Nancy Walsh

ABANO TERME, ITALY — The unexpected finding of increased rates of diabetes in patients with morphea suggests that metabolic factors may be involved in triggering the condition, Dr. Christiane Pfeiffer reported in a poster session at a congress on skin, rheumatism, and autoimmunity.

Several etiologic factors have been reported, though inconsistently, for morphea. Infection, particularly with Borrelia burgdorferi, has been suggested as a trigger, as have vaccination and trauma. But a questionnaire survey of 113 patients seeking care at a university-based dermatology department in Saxony, Germany, found twice the prevalence of diabetes in patients with morphea, compared with the normal population in the district. (See box.) This finding has not previously been reported for morphea, or cutaneous scleroderma, and the association may involve the effects of nonenzymatic glycosylation of extracellular matrix components in diabetes, she said.

Moreover, obesity was not implicated, because the increase in diabetes was seen even though body mass index was not significantly different in morphea patients than in age- and sex-matched controls, said Dr. Pfeiffer of the department of dermatology, University Hospital, Dresden, Germany.

Analysis of responses to questionnaires filled out by patients also revealed that the number of plaques correlated with the severity of disease and extracutaneous involvement.

In patients with five or more lesions, arthralgias were reported by 23.9% of the patients, myalgias by 15.2%, contractures by 10.9%, and esophageal dysmotility by 6.5%. In those with fewer than five lesions, the same complications were reported by 7.1%, 9.5%, 2.4%, and 2.4% of patients, respectively, she said. High numbers of lesions also correlated with increases in erythrocyte sedimentation rate and C-reactive protein levels.

A total of 78% of patients had the plaque variant of morphea, with the rest having the guttate variant, idiopathic atrophoderma of Pasini and Pierini, linear scleroderma, and profound scleroderma. In patients with all variants of morphea, lesions were found on the trunk in 81%, whereas only 8 patients had facial lesions. Overlap syndromes also were reported; 8 patients had morphea and lichen sclerosus et atrophicus; and two had morphea with eosinophilic fasciitis.

“Our data also suggest the existence of variant-specific organ involvement in morphea,” Dr. Pfeiffer said. Arthralgias were reported by 40% of patients with atrophoderma Pasini and Pierini, while linear scleroderma was associated with the presence of antinuclear antibodies, muscular atrophy, and contractures.

In patients with profound scleroderma, 45% had myalgias and myopathy. There were no increases in Raynaud symptoms, carpal tunnel syndrome, or lung disorders in patients with any of the variants, she said.

ABANO TERME, ITALY — The unexpected finding of increased rates of diabetes in patients with morphea suggests that metabolic factors may be involved in triggering the condition, Dr. Christiane Pfeiffer reported in a poster session at a congress on skin, rheumatism, and autoimmunity.

Several etiologic factors have been reported, though inconsistently, for morphea. Infection, particularly with Borrelia burgdorferi, has been suggested as a trigger, as have vaccination and trauma. But a questionnaire survey of 113 patients seeking care at a university-based dermatology department in Saxony, Germany, found twice the prevalence of diabetes in patients with morphea, compared with the normal population in the district. (See box.) This finding has not previously been reported for morphea, or cutaneous scleroderma, and the association may involve the effects of nonenzymatic glycosylation of extracellular matrix components in diabetes, she said.

Moreover, obesity was not implicated, because the increase in diabetes was seen even though body mass index was not significantly different in morphea patients than in age- and sex-matched controls, said Dr. Pfeiffer of the department of dermatology, University Hospital, Dresden, Germany.

Analysis of responses to questionnaires filled out by patients also revealed that the number of plaques correlated with the severity of disease and extracutaneous involvement.

In patients with five or more lesions, arthralgias were reported by 23.9% of the patients, myalgias by 15.2%, contractures by 10.9%, and esophageal dysmotility by 6.5%. In those with fewer than five lesions, the same complications were reported by 7.1%, 9.5%, 2.4%, and 2.4% of patients, respectively, she said. High numbers of lesions also correlated with increases in erythrocyte sedimentation rate and C-reactive protein levels.

A total of 78% of patients had the plaque variant of morphea, with the rest having the guttate variant, idiopathic atrophoderma of Pasini and Pierini, linear scleroderma, and profound scleroderma. In patients with all variants of morphea, lesions were found on the trunk in 81%, whereas only 8 patients had facial lesions. Overlap syndromes also were reported; 8 patients had morphea and lichen sclerosus et atrophicus; and two had morphea with eosinophilic fasciitis.

“Our data also suggest the existence of variant-specific organ involvement in morphea,” Dr. Pfeiffer said. Arthralgias were reported by 40% of patients with atrophoderma Pasini and Pierini, while linear scleroderma was associated with the presence of antinuclear antibodies, muscular atrophy, and contractures.

In patients with profound scleroderma, 45% had myalgias and myopathy. There were no increases in Raynaud symptoms, carpal tunnel syndrome, or lung disorders in patients with any of the variants, she said.

ABANO TERME, ITALY — The unexpected finding of increased rates of diabetes in patients with morphea suggests that metabolic factors may be involved in triggering the condition, Dr. Christiane Pfeiffer reported in a poster session at a congress on skin, rheumatism, and autoimmunity.

Several etiologic factors have been reported, though inconsistently, for morphea. Infection, particularly with Borrelia burgdorferi, has been suggested as a trigger, as have vaccination and trauma. But a questionnaire survey of 113 patients seeking care at a university-based dermatology department in Saxony, Germany, found twice the prevalence of diabetes in patients with morphea, compared with the normal population in the district. (See box.) This finding has not previously been reported for morphea, or cutaneous scleroderma, and the association may involve the effects of nonenzymatic glycosylation of extracellular matrix components in diabetes, she said.

Moreover, obesity was not implicated, because the increase in diabetes was seen even though body mass index was not significantly different in morphea patients than in age- and sex-matched controls, said Dr. Pfeiffer of the department of dermatology, University Hospital, Dresden, Germany.

Analysis of responses to questionnaires filled out by patients also revealed that the number of plaques correlated with the severity of disease and extracutaneous involvement.

In patients with five or more lesions, arthralgias were reported by 23.9% of the patients, myalgias by 15.2%, contractures by 10.9%, and esophageal dysmotility by 6.5%. In those with fewer than five lesions, the same complications were reported by 7.1%, 9.5%, 2.4%, and 2.4% of patients, respectively, she said. High numbers of lesions also correlated with increases in erythrocyte sedimentation rate and C-reactive protein levels.

A total of 78% of patients had the plaque variant of morphea, with the rest having the guttate variant, idiopathic atrophoderma of Pasini and Pierini, linear scleroderma, and profound scleroderma. In patients with all variants of morphea, lesions were found on the trunk in 81%, whereas only 8 patients had facial lesions. Overlap syndromes also were reported; 8 patients had morphea and lichen sclerosus et atrophicus; and two had morphea with eosinophilic fasciitis.

“Our data also suggest the existence of variant-specific organ involvement in morphea,” Dr. Pfeiffer said. Arthralgias were reported by 40% of patients with atrophoderma Pasini and Pierini, while linear scleroderma was associated with the presence of antinuclear antibodies, muscular atrophy, and contractures.

In patients with profound scleroderma, 45% had myalgias and myopathy. There were no increases in Raynaud symptoms, carpal tunnel syndrome, or lung disorders in patients with any of the variants, she said.

SAN DIEGO — The use of leukotriene modifiers to treat patients with asthma was not associated with the development of Churg-Strauss syndrome in a population-based, nested, case-control study.

Shortly after leukotriene modifiers were introduced in the mid-1990s, there were reports of more cases of this rare vasculitis than would be expected, suggesting there might be a link, Dr. Leslie R. Harrold said at the annual meeting of the American College of Rheumatology.

Subsequently, an investigation of reports of the syndrome to the Adverse Event Reporting System (AERS) database, maintained by the Food and Drug Administration, found a strong association with zafirlukast and montelukast, though not with zileuton (Clin. Ther. 2004;26:1092–104).

Several possible explanations for leukotriene modifiers being related to Churg-Strauss syndrome have been suggested, such as an increased awareness of the condition, and reductions in corticosteroid doses resulting in the unmasking of an underlying eosinophilic syndrome (J. Rheumatol. 2005;32:1076–80). It also is possible that patients receiving leukotriene modifiers tend to have more severe asthma, which may predispose them to Churg-Strauss syndrome.

“To investigate this relationship, we assembled a cohort of 382,377 adults who received three or more dispensings of an asthma drug during any calendar year between Jan. 1, 1996, and Dec. 31, 2002,” said Dr. Harrold of the University of Massachusetts, Worcester. The cohort came from a national health plan and three managed care plans, with a combined patient population of 13.9 million.

Patient age, gender, drugs dispensed, diagnoses, and procedures information were obtained from automated databases, and cases of Churg-Strauss syndrome were identified through the databases and confirmed by chart reviews.

Each patient with Churg-Strauss syndrome was then matched with 100 controls for age, sex, health plan region, and year of cohort entry. Dispensing information for the patients before they were diagnosed with Churg-Strauss syndrome also was obtained.

A total of 47 possible, probable, or definite cases of Churg-Strauss syndrome and their 4,700 matched controls were identified and analyzed, Dr. Harrold said.

Compared with controls, patients were significantly more likely to have received a greater number of asthma drug classes overall, and to have been given prescriptions for oral steroids, inhaled steroids, and leukotriene modifiers.

On multivariate analysis, the number of asthma drug classes used within the previous 6 months and the use of leukotriene modifiers in the previous 2–6 months were not associated with Churg-Strauss syndrome. Only oral and inhaled steroids were associated with the syndrome, with odds ratios of 5.1 and 4.4, respectively.

The study was funded by GlaxoSmithKline.

SAN DIEGO — The use of leukotriene modifiers to treat patients with asthma was not associated with the development of Churg-Strauss syndrome in a population-based, nested, case-control study.

Shortly after leukotriene modifiers were introduced in the mid-1990s, there were reports of more cases of this rare vasculitis than would be expected, suggesting there might be a link, Dr. Leslie R. Harrold said at the annual meeting of the American College of Rheumatology.

Subsequently, an investigation of reports of the syndrome to the Adverse Event Reporting System (AERS) database, maintained by the Food and Drug Administration, found a strong association with zafirlukast and montelukast, though not with zileuton (Clin. Ther. 2004;26:1092–104).

Several possible explanations for leukotriene modifiers being related to Churg-Strauss syndrome have been suggested, such as an increased awareness of the condition, and reductions in corticosteroid doses resulting in the unmasking of an underlying eosinophilic syndrome (J. Rheumatol. 2005;32:1076–80). It also is possible that patients receiving leukotriene modifiers tend to have more severe asthma, which may predispose them to Churg-Strauss syndrome.

“To investigate this relationship, we assembled a cohort of 382,377 adults who received three or more dispensings of an asthma drug during any calendar year between Jan. 1, 1996, and Dec. 31, 2002,” said Dr. Harrold of the University of Massachusetts, Worcester. The cohort came from a national health plan and three managed care plans, with a combined patient population of 13.9 million.

