Nancy Walsh

LAS VEGAS — Results of two large studies have shown that prophylaxis with oral posaconazole can prevent invasive fungal infections in bone marrow transplant recipients and patients with hematologic malignancies, Dr. Catherine J. Hardalo reported.

Invasive fungal infections have emerged as a potentially lethal complication for immunosuppressed patients, and some of the pathogens involved are resistant to standard antifungal therapy. Posaconazole is a broad-spectrum agent with activity against Aspergillus, Fusarium, Coccidioides, Candida, pigmented and hyaline molds, and the Zygomycetes, she said at a meeting on fungal infections sponsored by Imedex.

Previously, the drug had been used primarily as salvage therapy for patients with invasive aspergillosis, with about 40% of patients responding. “In salvage therapy you will see at best a 40% response rate with any antifungal,” said Dr. Hardalo, senior director of anti-infectives clinical research, Schering-Plough Research Institute, Kenilworth, N.J.

Studies performed in the 1990s suggested the potential benefit of prophylaxis against invasive fungal infections in high-risk patients. Current prophylaxis options include fluconazole and micafungin for patients undergoing hematopoietic stem cell transplantation, and itraconazole (in Europe only) for the prevention of fungal infections during prolonged neutropenia.

Posaconazole now has been evaluated in a multicenter, double-blind study that included 600 patients who had undergone allogeneic stem cell transplantation and had graft-versus-host disease. They were randomized to receive either posaconazole 200 mg three times daily, or fluconazole 400 mg/day, for 16 weeks. The incidence of invasive fungal infections and invasive aspergillosis were 2% and 1%, respectively, in the posaconazole group vs. 8% and 6% in the fluconazole group.

A total of 76 patients in the posaconazole group died, as did 84 in the fluconazole group. This difference was not significant. However, only 4 patients on posaconazole died from fungal causes, which was significantly fewer than the 12 patients with fungal-related deaths in the fluconazole group.

In a second study, 600 patients with acute myelogenous leukemia or myelodysplastic syndrome received the same dose of posaconazole or fluconazole, 400 mg once a day, or itraconazole, 200 mg twice a day. The number of cases of invasive fungal infection and invasive aspergillosis were “virtually the same” as in the other study: 2% and 1% for posaconazole, and 8% and 7% for the other azoles, Dr. Hardalo said.

There were 49 deaths among patients receiving posaconazole and 67 among patients receiving the other azoles. Five deaths in the posaconazole group were fungal related, as were 16 in the other-azole groups. These differences were statistically significant. Moreover, for the first time, a survival benefit was seen among neutropenic patients, she said.

Because posaconazole is an oral drug, concern has been expressed about its absorption by patients with gastrointestinal dysfunction related to graft-versus-host disease. In this experience, patients with neutropenia and mucositis didn't absorb the drug as well as healthy volunteers, but tissue levels were adequate for preventing infections, Dr. Hardalo said.

“We still have a lot of questions. We still don't know what is the best treatment for aspergillosis or for zygomycosis. We don't know what is the right moment to intervene in these high-risk patients. But we do know that randomized controlled trials are needed, and this will require an ongoing effort from a large group of clinicians in order to succeed,” Dr. Hardalo said.

She disclosed that she owns stock in Schering-Plough.

LAS VEGAS — Results of two large studies have shown that prophylaxis with oral posaconazole can prevent invasive fungal infections in bone marrow transplant recipients and patients with hematologic malignancies, Dr. Catherine J. Hardalo reported.

Invasive fungal infections have emerged as a potentially lethal complication for immunosuppressed patients, and some of the pathogens involved are resistant to standard antifungal therapy. Posaconazole is a broad-spectrum agent with activity against Aspergillus, Fusarium, Coccidioides, Candida, pigmented and hyaline molds, and the Zygomycetes, she said at a meeting on fungal infections sponsored by Imedex.

Previously, the drug had been used primarily as salvage therapy for patients with invasive aspergillosis, with about 40% of patients responding. “In salvage therapy you will see at best a 40% response rate with any antifungal,” said Dr. Hardalo, senior director of anti-infectives clinical research, Schering-Plough Research Institute, Kenilworth, N.J.

Studies performed in the 1990s suggested the potential benefit of prophylaxis against invasive fungal infections in high-risk patients. Current prophylaxis options include fluconazole and micafungin for patients undergoing hematopoietic stem cell transplantation, and itraconazole (in Europe only) for the prevention of fungal infections during prolonged neutropenia.

Posaconazole now has been evaluated in a multicenter, double-blind study that included 600 patients who had undergone allogeneic stem cell transplantation and had graft-versus-host disease. They were randomized to receive either posaconazole 200 mg three times daily, or fluconazole 400 mg/day, for 16 weeks. The incidence of invasive fungal infections and invasive aspergillosis were 2% and 1%, respectively, in the posaconazole group vs. 8% and 6% in the fluconazole group.

A total of 76 patients in the posaconazole group died, as did 84 in the fluconazole group. This difference was not significant. However, only 4 patients on posaconazole died from fungal causes, which was significantly fewer than the 12 patients with fungal-related deaths in the fluconazole group.

In a second study, 600 patients with acute myelogenous leukemia or myelodysplastic syndrome received the same dose of posaconazole or fluconazole, 400 mg once a day, or itraconazole, 200 mg twice a day. The number of cases of invasive fungal infection and invasive aspergillosis were “virtually the same” as in the other study: 2% and 1% for posaconazole, and 8% and 7% for the other azoles, Dr. Hardalo said.

There were 49 deaths among patients receiving posaconazole and 67 among patients receiving the other azoles. Five deaths in the posaconazole group were fungal related, as were 16 in the other-azole groups. These differences were statistically significant. Moreover, for the first time, a survival benefit was seen among neutropenic patients, she said.

Because posaconazole is an oral drug, concern has been expressed about its absorption by patients with gastrointestinal dysfunction related to graft-versus-host disease. In this experience, patients with neutropenia and mucositis didn't absorb the drug as well as healthy volunteers, but tissue levels were adequate for preventing infections, Dr. Hardalo said.

“We still have a lot of questions. We still don't know what is the best treatment for aspergillosis or for zygomycosis. We don't know what is the right moment to intervene in these high-risk patients. But we do know that randomized controlled trials are needed, and this will require an ongoing effort from a large group of clinicians in order to succeed,” Dr. Hardalo said.

She disclosed that she owns stock in Schering-Plough.

LAS VEGAS — Results of two large studies have shown that prophylaxis with oral posaconazole can prevent invasive fungal infections in bone marrow transplant recipients and patients with hematologic malignancies, Dr. Catherine J. Hardalo reported.

