- Email: [email protected]
Tolerability and safety of combination methotrexate and alefacept in rheumatoid arthritis: results of a pilot study 1
Connective Tissue Diseases P223 URTICARIA AND ADULT-ONSET STILL’S DISEASE Zendee Rose M. Plateros-Elaba, MD, Section of Dermatology, University of the East Ramon Magsaysay Memorial Medical Center, Quezon City, Philippines, Alberto Santos-Ocampo, MD, Section of Rheumatology, Cardinal Santos Medical Center, San Juan, Metro Manila, Philippines Adult-Onset Still’s Disease (AOSD) is a rare systemic autoimmune disorder of unknown etiology characterized by intermittent spiking fevers, arthritis or arthralgias, and an evanescent maculopapular rash. Because clinical presentation is variable and mimics other systemic diseases, the challenge with AOSD is early diagnosis and appropriate therapy. We report a 29-year old female patient who initially consulted her dermatologist for a pruritic urticarial rash on the thighs and trunk which started a day prior. She was prescribed an antihistamine which partially relieved the rash. A week after the onset of the rash, she developed synovitis of both wrists and knees, and migratory dactylitis of her fingers and toes. She consulted a rheumatologist and naproxen was prescribed with modest relief of arthritis symptoms. Ten days after the onset of the rash, she began to experience high-grade fevers ⬎39 C peaking by late evening. The urticarial rash, now involving the face, upper extremities, trunk, and thighs, would be more marked during febrile episodes and would fade in the morning. Initial laboratory studies revealed leukocytosis with 75% neutrophils. She was admitted for work-up including blood and urine cultures, chest radiographs, serum anti-streptolysin O titer, serum rheumatoid factor, and antinuclear antibodies which were all negative. Her erythrocyte sedimentation rate was 94 mm/hr and her serum ferritin (538 ng/ml) was elevated to seven times the upper limit of normal. Skin biopsy showed neutrophilic dermatosis without vasculitis. Prednisone at 0.5 mg/kg/day was started with a working impression of AOSD. Her fever resolved 24 hours later, along with marked improvement in her rash and arthritis. However, after 2 days, all her symptoms recurred. Prednisone was increased to 0.7 mg/kg/day and methotrexate 7.5 mg once weekly and hydroxychloroquine 200 mg twice daily were added. Her fever, arthritis, and rash resolved with this regimen. With tapering of prednisone, all medications were discontinued after 9 months and the patient remained symptom-free. We also review two previous case reports of urticaria and AOSD with similar histopathologic findings. Although urticaria as an initial manifestation is rare, AOSD should be entertained in patients presenting with fever, arthritis, and neutrophilic dermatosis without vasculitis. A high index of suspicion is necessary to minimize laboratory investigations and initiate appropriate therapy. Disclosure not available at press time.
P225 CLINICAL FEATURES OF PERIODONTAL EHLERS-DANLOS SYNDROME (TYPE VIII) Sonal Shankar, MBBS, Addenbrooke’s Hospital NHS Trust, Cambridge, England, Nigel Burrows, MBBS, MD Ehlers-Danlos syndrome is a heterogeneous group of inherited disorders of connective tissue, characterised by joint hypermobility, cutaneous hyperextensibility and tissue fragility. Different subgroups of the disease have been described, each having a characteristic clinical pattern or a unique biochemical defect. Ehlers-Danlos syndrome type VIII, a rare subtype, has distinctive clinical features that are important to recognise because of the development of premature and severe periodontal disease. Although the underlying molecular cause of Ehlers-Danlos syndrome type VIII is unknown, linkage studies have implicated a gene located on chromosome 12p13.1 We are presenting a family with Ehlers-Danlos syndrome type VIII in order to highlight the classical features of this rare disease and to emphasise the severe periodontitis that can occur. We have examined five of the seven affected individuals from a large two-generation family with Ehlers-Danlos syndrome type VIII who exhibit the distinctive features of this disease. They consisted of two sisters aged 24 and 28 years, their mother aged 57 years, a male cousin aged 20 years and his father aged 53 years. All developed symptoms in childhood. The two sisters had striking joint hypermobility but this was not observed in the others. Skin hyperextensibility was variable and all had skin fragility with easy bruising and scarring. Characteristic hyperpigmented pretibial plaques and premature periodontal disease, with gingival recession and irreversible destruction of periodontal tissues, were also seen in all five individuals. As expected, this family demonstrates a dominant pattern of inheritance. In summary, we have described five members of a large family with Ehlers-Danlos syndrome type VIII who exhibit the classical features seen in this rare condition. In 1998 the classification of Ehlers-Danlos syndrome was updated.2 Type VIII is now known as periodontal type, reflecting the major complication of this subtype, as seen in our family. References: 1. Rahman N, Dunstan M, Teare MD, Hanks S et al. Ehlers-Danlos syndrome with severe early onset periodontal disease (EDS VIII) is a distinct, heterogeneous disorder with one predisposition gene at chromosome 12p13. Am J Hum Genetics 2003;73(1):198-204 2 Beighton P, De Paepe A, Steinmann B et al. Ehlers-Danlos Syndromes: Revised nosology, Villefranche, 1997. Am J Med Genet 1998;77:31-7 Disclosure not available at press time.