Patient age, gender, drugs dispensed, diagnoses, and procedures information were obtained from automated databases, and cases of Churg-Strauss syndrome were identified through the databases and confirmed by chart reviews.

Each patient with Churg-Strauss syndrome was then matched with 100 controls for age, sex, health plan region, and year of cohort entry. Dispensing information for the patients before they were diagnosed with Churg-Strauss syndrome also was obtained.

A total of 47 possible, probable, or definite cases of Churg-Strauss syndrome and their 4,700 matched controls were identified and analyzed, Dr. Harrold said.

Compared with controls, patients were significantly more likely to have received a greater number of asthma drug classes overall, and to have been given prescriptions for oral steroids, inhaled steroids, and leukotriene modifiers.

On multivariate analysis, the number of asthma drug classes used within the previous 6 months and the use of leukotriene modifiers in the previous 2–6 months were not associated with Churg-Strauss syndrome. Only oral and inhaled steroids were associated with the syndrome, with odds ratios of 5.1 and 4.4, respectively.

The study was funded by GlaxoSmithKline.

SAN DIEGO — The use of leukotriene modifiers to treat patients with asthma was not associated with the development of Churg-Strauss syndrome in a population-based, nested, case-control study.

Shortly after leukotriene modifiers were introduced in the mid-1990s, there were reports of more cases of this rare vasculitis than would be expected, suggesting there might be a link, Dr. Leslie R. Harrold said at the annual meeting of the American College of Rheumatology.

Subsequently, an investigation of reports of the syndrome to the Adverse Event Reporting System (AERS) database, maintained by the Food and Drug Administration, found a strong association with zafirlukast and montelukast, though not with zileuton (Clin. Ther. 2004;26:1092–104).

Several possible explanations for leukotriene modifiers being related to Churg-Strauss syndrome have been suggested, such as an increased awareness of the condition, and reductions in corticosteroid doses resulting in the unmasking of an underlying eosinophilic syndrome (J. Rheumatol. 2005;32:1076–80). It also is possible that patients receiving leukotriene modifiers tend to have more severe asthma, which may predispose them to Churg-Strauss syndrome.

“To investigate this relationship, we assembled a cohort of 382,377 adults who received three or more dispensings of an asthma drug during any calendar year between Jan. 1, 1996, and Dec. 31, 2002,” said Dr. Harrold of the University of Massachusetts, Worcester. The cohort came from a national health plan and three managed care plans, with a combined patient population of 13.9 million.

Patient age, gender, drugs dispensed, diagnoses, and procedures information were obtained from automated databases, and cases of Churg-Strauss syndrome were identified through the databases and confirmed by chart reviews.

Each patient with Churg-Strauss syndrome was then matched with 100 controls for age, sex, health plan region, and year of cohort entry. Dispensing information for the patients before they were diagnosed with Churg-Strauss syndrome also was obtained.

A total of 47 possible, probable, or definite cases of Churg-Strauss syndrome and their 4,700 matched controls were identified and analyzed, Dr. Harrold said.

Compared with controls, patients were significantly more likely to have received a greater number of asthma drug classes overall, and to have been given prescriptions for oral steroids, inhaled steroids, and leukotriene modifiers.

On multivariate analysis, the number of asthma drug classes used within the previous 6 months and the use of leukotriene modifiers in the previous 2–6 months were not associated with Churg-Strauss syndrome. Only oral and inhaled steroids were associated with the syndrome, with odds ratios of 5.1 and 4.4, respectively.

The study was funded by GlaxoSmithKline.

NEW YORK — There's no doubt that systemic drugs used to treat skin disorders can interact in myriad ways, with results ranging from rashes to death, but some commonly held assumptions about drug interactions are either untrue or controversial.

At a meeting on medical and surgical dermatology sponsored by Mount Sinai School of Medicine, Dr. Mark G. Lebwohl offered his top 10 problematic or misconstrued combinations:

▸ Methotrexate and trimethoprim-sulfamethoxazole. “This is known as Kevorkian therapy for psoriasis,” Dr. Lebwohl said. Several deaths are reported every year from this combination, which can cause severe myelosuppression.

Many other interactions can occur with methotrexate. Aspirin and many of the NSAIDs—including salicylate, ibuprofen, and naproxen—can increase methotrexate levels. Moreover, the combination of methotrexate and naproxen also increases naproxen levels. The NSAIDs that do not affect methotrexate levels and are safe to use in combination are flurbiprofen, ketoprofen, and piroxicam. “And the [cyclo-oxygenase-2] inhibitors were fine until the lawyers got there,” he said.

▸ Bexarotene and gemfibrozil. “Bexarotene has been a godsend for patients with mycosis fungoides who are not doing well with PUVA or narrow-band UVB,” but the combination of bexarotene with gemfibrozil is dangerous and should never be given, said Dr. Lebwohl, professor and chairman of dermatology at Mount Sinai in New York.

Like other retinoids, bexarotene causes hyperlipidemia. The specific dyslipidemia associated with this agent is hypertriglyceridemia, and gemfibrozil is the best drug for lowering triglycerides. Unfortunately, gemfibrozil raises bexarotene levels, and there have been cases of patients developing massive hypertriglyceridemia and pancreatitis. Atorvastatin and simvastatin are acceptable alternatives to gemfibrozil.

▸ Erythromycin and theophylline. Erythromycin elevates levels of theophylline, and because the asthma drug has a narrow therapeutic window, toxicity can result. Manifestations of theophylline toxicity include sinus tachycardia, tremor, and gastrointestinal disturbances.

Numerous other interactions have been seen with erythromycin. There have been reports of inappropriate antidiuretic hormone secretion syndrome, which is characterized by hyponatremia and potentially lethal metabolic disturbances, when erythromycin is combined with carbamazepine, Dr. Lebwohl said.

Inhibitors of cytochrome P450 3A, including nitroimidazole antifungals and certain calcium channel blockers and antidepressants, also are hazardous for patients taking erythromycin because they can double plasma erythromycin concentrations.

Erythromycin prolongs cardiac repolarization, and a recent large review found that patients taking erythromycin plus a cytochrome P450 3A inhibitor had three sudden deaths in 194 person-years of follow-up, compared with no deaths in 254 person-years for those patients taking amoxicillin plus a cytochrome P450 3A inhibitor (N. Engl. J. Med. 2004;351:1089–96). If a macrolide antibiotic is needed, then azithromycin is a suitable choice, because it does not inactivate the cytochrome enzymes.

▸ Azathioprine and allopurinol. The gout medication allopurinol interferes with the metabolism of azathioprine, increasing plasma levels of 6-mercaptopurine; serious blood dyscrasias can result. There have been numerous reports of pancytopenia and death when these two agents were given together, Dr. Lebwohl said.

Approximately 11% of the population is partially or completely deficient in the enzyme thiopurine methyltransferase, which is involved in the metabolism of azathioprine. “If you really want to wipe out the bone marrow, give the combination of azathioprine and allopurinol to a patient who is genetically deficient in this enzyme,” he said. An assay for thiopurine methyltransferase should always be obtained before a patient is started on azathioprine.

▸ Cyclosporine and many drugs. Cyclosporine has numerous potential drug interactions, and elevated levels are associated with a host of side effects, Dr. Lebwohl said. Among the more common adverse effects are elevations of BUN and creatinine levels, and ultimately hypertension and renal failure. Drugs such as calcium channel blockers and erythromycin, when used in combination with cyclosporine, can cause elevated cyclosporine levels, but others such as phenobarbital and phenytoin can reduce cyclosporine levels.

Also be cautious in giving cyclosporine to patients on atorvastatin, and monitor the serum creatine phosphokinase levels. The concern is the possible development of rhabdomyolysis, he said.

▸ Retinoids and tetracycline. This combination can result in pseudotumor cerebri, in which patients present with severe headache, vision abnormalities, and nausea and vomiting. Ophthalmologic examination is needed, as papilledema can occur.

▸ Ampicillin and allopurinol. In virtually every survey, the frequency of morbilliform drug reaction on first-time exposure to ampicillin and amoxicillin is 5%. One report found that the rate increased to 22.5% when ampicillin was given with allopurinol, however, so that's another combination to avoid, he said.

▸ Epinephrine and β-blockers. This is an old story, Dr. Lebwohl said. There have been many reports of malignant hypertension among patients on β-blockers who are given epinephrine, but these have involved massive quantities of epinephrine. “We're not talking about a punch biopsy here,” he said.

For most dermatologic procedures—with the notable exception of large-quantity liposuction—malignant hypertension is not an issue because so little epinephrine is used.

▸ Antibiotics and oral contraceptives. Whether antibiotics interfere with oral contraceptives has been controversial for years, Dr. Lebwohl said.

In one study, women taking antibiotics and birth control pills had a contraceptive failure rate of 1.6%. The failure rate, however, is 1% in women on oral contraceptives alone, so the difference is not statistically significant. Nonetheless, there have been numerous reports of pregnancies, particularly in women on low-dose estrogen pills, so “be cautious and warn them about the potential interaction,” he said.

▸ Acitretin and ethanol. The belief that postmenopausal women and men must avoid alcohol while taking acitretin is incorrect. “I don't think a month goes by in my practice where a male or a postmenopausal female comes in saying they can't take acitretin because they would have to give up all alcohol,” Dr. Lebwohl said.

The risk with this combination is that, in the presence in alcohol, acitretin is converted to etretinate, which has a much longer period of teratogenicity. The real risk is only in women with childbearing potential.

Combining methotrexate and trimethoprim-sulfamethoxazole 'is known as Kevorkian therapy for psoriasis.' DR. LEBWOHL

NEW YORK — There's no doubt that systemic drugs used to treat skin disorders can interact in myriad ways, with results ranging from rashes to death, but some commonly held assumptions about drug interactions are either untrue or controversial.

At a meeting on medical and surgical dermatology sponsored by Mount Sinai School of Medicine, Dr. Mark G. Lebwohl offered his top 10 problematic or misconstrued combinations:

▸ Methotrexate and trimethoprim-sulfamethoxazole. “This is known as Kevorkian therapy for psoriasis,” Dr. Lebwohl said. Several deaths are reported every year from this combination, which can cause severe myelosuppression.

Many other interactions can occur with methotrexate. Aspirin and many of the NSAIDs—including salicylate, ibuprofen, and naproxen—can increase methotrexate levels. Moreover, the combination of methotrexate and naproxen also increases naproxen levels. The NSAIDs that do not affect methotrexate levels and are safe to use in combination are flurbiprofen, ketoprofen, and piroxicam. “And the [cyclo-oxygenase-2] inhibitors were fine until the lawyers got there,” he said.

▸ Bexarotene and gemfibrozil. “Bexarotene has been a godsend for patients with mycosis fungoides who are not doing well with PUVA or narrow-band UVB,” but the combination of bexarotene with gemfibrozil is dangerous and should never be given, said Dr. Lebwohl, professor and chairman of dermatology at Mount Sinai in New York.

Like other retinoids, bexarotene causes hyperlipidemia. The specific dyslipidemia associated with this agent is hypertriglyceridemia, and gemfibrozil is the best drug for lowering triglycerides. Unfortunately, gemfibrozil raises bexarotene levels, and there have been cases of patients developing massive hypertriglyceridemia and pancreatitis. Atorvastatin and simvastatin are acceptable alternatives to gemfibrozil.

