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Alefacept in combination with methotrexate for treatment of active psoriatic arthritis: rationale and design of a randomized, double-blind, placebo-controlled study 1
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ALEFACEPT IN COMBINATION WITH METHOTREXATE FOR TREATMENT OF ACTIVE PSORIATIC ARTHRITIS: RATIONALE AND DESIGN OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY Dafna Gladman, MD, Center for Prognosis Studies, Toronto Hospital Western Division, Toronto, ON, Canada, Edward Keystone, MD, Mt. Sinai Hospital, Toronto, ON, Canada, Alice Gottlieb, MD, PhD, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, United States Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis that may result in considerable joint damage if left untreated. Although the pathogenesis of PsA is uncertain, evidence suggests that T cells play an important role in this inflammatory disease. Alefacept selectively reduces memory (CD45RO⫹) T cells by interacting with the CD2 receptor. It is efficacious in moderate to severe plaque psoriasis— clinical improvements correlate with reductions in the memory T-cell subset. Preliminary data in active PsA showed that alefacept was well tolerated. Patients who responded with 20%, 50%, or 70% reduction in global assessments of disease activity had the greatest reductions in memory T cells, both in the circulation and synovial tissue. Based on these favorable results, a randomized, double-blind, placebo-controlled study is underway to further evaluate the efficacy and safety of alefacept when administered in combination with methotrexate in a larger population of patients with PsA. It is anticipated that the combination of alefacept and methotrexate will be used in clinical practice. Eligible patients must be 18-70 years of age, have CD4⫹ T-cell counts at or above the lower limit of normal, and have active PsA (at least 3 swollen joints and at least 3 tender joints) despite treatment with methotrexate (10 mg/week up to 25 mg/week) for at least 3 months before the study. The dose of methotrexate must be stable for at least 4 weeks before enrollment. Randomization will be stratified based on body surface area (BSA) involvement of chronic plaque psoriasis (3% or greater, ⬍3%) to maintain a 2:1 ratio of alefacept versus matching placebo. Alefacept 15 mg and placebo will be administered by intramuscular injection once weekly for 12 weeks followed by a 12-week observation period. All patients will continue to receive their stable dose of methotrexate for the entire 24-week study period. Stable doses of NSAIDs and steroids (up to 10 mg/day) will be permitted. The primary efficacy endpoint will be the proportion of patients achieving ACR 20, ACR 50, and ACR 70 responses at 24 weeks and at any time during the study. Additional efficacy evaluations will include PASI and PGA for psoriasis patients with BSA involvement of at least 3%, erythrocyte sedimentation rate, and C-reactive protein. Safety will be assessed by adverse events, infections, hematology, blood chemistry, urinalysis, vital signs, physical examinations, and anti-alefacept antibodies.
SUPERFICIAL VENOUS THROMBOSIS REVEALING NODOUS PERIARTERITIS Ghafour Siham, CHU IBN Rochd, Casablanca Introduction: Among the cutaneous signs of the PAN, the superficial thrombophlebites are rare.1 We report a specific observation of PAN reveald through venous thromboses of the lower limbs. Observation: FN aged 16 years, was admitted for painful inflammatory indured cordons of the legs associated with gonalgias. The palpation detected many nodules of diameter lower than 1 cm on the inside face of the lower limbs. An initial biologic assessment conveyed a sedimentation ratio of 85 mm in the first hour, an inflammatory anemia without hyperleucocytosis. The echodoppler lower limbs revealed a superficial thrombosis extended bilateral of the saphenas reacting 2 cm distance from the ostium. The biopsy of the subcutaneous nodule conclued to a nodular hypodermitis with no specifity. The evolution was marked by the apparition of livedoid lesions of the thighs with no arterial hypertension nor any neurologic signs, nor abdominal or renal ones conveying other affections. Biologicaly, the deficit in proteins C, S and anti-thrombine III were discarted. The hemostasis assessment was negative together with the hepatitic serology. The kidney assessment showed no specifity. The histologic exam of a venous cordon that was nuder biopsy confirmed the PAN diagnosis by non-necrosing showing the granulomatous angeatis aspect of on eosinophilic predominance. A general corticotheray associated to an anticoagulant treatment based on AVK yieled a good clinical evolution. Discussion: In our context, the superficial venous thrombosis (SVT) are essentialley associated to the Behc¸et disease2 or to infections (rickettsiosis, borreliosis). Although exceptionally reported during PAN, the SVT must however evoke this diagnosis as illustrated by our observation. 3 other cases of PAN followed up did not show any venous affection.3 The existence of SVT would be an element in favour of systematic type PAN and this is even when the visceral affection does not exist and would this constitute a prognosis element. On the other hand, only the evolutions allow the distinction between cutaneous and systemic forms. In our case, the PAN diagnosis was maintained based on the clinical and histologic arguments (nodules, livedo). The AVK-based anticoagulant treatment was justified by the closeness of the thrombosis to the deep venous net.4 References 1. Lighman HI. Cutaneous polyyarteritis nodosa and thrombose of the superior andinferiour vena cavae. J. Rhemato. 1998,15:113 2. Benamour S. Maladie de behc¸et (A propos de 316 cas). Press me´dicale, octobre 1990. Vol 19 N) 32. 3. Benchikhi H.: Pe´riarte´rite noueuse de l’enfant (A propos de 3 cas). Maroc me´dical 1999, tom 21, (3):172-176 4. Beker F. Thromboses veineuses superficielles des membres infe´rieurs. Rev. prat. 1996,46 (10):1225-28.
