

Classic drug-induced lupus is characterized by flulike symptoms and significant musculoskeletal involvement, with most patients being ANA and antihistone antibody positive. “Patients starting hydralazine or any drug in the big five should have a baseline test for ANA, although that is somewhat controversial,” Dr. Franks said.

The third main type of drug-induced lupus is subacute cutaneous lupus erythematosus (SCLE), which also is associated with an ever-widening variety of agents, including the thiazide diuretics, antifungals, calcium channel blockers, and ACE inhibitors. There also have been reports involving statins, leflunomide, and tumor necrosis factor inhibitors.

Clinically, SCLE can be difficult to sort out, he said, with targetoid lesions mixed with papulosquamous or annular lesions. The presentation can also resemble erythema multiforme or toxic epidermal necrolysis, with disadhesion of the epidermal layer and sloughing of the skin. “Patients with this subtype have very high morbidity and mortality.”

An audience member asked what happens when the offending drug is withdrawn. Dr. Franks explained that the situation is different from that with an allergic reaction, where the process should resolve in a week or two. “It can sometimes take months for this to remit, and some patients require additional therapy, but 95% of patients ultimately do remit,” he said at a rheumatology meeting sponsored by New York University.

Another audience member asked what to do if a patient's baseline ANA is positive, and whether that represents a contraindication to hydralazine therapy, for example. “That is why I said doing a baseline ANA is controversial,” Dr. Franks replied. “A number of groups do not suggest doing this, but clearly autoantibodies and a loss of tolerance precede the development of lupus, so one could be prudent and repeat the ANA yearly and see if it turns positive and the titer starts rising.”

No single mechanism has been identified to explain the variety of drugs associated with drug-induced lupus or the varied clinical and laboratory manifestations. Hypotheses include the possibility that the drugs can act as haptens or antigens that drive an immune response, or as immune system modulators that permit development of self-directed responses (Semin. Arthritis Rheum. 2007 Dec. 31 [doi:10.1016/j.sem arthrit.2007. 10.001]).

Dr. Franks reported having no financial relationships to disclose.

The likelihood of developing a lupus-like syndrome is elevated 8.5-fold with minocycline. DR. FRANKS

NEW YORK — The contemporary use of minocycline for acne and hydralazine for heart failure is expanding the spectrum of drug-induced lupus, and physicians need to heighten their index of suspicion for these as well as for other types of drug-induced lupus.

Minocycline-induced lupus was first reported in the early 1990s, and more than 250 cases have now been reported to the World Health Organization. There is a 5:1 female- to-male predominance. The clinical features include fever, morning stiffness, myalgias, polyarthralgias, and symmetric arthritis.

It is also characterized by large vessel vasculitis, and in more than 60% of patients, antineutrophil cytoplasmic antibodies are present and antihistone antibodies are not. This is in contrast to “classic” drug-induced lupus, in which antihistone antibodies are prominent.

Other autoantibodies also can be seen in minocycline-induced lupus, including antinuclear antibody (ANA) and anti-double-stranded DNA, said Dr. Andrew G. Franks Jr., of the department of dermatology at New York University Medical Center, New York.

“The likelihood of developing a lupus-like syndrome is elevated 8.5-fold with minocycline, so many clinicians are moving away from using minocycline for acne and rosacea and switching to doxycycline, which doesn't have this effect. I haven't used minocycline for 5 years,” he said.

Hydralazine, which had fallen out of favor as an antihypertensive, has regained popularity as part of combination therapy for heart failure in African Americans following the benefits seen in the African-American Heart Failure Trial (N. Engl. J. Med. 2004;351:2049-57).

Younger physicians might not be familiar with the association of hydralazine with drug-induced lupus, Dr. Franks said. The drug is one of the “big five” causes of classic drug-induced lupus, along with procainamide, isoniazid, quinidine, and phenytoin, but more than 100 drugs have been implicated in the 15,000-20,000 cases reported in the United States annually.

Classic drug-induced lupus is characterized by flulike symptoms and significant musculoskeletal involvement, with most patients being ANA and antihistone antibody positive. “Patients starting hydralazine or any drug in the big five should have a baseline test for ANA, although that is somewhat controversial,” Dr. Franks said.

The third main type of drug-induced lupus is subacute cutaneous lupus erythematosus (SCLE), which also is associated with an ever-widening variety of agents, including the thiazide diuretics, antifungals, calcium channel blockers, and ACE inhibitors. There also have been reports involving statins, leflunomide, and tumor necrosis factor inhibitors.

Clinically, SCLE can be difficult to sort out, he said, with targetoid lesions mixed with papulosquamous or annular lesions. The presentation can also resemble erythema multiforme or toxic epidermal necrolysis, with disadhesion of the epidermal layer and sloughing of the skin. “Patients with this subtype have very high morbidity and mortality.”

An audience member asked what happens when the offending drug is withdrawn. Dr. Franks explained that the situation is different from that with an allergic reaction, where the process should resolve in a week or two. “It can sometimes take months for this to remit, and some patients require additional therapy, but 95% of patients ultimately do remit,” he said at a rheumatology meeting sponsored by New York University.

Another audience member asked what to do if a patient's baseline ANA is positive, and whether that represents a contraindication to hydralazine therapy, for example. “That is why I said doing a baseline ANA is controversial,” Dr. Franks replied. “A number of groups do not suggest doing this, but clearly autoantibodies and a loss of tolerance precede the development of lupus, so one could be prudent and repeat the ANA yearly and see if it turns positive and the titer starts rising.”

No single mechanism has been identified to explain the variety of drugs associated with drug-induced lupus or the varied clinical and laboratory manifestations. Hypotheses include the possibility that the drugs can act as haptens or antigens that drive an immune response, or as immune system modulators that permit development of self-directed responses (Semin. Arthritis Rheum. 2007 Dec. 31 [doi:10.1016/j.sem arthrit.2007. 10.001]).

Dr. Franks reported having no financial relationships to disclose.

The likelihood of developing a lupus-like syndrome is elevated 8.5-fold with minocycline. DR. FRANKS