▸ Erythromycin and theophylline. Erythromycin elevates levels of theophylline, and because the asthma drug has a narrow therapeutic window, toxicity can result. Manifestations of theophylline toxicity include sinus tachycardia, tremor, and gastrointestinal disturbances.

Numerous other interactions have been seen with erythromycin. There have been reports of inappropriate antidiuretic hormone secretion syndrome, which is characterized by hyponatremia and potentially lethal metabolic disturbances, when erythromycin is combined with carbamazepine, Dr. Lebwohl said.

Inhibitors of cytochrome P450 3A, including nitroimidazole antifungals and certain calcium channel blockers and antidepressants, also are hazardous for patients taking erythromycin because they can double plasma erythromycin concentrations.

Erythromycin prolongs cardiac repolarization, and a recent large review found that patients taking erythromycin plus a cytochrome P450 3A inhibitor had three sudden deaths in 194 person-years of follow-up, compared with no deaths in 254 person-years for those patients taking amoxicillin plus a cytochrome P450 3A inhibitor (N. Engl. J. Med. 2004;351:1089–96). If a macrolide antibiotic is needed, then azithromycin is a suitable choice, because it does not inactivate the cytochrome enzymes.

▸ Azathioprine and allopurinol. The gout medication allopurinol interferes with the metabolism of azathioprine, increasing plasma levels of 6-mercaptopurine; serious blood dyscrasias can result. There have been numerous reports of pancytopenia and death when these two agents were given together, Dr. Lebwohl said.

Approximately 11% of the population is partially or completely deficient in the enzyme thiopurine methyltransferase, which is involved in the metabolism of azathioprine. “If you really want to wipe out the bone marrow, give the combination of azathioprine and allopurinol to a patient who is genetically deficient in this enzyme,” he said. An assay for thiopurine methyltransferase should always be obtained before a patient is started on azathioprine.

▸ Cyclosporine and many drugs. Cyclosporine has numerous potential drug interactions, and elevated levels are associated with a host of side effects, Dr. Lebwohl said. Among the more common adverse effects are elevations of BUN and creatinine levels, and ultimately hypertension and renal failure. Drugs such as calcium channel blockers and erythromycin, when used in combination with cyclosporine, can cause elevated cyclosporine levels, but others such as phenobarbital and phenytoin can reduce cyclosporine levels.

Also be cautious in giving cyclosporine to patients on atorvastatin, and monitor the serum creatine phosphokinase levels. The concern is the possible development of rhabdomyolysis, he said.

▸ Retinoids and tetracycline. This combination can result in pseudotumor cerebri, in which patients present with severe headache, vision abnormalities, and nausea and vomiting. Ophthalmologic examination is needed, as papilledema can occur.

▸ Ampicillin and allopurinol. In virtually every survey, the frequency of morbilliform drug reaction on first-time exposure to ampicillin and amoxicillin is 5%. One report found that the rate increased to 22.5% when ampicillin was given with allopurinol, however, so that's another combination to avoid, he said.

▸ Epinephrine and β-blockers. This is an old story, Dr. Lebwohl said. There have been many reports of malignant hypertension among patients on β-blockers who are given epinephrine, but these have involved massive quantities of epinephrine. “We're not talking about a punch biopsy here,” he said.

For most dermatologic procedures—with the notable exception of large-quantity liposuction—malignant hypertension is not an issue because so little epinephrine is used.

▸ Antibiotics and oral contraceptives. Whether antibiotics interfere with oral contraceptives has been controversial for years, Dr. Lebwohl said.

In one study, women taking antibiotics and birth control pills had a contraceptive failure rate of 1.6%. The failure rate, however, is 1% in women on oral contraceptives alone, so the difference is not statistically significant. Nonetheless, there have been numerous reports of pregnancies, particularly in women on low-dose estrogen pills, so “be cautious and warn them about the potential interaction,” he said.

▸ Acitretin and ethanol. The belief that postmenopausal women and men must avoid alcohol while taking acitretin is incorrect. “I don't think a month goes by in my practice where a male or a postmenopausal female comes in saying they can't take acitretin because they would have to give up all alcohol,” Dr. Lebwohl said.

The risk with this combination is that, in the presence in alcohol, acitretin is converted to etretinate, which has a much longer period of teratogenicity. The real risk is only in women with childbearing potential.

Combining methotrexate and trimethoprim-sulfamethoxazole 'is known as Kevorkian therapy for psoriasis.' DR. LEBWOHL

NEW YORK — There's no doubt that systemic drugs used to treat skin disorders can interact in myriad ways, with results ranging from rashes to death, but some commonly held assumptions about drug interactions are either untrue or controversial.

At a meeting on medical and surgical dermatology sponsored by Mount Sinai School of Medicine, Dr. Mark G. Lebwohl offered his top 10 problematic or misconstrued combinations:

▸ Methotrexate and trimethoprim-sulfamethoxazole. “This is known as Kevorkian therapy for psoriasis,” Dr. Lebwohl said. Several deaths are reported every year from this combination, which can cause severe myelosuppression.

Many other interactions can occur with methotrexate. Aspirin and many of the NSAIDs—including salicylate, ibuprofen, and naproxen—can increase methotrexate levels. Moreover, the combination of methotrexate and naproxen also increases naproxen levels. The NSAIDs that do not affect methotrexate levels and are safe to use in combination are flurbiprofen, ketoprofen, and piroxicam. “And the [cyclo-oxygenase-2] inhibitors were fine until the lawyers got there,” he said.

▸ Bexarotene and gemfibrozil. “Bexarotene has been a godsend for patients with mycosis fungoides who are not doing well with PUVA or narrow-band UVB,” but the combination of bexarotene with gemfibrozil is dangerous and should never be given, said Dr. Lebwohl, professor and chairman of dermatology at Mount Sinai in New York.

Like other retinoids, bexarotene causes hyperlipidemia. The specific dyslipidemia associated with this agent is hypertriglyceridemia, and gemfibrozil is the best drug for lowering triglycerides. Unfortunately, gemfibrozil raises bexarotene levels, and there have been cases of patients developing massive hypertriglyceridemia and pancreatitis. Atorvastatin and simvastatin are acceptable alternatives to gemfibrozil.

▸ Erythromycin and theophylline. Erythromycin elevates levels of theophylline, and because the asthma drug has a narrow therapeutic window, toxicity can result. Manifestations of theophylline toxicity include sinus tachycardia, tremor, and gastrointestinal disturbances.

Numerous other interactions have been seen with erythromycin. There have been reports of inappropriate antidiuretic hormone secretion syndrome, which is characterized by hyponatremia and potentially lethal metabolic disturbances, when erythromycin is combined with carbamazepine, Dr. Lebwohl said.

Inhibitors of cytochrome P450 3A, including nitroimidazole antifungals and certain calcium channel blockers and antidepressants, also are hazardous for patients taking erythromycin because they can double plasma erythromycin concentrations.

Erythromycin prolongs cardiac repolarization, and a recent large review found that patients taking erythromycin plus a cytochrome P450 3A inhibitor had three sudden deaths in 194 person-years of follow-up, compared with no deaths in 254 person-years for those patients taking amoxicillin plus a cytochrome P450 3A inhibitor (N. Engl. J. Med. 2004;351:1089–96). If a macrolide antibiotic is needed, then azithromycin is a suitable choice, because it does not inactivate the cytochrome enzymes.

▸ Azathioprine and allopurinol. The gout medication allopurinol interferes with the metabolism of azathioprine, increasing plasma levels of 6-mercaptopurine; serious blood dyscrasias can result. There have been numerous reports of pancytopenia and death when these two agents were given together, Dr. Lebwohl said.

Approximately 11% of the population is partially or completely deficient in the enzyme thiopurine methyltransferase, which is involved in the metabolism of azathioprine. “If you really want to wipe out the bone marrow, give the combination of azathioprine and allopurinol to a patient who is genetically deficient in this enzyme,” he said. An assay for thiopurine methyltransferase should always be obtained before a patient is started on azathioprine.

▸ Cyclosporine and many drugs. Cyclosporine has numerous potential drug interactions, and elevated levels are associated with a host of side effects, Dr. Lebwohl said. Among the more common adverse effects are elevations of BUN and creatinine levels, and ultimately hypertension and renal failure. Drugs such as calcium channel blockers and erythromycin, when used in combination with cyclosporine, can cause elevated cyclosporine levels, but others such as phenobarbital and phenytoin can reduce cyclosporine levels.

Also be cautious in giving cyclosporine to patients on atorvastatin, and monitor the serum creatine phosphokinase levels. The concern is the possible development of rhabdomyolysis, he said.

▸ Retinoids and tetracycline. This combination can result in pseudotumor cerebri, in which patients present with severe headache, vision abnormalities, and nausea and vomiting. Ophthalmologic examination is needed, as papilledema can occur.

▸ Ampicillin and allopurinol. In virtually every survey, the frequency of morbilliform drug reaction on first-time exposure to ampicillin and amoxicillin is 5%. One report found that the rate increased to 22.5% when ampicillin was given with allopurinol, however, so that's another combination to avoid, he said.

▸ Epinephrine and β-blockers. This is an old story, Dr. Lebwohl said. There have been many reports of malignant hypertension among patients on β-blockers who are given epinephrine, but these have involved massive quantities of epinephrine. “We're not talking about a punch biopsy here,” he said.

For most dermatologic procedures—with the notable exception of large-quantity liposuction—malignant hypertension is not an issue because so little epinephrine is used.

▸ Antibiotics and oral contraceptives. Whether antibiotics interfere with oral contraceptives has been controversial for years, Dr. Lebwohl said.

In one study, women taking antibiotics and birth control pills had a contraceptive failure rate of 1.6%. The failure rate, however, is 1% in women on oral contraceptives alone, so the difference is not statistically significant. Nonetheless, there have been numerous reports of pregnancies, particularly in women on low-dose estrogen pills, so “be cautious and warn them about the potential interaction,” he said.

▸ Acitretin and ethanol. The belief that postmenopausal women and men must avoid alcohol while taking acitretin is incorrect. “I don't think a month goes by in my practice where a male or a postmenopausal female comes in saying they can't take acitretin because they would have to give up all alcohol,” Dr. Lebwohl said.

The risk with this combination is that, in the presence in alcohol, acitretin is converted to etretinate, which has a much longer period of teratogenicity. The real risk is only in women with childbearing potential.

Combining methotrexate and trimethoprim-sulfamethoxazole 'is known as Kevorkian therapy for psoriasis.' DR. LEBWOHL

SAN DIEGO — Progress is being made in establishing a safe, effective, global treatment strategy for Wegener's granulomatosis and microscopic polyangiitis, but relapses are still common and the optimal maintenance therapy remains to be established, according to Dr. Christian Pagnoux.

Speaking on behalf of the French Vasculitis Study Group at the annual meeting of the American College of Rheumatology, Dr. Pagnoux said that an induction regimen of pulsed intravenous cyclophosphamide plus corticosteroids followed by maintenance therapy with either methotrexate or azathioprine had been effective in a prospective, multicenter trial.