Invasive fungal infections have emerged as a potentially lethal complication for immunosuppressed patients, and some of the pathogens involved are resistant to standard antifungal therapy. Posaconazole is a broad-spectrum agent with activity against Aspergillus, Fusarium, Coccidioides, Candida, pigmented and hyaline molds, and the Zygomycetes, she said at a meeting on fungal infections sponsored by Imedex.

Previously, the drug had been used primarily as salvage therapy for patients with invasive aspergillosis, with about 40% of patients responding. “In salvage therapy you will see at best a 40% response rate with any antifungal,” said Dr. Hardalo, senior director of anti-infectives clinical research, Schering-Plough Research Institute, Kenilworth, N.J.

Studies performed in the 1990s suggested the potential benefit of prophylaxis against invasive fungal infections in high-risk patients. Current prophylaxis options include fluconazole and micafungin for patients undergoing hematopoietic stem cell transplantation, and itraconazole (in Europe only) for the prevention of fungal infections during prolonged neutropenia.

Posaconazole now has been evaluated in a multicenter, double-blind study that included 600 patients who had undergone allogeneic stem cell transplantation and had graft-versus-host disease. They were randomized to receive either posaconazole 200 mg three times daily, or fluconazole 400 mg/day, for 16 weeks. The incidence of invasive fungal infections and invasive aspergillosis were 2% and 1%, respectively, in the posaconazole group vs. 8% and 6% in the fluconazole group.

A total of 76 patients in the posaconazole group died, as did 84 in the fluconazole group. This difference was not significant. However, only 4 patients on posaconazole died from fungal causes, which was significantly fewer than the 12 patients with fungal-related deaths in the fluconazole group.

In a second study, 600 patients with acute myelogenous leukemia or myelodysplastic syndrome received the same dose of posaconazole or fluconazole, 400 mg once a day, or itraconazole, 200 mg twice a day. The number of cases of invasive fungal infection and invasive aspergillosis were “virtually the same” as in the other study: 2% and 1% for posaconazole, and 8% and 7% for the other azoles, Dr. Hardalo said.

There were 49 deaths among patients receiving posaconazole and 67 among patients receiving the other azoles. Five deaths in the posaconazole group were fungal related, as were 16 in the other-azole groups. These differences were statistically significant. Moreover, for the first time, a survival benefit was seen among neutropenic patients, she said.

Because posaconazole is an oral drug, concern has been expressed about its absorption by patients with gastrointestinal dysfunction related to graft-versus-host disease. In this experience, patients with neutropenia and mucositis didn't absorb the drug as well as healthy volunteers, but tissue levels were adequate for preventing infections, Dr. Hardalo said.

“We still have a lot of questions. We still don't know what is the best treatment for aspergillosis or for zygomycosis. We don't know what is the right moment to intervene in these high-risk patients. But we do know that randomized controlled trials are needed, and this will require an ongoing effort from a large group of clinicians in order to succeed,” Dr. Hardalo said.

She disclosed that she owns stock in Schering-Plough.

LAS VEGAS — Dematiaceous, or darkly pigmented, fungi are emerging as an important cause of disease, and certain types of infections with these pathogens are associated with high rates of mortality, even among the immunocompetent, Dr. Sanjay G. Revankar said at a meeting on fungal infections sponsored by Imedex.

This is a heterogeneous group of fungi that includes more than 60 genera and 100 species found worldwide in soil and air. Melanin, present in the cell wall, provides the coloration of these pathogens and appears to be a virulence factor, providing protection from free radicals, hydrolytic enzymes, and ultraviolet damage.

One of the clinical syndromes associated with various species of dematiaceous fungi increasingly being seen is phaeohyphomycosis. Most of the species implicated are opportunists, but some may be true pathogens, said Dr. Revankar of the University of Texas Southwestern Medical Center, Dallas.

The diagnosis of phaeohyphomycosis requires expert interpretation of colony and microscopic morphology. The typical histologic findings include irregularly swollen hyphae and yeastlike forms. In contrast to many other fungi, there are no adequate serologic or antigen tests for the species that cause phaeohyphomycosis, he said.

The range of clinical syndromes composing phaeohyphomycosis includes the following:

▸ Superficial infections. These typically manifest as subcutaneous nodules appearing after minor trauma to the skin and inoculation with species of Exophiala, Alternaria, or Phialophora. Successful treatment often requires only excision, although an azole is sometimes also given.

▸ Allergic disease. Most cases of sinusitis and bronchopulmonary mycosis are caused by species of Curvularia or Bipolaris. Sinusitis is characterized by the presence of allergic mucin and elevated IgE; treatment includes surgery plus corticosteroids. Bronchopulmonary mycosis is associated with elevated IgE or eosinophilia, and treatment relies on corticosteroids. Antifungal therapy is not routinely used for these infections, Dr. Revankar said.

▸ Pneumonia. This has been seen most in immunocompromised patients, and may be characterized by hemoptysis. Among the pathogens implicated are species of Exophiala and Chaetomium. Lipid amphotericin B is the preferred treatment for these seriously ill patients, followed by an azole if the patient stabilizes, but mortality is high, he said.

▸ CNS phaeohyphomycosis. This infection shows a 3:1 male predominance and occurs worldwide. “What is really unusual is that more than half of patients seem to have no risk factors—no chemotherapy, HIV, or other immunodeficiency,” Dr. Revankar said. In a series of 101 patients with CNS infection, the classic triad seen with bacterial brain abscess—fever, headache, and neurologic deficits—was present in fewer than 5% of patients (Clin. Infect. Dis. 2004;38:206–16). Overall mortality was 72%. Many species have been isolated in CNS infections, but in nearly half of cases Cladophialophora bantiana was implicated.

There was little evidence of efficacy for any particular antifungal regimen in these patients with CNS disease. A combination of amphotericin B, 5-fluorocytosine, and itraconazole was associated with improved survival, but only six patients in the series received this combination. Voriconazole and posaconazole have shown in vitro activity, but there is very little clinical experience with these agents for this indication, he said.

▸ Disseminated phaeohyphomycosis. “This has been seen increasingly during the past 10–15 years, probably reflecting the type of patients we are seeing, such as those who are immunocompromised from treatment for other diseases,” Dr. Revankar said. Prior cardiac surgery, particularly involving bioprosthetic valve replacements, also has been identified as a risk factor.

In a series of 72 patients, fever was present in only 76%. Skin lesions were seen in 33%, sepsis in 11%, and eosinophilia in 11% (Clin. Infect. Dis. 2002;34:467–76). Blood cultures were positive, most commonly revealing Scedosporium prolificans in more than half of patients. Most of the cases were in Spain and Australia.