P226
P224 DISABLING PANSCLEROTIC MORPHEA: DIAGNOSIS AND PROGRESSION OF ADULT-ONSET DISEASE Sherry L Henderson, MD, Mayo Clinic Department of Dermatology, Rochester, MN, United States, Mark Davis, MD, Mayo Clinic Department of Dermatology, Rochester, MN, United States Disabling pansclerotic morphea (DPM) is a rare form of morphea which involves all layers of the skin extending through the dermis and subcutaneous tissues to involve muscle, tendon and bone. It is distinguished from generalized scleroderma by its lack of systemic involvement. Onset usually occurs before the age of 14 years. We describe adult-onset disabling pansclerotic morphea in 2 previously healthy young men. In both cases, the onset of disease was explosive, with rapid progression, widespread cutaneous involvement, and severe disablement due to mutilating contracture deformities. Increased susceptibility of sclerodermatous tissue to recalcitrant ulceration and malignant transformation with development of nonmelanoma skin cancers was also observed. Treatment of this disease continues to present a therapeutic dilemma with only sporadic remission despite multi-modality therapy. No conflict of interest with any authors.
MARCH 2004
TOLERABILITY AND SAFETY OF COMBINATION METHOTREXATE AND ALEFACEPT IN RHEUMATOID ARTHRITIS: RESULTS OF A PILOT STUDY Matthias Schneider, MD, Heinrich-Heine-University Dusseldorf, Dusseldorf, Germany, Hans-Detlev Stahl, MD, ZET Leipzig, Leipzig, Germany, Theresa Podrebarac, MD, Biogen, Inc., Cambridge, MA, United States, Juergen Braun, MD, St Joseph’s Krankenhaus, Herne, Germany Objective: To assess the safety and tolerability of alefacept in combination with methotrexate in patients with active rheumatoid arthritis (RA). Methods: Alefacept (human LFA-3/IgG1 fusion protein) selectively depletes memory (CD45RO⫹) T cells by interacting with the CD2 receptor. A randomized, double-blind, placebo-controlled, pilot study was conducted comparing alefacept (3.75 mg or 7.5 mg) to placebo with respect to adverse events and laboratory parameters. Study drug was administered as an intravenous bolus injection weekly for 12 weeks. Patients were observed for an additional 12 weeks. All patients remained on stable doses of methotrexate. Results: A total of 36 patients were randomized into the 3 treatment arms with 12 patients in each. Seventy-eight percent of patients were female, and the median age was 57 years. The median dosage of methotrexate was 12.5-15 mg per week. Three quarters of placebo-treated patients received concomitant corticosteroids compared with 50% of alefacept-treated patients. Alefacept selectively reduced circulating CD4⫹ and CD8⫹ memory T cells during the dosing period with a return toward baseline levels during the follow-up phase. No patient required permanent placebo substitutions due to a persistently low CD4⫹ T-cell count. Adverse events were balanced between the placebo and alefacept groups. The most common adverse event was viral respiratory infection: 3/12 placebo vs 8/24 alefacept patients. No patient discontinued because of adverse events. One serious staphylococcus aureus infection of a rheumatoid nodule was observed in an alefacept-treated patient that was easily treated with antibiotics. Low titers of antialefacept antibodies were detected in 2 placebo patients and in 2 alefacept patients. These patients had significant levels of rheumatoid factor, which can interfere with the assay. Liver function tests remained stable throughout the study. No safety concerns were identified. Conclusion: For the treatment of RA, a single 12-week course of alefacept combined with methotrexate was safe and well tolerated at the doses tested in combination. These results are consistent with the safety profile of alefacept used as monotherapy for the treatment of chronic plaque psoriasis. This combination therapy warrants further study of alefacept for the treatment of inflammatory synovitis. Disclosure not available at press time. Sponsored in part by Biogen, Inc.