Disclosure not available at press time. Sponsored in part by Biogen, Inc.
Disclosure not available at press time.
P230
PSEUDOXANTHOMA ELASTICUM-LIKE SYNDROME IN A PATIENT WITH SICKLE CELL DISEASE Sachin S Bhardwaj, MD, University of Minnesota, Minneapolis, MN, United States, Lynn Glesne, MD, University of Minnesota, Minneapolis, MN, United States, Bruce Bart, MD, University of Minnesota, Minneapolis, MN, United States Increasingly effective treatments for sickle cell disease (SCD) have lead to increasing life expectancies, and the recognition of previously unknown disease associations. One such association is that of a syndrome similar to pseudoxanthoma elasticum (PXE). This syndrome consists of cutaneous and systemic findings identical to those described in heritable PXE in patients without evidence of the genetic mutation. A 22 year-old Gambian female presented to the dermatology clinic at Hennepin County Medical Center for evaluation of bumps located around her umbilicus. These lesions were asymptomatic, and had been present, unchanged, for approximately one year. Her past medical history included SCD (homozygous HbS genotype by hemoglobin electrophoresis). Examination revealed 20-25 three to five millimeter in diameter well demarcated flesh-colored and hyperpigmented papules clustered superior and lateral to the umbilicus. There were no similar lesions of other skin. A punch biopsy of involved skin demonstrated amorphous, faintly basophilic fibers located in the mid-dermis. These fibers stained black with Verhoeff’s stain, and prominent calcification in the mid-dermis was demonstrated with the von Kossa method. Pseudoxanthoma elasticum-like lesions have been reported in association with various hemoglobinopathies, although the association with SCD is not well documented in the dermatology literature. To our knowledge, this is the first report of this association without cutaneous lesions in the more typical areas of the axillae, lateral neck, or antecubital fossae. In SCD and b-thalassemia, a genetic link with PXE is unlikely, given the disparate locations of the MRP6 gene on chromosome 16 and the b-globin gene defects responsible for the hemoglobinopathies, on chromosome 11. The role of the MRP6 transporter in heritable PXE is unclear, but evidence suggests that it is an ATP dependent transporter molecule. If MRP6 does lose its function as a metabolic pump, PXE could be considered a metabolic disorder. If the endpoint of this defect results in the accumulation of compounds that adversely affect the structure and function of elastic tissue, a similar accumulation in some patients with chronic hemoglobinopathies may lead to the PXE-like phenotype. The full spectrum of PXE has not been described in diseases other than the hemoglobinopathies, and further investigation of this relationship may lead to an improved understanding of inherited PXE.