Overall mortality was 79%. In the immunocompromised it was 84%, and in the immunocompetent it was 65%. S. prolificans is resistant to all available agents, and no single drug or combination of drugs was associated with improved outcome in this series. In two cases, however, the combination of an azole plus terbinafine was successful. “I wouldn't recommend this routinely, but if you have no other options it might be something to consider,” he said.

LAS VEGAS — Dematiaceous, or darkly pigmented, fungi are emerging as an important cause of disease, and certain types of infections with these pathogens are associated with high rates of mortality, even among the immunocompetent, Dr. Sanjay G. Revankar said at a meeting on fungal infections sponsored by Imedex.

This is a heterogeneous group of fungi that includes more than 60 genera and 100 species found worldwide in soil and air. Melanin, present in the cell wall, provides the coloration of these pathogens and appears to be a virulence factor, providing protection from free radicals, hydrolytic enzymes, and ultraviolet damage.

One of the clinical syndromes associated with various species of dematiaceous fungi increasingly being seen is phaeohyphomycosis. Most of the species implicated are opportunists, but some may be true pathogens, said Dr. Revankar of the University of Texas Southwestern Medical Center, Dallas.

The diagnosis of phaeohyphomycosis requires expert interpretation of colony and microscopic morphology. The typical histologic findings include irregularly swollen hyphae and yeastlike forms. In contrast to many other fungi, there are no adequate serologic or antigen tests for the species that cause phaeohyphomycosis, he said.

The range of clinical syndromes composing phaeohyphomycosis includes the following:

▸ Superficial infections. These typically manifest as subcutaneous nodules appearing after minor trauma to the skin and inoculation with species of Exophiala, Alternaria, or Phialophora. Successful treatment often requires only excision, although an azole is sometimes also given.

▸ Allergic disease. Most cases of sinusitis and bronchopulmonary mycosis are caused by species of Curvularia or Bipolaris. Sinusitis is characterized by the presence of allergic mucin and elevated IgE; treatment includes surgery plus corticosteroids. Bronchopulmonary mycosis is associated with elevated IgE or eosinophilia, and treatment relies on corticosteroids. Antifungal therapy is not routinely used for these infections, Dr. Revankar said.

▸ Pneumonia. This has been seen most in immunocompromised patients, and may be characterized by hemoptysis. Among the pathogens implicated are species of Exophiala and Chaetomium. Lipid amphotericin B is the preferred treatment for these seriously ill patients, followed by an azole if the patient stabilizes, but mortality is high, he said.

▸ CNS phaeohyphomycosis. This infection shows a 3:1 male predominance and occurs worldwide. “What is really unusual is that more than half of patients seem to have no risk factors—no chemotherapy, HIV, or other immunodeficiency,” Dr. Revankar said. In a series of 101 patients with CNS infection, the classic triad seen with bacterial brain abscess—fever, headache, and neurologic deficits—was present in fewer than 5% of patients (Clin. Infect. Dis. 2004;38:206–16). Overall mortality was 72%. Many species have been isolated in CNS infections, but in nearly half of cases Cladophialophora bantiana was implicated.

There was little evidence of efficacy for any particular antifungal regimen in these patients with CNS disease. A combination of amphotericin B, 5-fluorocytosine, and itraconazole was associated with improved survival, but only six patients in the series received this combination. Voriconazole and posaconazole have shown in vitro activity, but there is very little clinical experience with these agents for this indication, he said.

▸ Disseminated phaeohyphomycosis. “This has been seen increasingly during the past 10–15 years, probably reflecting the type of patients we are seeing, such as those who are immunocompromised from treatment for other diseases,” Dr. Revankar said. Prior cardiac surgery, particularly involving bioprosthetic valve replacements, also has been identified as a risk factor.

In a series of 72 patients, fever was present in only 76%. Skin lesions were seen in 33%, sepsis in 11%, and eosinophilia in 11% (Clin. Infect. Dis. 2002;34:467–76). Blood cultures were positive, most commonly revealing Scedosporium prolificans in more than half of patients. Most of the cases were in Spain and Australia.

Overall mortality was 79%. In the immunocompromised it was 84%, and in the immunocompetent it was 65%. S. prolificans is resistant to all available agents, and no single drug or combination of drugs was associated with improved outcome in this series. In two cases, however, the combination of an azole plus terbinafine was successful. “I wouldn't recommend this routinely, but if you have no other options it might be something to consider,” he said.

LAS VEGAS — Dematiaceous, or darkly pigmented, fungi are emerging as an important cause of disease, and certain types of infections with these pathogens are associated with high rates of mortality, even among the immunocompetent, Dr. Sanjay G. Revankar said at a meeting on fungal infections sponsored by Imedex.

This is a heterogeneous group of fungi that includes more than 60 genera and 100 species found worldwide in soil and air. Melanin, present in the cell wall, provides the coloration of these pathogens and appears to be a virulence factor, providing protection from free radicals, hydrolytic enzymes, and ultraviolet damage.

One of the clinical syndromes associated with various species of dematiaceous fungi increasingly being seen is phaeohyphomycosis. Most of the species implicated are opportunists, but some may be true pathogens, said Dr. Revankar of the University of Texas Southwestern Medical Center, Dallas.

The diagnosis of phaeohyphomycosis requires expert interpretation of colony and microscopic morphology. The typical histologic findings include irregularly swollen hyphae and yeastlike forms. In contrast to many other fungi, there are no adequate serologic or antigen tests for the species that cause phaeohyphomycosis, he said.

The range of clinical syndromes composing phaeohyphomycosis includes the following:

▸ Superficial infections. These typically manifest as subcutaneous nodules appearing after minor trauma to the skin and inoculation with species of Exophiala, Alternaria, or Phialophora. Successful treatment often requires only excision, although an azole is sometimes also given.

▸ Allergic disease. Most cases of sinusitis and bronchopulmonary mycosis are caused by species of Curvularia or Bipolaris. Sinusitis is characterized by the presence of allergic mucin and elevated IgE; treatment includes surgery plus corticosteroids. Bronchopulmonary mycosis is associated with elevated IgE or eosinophilia, and treatment relies on corticosteroids. Antifungal therapy is not routinely used for these infections, Dr. Revankar said.

▸ Pneumonia. This has been seen most in immunocompromised patients, and may be characterized by hemoptysis. Among the pathogens implicated are species of Exophiala and Chaetomium. Lipid amphotericin B is the preferred treatment for these seriously ill patients, followed by an azole if the patient stabilizes, but mortality is high, he said.