It had been shown previously that pulsed intravenous cyclophosphamide was as effective as daily oral cyclophosphamide for inducing remission in these antineutrophil cytoplasmic antibody-associated vasculitides, and was less toxic. In this trial, 159 patients were given the drug in a dose of 700 mg/m

Then they were randomized to receive either oral azathioprine, 2 mg/kg per day, or methotrexate, 0.3 mg/kg per week, for 12 months.

The primary end point was the number of adverse events in each maintenance arm, while secondary end points were survival and relapse-free survival 5 years after enrollment of the first patient.

The induction regimen was effective for 126 (79%) patients. A mean of 10 cyclophosphamide pulses were given before remission was achieved, and the mean cumulative dose was 10.4 g. Corticosteroids were tapered rapidly, but the daily dose remained above 20 mg/day for more than 5 months.

Among patients who did not achieve remission, 32 did not respond to cyclophosphamide and one had an allergic reaction. Twenty of the 33 were switched to oral daily cyclophosphamide, and 15 responded, but 14 of the nonresponders ultimately died, 10 without having time to receive any further therapy, said Dr. Pagnoux of Hôpital Cochin, Paris.

An additional 12 patients were excluded from the analysis because they had remained on maintenance therapy for periods exceeding 12 months for no justified reason, he said. Among the 114 patients who were evaluated, 55 had been randomized to receive azathioprine and 59 to receive methotrexate. Baseline characteristics in the two groups were comparable.

Adverse events occurred in 47% of the azathioprine group and in 56% of the methotrexate group, while serious adverse events requiring withdrawal occurred in 13% and 20%, respectively.

Although there were more adverse events among patients in the methotrexate arm, the differences were not statistically significant.

However, three patients in the methotrexate group died, two from sepsis “directly related” to methotrexate, he said.

“Notably, the one patient who died in the azathioprine group had a pulmonary embolism 7 months after being switched to methotrexate because of an adverse event related to azathioprine,” Dr. Pagnoux said.

A total of 40% of patients in the azathioprine group had at least one relapse during the trial, as did 31% of the methotrexate patients. Again, this difference was not statistically significant.

Relapse-free survival rates at 18 and 30 months after diagnosis were 87% and 73% for the azathioprine group and 90% and 78% for the methotrexate group.

“This trial showed the efficacy of intravenous cyclophosphamide as induction, and good outcome with overall mortality of 11.3%,” he said.

“Hopefully, ongoing trials will probably tell us whether longer maintenance treatment or other drugs like mycophenolate mofetil can further improve outcome,” Dr. Pagnoux said.

SAN DIEGO — Progress is being made in establishing a safe, effective, global treatment strategy for Wegener's granulomatosis and microscopic polyangiitis, but relapses are still common and the optimal maintenance therapy remains to be established, according to Dr. Christian Pagnoux.

Speaking on behalf of the French Vasculitis Study Group at the annual meeting of the American College of Rheumatology, Dr. Pagnoux said that an induction regimen of pulsed intravenous cyclophosphamide plus corticosteroids followed by maintenance therapy with either methotrexate or azathioprine had been effective in a prospective, multicenter trial.

It had been shown previously that pulsed intravenous cyclophosphamide was as effective as daily oral cyclophosphamide for inducing remission in these antineutrophil cytoplasmic antibody-associated vasculitides, and was less toxic. In this trial, 159 patients were given the drug in a dose of 700 mg/m

Then they were randomized to receive either oral azathioprine, 2 mg/kg per day, or methotrexate, 0.3 mg/kg per week, for 12 months.

The primary end point was the number of adverse events in each maintenance arm, while secondary end points were survival and relapse-free survival 5 years after enrollment of the first patient.

The induction regimen was effective for 126 (79%) patients. A mean of 10 cyclophosphamide pulses were given before remission was achieved, and the mean cumulative dose was 10.4 g. Corticosteroids were tapered rapidly, but the daily dose remained above 20 mg/day for more than 5 months.

Among patients who did not achieve remission, 32 did not respond to cyclophosphamide and one had an allergic reaction. Twenty of the 33 were switched to oral daily cyclophosphamide, and 15 responded, but 14 of the nonresponders ultimately died, 10 without having time to receive any further therapy, said Dr. Pagnoux of Hôpital Cochin, Paris.

An additional 12 patients were excluded from the analysis because they had remained on maintenance therapy for periods exceeding 12 months for no justified reason, he said. Among the 114 patients who were evaluated, 55 had been randomized to receive azathioprine and 59 to receive methotrexate. Baseline characteristics in the two groups were comparable.

Adverse events occurred in 47% of the azathioprine group and in 56% of the methotrexate group, while serious adverse events requiring withdrawal occurred in 13% and 20%, respectively.

Although there were more adverse events among patients in the methotrexate arm, the differences were not statistically significant.

However, three patients in the methotrexate group died, two from sepsis “directly related” to methotrexate, he said.

“Notably, the one patient who died in the azathioprine group had a pulmonary embolism 7 months after being switched to methotrexate because of an adverse event related to azathioprine,” Dr. Pagnoux said.

A total of 40% of patients in the azathioprine group had at least one relapse during the trial, as did 31% of the methotrexate patients. Again, this difference was not statistically significant.

Relapse-free survival rates at 18 and 30 months after diagnosis were 87% and 73% for the azathioprine group and 90% and 78% for the methotrexate group.

“This trial showed the efficacy of intravenous cyclophosphamide as induction, and good outcome with overall mortality of 11.3%,” he said.

“Hopefully, ongoing trials will probably tell us whether longer maintenance treatment or other drugs like mycophenolate mofetil can further improve outcome,” Dr. Pagnoux said.

SAN DIEGO — Progress is being made in establishing a safe, effective, global treatment strategy for Wegener's granulomatosis and microscopic polyangiitis, but relapses are still common and the optimal maintenance therapy remains to be established, according to Dr. Christian Pagnoux.

Speaking on behalf of the French Vasculitis Study Group at the annual meeting of the American College of Rheumatology, Dr. Pagnoux said that an induction regimen of pulsed intravenous cyclophosphamide plus corticosteroids followed by maintenance therapy with either methotrexate or azathioprine had been effective in a prospective, multicenter trial.

It had been shown previously that pulsed intravenous cyclophosphamide was as effective as daily oral cyclophosphamide for inducing remission in these antineutrophil cytoplasmic antibody-associated vasculitides, and was less toxic. In this trial, 159 patients were given the drug in a dose of 700 mg/m

Then they were randomized to receive either oral azathioprine, 2 mg/kg per day, or methotrexate, 0.3 mg/kg per week, for 12 months.

The primary end point was the number of adverse events in each maintenance arm, while secondary end points were survival and relapse-free survival 5 years after enrollment of the first patient.

The induction regimen was effective for 126 (79%) patients. A mean of 10 cyclophosphamide pulses were given before remission was achieved, and the mean cumulative dose was 10.4 g. Corticosteroids were tapered rapidly, but the daily dose remained above 20 mg/day for more than 5 months.

Among patients who did not achieve remission, 32 did not respond to cyclophosphamide and one had an allergic reaction. Twenty of the 33 were switched to oral daily cyclophosphamide, and 15 responded, but 14 of the nonresponders ultimately died, 10 without having time to receive any further therapy, said Dr. Pagnoux of Hôpital Cochin, Paris.

An additional 12 patients were excluded from the analysis because they had remained on maintenance therapy for periods exceeding 12 months for no justified reason, he said. Among the 114 patients who were evaluated, 55 had been randomized to receive azathioprine and 59 to receive methotrexate. Baseline characteristics in the two groups were comparable.

Adverse events occurred in 47% of the azathioprine group and in 56% of the methotrexate group, while serious adverse events requiring withdrawal occurred in 13% and 20%, respectively.

Although there were more adverse events among patients in the methotrexate arm, the differences were not statistically significant.

However, three patients in the methotrexate group died, two from sepsis “directly related” to methotrexate, he said.

“Notably, the one patient who died in the azathioprine group had a pulmonary embolism 7 months after being switched to methotrexate because of an adverse event related to azathioprine,” Dr. Pagnoux said.

A total of 40% of patients in the azathioprine group had at least one relapse during the trial, as did 31% of the methotrexate patients. Again, this difference was not statistically significant.

Relapse-free survival rates at 18 and 30 months after diagnosis were 87% and 73% for the azathioprine group and 90% and 78% for the methotrexate group.

“This trial showed the efficacy of intravenous cyclophosphamide as induction, and good outcome with overall mortality of 11.3%,” he said.

“Hopefully, ongoing trials will probably tell us whether longer maintenance treatment or other drugs like mycophenolate mofetil can further improve outcome,” Dr. Pagnoux said.

SAN DIEGO — A second or third course of treatment with rituximab was safe and effective in patients with active rheumatoid arthritis enrolled in an open-label extension study, according to two poster presentations at the annual meeting of the American College of Rheumatology.

The monoclonal antibody rituximab had previously been investigated in two phase II studies in rheumatoid arthritis, and patients who had demonstrated improvement in the first treatment course (C1) were eligible to enroll in the extension phase.

Thus far 192 have enrolled; 141 have received a second course (C2) of rituximab treatment, and 25 received a third course (C3), according to Dr. Paul Emery of the Leeds (England) General Infirmary.

During C1, patients received intravenous rituximab in a dosage of 500 mg or 1,000 mg on days 1 and 15, along with methotrexate, cyclophosphamide, or no disease-modifying antirheumatic drug. They also received corticosteroids or placebo.

During C2, patients received 1,000-mg rituximab on days 1 and 15, 10–25 mg/week of methotrexate, and intravenous glucocorticoid premedication; they also received oral glucocorticoids for two weeks. Responses at week 24 were compared with the C1 and C2 baselines.

In the poster that summarized the safety data from C2, Dr. Emery reported that the percentage of patients who experienced serious adverse events after C2 was similar to that after C1 (11% and 10%, respectively).

There was no evidence of cumulative toxicity with repeat courses of the drug, he noted.

Following C1, there was one serious infection (bacterial arthritis). Four patients experienced serious infections following C2—one each of appendicitis, otitis media, bronchopneumonia, and urinary tract infection.

There have been no reports of serious infections following C3, wrote Dr. Emery.

The majority of infusion-related adverse events were mild to moderate.

A separate poster presented efficacy data from the first 78 patients who have either been followed for 24 weeks following C2 or who withdrew from the trial.

“By all measures, rituximab retreatment following C2 was effective,” wrote Dr. Roy M. Fleischmann of the University of Texas Southwestern Medical Center, Dallas.

Disease Activity Score (DAS)-28 fell from a mean of 6.95 at C1 baseline to 4.58 at week 24, and then from a mean of 6.43 at C2 baseline to 4.16.

A total of 47 patients achieved ACR20 responses from the C2 baseline, and 57 achieved good to moderate EULAR responses.

C-reactive protein levels and rheumatoid factor titers both were significantly reduced during the observation periods after C1 and C2.

Rituximab targets CD20-positive B cells, and by binding CD20 it depletes B cells. However, because CD20 is not expressed on stem or plasma cells, B-cell recovery subsequently occurs.