RHEUMATOID ARTHRITIS AND SKIN DISEASE Effie Ladoyanni, MD, City Hospital, Birmingham, UK, Birmingham, Niki Erb, MBChB, Dudley Group of Hospitals, Dudley, England, Iosif Beloukas, MS, Dudley Group of Hospitals, Dudley, England, George Kitas, MBBS, MS, PhD, Dudley Group of Hospitals, Dudley, England Background: Skin disease occurs more frequently in patients with rheumatoid arthritis (RA) than the general population. Cutaneous disease in RA is multi-factorial. Skin lesions can be related to the disease process itself, be due to antirheumatic drug therapy, or be completely independent of the above factors. Aim: To identify the prevalence of skin disease in patients with rheumatoid arthritis in an out patient setting. Methods: Cross-sectional observational study. 349 patients attending rheumatology follow-up appointments were consecutively recruited. 205 of these patients had a diagnosis of RA according to the ACR criteria and 144 patients had non-inflammatory musculosketal disease and acted as a control group. Data was collected on disease duration and seropositivity in the RA patients. Drug treatment, drug complications, skin symptoms and skin changes were assessed in all patients. All patients underwent a dermatological examination. Results: Significantly more patients with RA reported skin changes than control patients (RA 60.7% vs. Control 47.2% p ⫽ 0.01), and contributed this to their RA therapy (RA 23.9% vs. Control 4.9% p ⫽) 27.3% of the RA patients with skin disease had RA related cutaneous manifestations (rheumatoid nodules 18.9%, leg ulcers 6.4%, vasculitis 4.4%). In the RA group the incidence of skin atrophy (p ⫽ 0.001), bruises (p ⫽ 0.0001), athlete’s foot (p ⫽ 0.0002), onycholysis (p ⫽ 0.0001), nail ridging (p ⫽ 0.0001) and previous herpes zoster infection (p ⫽ 0.007) was significantly higher. More RA patients were receiving steroid and immunosuppressant medication (p ⫽ 0.000001) then controls Discussion: Skin disease is common in RA. The prevalence of disease related skin findings in RA was approximately 20% and this figure is similar to previous estimates of prevalence. A significant difference was seen regarding self-reported skin changes as well as objectively appreciated steroid and immunosuppressant related skin disease, dermatological infections and, nail findings between RA and control patients. One can agree with the RA patients, that their RA therapy does have an impact on their skin.1-2 References 1. T. Yamamoto, H. Ohkubo, K. Nishioka: Skin Manifestations associated with Rheumatoid Arthritis, Journal of Dermatology, 22:324-329,1995 2. WL Sibbitt Jr, RC Williams Jr: Cutaneous Manifestations of Rheumatoid Arthritis, Int J Dermatol, 21:563-572,1982
Disclosure not available at press time.
Disclosure not available at press time.
P228
P60
J AM ACAD DERMATOL
MARCH 2004
P229
ALEFACEPT IN COMBINATION WITH METHOTREXATE FOR TREATMENT OF ACTIVE PSORIATIC ARTHRITIS: RATIONALE AND DESIGN OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY Dafna Gladman, MD, Center for Prognosis Studies, Toronto Hospital Western Division, Toronto, ON, Canada, Edward Keystone, MD, Mt. Sinai Hospital, Toronto, ON, Canada, Alice Gottlieb, MD, PhD, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, United States Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis that may result in considerable joint damage if left untreated. Although the pathogenesis of PsA is uncertain, evidence suggests that T cells play an important role in this inflammatory disease. Alefacept selectively reduces memory (CD45RO⫹) T cells by interacting with the CD2 receptor. It is efficacious in moderate to severe plaque psoriasis— clinical improvements correlate with reductions in the memory T-cell subset. Preliminary data in active PsA showed that alefacept was well tolerated. Patients who responded with 20%, 50%, or 70% reduction in global assessments of disease activity had the greatest reductions in memory T cells, both in the circulation and synovial tissue. Based on these favorable results, a randomized, double-blind, placebo-controlled study is underway to further evaluate the efficacy and safety of alefacept when administered in combination with methotrexate in a larger population of patients with PsA. It is anticipated that the combination of alefacept and methotrexate will be used in clinical practice. Eligible patients must be 18-70 years of age, have CD4⫹ T-cell counts at or above the lower limit of normal, and have active PsA (at least 3 swollen joints and at least 3 tender joints) despite treatment with methotrexate (10 mg/week up to 25 mg/week) for at least 3 months before the study. The dose of methotrexate must be stable for at least 4 weeks before enrollment. Randomization will be stratified based on body surface area (BSA) involvement of chronic plaque psoriasis (3% or greater, ⬍3%) to maintain a 2:1 ratio of alefacept versus matching placebo. Alefacept 15 mg and placebo will be administered by intramuscular injection once weekly for 12 weeks followed by a 12-week observation period. All patients will continue to receive their stable dose of methotrexate for the entire 24-week study period. Stable doses of NSAIDs and steroids (up to 10 mg/day) will be permitted. The primary efficacy endpoint will be the proportion of patients achieving ACR 20, ACR 50, and ACR 70 responses at 24 weeks and at any time during the study. Additional efficacy evaluations will include PASI and PGA for psoriasis patients with BSA involvement of at least 3%, erythrocyte sedimentation rate, and C-reactive protein. Safety will be assessed by adverse events, infections, hematology, blood chemistry, urinalysis, vital signs, physical examinations, and anti-alefacept antibodies.