▸ CNS phaeohyphomycosis. This infection shows a 3:1 male predominance and occurs worldwide. “What is really unusual is that more than half of patients seem to have no risk factors—no chemotherapy, HIV, or other immunodeficiency,” Dr. Revankar said. In a series of 101 patients with CNS infection, the classic triad seen with bacterial brain abscess—fever, headache, and neurologic deficits—was present in fewer than 5% of patients (Clin. Infect. Dis. 2004;38:206–16). Overall mortality was 72%. Many species have been isolated in CNS infections, but in nearly half of cases Cladophialophora bantiana was implicated.

There was little evidence of efficacy for any particular antifungal regimen in these patients with CNS disease. A combination of amphotericin B, 5-fluorocytosine, and itraconazole was associated with improved survival, but only six patients in the series received this combination. Voriconazole and posaconazole have shown in vitro activity, but there is very little clinical experience with these agents for this indication, he said.

▸ Disseminated phaeohyphomycosis. “This has been seen increasingly during the past 10–15 years, probably reflecting the type of patients we are seeing, such as those who are immunocompromised from treatment for other diseases,” Dr. Revankar said. Prior cardiac surgery, particularly involving bioprosthetic valve replacements, also has been identified as a risk factor.

In a series of 72 patients, fever was present in only 76%. Skin lesions were seen in 33%, sepsis in 11%, and eosinophilia in 11% (Clin. Infect. Dis. 2002;34:467–76). Blood cultures were positive, most commonly revealing Scedosporium prolificans in more than half of patients. Most of the cases were in Spain and Australia.

Overall mortality was 79%. In the immunocompromised it was 84%, and in the immunocompetent it was 65%. S. prolificans is resistant to all available agents, and no single drug or combination of drugs was associated with improved outcome in this series. In two cases, however, the combination of an azole plus terbinafine was successful. “I wouldn't recommend this routinely, but if you have no other options it might be something to consider,” he said.

ABANO TERME, ITALY — Childhood-onset systemic sclerosis is different from adult-onset scleroderma, typically being characterized by less internal organ involvement and lower mortality rates, Dr. Francesco Zulian reported at a congress on skin, rheumatism, and autoimmunity.

According to data from the Padua international database that includes 1,000 juvenile patients with various types of scleroderma, 153 have systemic sclerosis, said Dr. Zulian of the pediatrics/rheumatology division at the University of Padua (Italy).

The average age of systemic sclerosis onset was 8.1 years, and the disease duration at diagnosis was 1.9 years. The female to male ratio was 3.6:1.0, and 139 of the patients had the diffuse subtype of systemic sclerosis, he said. The limited subtype is more common among adults.

The first manifestation of systemic sclerosis in children typically is Raynaud's phenomenon. This is followed by the appearance of autoantibodies, and then capillaroscopy changes.

The pattern of autoantibodies is different from that seen in adults with scleroderma. Antinuclear antibodies were seen in 81% of the pediatric patients, compared with 94% of adults, whereas anti-Scl-70 antibodies were seen in 34% vs. 43%, respectively, Dr. Zulian said.

Rheumatoid factor was found in 17% of the children, compared with 23% of the adults, he added.

Anticentromere antibodies were found in 7.1% of children in the database, compared with 23% of adults, which reflects the lower prevalence of the limited subtype of systemic sclerosis in children, he said.

The most frequent manifestations were Raynaud's phenomenon, which was seen in 84% of the juvenile patients, and skin induration, which was found in 76%. Abnormal lung function tests were seen in 40% of the patients and pulmonary fibrosis in 25%.

Skin involvement accounts for 60% of symptoms in children, which is much lower than in adults. It is also more difficult to make the diagnosis in young patients, Dr. Zulian said.

Musculoskeletal involvement also was quite common, with arthralgias reported by 36%, arthritis by 27.5%, and muscle weakness by 24.2%. Gastroesophageal reflux was found in 30%, but small-bowel involvement was rare.

“In 127 patients we have enough data to make some conclusions about outcome,” Dr. Zulian said. At present, 15 (11.8%) of the patients have died, 10 of cardiac failure, 2 of renal failure, 2 of respiratory failure, and 1 of septicemia. Of these 15, 4 died within the first year after diagnosis, and 11 within 5 years of diagnosis. “This means that there is a group of patients who have a very aggressive course of disease and who did not respond to treatment,” he said.

Organ involvement is the major predictor of poor outcome, so those who present with early respiratory, cardiac, or gastrointestinal involvement must be evaluated and treated aggressively, he said.

Capillaroscopy changes typical of juvenile systemic sclerosis usually appear after Raynaud's phenomenon and the appearance of serum autoantibodies. COURTESY DR. FRANCESCO ZULIAN

ABANO TERME, ITALY — Childhood-onset systemic sclerosis is different from adult-onset scleroderma, typically being characterized by less internal organ involvement and lower mortality rates, Dr. Francesco Zulian reported at a congress on skin, rheumatism, and autoimmunity.

According to data from the Padua international database that includes 1,000 juvenile patients with various types of scleroderma, 153 have systemic sclerosis, said Dr. Zulian of the pediatrics/rheumatology division at the University of Padua (Italy).

The average age of systemic sclerosis onset was 8.1 years, and the disease duration at diagnosis was 1.9 years. The female to male ratio was 3.6:1.0, and 139 of the patients had the diffuse subtype of systemic sclerosis, he said. The limited subtype is more common among adults.

The first manifestation of systemic sclerosis in children typically is Raynaud's phenomenon. This is followed by the appearance of autoantibodies, and then capillaroscopy changes.

The pattern of autoantibodies is different from that seen in adults with scleroderma. Antinuclear antibodies were seen in 81% of the pediatric patients, compared with 94% of adults, whereas anti-Scl-70 antibodies were seen in 34% vs. 43%, respectively, Dr. Zulian said.

Rheumatoid factor was found in 17% of the children, compared with 23% of the adults, he added.

Anticentromere antibodies were found in 7.1% of children in the database, compared with 23% of adults, which reflects the lower prevalence of the limited subtype of systemic sclerosis in children, he said.

The most frequent manifestations were Raynaud's phenomenon, which was seen in 84% of the juvenile patients, and skin induration, which was found in 76%. Abnormal lung function tests were seen in 40% of the patients and pulmonary fibrosis in 25%.

Skin involvement accounts for 60% of symptoms in children, which is much lower than in adults. It is also more difficult to make the diagnosis in young patients, Dr. Zulian said.

Musculoskeletal involvement also was quite common, with arthralgias reported by 36%, arthritis by 27.5%, and muscle weakness by 24.2%. Gastroesophageal reflux was found in 30%, but small-bowel involvement was rare.