Both B-cell depleted and B-cell recovered patients responded following C2, Dr. Fleischmann wrote.

Dr. Fleischmann disclosed that he has received research grants and consulting fees and is on the speakers' bureau of Genentech Inc.

Dr. Emery disclosed that he has received research grants and consulting fees from Roche.

There was no evidence of cumulative toxicity with repeated courses of rituximab. DR. EMERY

SAN DIEGO — A second or third course of treatment with rituximab was safe and effective in patients with active rheumatoid arthritis enrolled in an open-label extension study, according to two poster presentations at the annual meeting of the American College of Rheumatology.

The monoclonal antibody rituximab had previously been investigated in two phase II studies in rheumatoid arthritis, and patients who had demonstrated improvement in the first treatment course (C1) were eligible to enroll in the extension phase.

Thus far 192 have enrolled; 141 have received a second course (C2) of rituximab treatment, and 25 received a third course (C3), according to Dr. Paul Emery of the Leeds (England) General Infirmary.

During C1, patients received intravenous rituximab in a dosage of 500 mg or 1,000 mg on days 1 and 15, along with methotrexate, cyclophosphamide, or no disease-modifying antirheumatic drug. They also received corticosteroids or placebo.

During C2, patients received 1,000-mg rituximab on days 1 and 15, 10–25 mg/week of methotrexate, and intravenous glucocorticoid premedication; they also received oral glucocorticoids for two weeks. Responses at week 24 were compared with the C1 and C2 baselines.

In the poster that summarized the safety data from C2, Dr. Emery reported that the percentage of patients who experienced serious adverse events after C2 was similar to that after C1 (11% and 10%, respectively).

There was no evidence of cumulative toxicity with repeat courses of the drug, he noted.

Following C1, there was one serious infection (bacterial arthritis). Four patients experienced serious infections following C2—one each of appendicitis, otitis media, bronchopneumonia, and urinary tract infection.

There have been no reports of serious infections following C3, wrote Dr. Emery.

The majority of infusion-related adverse events were mild to moderate.

A separate poster presented efficacy data from the first 78 patients who have either been followed for 24 weeks following C2 or who withdrew from the trial.

“By all measures, rituximab retreatment following C2 was effective,” wrote Dr. Roy M. Fleischmann of the University of Texas Southwestern Medical Center, Dallas.

Disease Activity Score (DAS)-28 fell from a mean of 6.95 at C1 baseline to 4.58 at week 24, and then from a mean of 6.43 at C2 baseline to 4.16.

A total of 47 patients achieved ACR20 responses from the C2 baseline, and 57 achieved good to moderate EULAR responses.

C-reactive protein levels and rheumatoid factor titers both were significantly reduced during the observation periods after C1 and C2.

Rituximab targets CD20-positive B cells, and by binding CD20 it depletes B cells. However, because CD20 is not expressed on stem or plasma cells, B-cell recovery subsequently occurs.

Both B-cell depleted and B-cell recovered patients responded following C2, Dr. Fleischmann wrote.

Dr. Fleischmann disclosed that he has received research grants and consulting fees and is on the speakers' bureau of Genentech Inc.

Dr. Emery disclosed that he has received research grants and consulting fees from Roche.

There was no evidence of cumulative toxicity with repeated courses of rituximab. DR. EMERY

SAN DIEGO — A second or third course of treatment with rituximab was safe and effective in patients with active rheumatoid arthritis enrolled in an open-label extension study, according to two poster presentations at the annual meeting of the American College of Rheumatology.

The monoclonal antibody rituximab had previously been investigated in two phase II studies in rheumatoid arthritis, and patients who had demonstrated improvement in the first treatment course (C1) were eligible to enroll in the extension phase.

Thus far 192 have enrolled; 141 have received a second course (C2) of rituximab treatment, and 25 received a third course (C3), according to Dr. Paul Emery of the Leeds (England) General Infirmary.

During C1, patients received intravenous rituximab in a dosage of 500 mg or 1,000 mg on days 1 and 15, along with methotrexate, cyclophosphamide, or no disease-modifying antirheumatic drug. They also received corticosteroids or placebo.

During C2, patients received 1,000-mg rituximab on days 1 and 15, 10–25 mg/week of methotrexate, and intravenous glucocorticoid premedication; they also received oral glucocorticoids for two weeks. Responses at week 24 were compared with the C1 and C2 baselines.

In the poster that summarized the safety data from C2, Dr. Emery reported that the percentage of patients who experienced serious adverse events after C2 was similar to that after C1 (11% and 10%, respectively).

There was no evidence of cumulative toxicity with repeat courses of the drug, he noted.

Following C1, there was one serious infection (bacterial arthritis). Four patients experienced serious infections following C2—one each of appendicitis, otitis media, bronchopneumonia, and urinary tract infection.

There have been no reports of serious infections following C3, wrote Dr. Emery.

The majority of infusion-related adverse events were mild to moderate.

A separate poster presented efficacy data from the first 78 patients who have either been followed for 24 weeks following C2 or who withdrew from the trial.

“By all measures, rituximab retreatment following C2 was effective,” wrote Dr. Roy M. Fleischmann of the University of Texas Southwestern Medical Center, Dallas.

Disease Activity Score (DAS)-28 fell from a mean of 6.95 at C1 baseline to 4.58 at week 24, and then from a mean of 6.43 at C2 baseline to 4.16.

A total of 47 patients achieved ACR20 responses from the C2 baseline, and 57 achieved good to moderate EULAR responses.

C-reactive protein levels and rheumatoid factor titers both were significantly reduced during the observation periods after C1 and C2.

Rituximab targets CD20-positive B cells, and by binding CD20 it depletes B cells. However, because CD20 is not expressed on stem or plasma cells, B-cell recovery subsequently occurs.

Both B-cell depleted and B-cell recovered patients responded following C2, Dr. Fleischmann wrote.

Dr. Fleischmann disclosed that he has received research grants and consulting fees and is on the speakers' bureau of Genentech Inc.

Dr. Emery disclosed that he has received research grants and consulting fees from Roche.

There was no evidence of cumulative toxicity with repeated courses of rituximab. DR. EMERY

SAN DIEGO — Patients in the Utrecht Rheumatoid Arthritis Cohort who began treatment early in the course of disease were less likely to need joint surgery later on, Dr. Suzan M.M. Verstappen said at the annual meeting of the American College of Rheumatology.

In the ongoing Utrecht cohort study, begun in 1990, patients initially were randomized to early treatment with methotrexate, intramuscular gold, or hydroxychloroquine—or to a “pyramid” treatment approach, which was at that time the traditional paradigm.

In the pyramid strategy patients first take aspirin and other NSAIDs, delaying treatment with the DMARDs until later in the course of disease.

At the time of the first analysis, in 1994, it was apparent that patients in the early DMARD group were faring better, and henceforth, all patients were randomized to one of the three drugs, she said.

“In the present study we investigated the prevalence of joint surgery and looked at which clinical, radiographic, and demographic variables in the first 2 years of treatment—when we all know a lot of disease activity occurs—predicted later joint surgery,” said Dr. Verstappen of University Medical Center Utrecht (the Netherlands).

The cohort included 482 patients, whose mean age was 56 years and mean disease duration was 7.2 years. A total of 70% of the patients were female, and 65% were rheumatoid factor positive.

Overall, 144 patients underwent a total of 256 surgeries. Of these interventions, 32% were major surgeries such as total joint replacement, 50% were intermediate procedures such as arthrodesis, and 18% were minor interventions such as arthroscopy.

By the end of the fifth year, approximately 18% of patients had required at least one type of surgical intervention, according to Kaplan-Meier survival analysis. Overall mean survival time until surgery was 10 years, and for the major surgical interventions, the mean survival time was 12 years.

With regard to the need for surgical intervention among patients who responded to drug therapy, compared with those who were nonresponders, at the end of the first year no significant difference was seen between the two groups.

But by the end of the second year patients who responded to drug therapy had fewer surgical interventions, she said.

Furthermore, surgical interventions were significantly more common in two patient subsets: those whose functional disability was worse at baseline and those who initially were randomized to NSAID therapy.

Multivariate Cox regression analyses of the 1-year data found that female gender, delayed start with DMARDs, and radiographic progression were predictive of later surgery.

Hazard ratios for these variables were 1.55, 1.68, and 1.016, respectively, Dr. Verstappen said.

At the end of the second year, only a delayed start of DMARD therapy and radiographic progression were predictors, with hazard ratios of 1.73 and 1.029, respectively, on the multivariate analysis.

The need for joint surgery can be considered an outcome measure reflecting an unfavorable course of rheumatoid arthritis, and a significant number of patients still require some type of surgical intervention, Dr. Verstappen said.

“This is the first study to demonstrate that early treatment prevents later surgical intervention, and we hope that with more early aggressive treatment the percentage of patients requiring surgery later on will decrease further,” she said.

SAN DIEGO — Patients in the Utrecht Rheumatoid Arthritis Cohort who began treatment early in the course of disease were less likely to need joint surgery later on, Dr. Suzan M.M. Verstappen said at the annual meeting of the American College of Rheumatology.

In the ongoing Utrecht cohort study, begun in 1990, patients initially were randomized to early treatment with methotrexate, intramuscular gold, or hydroxychloroquine—or to a “pyramid” treatment approach, which was at that time the traditional paradigm.

In the pyramid strategy patients first take aspirin and other NSAIDs, delaying treatment with the DMARDs until later in the course of disease.

At the time of the first analysis, in 1994, it was apparent that patients in the early DMARD group were faring better, and henceforth, all patients were randomized to one of the three drugs, she said.

“In the present study we investigated the prevalence of joint surgery and looked at which clinical, radiographic, and demographic variables in the first 2 years of treatment—when we all know a lot of disease activity occurs—predicted later joint surgery,” said Dr. Verstappen of University Medical Center Utrecht (the Netherlands).

The cohort included 482 patients, whose mean age was 56 years and mean disease duration was 7.2 years. A total of 70% of the patients were female, and 65% were rheumatoid factor positive.

Overall, 144 patients underwent a total of 256 surgeries. Of these interventions, 32% were major surgeries such as total joint replacement, 50% were intermediate procedures such as arthrodesis, and 18% were minor interventions such as arthroscopy.

By the end of the fifth year, approximately 18% of patients had required at least one type of surgical intervention, according to Kaplan-Meier survival analysis. Overall mean survival time until surgery was 10 years, and for the major surgical interventions, the mean survival time was 12 years.

With regard to the need for surgical intervention among patients who responded to drug therapy, compared with those who were nonresponders, at the end of the first year no significant difference was seen between the two groups.

But by the end of the second year patients who responded to drug therapy had fewer surgical interventions, she said.

Furthermore, surgical interventions were significantly more common in two patient subsets: those whose functional disability was worse at baseline and those who initially were randomized to NSAID therapy.

Multivariate Cox regression analyses of the 1-year data found that female gender, delayed start with DMARDs, and radiographic progression were predictive of later surgery.

Hazard ratios for these variables were 1.55, 1.68, and 1.016, respectively, Dr. Verstappen said.