SUPERFICIAL VENOUS THROMBOSIS REVEALING NODOUS PERIARTERITIS Ghafour Siham, CHU IBN Rochd, Casablanca Introduction: Among the cutaneous signs of the PAN, the superficial thrombophlebites are rare.1 We report a specific observation of PAN reveald through venous thromboses of the lower limbs. Observation: FN aged 16 years, was admitted for painful inflammatory indured cordons of the legs associated with gonalgias. The palpation detected many nodules of diameter lower than 1 cm on the inside face of the lower limbs. An initial biologic assessment conveyed a sedimentation ratio of 85 mm in the first hour, an inflammatory anemia without hyperleucocytosis. The echodoppler lower limbs revealed a superficial thrombosis extended bilateral of the saphenas reacting 2 cm distance from the ostium. The biopsy of the subcutaneous nodule conclued to a nodular hypodermitis with no specifity. The evolution was marked by the apparition of livedoid lesions of the thighs with no arterial hypertension nor any neurologic signs, nor abdominal or renal ones conveying other affections. Biologicaly, the deficit in proteins C, S and anti-thrombine III were discarted. The hemostasis assessment was negative together with the hepatitic serology. The kidney assessment showed no specifity. The histologic exam of a venous cordon that was nuder biopsy confirmed the PAN diagnosis by non-necrosing showing the granulomatous angeatis aspect of on eosinophilic predominance. A general corticotheray associated to an anticoagulant treatment based on AVK yieled a good clinical evolution. Discussion: In our context, the superficial venous thrombosis (SVT) are essentialley associated to the Behc¸et disease2 or to infections (rickettsiosis, borreliosis). Although exceptionally reported during PAN, the SVT must however evoke this diagnosis as illustrated by our observation. 3 other cases of PAN followed up did not show any venous affection.3 The existence of SVT would be an element in favour of systematic type PAN and this is even when the visceral affection does not exist and would this constitute a prognosis element. On the other hand, only the evolutions allow the distinction between cutaneous and systemic forms. In our case, the PAN diagnosis was maintained based on the clinical and histologic arguments (nodules, livedo). The AVK-based anticoagulant treatment was justified by the closeness of the thrombosis to the deep venous net.4 References 1. Lighman HI. Cutaneous polyyarteritis nodosa and thrombose of the superior andinferiour vena cavae. J. Rhemato. 1998,15:113 2. Benamour S. Maladie de behc¸et (A propos de 316 cas). Press me´dicale, octobre 1990. Vol 19 N) 32. 3. Benchikhi H.: Pe´riarte´rite noueuse de l’enfant (A propos de 3 cas). Maroc me´dical 1999, tom 21, (3):172-176 4. Beker F. Thromboses veineuses superficielles des membres infe´rieurs. Rev. prat. 1996,46 (10):1225-28.
Disclosure not available at press time. Sponsored in part by Biogen, Inc.
Disclosure not available at press time.