“In 127 patients we have enough data to make some conclusions about outcome,” Dr. Zulian said. At present, 15 (11.8%) of the patients have died, 10 of cardiac failure, 2 of renal failure, 2 of respiratory failure, and 1 of septicemia. Of these 15, 4 died within the first year after diagnosis, and 11 within 5 years of diagnosis. “This means that there is a group of patients who have a very aggressive course of disease and who did not respond to treatment,” he said.

Organ involvement is the major predictor of poor outcome, so those who present with early respiratory, cardiac, or gastrointestinal involvement must be evaluated and treated aggressively, he said.

Capillaroscopy changes typical of juvenile systemic sclerosis usually appear after Raynaud's phenomenon and the appearance of serum autoantibodies. COURTESY DR. FRANCESCO ZULIAN

ABANO TERME, ITALY — Childhood-onset systemic sclerosis is different from adult-onset scleroderma, typically being characterized by less internal organ involvement and lower mortality rates, Dr. Francesco Zulian reported at a congress on skin, rheumatism, and autoimmunity.

According to data from the Padua international database that includes 1,000 juvenile patients with various types of scleroderma, 153 have systemic sclerosis, said Dr. Zulian of the pediatrics/rheumatology division at the University of Padua (Italy).

The average age of systemic sclerosis onset was 8.1 years, and the disease duration at diagnosis was 1.9 years. The female to male ratio was 3.6:1.0, and 139 of the patients had the diffuse subtype of systemic sclerosis, he said. The limited subtype is more common among adults.

The first manifestation of systemic sclerosis in children typically is Raynaud's phenomenon. This is followed by the appearance of autoantibodies, and then capillaroscopy changes.

The pattern of autoantibodies is different from that seen in adults with scleroderma. Antinuclear antibodies were seen in 81% of the pediatric patients, compared with 94% of adults, whereas anti-Scl-70 antibodies were seen in 34% vs. 43%, respectively, Dr. Zulian said.

Rheumatoid factor was found in 17% of the children, compared with 23% of the adults, he added.

Anticentromere antibodies were found in 7.1% of children in the database, compared with 23% of adults, which reflects the lower prevalence of the limited subtype of systemic sclerosis in children, he said.

The most frequent manifestations were Raynaud's phenomenon, which was seen in 84% of the juvenile patients, and skin induration, which was found in 76%. Abnormal lung function tests were seen in 40% of the patients and pulmonary fibrosis in 25%.

Skin involvement accounts for 60% of symptoms in children, which is much lower than in adults. It is also more difficult to make the diagnosis in young patients, Dr. Zulian said.

Musculoskeletal involvement also was quite common, with arthralgias reported by 36%, arthritis by 27.5%, and muscle weakness by 24.2%. Gastroesophageal reflux was found in 30%, but small-bowel involvement was rare.

“In 127 patients we have enough data to make some conclusions about outcome,” Dr. Zulian said. At present, 15 (11.8%) of the patients have died, 10 of cardiac failure, 2 of renal failure, 2 of respiratory failure, and 1 of septicemia. Of these 15, 4 died within the first year after diagnosis, and 11 within 5 years of diagnosis. “This means that there is a group of patients who have a very aggressive course of disease and who did not respond to treatment,” he said.

Organ involvement is the major predictor of poor outcome, so those who present with early respiratory, cardiac, or gastrointestinal involvement must be evaluated and treated aggressively, he said.

Capillaroscopy changes typical of juvenile systemic sclerosis usually appear after Raynaud's phenomenon and the appearance of serum autoantibodies. COURTESY DR. FRANCESCO ZULIAN

NEW YORK — The unique inflammatory cytokine profile associated with systemic juvenile idiopathic arthritis may offer therapeutic targets that could ultimately lead to symptom control and prevention of long-term disability in this difficult-to-treat condition.

Systemic juvenile idiopathic arthritis (JIA) turns out to be a very different disease than juvenile polyarthritis, Dr. Daniel J. Lovell said at a rheumatology meeting sponsored by New York University. The disease has a more severe outcome, with up to half of patients continuing to have active arthritis 5–10 years after diagnosis. Most patients have required treatment with methotrexate for their arthritis and corticosteroids for their systemic symptoms such as fever and rash, but the steroid treatment itself can result in significant morbidity, with patients experiencing growth retardation and developing osteoporosis.

It is now known that systemic JIA also differs in pathogenesis. In a cohort that included 82 patients treated with etanercept for a mean of 25 months, response to an anti-TNF-α agent was fair or poor in more than half (J. Rheumatol. 2005;32:935–42). Rather, it appears that interleukin (IL)-6 and IL-1 are the dominant inflammatory cytokines in systemic JIA.

A dose-finding study conducted in Japan found “profound and rapid responses” to treatment with tocilizumab, a humanized monoclonal antibody to the IL-6 receptor, said Dr. Lovell, professor of pediatrics, Cincinnati Children's Hospital Medical Center.

The study included 11 patients whose median age was 9 years and whose median duration of disease was 3 years. The drug was given in doses of 2 mg/kg every 2 weeks for three courses of treatment unless response was inadequate, in which case doses were increased to 4 mg/kg and then 8 mg/kg, depending on effect. Clinical responses were evident 3–4 days after the first treatment, and in some cases, the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) began to fall within hours after the initial infusion, he said.

Within 2 weeks after the third dose, 90.9% of patients had reached an American College of Rheumatology (ACR) pediatric 30 response, the same number also achieved an ACR 50 response, and 63.6% had achieved an ACR 70 (Arthritis Rheum. 2005;52:818–25).

In another study, nine patients whose disease had been resistant to aggressive conventional treatment received anakinra for an average of 6.6 months, and all responded. Complete remission, including resolution of fever and rash, was seen in seven (J. Exp. Med. 2005;201:1479–86). Prior treatments included oral prednisone, intravenous methylprednisolone, and infliximab.

In describing his experience using biologic treatments for juvenile systemic and polyarticular rheumatoid arthritis, Dr. Lovell emphasized that there is a need for better ways of evaluating outcomes. The ACR pediatric 30, typically used as the primary end point in drug trials, is a composite index requiring a 30% improvement in three of six disease components. This end point has been met so commonly in studies evaluating biologics that more stringent criteria are now needed, so Dr. Lovell and a group of international experts recently proposed a new outcome measure termed “inactive disease.” To achieve this, all five of the following criteria must be met:

▸ No joints with active arthritis.

▸ No fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable to systemic JIA.

▸ No active uveitis.

▸ Normal ESR and CRP.

▸ Physician's global assessment indicating no disease activity.

Patients who maintain inactive disease for 6 months are classified as being in clinical remission on medication, those who maintain inactive disease for 12 months while off medications are said to be in clinical remission off medication.