At the end of the second year, only a delayed start of DMARD therapy and radiographic progression were predictors, with hazard ratios of 1.73 and 1.029, respectively, on the multivariate analysis.

The need for joint surgery can be considered an outcome measure reflecting an unfavorable course of rheumatoid arthritis, and a significant number of patients still require some type of surgical intervention, Dr. Verstappen said.

“This is the first study to demonstrate that early treatment prevents later surgical intervention, and we hope that with more early aggressive treatment the percentage of patients requiring surgery later on will decrease further,” she said.

SAN DIEGO — Patients in the Utrecht Rheumatoid Arthritis Cohort who began treatment early in the course of disease were less likely to need joint surgery later on, Dr. Suzan M.M. Verstappen said at the annual meeting of the American College of Rheumatology.

In the ongoing Utrecht cohort study, begun in 1990, patients initially were randomized to early treatment with methotrexate, intramuscular gold, or hydroxychloroquine—or to a “pyramid” treatment approach, which was at that time the traditional paradigm.

In the pyramid strategy patients first take aspirin and other NSAIDs, delaying treatment with the DMARDs until later in the course of disease.

At the time of the first analysis, in 1994, it was apparent that patients in the early DMARD group were faring better, and henceforth, all patients were randomized to one of the three drugs, she said.

“In the present study we investigated the prevalence of joint surgery and looked at which clinical, radiographic, and demographic variables in the first 2 years of treatment—when we all know a lot of disease activity occurs—predicted later joint surgery,” said Dr. Verstappen of University Medical Center Utrecht (the Netherlands).

The cohort included 482 patients, whose mean age was 56 years and mean disease duration was 7.2 years. A total of 70% of the patients were female, and 65% were rheumatoid factor positive.

Overall, 144 patients underwent a total of 256 surgeries. Of these interventions, 32% were major surgeries such as total joint replacement, 50% were intermediate procedures such as arthrodesis, and 18% were minor interventions such as arthroscopy.

By the end of the fifth year, approximately 18% of patients had required at least one type of surgical intervention, according to Kaplan-Meier survival analysis. Overall mean survival time until surgery was 10 years, and for the major surgical interventions, the mean survival time was 12 years.

With regard to the need for surgical intervention among patients who responded to drug therapy, compared with those who were nonresponders, at the end of the first year no significant difference was seen between the two groups.

But by the end of the second year patients who responded to drug therapy had fewer surgical interventions, she said.

Furthermore, surgical interventions were significantly more common in two patient subsets: those whose functional disability was worse at baseline and those who initially were randomized to NSAID therapy.

Multivariate Cox regression analyses of the 1-year data found that female gender, delayed start with DMARDs, and radiographic progression were predictive of later surgery.

Hazard ratios for these variables were 1.55, 1.68, and 1.016, respectively, Dr. Verstappen said.

At the end of the second year, only a delayed start of DMARD therapy and radiographic progression were predictors, with hazard ratios of 1.73 and 1.029, respectively, on the multivariate analysis.

The need for joint surgery can be considered an outcome measure reflecting an unfavorable course of rheumatoid arthritis, and a significant number of patients still require some type of surgical intervention, Dr. Verstappen said.

“This is the first study to demonstrate that early treatment prevents later surgical intervention, and we hope that with more early aggressive treatment the percentage of patients requiring surgery later on will decrease further,” she said.

NEW YORK — Despite bugs in the system that have delayed implementation of the iPLEDGE isotretinoin registry and physicians' dismay at the increased red tape and monitoring they are facing, the program is moving forward—and ultimately may be beneficial for clinicians, Dr. Hilary Baldwin said.

“The biggest asset of this system is that, in the case of a horrible event, with pregnancy and fetal malformations, it's no longer her word against yours in a court of law,” Dr. Baldwin said at a meeting on medical and surgical dermatology sponsored by Mount Sinai School of Medicine in New York.

“Patients are assuming more responsibility, and there is less liability on our shoulders,” she said.

Because the voluntary SMART program failed to decrease the number of pregnancies among women taking isotretinoin, women of childbearing potential now must not only have monthly pregnancy tests, physician visits, and counseling, but must also attest that they have done so by filling out the required forms on the iPLEDGE Web site.

“If she gets pregnant and a year later wants to sue you because of birth defects, she can't claim that you didn't tell her she needed to use two forms of birth control, because she has attested to this not once, but monthly,” said Dr. Baldwin of the State University of New York Health Science Center at Brooklyn.

The patient also will be responsible for contacting iPLEDGE if she is given a “red light” at the pharmacy.

The pharmacist will not know the reason—whether she failed to interact with the system, or the two forms of birth control entered by the patient and physician did not match, or if she did not have a pregnancy test—and it will be up to her to contact the system.

The iPLEDGE card she is given when she is registered will have the registry phone number and her password.

Because of delays and difficulties in getting the program up and running, the compliance date for physicians and patients was pushed back to March 1, 2006 (FAMILY PRACTICE NEWS, Dec. 15, 2005, p. 32).

A total of 17,000 prescribers have registered for the program, and about 5,000 have been activated.

At the meeting, though, a number of attendees complained that they still had not received the materials they needed to register and activate their registrations, while others said they had not been given the requisite passwords. (Physicians and other prescribers such as nurse practitioners, physician assistants, and residents can call the program at 866-495-0654 or visit www.ipledgeprogram.com

Women of non-childbearing potential and men also must register with iPLEDGE, though they do not need to interact with the system monthly as do women of childbearing potential. They still must be seen and counseled each month, however, on the risk of fetal malformations should they share the drug with a woman of childbearing potential, and reminded not to do so and also not to donate blood.

Physicians who have in the past treated men with low-dose isotretinoin face a particular obstacle: Each prescription must be for a 1-month supply, so writing a prescription for 30 pills for a man who intends to take two pills a week for several months without being seen by his physician will not be a prudent option.

“If you do this, it's your risk, and you have to remember to document in the system every month that you have seen and counseled him. You will have to keep that lie going, which I think is a very bad idea,” Dr. Baldwin said, adding “Big brother is watching.”

It also will not be possible to use alternating 40- and 80-mg pills to achieve a 60-mg dose, because that regimen involves 45 pills, and the pharmacist can't cut up a foil of 10.

One area in which the Food and Drug Administration has relented is in permitting abstinence to count as both forms of birth control. Originally, the FDA wanted abstinence to count only once, but for patients such as minors, nuns, or lesbians it may count as both forms.

“You may not be willing to do that, though. If I have a 16-year-old who claims abstinence/abstinence, I don't feel real comfortable with that. You can still require them to be on birth control. Just because the system doesn't require it doesn't mean you can't do what you feel comfortable with,” she said.

Don't delay in registering patients, because those who are not registered and activated by March 1 will not be prescribed the drug, Dr. Baldwin advised.

“The time for arguing is gone. Every time I give one of these talks there's a lot of argument as to why it shouldn't happen and how silly it is and how angry we are. You might very well be angry, but it's too late. It's time now to accept it or not accept it and move on because it's mandatory and it's done,” she said.

NEW YORK — Despite bugs in the system that have delayed implementation of the iPLEDGE isotretinoin registry and physicians' dismay at the increased red tape and monitoring they are facing, the program is moving forward—and ultimately may be beneficial for clinicians, Dr. Hilary Baldwin said.

“The biggest asset of this system is that, in the case of a horrible event, with pregnancy and fetal malformations, it's no longer her word against yours in a court of law,” Dr. Baldwin said at a meeting on medical and surgical dermatology sponsored by Mount Sinai School of Medicine in New York.

“Patients are assuming more responsibility, and there is less liability on our shoulders,” she said.

Because the voluntary SMART program failed to decrease the number of pregnancies among women taking isotretinoin, women of childbearing potential now must not only have monthly pregnancy tests, physician visits, and counseling, but must also attest that they have done so by filling out the required forms on the iPLEDGE Web site.

“If she gets pregnant and a year later wants to sue you because of birth defects, she can't claim that you didn't tell her she needed to use two forms of birth control, because she has attested to this not once, but monthly,” said Dr. Baldwin of the State University of New York Health Science Center at Brooklyn.

The patient also will be responsible for contacting iPLEDGE if she is given a “red light” at the pharmacy.

The pharmacist will not know the reason—whether she failed to interact with the system, or the two forms of birth control entered by the patient and physician did not match, or if she did not have a pregnancy test—and it will be up to her to contact the system.

The iPLEDGE card she is given when she is registered will have the registry phone number and her password.

Because of delays and difficulties in getting the program up and running, the compliance date for physicians and patients was pushed back to March 1, 2006 (FAMILY PRACTICE NEWS, Dec. 15, 2005, p. 32).

A total of 17,000 prescribers have registered for the program, and about 5,000 have been activated.

At the meeting, though, a number of attendees complained that they still had not received the materials they needed to register and activate their registrations, while others said they had not been given the requisite passwords. (Physicians and other prescribers such as nurse practitioners, physician assistants, and residents can call the program at 866-495-0654 or visit www.ipledgeprogram.com

Women of non-childbearing potential and men also must register with iPLEDGE, though they do not need to interact with the system monthly as do women of childbearing potential. They still must be seen and counseled each month, however, on the risk of fetal malformations should they share the drug with a woman of childbearing potential, and reminded not to do so and also not to donate blood.

Physicians who have in the past treated men with low-dose isotretinoin face a particular obstacle: Each prescription must be for a 1-month supply, so writing a prescription for 30 pills for a man who intends to take two pills a week for several months without being seen by his physician will not be a prudent option.

“If you do this, it's your risk, and you have to remember to document in the system every month that you have seen and counseled him. You will have to keep that lie going, which I think is a very bad idea,” Dr. Baldwin said, adding “Big brother is watching.”

It also will not be possible to use alternating 40- and 80-mg pills to achieve a 60-mg dose, because that regimen involves 45 pills, and the pharmacist can't cut up a foil of 10.

One area in which the Food and Drug Administration has relented is in permitting abstinence to count as both forms of birth control. Originally, the FDA wanted abstinence to count only once, but for patients such as minors, nuns, or lesbians it may count as both forms.

“You may not be willing to do that, though. If I have a 16-year-old who claims abstinence/abstinence, I don't feel real comfortable with that. You can still require them to be on birth control. Just because the system doesn't require it doesn't mean you can't do what you feel comfortable with,” she said.

Don't delay in registering patients, because those who are not registered and activated by March 1 will not be prescribed the drug, Dr. Baldwin advised.

“The time for arguing is gone. Every time I give one of these talks there's a lot of argument as to why it shouldn't happen and how silly it is and how angry we are. You might very well be angry, but it's too late. It's time now to accept it or not accept it and move on because it's mandatory and it's done,” she said.

NEW YORK — Despite bugs in the system that have delayed implementation of the iPLEDGE isotretinoin registry and physicians' dismay at the increased red tape and monitoring they are facing, the program is moving forward—and ultimately may be beneficial for clinicians, Dr. Hilary Baldwin said.

“The biggest asset of this system is that, in the case of a horrible event, with pregnancy and fetal malformations, it's no longer her word against yours in a court of law,” Dr. Baldwin said at a meeting on medical and surgical dermatology sponsored by Mount Sinai School of Medicine in New York.