J AM ACAD DERMATOL
P59
P225 CLINICAL FEATURES OF PERIODONTAL EHLERS-DANLOS SYNDROME (TYPE VIII) Sonal Shankar, MBBS, Addenbrooke’s Hospital NHS Trust, Cambridge, England, Nigel Burrows, MBBS, MD Ehlers-Danlos syndrome is a heterogeneous group of inherited disorders of connective tissue, characterised by joint hypermobility, cutaneous hyperextensibility and tissue fragility. Different subgroups of the disease have been described, each having a characteristic clinical pattern or a unique biochemical defect. Ehlers-Danlos syndrome type VIII, a rare subtype, has distinctive clinical features that are important to recognise because of the development of premature and severe periodontal disease. Although the underlying molecular cause of Ehlers-Danlos syndrome type VIII is unknown, linkage studies have implicated a gene located on chromosome 12p13.1 We are presenting a family with Ehlers-Danlos syndrome type VIII in order to highlight the classical features of this rare disease and to emphasise the severe periodontitis that can occur. We have examined five of the seven affected individuals from a large two-generation family with Ehlers-Danlos syndrome type VIII who exhibit the distinctive features of this disease. They consisted of two sisters aged 24 and 28 years, their mother aged 57 years, a male cousin aged 20 years and his father aged 53 years. All developed symptoms in childhood. The two sisters had striking joint hypermobility but this was not observed in the others. Skin hyperextensibility was variable and all had skin fragility with easy bruising and scarring. Characteristic hyperpigmented pretibial plaques and premature periodontal disease, with gingival recession and irreversible destruction of periodontal tissues, were also seen in all five individuals. As expected, this family demonstrates a dominant pattern of inheritance. In summary, we have described five members of a large family with Ehlers-Danlos syndrome type VIII who exhibit the classical features seen in this rare condition. In 1998 the classification of Ehlers-Danlos syndrome was updated.2 Type VIII is now known as periodontal type, reflecting the major complication of this subtype, as seen in our family. References: 1. Rahman N, Dunstan M, Teare MD, Hanks S et al. Ehlers-Danlos syndrome with severe early onset periodontal disease (EDS VIII) is a distinct, heterogeneous disorder with one predisposition gene at chromosome 12p13. Am J Hum Genetics 2003;73(1):198-204 2 Beighton P, De Paepe A, Steinmann B et al. Ehlers-Danlos Syndromes: Revised nosology, Villefranche, 1997. Am J Med Genet 1998;77:31-7 Disclosure not available at press time.
P226
P224 DISABLING PANSCLEROTIC MORPHEA: DIAGNOSIS AND PROGRESSION OF ADULT-ONSET DISEASE Sherry L Henderson, MD, Mayo Clinic Department of Dermatology, Rochester, MN, United States, Mark Davis, MD, Mayo Clinic Department of Dermatology, Rochester, MN, United States Disabling pansclerotic morphea (DPM) is a rare form of morphea which involves all layers of the skin extending through the dermis and subcutaneous tissues to involve muscle, tendon and bone. It is distinguished from generalized scleroderma by its lack of systemic involvement. Onset usually occurs before the age of 14 years. We describe adult-onset disabling pansclerotic morphea in 2 previously healthy young men. In both cases, the onset of disease was explosive, with rapid progression, widespread cutaneous involvement, and severe disablement due to mutilating contracture deformities. Increased susceptibility of sclerodermatous tissue to recalcitrant ulceration and malignant transformation with development of nonmelanoma skin cancers was also observed. Treatment of this disease continues to present a therapeutic dilemma with only sporadic remission despite multi-modality therapy. No conflict of interest with any authors.
MARCH 2004
TOLERABILITY AND SAFETY OF COMBINATION METHOTREXATE AND ALEFACEPT IN RHEUMATOID ARTHRITIS: RESULTS OF A PILOT STUDY Matthias Schneider, MD, Heinrich-Heine-University Dusseldorf, Dusseldorf, Germany, Hans-Detlev Stahl, MD, ZET Leipzig, Leipzig, Germany, Theresa Podrebarac, MD, Biogen, Inc., Cambridge, MA, United States, Juergen Braun, MD, St Joseph’s Krankenhaus, Herne, Germany Objective: To assess the safety and tolerability of alefacept in combination with methotrexate in patients with active rheumatoid arthritis (RA). Methods: Alefacept (human LFA-3/IgG1 fusion protein) selectively depletes memory (CD45RO⫹) T cells by interacting with the CD2 receptor. A randomized, double-blind, placebo-controlled, pilot study was conducted comparing alefacept (3.75 mg or 7.5 mg) to placebo with respect to adverse events and laboratory parameters. Study drug was administered as an intravenous bolus injection weekly for 12 weeks. Patients were observed for an additional 12 weeks. All patients remained on stable doses of methotrexate. Results: A total of 36 patients were randomized into the 3 treatment arms with 12 patients in each. Seventy-eight percent of patients were female, and the median age was 57 years. The median dosage of methotrexate was 12.5-15 mg per week. Three quarters of placebo-treated patients received concomitant corticosteroids compared with 50% of alefacept-treated patients. Alefacept selectively reduced circulating CD4⫹ and CD8⫹ memory T cells during the dosing period with a return toward baseline levels during the follow-up phase. No patient required permanent placebo substitutions due to a persistently low CD4⫹ T-cell count. Adverse events were balanced between the placebo and alefacept groups. The most common adverse event was viral respiratory infection: 3/12 placebo vs 8/24 alefacept patients. No patient discontinued because of adverse events. One serious staphylococcus aureus infection of a rheumatoid nodule was observed in an alefacept-treated patient that was easily treated with antibiotics. Low titers of antialefacept antibodies were detected in 2 placebo patients and in 2 alefacept patients. These patients had significant levels of rheumatoid factor, which can interfere with the assay. Liver function tests remained stable throughout the study. No safety concerns were identified. Conclusion: For the treatment of RA, a single 12-week course of alefacept combined with methotrexate was safe and well tolerated at the doses tested in combination. These results are consistent with the safety profile of alefacept used as monotherapy for the treatment of chronic plaque psoriasis. This combination therapy warrants further study of alefacept for the treatment of inflammatory synovitis. Disclosure not available at press time. Sponsored in part by Biogen, Inc.
J AM ACAD DERMATOL
P59