NEW YORK — The unique inflammatory cytokine profile associated with systemic juvenile idiopathic arthritis may offer therapeutic targets that could ultimately lead to symptom control and prevention of long-term disability in this difficult-to-treat condition.

Systemic juvenile idiopathic arthritis (JIA) turns out to be a very different disease than juvenile polyarthritis, Dr. Daniel J. Lovell said at a rheumatology meeting sponsored by New York University. The disease has a more severe outcome, with up to half of patients continuing to have active arthritis 5–10 years after diagnosis. Most patients have required treatment with methotrexate for their arthritis and corticosteroids for their systemic symptoms such as fever and rash, but the steroid treatment itself can result in significant morbidity, with patients experiencing growth retardation and developing osteoporosis.

It is now known that systemic JIA also differs in pathogenesis. In a cohort that included 82 patients treated with etanercept for a mean of 25 months, response to an anti-TNF-α agent was fair or poor in more than half (J. Rheumatol. 2005;32:935–42). Rather, it appears that interleukin (IL)-6 and IL-1 are the dominant inflammatory cytokines in systemic JIA.

A dose-finding study conducted in Japan found “profound and rapid responses” to treatment with tocilizumab, a humanized monoclonal antibody to the IL-6 receptor, said Dr. Lovell, professor of pediatrics, Cincinnati Children's Hospital Medical Center.

The study included 11 patients whose median age was 9 years and whose median duration of disease was 3 years. The drug was given in doses of 2 mg/kg every 2 weeks for three courses of treatment unless response was inadequate, in which case doses were increased to 4 mg/kg and then 8 mg/kg, depending on effect. Clinical responses were evident 3–4 days after the first treatment, and in some cases, the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) began to fall within hours after the initial infusion, he said.

Within 2 weeks after the third dose, 90.9% of patients had reached an American College of Rheumatology (ACR) pediatric 30 response, the same number also achieved an ACR 50 response, and 63.6% had achieved an ACR 70 (Arthritis Rheum. 2005;52:818–25).

In another study, nine patients whose disease had been resistant to aggressive conventional treatment received anakinra for an average of 6.6 months, and all responded. Complete remission, including resolution of fever and rash, was seen in seven (J. Exp. Med. 2005;201:1479–86). Prior treatments included oral prednisone, intravenous methylprednisolone, and infliximab.

In describing his experience using biologic treatments for juvenile systemic and polyarticular rheumatoid arthritis, Dr. Lovell emphasized that there is a need for better ways of evaluating outcomes. The ACR pediatric 30, typically used as the primary end point in drug trials, is a composite index requiring a 30% improvement in three of six disease components. This end point has been met so commonly in studies evaluating biologics that more stringent criteria are now needed, so Dr. Lovell and a group of international experts recently proposed a new outcome measure termed “inactive disease.” To achieve this, all five of the following criteria must be met:

▸ No joints with active arthritis.

▸ No fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable to systemic JIA.

▸ No active uveitis.

▸ Normal ESR and CRP.

▸ Physician's global assessment indicating no disease activity.

Patients who maintain inactive disease for 6 months are classified as being in clinical remission on medication, those who maintain inactive disease for 12 months while off medications are said to be in clinical remission off medication.

NEW YORK — The unique inflammatory cytokine profile associated with systemic juvenile idiopathic arthritis may offer therapeutic targets that could ultimately lead to symptom control and prevention of long-term disability in this difficult-to-treat condition.

Systemic juvenile idiopathic arthritis (JIA) turns out to be a very different disease than juvenile polyarthritis, Dr. Daniel J. Lovell said at a rheumatology meeting sponsored by New York University. The disease has a more severe outcome, with up to half of patients continuing to have active arthritis 5–10 years after diagnosis. Most patients have required treatment with methotrexate for their arthritis and corticosteroids for their systemic symptoms such as fever and rash, but the steroid treatment itself can result in significant morbidity, with patients experiencing growth retardation and developing osteoporosis.

It is now known that systemic JIA also differs in pathogenesis. In a cohort that included 82 patients treated with etanercept for a mean of 25 months, response to an anti-TNF-α agent was fair or poor in more than half (J. Rheumatol. 2005;32:935–42). Rather, it appears that interleukin (IL)-6 and IL-1 are the dominant inflammatory cytokines in systemic JIA.

A dose-finding study conducted in Japan found “profound and rapid responses” to treatment with tocilizumab, a humanized monoclonal antibody to the IL-6 receptor, said Dr. Lovell, professor of pediatrics, Cincinnati Children's Hospital Medical Center.

The study included 11 patients whose median age was 9 years and whose median duration of disease was 3 years. The drug was given in doses of 2 mg/kg every 2 weeks for three courses of treatment unless response was inadequate, in which case doses were increased to 4 mg/kg and then 8 mg/kg, depending on effect. Clinical responses were evident 3–4 days after the first treatment, and in some cases, the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) began to fall within hours after the initial infusion, he said.

Within 2 weeks after the third dose, 90.9% of patients had reached an American College of Rheumatology (ACR) pediatric 30 response, the same number also achieved an ACR 50 response, and 63.6% had achieved an ACR 70 (Arthritis Rheum. 2005;52:818–25).

In another study, nine patients whose disease had been resistant to aggressive conventional treatment received anakinra for an average of 6.6 months, and all responded. Complete remission, including resolution of fever and rash, was seen in seven (J. Exp. Med. 2005;201:1479–86). Prior treatments included oral prednisone, intravenous methylprednisolone, and infliximab.

In describing his experience using biologic treatments for juvenile systemic and polyarticular rheumatoid arthritis, Dr. Lovell emphasized that there is a need for better ways of evaluating outcomes. The ACR pediatric 30, typically used as the primary end point in drug trials, is a composite index requiring a 30% improvement in three of six disease components. This end point has been met so commonly in studies evaluating biologics that more stringent criteria are now needed, so Dr. Lovell and a group of international experts recently proposed a new outcome measure termed “inactive disease.” To achieve this, all five of the following criteria must be met:

▸ No joints with active arthritis.

▸ No fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable to systemic JIA.

▸ No active uveitis.

▸ Normal ESR and CRP.

▸ Physician's global assessment indicating no disease activity.

Patients who maintain inactive disease for 6 months are classified as being in clinical remission on medication, those who maintain inactive disease for 12 months while off medications are said to be in clinical remission off medication.

NEW YORK — Early studies evaluating biologic therapies for juvenile idiopathic arthritis are showing benefits that in many cases are profound and persistent, even among patients with the most severe disease.

These trials also have taught some important lessons about study design, placebo responses, and the importance of correct dosing, according to Dr. Daniel J. Lovell.