“Patients are assuming more responsibility, and there is less liability on our shoulders,” she said.

Because the voluntary SMART program failed to decrease the number of pregnancies among women taking isotretinoin, women of childbearing potential now must not only have monthly pregnancy tests, physician visits, and counseling, but must also attest that they have done so by filling out the required forms on the iPLEDGE Web site.

“If she gets pregnant and a year later wants to sue you because of birth defects, she can't claim that you didn't tell her she needed to use two forms of birth control, because she has attested to this not once, but monthly,” said Dr. Baldwin of the State University of New York Health Science Center at Brooklyn.

The patient also will be responsible for contacting iPLEDGE if she is given a “red light” at the pharmacy.

The pharmacist will not know the reason—whether she failed to interact with the system, or the two forms of birth control entered by the patient and physician did not match, or if she did not have a pregnancy test—and it will be up to her to contact the system.

The iPLEDGE card she is given when she is registered will have the registry phone number and her password.

Because of delays and difficulties in getting the program up and running, the compliance date for physicians and patients was pushed back to March 1, 2006 (FAMILY PRACTICE NEWS, Dec. 15, 2005, p. 32).

A total of 17,000 prescribers have registered for the program, and about 5,000 have been activated.

At the meeting, though, a number of attendees complained that they still had not received the materials they needed to register and activate their registrations, while others said they had not been given the requisite passwords. (Physicians and other prescribers such as nurse practitioners, physician assistants, and residents can call the program at 866-495-0654 or visit www.ipledgeprogram.com

Women of non-childbearing potential and men also must register with iPLEDGE, though they do not need to interact with the system monthly as do women of childbearing potential. They still must be seen and counseled each month, however, on the risk of fetal malformations should they share the drug with a woman of childbearing potential, and reminded not to do so and also not to donate blood.

Physicians who have in the past treated men with low-dose isotretinoin face a particular obstacle: Each prescription must be for a 1-month supply, so writing a prescription for 30 pills for a man who intends to take two pills a week for several months without being seen by his physician will not be a prudent option.

“If you do this, it's your risk, and you have to remember to document in the system every month that you have seen and counseled him. You will have to keep that lie going, which I think is a very bad idea,” Dr. Baldwin said, adding “Big brother is watching.”

It also will not be possible to use alternating 40- and 80-mg pills to achieve a 60-mg dose, because that regimen involves 45 pills, and the pharmacist can't cut up a foil of 10.

One area in which the Food and Drug Administration has relented is in permitting abstinence to count as both forms of birth control. Originally, the FDA wanted abstinence to count only once, but for patients such as minors, nuns, or lesbians it may count as both forms.

“You may not be willing to do that, though. If I have a 16-year-old who claims abstinence/abstinence, I don't feel real comfortable with that. You can still require them to be on birth control. Just because the system doesn't require it doesn't mean you can't do what you feel comfortable with,” she said.

Don't delay in registering patients, because those who are not registered and activated by March 1 will not be prescribed the drug, Dr. Baldwin advised.

“The time for arguing is gone. Every time I give one of these talks there's a lot of argument as to why it shouldn't happen and how silly it is and how angry we are. You might very well be angry, but it's too late. It's time now to accept it or not accept it and move on because it's mandatory and it's done,” she said.

SAN DIEGO — A second randomized clinical trial has confirmed that treatment with bosentan can help prevent the formation of digital ulcers in patients with scleroderma, Dr. James R. Seibold reported at the annual meeting of the American College of Rheumatology.

A total of 188 patients from 41 centers in North America and Europe were enrolled in the Randomized Placebo-Controlled Investigation of Digital Ulcers in Scleroderma (RAPIDS-2). All had scleroderma and at least one recent active digital ulcer, and their mean disease duration was 8.7 years.

At baseline, patients randomized to the placebo and bosentan groups had a mean of 3.6 and 3.7 digital ulcers, respectively. By 24 weeks, a mean of 2.7 new ulcers were seen in the placebo group, compared with a mean of 1.9 in the active treatment group, Dr. Seibold said in a late-breaking poster session. This difference was statistically significant.

Statistically significant differences were already apparent by week 12, at which time the placebo group had a mean of 1.3 new digital ulcers, whereas the bosentan group had a mean of 0.8 new ulcers.

The effects were particularly marked in patients with more severe peripheral vascular injury, said Dr. Seibold, director of the University of Michigan Scleroderma Program, Ann Arbor.

Among patients who had more than 3 ulcers at baseline, those receiving placebo developed 4.4 new ulcers during the 24 weeks of the trial, while those receiving bosentan had 2.3 new ulcers, which was a statistically significant difference, he said.

“These data suggest that if a patient with scleroderma were to present at a physician's office with three digital ulcers, he or she would be likely to develop an additional four to five ulcers over the next 24 weeks, and the risk of that occurring would be reduced by nearly 50% on bosentan,” Dr. Seibold said in a discussion of the trial at a satellite symposium.

Bosentan treatment did not, however, shorten the time to healing of active digital ulcers. In 6 months, only 50% of ulcers had healed despite treatment with topical and systemic antibiotics and adjustments to therapy for Raynaud's phenomenon. “These data are quite instructive in terms of getting a handle on how intractable this problem is. We are treating the untreatable,” he said.

The study also evaluated the effects of treatment on hand functionality as measured by the Scleroderma Health Assessment Questionnaire. Most notable was a significant improvement in patients' ability to dress. On this domain, change from baseline was −0.35 in the bosentan group; a change of −0.22 is considered clinically meaningful.

The findings of this study are in agreement with those in RAPIDS-1, which evaluated bosentan in 122 patients with scleroderma for 16 weeks, and found a 48% reduction in the mean number of new ulcers (Arthritis Rheum. 2004;50:3985–93).

Serious adverse events were uncommon. As in RAPIDS-1, more patients in the active treatment group had elevations of liver enzymes greater than 3 times the upper limit of normal (10.5%) than in the placebo group (1.1%).

Bosentan (Tracleer) is a dual endothelin receptor antagonist. Endothelin-1 and its receptors, particularly the ETB receptor, are overexpressed in scleroderma, and the vasoconstrictive and pro-proliferative effects of endothelin-1 contribute to the vasculopathy associated with the disease. The RAPIDS data “support the contention that chronic endothelin receptor antagonism has an important effect on vascular integrity and function in systemic sclerosis,” he said.

Dr. Seibold disclosed that he has received research grants and consulting fees from Actelion Pharmaceuticals Ltd., the sponsor of the trial.

Bosentan group patients had 2.3 new ulcers versus 4.4 new lesions in the control group. Courtesy Dr. James R. Seibold

SAN DIEGO — A second randomized clinical trial has confirmed that treatment with bosentan can help prevent the formation of digital ulcers in patients with scleroderma, Dr. James R. Seibold reported at the annual meeting of the American College of Rheumatology.

A total of 188 patients from 41 centers in North America and Europe were enrolled in the Randomized Placebo-Controlled Investigation of Digital Ulcers in Scleroderma (RAPIDS-2). All had scleroderma and at least one recent active digital ulcer, and their mean disease duration was 8.7 years.

At baseline, patients randomized to the placebo and bosentan groups had a mean of 3.6 and 3.7 digital ulcers, respectively. By 24 weeks, a mean of 2.7 new ulcers were seen in the placebo group, compared with a mean of 1.9 in the active treatment group, Dr. Seibold said in a late-breaking poster session. This difference was statistically significant.

Statistically significant differences were already apparent by week 12, at which time the placebo group had a mean of 1.3 new digital ulcers, whereas the bosentan group had a mean of 0.8 new ulcers.

The effects were particularly marked in patients with more severe peripheral vascular injury, said Dr. Seibold, director of the University of Michigan Scleroderma Program, Ann Arbor.

Among patients who had more than 3 ulcers at baseline, those receiving placebo developed 4.4 new ulcers during the 24 weeks of the trial, while those receiving bosentan had 2.3 new ulcers, which was a statistically significant difference, he said.

“These data suggest that if a patient with scleroderma were to present at a physician's office with three digital ulcers, he or she would be likely to develop an additional four to five ulcers over the next 24 weeks, and the risk of that occurring would be reduced by nearly 50% on bosentan,” Dr. Seibold said in a discussion of the trial at a satellite symposium.

Bosentan treatment did not, however, shorten the time to healing of active digital ulcers. In 6 months, only 50% of ulcers had healed despite treatment with topical and systemic antibiotics and adjustments to therapy for Raynaud's phenomenon. “These data are quite instructive in terms of getting a handle on how intractable this problem is. We are treating the untreatable,” he said.

The study also evaluated the effects of treatment on hand functionality as measured by the Scleroderma Health Assessment Questionnaire. Most notable was a significant improvement in patients' ability to dress. On this domain, change from baseline was −0.35 in the bosentan group; a change of −0.22 is considered clinically meaningful.

The findings of this study are in agreement with those in RAPIDS-1, which evaluated bosentan in 122 patients with scleroderma for 16 weeks, and found a 48% reduction in the mean number of new ulcers (Arthritis Rheum. 2004;50:3985–93).

Serious adverse events were uncommon. As in RAPIDS-1, more patients in the active treatment group had elevations of liver enzymes greater than 3 times the upper limit of normal (10.5%) than in the placebo group (1.1%).

Bosentan (Tracleer) is a dual endothelin receptor antagonist. Endothelin-1 and its receptors, particularly the ETB receptor, are overexpressed in scleroderma, and the vasoconstrictive and pro-proliferative effects of endothelin-1 contribute to the vasculopathy associated with the disease. The RAPIDS data “support the contention that chronic endothelin receptor antagonism has an important effect on vascular integrity and function in systemic sclerosis,” he said.

Dr. Seibold disclosed that he has received research grants and consulting fees from Actelion Pharmaceuticals Ltd., the sponsor of the trial.

Bosentan group patients had 2.3 new ulcers versus 4.4 new lesions in the control group. Courtesy Dr. James R. Seibold

SAN DIEGO — A second randomized clinical trial has confirmed that treatment with bosentan can help prevent the formation of digital ulcers in patients with scleroderma, Dr. James R. Seibold reported at the annual meeting of the American College of Rheumatology.

A total of 188 patients from 41 centers in North America and Europe were enrolled in the Randomized Placebo-Controlled Investigation of Digital Ulcers in Scleroderma (RAPIDS-2). All had scleroderma and at least one recent active digital ulcer, and their mean disease duration was 8.7 years.

At baseline, patients randomized to the placebo and bosentan groups had a mean of 3.6 and 3.7 digital ulcers, respectively. By 24 weeks, a mean of 2.7 new ulcers were seen in the placebo group, compared with a mean of 1.9 in the active treatment group, Dr. Seibold said in a late-breaking poster session. This difference was statistically significant.

Statistically significant differences were already apparent by week 12, at which time the placebo group had a mean of 1.3 new digital ulcers, whereas the bosentan group had a mean of 0.8 new ulcers.

The effects were particularly marked in patients with more severe peripheral vascular injury, said Dr. Seibold, director of the University of Michigan Scleroderma Program, Ann Arbor.