P230
PSEUDOXANTHOMA ELASTICUM-LIKE SYNDROME IN A PATIENT WITH SICKLE CELL DISEASE Sachin S Bhardwaj, MD, University of Minnesota, Minneapolis, MN, United States, Lynn Glesne, MD, University of Minnesota, Minneapolis, MN, United States, Bruce Bart, MD, University of Minnesota, Minneapolis, MN, United States Increasingly effective treatments for sickle cell disease (SCD) have lead to increasing life expectancies, and the recognition of previously unknown disease associations. One such association is that of a syndrome similar to pseudoxanthoma elasticum (PXE). This syndrome consists of cutaneous and systemic findings identical to those described in heritable PXE in patients without evidence of the genetic mutation. A 22 year-old Gambian female presented to the dermatology clinic at Hennepin County Medical Center for evaluation of bumps located around her umbilicus. These lesions were asymptomatic, and had been present, unchanged, for approximately one year. Her past medical history included SCD (homozygous HbS genotype by hemoglobin electrophoresis). Examination revealed 20-25 three to five millimeter in diameter well demarcated flesh-colored and hyperpigmented papules clustered superior and lateral to the umbilicus. There were no similar lesions of other skin. A punch biopsy of involved skin demonstrated amorphous, faintly basophilic fibers located in the mid-dermis. These fibers stained black with Verhoeff’s stain, and prominent calcification in the mid-dermis was demonstrated with the von Kossa method. Pseudoxanthoma elasticum-like lesions have been reported in association with various hemoglobinopathies, although the association with SCD is not well documented in the dermatology literature. To our knowledge, this is the first report of this association without cutaneous lesions in the more typical areas of the axillae, lateral neck, or antecubital fossae. In SCD and b-thalassemia, a genetic link with PXE is unlikely, given the disparate locations of the MRP6 gene on chromosome 16 and the b-globin gene defects responsible for the hemoglobinopathies, on chromosome 11. The role of the MRP6 transporter in heritable PXE is unclear, but evidence suggests that it is an ATP dependent transporter molecule. If MRP6 does lose its function as a metabolic pump, PXE could be considered a metabolic disorder. If the endpoint of this defect results in the accumulation of compounds that adversely affect the structure and function of elastic tissue, a similar accumulation in some patients with chronic hemoglobinopathies may lead to the PXE-like phenotype. The full spectrum of PXE has not been described in diseases other than the hemoglobinopathies, and further investigation of this relationship may lead to an improved understanding of inherited PXE.
RHEUMATOID ARTHRITIS AND SKIN DISEASE Effie Ladoyanni, MD, City Hospital, Birmingham, UK, Birmingham, Niki Erb, MBChB, Dudley Group of Hospitals, Dudley, England, Iosif Beloukas, MS, Dudley Group of Hospitals, Dudley, England, George Kitas, MBBS, MS, PhD, Dudley Group of Hospitals, Dudley, England Background: Skin disease occurs more frequently in patients with rheumatoid arthritis (RA) than the general population. Cutaneous disease in RA is multi-factorial. Skin lesions can be related to the disease process itself, be due to antirheumatic drug therapy, or be completely independent of the above factors. Aim: To identify the prevalence of skin disease in patients with rheumatoid arthritis in an out patient setting. Methods: Cross-sectional observational study. 349 patients attending rheumatology follow-up appointments were consecutively recruited. 205 of these patients had a diagnosis of RA according to the ACR criteria and 144 patients had non-inflammatory musculosketal disease and acted as a control group. Data was collected on disease duration and seropositivity in the RA patients. Drug treatment, drug complications, skin symptoms and skin changes were assessed in all patients. All patients underwent a dermatological examination. Results: Significantly more patients with RA reported skin changes than control patients (RA 60.7% vs. Control 47.2% p ⫽ 0.01), and contributed this to their RA therapy (RA 23.9% vs. Control 4.9% p ⫽) 27.3% of the RA patients with skin disease had RA related cutaneous manifestations (rheumatoid nodules 18.9%, leg ulcers 6.4%, vasculitis 4.4%). In the RA group the incidence of skin atrophy (p ⫽ 0.001), bruises (p ⫽ 0.0001), athlete’s foot (p ⫽ 0.0002), onycholysis (p ⫽ 0.0001), nail ridging (p ⫽ 0.0001) and previous herpes zoster infection (p ⫽ 0.007) was significantly higher. More RA patients were receiving steroid and immunosuppressant medication (p ⫽ 0.000001) then controls Discussion: Skin disease is common in RA. The prevalence of disease related skin findings in RA was approximately 20% and this figure is similar to previous estimates of prevalence. A significant difference was seen regarding self-reported skin changes as well as objectively appreciated steroid and immunosuppressant related skin disease, dermatological infections and, nail findings between RA and control patients. One can agree with the RA patients, that their RA therapy does have an impact on their skin.1-2 References 1. T. Yamamoto, H. Ohkubo, K. Nishioka: Skin Manifestations associated with Rheumatoid Arthritis, Journal of Dermatology, 22:324-329,1995 2. WL Sibbitt Jr, RC Williams Jr: Cutaneous Manifestations of Rheumatoid Arthritis, Int J Dermatol, 21:563-572,1982
Disclosure not available at press time.
Disclosure not available at press time.
P228
P60
J AM ACAD DERMATOL
MARCH 2004