In an initial trial investigating etanercept (Enbrel) in 58 patients (mean age 10.5 years) treatment-resistant polyarticular juvenile idiopathic arthritis (JIA) a unique study design was used, Dr. Lovell said at a rheumatology meeting sponsored by New York University.

All patients received a 0.4-mg/kg dose of the drug twice weekly on an open-label basis for 3 months, and those who achieved an American College of Rheumatology pediatric 30 response, which is equivalent to the adult ACR 20 response, were entered into the 4-month double-blind, placebo- controlled phase. As soon as a patient flared he or she could leave the blinded phase and go back on the drug. Flare was defined as a 30% worsening in disease activity.

On average these patients had 25 active joints at baseline; this fell to 4 after 3 months of etanercept, said Dr. Lovell, professor of pediatrics, Cincinnati Children's Hospital Medical Center.

Moreover, only those patients who initially demonstrated a response to etanercept—74% of the cohort—were enrolled in the blinded phase, he said.

Flares typically occurred quickly among patients randomized to placebo, but clinical benefits were regained once the patients restarted etanercept. Some patients have now been followed for 4 years, with persistent benefits in many disease domains. (See chart.) “It's also important to note that on each of these parameters 20%–40% of the population actually normalized, meaning they could have a pain assessment score of zero or no active joints,” he said.

Another double-blind study that enrolled 171 patients (mean age 11.4 years) with polyarticular JIA to adalimumab (Humira) at a dose of 24 mg/m

Among patients receiving adalimumab without background methotrexate, 67% achieved an ACR pediatric 30 response, while 63% and 45% achieved ACR 50 and 70 responses, respectively. Among those with background methotrexate, 88%, 85%, and 69% reached ACR 30, 50, and 70 levels of response, respectively.

“The lesson we can take home as clinicians is that if you're going to use [adalimumab] in patients with juvenile [idiopathic] arthritis it makes sense to combine it with methotrexate,” he said. The combination was as safe as adalimumab alone.

Responses were rapid: By week 8 all the patients who were going to respond to the drug had done so.

Another trial that was recently completed evaluated infliximab (Remicade) in doses of 3 mg/kg or 6 mg/kg. This was a more traditional study design, with patients receiving either placebo infusions or infliximab 3 mg/kg at prespecified intervals for 14 weeks. At that time, patients who had been on placebo received infusions of 6 mg/kg of infliximab, while those on the 3 mg/kg regimen continued at that dose.

At week 14, 65% of 122 patients on infliximab had achieved an ACR 30 response, which was the primary end point, as had 48% of those on placebo.

The difference in response rate from placebo for the 3 mg/kg dose, with a P value of .051, did not reach statistical significance, so this dose will not be approved by the FDA, Dr. Lovell said.

In the second phase of the trial, however, when patients were receiving infusions of either 3 mg/kg or 6 mg/kg every 8 weeks, approximately 70% of patients in both groups had an ACR 30 response. Among patients receiving the lower dose, 38% developed anti-infliximab antibodies, compared with 12% of those receiving the higher dose. Patients with these antibodies, which develop in response to the mouse component of this chimeric drug, have a three- to fourfold increased risk of having an infusion reaction and also have lower serum concentrations of the drug.

ELSEVIER GLOBAL MEDICAL NEWS

NEW YORK — Early studies evaluating biologic therapies for juvenile idiopathic arthritis are showing benefits that in many cases are profound and persistent, even among patients with the most severe disease.

These trials also have taught some important lessons about study design, placebo responses, and the importance of correct dosing, according to Dr. Daniel J. Lovell.

In an initial trial investigating etanercept (Enbrel) in 58 patients (mean age 10.5 years) treatment-resistant polyarticular juvenile idiopathic arthritis (JIA) a unique study design was used, Dr. Lovell said at a rheumatology meeting sponsored by New York University.

All patients received a 0.4-mg/kg dose of the drug twice weekly on an open-label basis for 3 months, and those who achieved an American College of Rheumatology pediatric 30 response, which is equivalent to the adult ACR 20 response, were entered into the 4-month double-blind, placebo- controlled phase. As soon as a patient flared he or she could leave the blinded phase and go back on the drug. Flare was defined as a 30% worsening in disease activity.

On average these patients had 25 active joints at baseline; this fell to 4 after 3 months of etanercept, said Dr. Lovell, professor of pediatrics, Cincinnati Children's Hospital Medical Center.

Moreover, only those patients who initially demonstrated a response to etanercept—74% of the cohort—were enrolled in the blinded phase, he said.

Flares typically occurred quickly among patients randomized to placebo, but clinical benefits were regained once the patients restarted etanercept. Some patients have now been followed for 4 years, with persistent benefits in many disease domains. (See chart.) “It's also important to note that on each of these parameters 20%–40% of the population actually normalized, meaning they could have a pain assessment score of zero or no active joints,” he said.

Another double-blind study that enrolled 171 patients (mean age 11.4 years) with polyarticular JIA to adalimumab (Humira) at a dose of 24 mg/m

Among patients receiving adalimumab without background methotrexate, 67% achieved an ACR pediatric 30 response, while 63% and 45% achieved ACR 50 and 70 responses, respectively. Among those with background methotrexate, 88%, 85%, and 69% reached ACR 30, 50, and 70 levels of response, respectively.

“The lesson we can take home as clinicians is that if you're going to use [adalimumab] in patients with juvenile [idiopathic] arthritis it makes sense to combine it with methotrexate,” he said. The combination was as safe as adalimumab alone.

Responses were rapid: By week 8 all the patients who were going to respond to the drug had done so.

Another trial that was recently completed evaluated infliximab (Remicade) in doses of 3 mg/kg or 6 mg/kg. This was a more traditional study design, with patients receiving either placebo infusions or infliximab 3 mg/kg at prespecified intervals for 14 weeks. At that time, patients who had been on placebo received infusions of 6 mg/kg of infliximab, while those on the 3 mg/kg regimen continued at that dose.

At week 14, 65% of 122 patients on infliximab had achieved an ACR 30 response, which was the primary end point, as had 48% of those on placebo.

The difference in response rate from placebo for the 3 mg/kg dose, with a P value of .051, did not reach statistical significance, so this dose will not be approved by the FDA, Dr. Lovell said.

In the second phase of the trial, however, when patients were receiving infusions of either 3 mg/kg or 6 mg/kg every 8 weeks, approximately 70% of patients in both groups had an ACR 30 response. Among patients receiving the lower dose, 38% developed anti-infliximab antibodies, compared with 12% of those receiving the higher dose. Patients with these antibodies, which develop in response to the mouse component of this chimeric drug, have a three- to fourfold increased risk of having an infusion reaction and also have lower serum concentrations of the drug.