Among patients who had more than 3 ulcers at baseline, those receiving placebo developed 4.4 new ulcers during the 24 weeks of the trial, while those receiving bosentan had 2.3 new ulcers, which was a statistically significant difference, he said.

“These data suggest that if a patient with scleroderma were to present at a physician's office with three digital ulcers, he or she would be likely to develop an additional four to five ulcers over the next 24 weeks, and the risk of that occurring would be reduced by nearly 50% on bosentan,” Dr. Seibold said in a discussion of the trial at a satellite symposium.

Bosentan treatment did not, however, shorten the time to healing of active digital ulcers. In 6 months, only 50% of ulcers had healed despite treatment with topical and systemic antibiotics and adjustments to therapy for Raynaud's phenomenon. “These data are quite instructive in terms of getting a handle on how intractable this problem is. We are treating the untreatable,” he said.

The study also evaluated the effects of treatment on hand functionality as measured by the Scleroderma Health Assessment Questionnaire. Most notable was a significant improvement in patients' ability to dress. On this domain, change from baseline was −0.35 in the bosentan group; a change of −0.22 is considered clinically meaningful.

The findings of this study are in agreement with those in RAPIDS-1, which evaluated bosentan in 122 patients with scleroderma for 16 weeks, and found a 48% reduction in the mean number of new ulcers (Arthritis Rheum. 2004;50:3985–93).

Serious adverse events were uncommon. As in RAPIDS-1, more patients in the active treatment group had elevations of liver enzymes greater than 3 times the upper limit of normal (10.5%) than in the placebo group (1.1%).

Bosentan (Tracleer) is a dual endothelin receptor antagonist. Endothelin-1 and its receptors, particularly the ETB receptor, are overexpressed in scleroderma, and the vasoconstrictive and pro-proliferative effects of endothelin-1 contribute to the vasculopathy associated with the disease. The RAPIDS data “support the contention that chronic endothelin receptor antagonism has an important effect on vascular integrity and function in systemic sclerosis,” he said.

Dr. Seibold disclosed that he has received research grants and consulting fees from Actelion Pharmaceuticals Ltd., the sponsor of the trial.

Bosentan group patients had 2.3 new ulcers versus 4.4 new lesions in the control group. Courtesy Dr. James R. Seibold

SAN DIEGO — For the first time, a randomized trial has demonstrated that treatment of early undifferentiated arthritis with methotrexate can prevent progression to rheumatoid arthritis, Dr. Henrike van Dongen reported in a late-breaking poster session at the annual meeting of the American College of Rheumatology.

Findings from previous studies have suggested that early treatment of rheumatoid arthritis (RA) can lessen severity or induce remission, but until now there have been no data to show that the same benefits can occur in patients with undifferentiated, or “probable,” arthritis.

In the Early Treatment of Probable Rheumatoid Arthritis Patients with Methotrexate (PROBAAT) trial, 110 patients who did not yet fulfill ACR criteria for RA were randomized to 15 mg/week of methotrexate or placebo.

The methotrexate dose was adjusted over time based on disease severity.

At 3 months, the mean decrease in Disease Activity Severity (DAS) score was 0.39 in the methotrexate and 0.005 in the placebo group, a difference that was statistically significant.

At 18 months, fewer patients in the methotrexate group had developed RA and more had achieved remission, compared with those in the placebo group (see chart). Radiographic progression was significantly higher in the placebo group, noted Dr. van Dongen of Leiden (the Netherlands) University Medical Center.

SAN DIEGO — For the first time, a randomized trial has demonstrated that treatment of early undifferentiated arthritis with methotrexate can prevent progression to rheumatoid arthritis, Dr. Henrike van Dongen reported in a late-breaking poster session at the annual meeting of the American College of Rheumatology.

Findings from previous studies have suggested that early treatment of rheumatoid arthritis (RA) can lessen severity or induce remission, but until now there have been no data to show that the same benefits can occur in patients with undifferentiated, or “probable,” arthritis.

In the Early Treatment of Probable Rheumatoid Arthritis Patients with Methotrexate (PROBAAT) trial, 110 patients who did not yet fulfill ACR criteria for RA were randomized to 15 mg/week of methotrexate or placebo.

The methotrexate dose was adjusted over time based on disease severity.

At 3 months, the mean decrease in Disease Activity Severity (DAS) score was 0.39 in the methotrexate and 0.005 in the placebo group, a difference that was statistically significant.

At 18 months, fewer patients in the methotrexate group had developed RA and more had achieved remission, compared with those in the placebo group (see chart). Radiographic progression was significantly higher in the placebo group, noted Dr. van Dongen of Leiden (the Netherlands) University Medical Center.

SAN DIEGO — For the first time, a randomized trial has demonstrated that treatment of early undifferentiated arthritis with methotrexate can prevent progression to rheumatoid arthritis, Dr. Henrike van Dongen reported in a late-breaking poster session at the annual meeting of the American College of Rheumatology.

Findings from previous studies have suggested that early treatment of rheumatoid arthritis (RA) can lessen severity or induce remission, but until now there have been no data to show that the same benefits can occur in patients with undifferentiated, or “probable,” arthritis.

In the Early Treatment of Probable Rheumatoid Arthritis Patients with Methotrexate (PROBAAT) trial, 110 patients who did not yet fulfill ACR criteria for RA were randomized to 15 mg/week of methotrexate or placebo.

The methotrexate dose was adjusted over time based on disease severity.

At 3 months, the mean decrease in Disease Activity Severity (DAS) score was 0.39 in the methotrexate and 0.005 in the placebo group, a difference that was statistically significant.

At 18 months, fewer patients in the methotrexate group had developed RA and more had achieved remission, compared with those in the placebo group (see chart). Radiographic progression was significantly higher in the placebo group, noted Dr. van Dongen of Leiden (the Netherlands) University Medical Center.

SAN DIEGO — A topical pain-relieving cream found to be safe and effective for knee osteoarthritis in a double-blind controlled study may offer a new approach to treatment that avoids the cardiovascular and gastrointestinal hazards of many oral agents, according to Dr. Thomas J. Schnitzer.

Topical civamide cream 0.075% (Winston Laboratories, Vernon Hills, Ill.) was tested in a multicenter study that included 695 patients with radiographically confirmed osteoarthritis who ranged in age from 40 to 75 years.

At baseline, all study participants had a Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score greater than 9 (out of a total 20), despite treatment with NSAIDs or cyclo-oxgenase-2 (COX-2) inhibitors.

They were randomized to a regimen of civamide cream 0.075% to be applied three times daily, or a control cream containing low-dose (0.01%) civamide.

Blinding was therefore maintained, as both creams cause an initial burning sensation, Dr. Schnitzer reported in a late-breaking abstract session at the annual meeting of the American College of Rheumatology.

The three primary efficacy variables were WOMAC pain, WOMAC physical function, and subject global evaluation, and the primary efficacy analysis was the time-weighted average of change from baseline to day 84.

Statistically significant differences were seen in all variables and on the time-weighted average between the two groups at the conclusion of the study, wrote Dr. Schnitzer, professor of medicine at Northwestern University, Chicago.

The time-weighted average of change from a baseline mean score of 11.97 for WOMAC pain was 3.64 in the active treatment group, compared with a change of 3.3 from a baseline of 11.75 in the control group.

For WOMAC function, the time-weighted average change was 9.99 from a baseline of 38.88 in the active treatment group, while in the control group there was a change of 8.21 from a baseline of 38.2. Significant differences also were seen at the majority of interim time points, which were days 21, 42, and 63.

Dr. Schnitzer disclosed that he has received research grants and consulting fees from Winston Laboratories.

SAN DIEGO — A topical pain-relieving cream found to be safe and effective for knee osteoarthritis in a double-blind controlled study may offer a new approach to treatment that avoids the cardiovascular and gastrointestinal hazards of many oral agents, according to Dr. Thomas J. Schnitzer.

Topical civamide cream 0.075% (Winston Laboratories, Vernon Hills, Ill.) was tested in a multicenter study that included 695 patients with radiographically confirmed osteoarthritis who ranged in age from 40 to 75 years.

At baseline, all study participants had a Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score greater than 9 (out of a total 20), despite treatment with NSAIDs or cyclo-oxgenase-2 (COX-2) inhibitors.

They were randomized to a regimen of civamide cream 0.075% to be applied three times daily, or a control cream containing low-dose (0.01%) civamide.

Blinding was therefore maintained, as both creams cause an initial burning sensation, Dr. Schnitzer reported in a late-breaking abstract session at the annual meeting of the American College of Rheumatology.

The three primary efficacy variables were WOMAC pain, WOMAC physical function, and subject global evaluation, and the primary efficacy analysis was the time-weighted average of change from baseline to day 84.

Statistically significant differences were seen in all variables and on the time-weighted average between the two groups at the conclusion of the study, wrote Dr. Schnitzer, professor of medicine at Northwestern University, Chicago.

The time-weighted average of change from a baseline mean score of 11.97 for WOMAC pain was 3.64 in the active treatment group, compared with a change of 3.3 from a baseline of 11.75 in the control group.

For WOMAC function, the time-weighted average change was 9.99 from a baseline of 38.88 in the active treatment group, while in the control group there was a change of 8.21 from a baseline of 38.2. Significant differences also were seen at the majority of interim time points, which were days 21, 42, and 63.

Dr. Schnitzer disclosed that he has received research grants and consulting fees from Winston Laboratories.

SAN DIEGO — A topical pain-relieving cream found to be safe and effective for knee osteoarthritis in a double-blind controlled study may offer a new approach to treatment that avoids the cardiovascular and gastrointestinal hazards of many oral agents, according to Dr. Thomas J. Schnitzer.

Topical civamide cream 0.075% (Winston Laboratories, Vernon Hills, Ill.) was tested in a multicenter study that included 695 patients with radiographically confirmed osteoarthritis who ranged in age from 40 to 75 years.

At baseline, all study participants had a Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score greater than 9 (out of a total 20), despite treatment with NSAIDs or cyclo-oxgenase-2 (COX-2) inhibitors.

They were randomized to a regimen of civamide cream 0.075% to be applied three times daily, or a control cream containing low-dose (0.01%) civamide.

Blinding was therefore maintained, as both creams cause an initial burning sensation, Dr. Schnitzer reported in a late-breaking abstract session at the annual meeting of the American College of Rheumatology.

The three primary efficacy variables were WOMAC pain, WOMAC physical function, and subject global evaluation, and the primary efficacy analysis was the time-weighted average of change from baseline to day 84.

Statistically significant differences were seen in all variables and on the time-weighted average between the two groups at the conclusion of the study, wrote Dr. Schnitzer, professor of medicine at Northwestern University, Chicago.

The time-weighted average of change from a baseline mean score of 11.97 for WOMAC pain was 3.64 in the active treatment group, compared with a change of 3.3 from a baseline of 11.75 in the control group.

For WOMAC function, the time-weighted average change was 9.99 from a baseline of 38.88 in the active treatment group, while in the control group there was a change of 8.21 from a baseline of 38.2. Significant differences also were seen at the majority of interim time points, which were days 21, 42, and 63.

Dr. Schnitzer disclosed that he has received research grants and consulting fees from Winston Laboratories.