ELSEVIER GLOBAL MEDICAL NEWS

NEW YORK — Early studies evaluating biologic therapies for juvenile idiopathic arthritis are showing benefits that in many cases are profound and persistent, even among patients with the most severe disease.

These trials also have taught some important lessons about study design, placebo responses, and the importance of correct dosing, according to Dr. Daniel J. Lovell.

In an initial trial investigating etanercept (Enbrel) in 58 patients (mean age 10.5 years) treatment-resistant polyarticular juvenile idiopathic arthritis (JIA) a unique study design was used, Dr. Lovell said at a rheumatology meeting sponsored by New York University.

All patients received a 0.4-mg/kg dose of the drug twice weekly on an open-label basis for 3 months, and those who achieved an American College of Rheumatology pediatric 30 response, which is equivalent to the adult ACR 20 response, were entered into the 4-month double-blind, placebo- controlled phase. As soon as a patient flared he or she could leave the blinded phase and go back on the drug. Flare was defined as a 30% worsening in disease activity.

On average these patients had 25 active joints at baseline; this fell to 4 after 3 months of etanercept, said Dr. Lovell, professor of pediatrics, Cincinnati Children's Hospital Medical Center.

Moreover, only those patients who initially demonstrated a response to etanercept—74% of the cohort—were enrolled in the blinded phase, he said.

Flares typically occurred quickly among patients randomized to placebo, but clinical benefits were regained once the patients restarted etanercept. Some patients have now been followed for 4 years, with persistent benefits in many disease domains. (See chart.) “It's also important to note that on each of these parameters 20%–40% of the population actually normalized, meaning they could have a pain assessment score of zero or no active joints,” he said.

Another double-blind study that enrolled 171 patients (mean age 11.4 years) with polyarticular JIA to adalimumab (Humira) at a dose of 24 mg/m

Among patients receiving adalimumab without background methotrexate, 67% achieved an ACR pediatric 30 response, while 63% and 45% achieved ACR 50 and 70 responses, respectively. Among those with background methotrexate, 88%, 85%, and 69% reached ACR 30, 50, and 70 levels of response, respectively.

“The lesson we can take home as clinicians is that if you're going to use [adalimumab] in patients with juvenile [idiopathic] arthritis it makes sense to combine it with methotrexate,” he said. The combination was as safe as adalimumab alone.

Responses were rapid: By week 8 all the patients who were going to respond to the drug had done so.

Another trial that was recently completed evaluated infliximab (Remicade) in doses of 3 mg/kg or 6 mg/kg. This was a more traditional study design, with patients receiving either placebo infusions or infliximab 3 mg/kg at prespecified intervals for 14 weeks. At that time, patients who had been on placebo received infusions of 6 mg/kg of infliximab, while those on the 3 mg/kg regimen continued at that dose.

At week 14, 65% of 122 patients on infliximab had achieved an ACR 30 response, which was the primary end point, as had 48% of those on placebo.

The difference in response rate from placebo for the 3 mg/kg dose, with a P value of .051, did not reach statistical significance, so this dose will not be approved by the FDA, Dr. Lovell said.

In the second phase of the trial, however, when patients were receiving infusions of either 3 mg/kg or 6 mg/kg every 8 weeks, approximately 70% of patients in both groups had an ACR 30 response. Among patients receiving the lower dose, 38% developed anti-infliximab antibodies, compared with 12% of those receiving the higher dose. Patients with these antibodies, which develop in response to the mouse component of this chimeric drug, have a three- to fourfold increased risk of having an infusion reaction and also have lower serum concentrations of the drug.

ELSEVIER GLOBAL MEDICAL NEWS

ABANO TERME, ITALY — Juvenile localized scleroderma—traditionally considered a relatively benign condition with manifestations limited to skin and subcutaneous tissue—is not just simply a skin disease in close to one-quarter of affected children, Dr. Francesco Zulian said at a congress on skin, rheumatism, and autoimmunity.

Investigations of a worldwide database of 727 patients have shown that 22.4% of patients have extracutaneous disease manifestations, said Dr. Zulian of the University of Padua (Italy).

Among patients with extracutaneous manifestations, 66% had the linear subtype of juvenile scleroderma, while 25% had the plaque subtype. An additional 7% had generalized morphea, and 2% had deep morphea. “The mean age of onset was 7 years, but we have 17 patients with onset in the first year of life and 6 with congenital lesions,” he said. There was a family history of autoimmune disease in 12%, and a recent history of trauma in 14%. Juvenile localized scleroderma still was not well recognized, and the mean delay in diagnosis was 18 months.

The most common extracutaneous manifestation was arthritis, reported in 12.1%. Neurologic involvement was seen in 4.4%, vascular involvement in 2.4%, and ocular involvement in 2.1%.

The arthritis often is seen on the same side of the body as the cutaneous lesion, which raises the possibility that linear bands of sclerosis spreading across joints could cause inflammation by local mechanisms (Arthritis Rheum. 2005;52:2873–81).

But the observation that articular involvement sometimes occurred on the opposite side “makes us suspect that some systemic inflammation was going on,” Dr. Zulian said.

Neurologic manifestations were seen primarily among children with linear scleroderma of the face. Accordingly, any child with this presentation should be evaluated with an electroencephalogram and CT or MRI, particularly because abnormalities on MRI were found in seven of the children who had no neurologic symptoms, he said.

Treatment of the condition was addressed in a separate session by Dr. Davide Meneghesso, one of Dr. Zulian's colleagues at the University of Padua.

“There is no universally accepted treatment,” Dr. Meneghesso said. Topical, oral, and parenteral steroids have been used, as has D-penicillamine, vitamin D, and nonsteroidal anti-inflammatory drugs. Various supportive treatments such as anticonvulsants also have been used in patients with extracutaneous complications (Rheumatology 2005 Dec. 20 [Epub ahead of print];doi 10.1093/rheumatology/kei251).

But now, a prospective trial evaluating methotrexate, 15 mg/m

Mean age of the patients was 8.3 years, mean disease duration was 49 months, and the female to male ratio was 2.8:1.0. Nineteen children had linear scleroderma and eight had generalized morphea, he said.

Only two patients did not respond to the treatment. The remaining 11 patients remained stable during 12 months of follow-up, he said. Histologic evaluation in 16 of the patients found improvements in inflammation and fibrosis in nine and stable disease in seven. Side effects were seen in 55% of patients, but none were severe.

Among children with extracutaneous manifestations of scleroderma, the linear subtype (left) was found in two-thirds. Generalized morphea (right) is much more uncommon. PHOTOS COURTESY DR. FRANCESCO ZULIAN

ABANO TERME, ITALY — Juvenile localized scleroderma—traditionally considered a relatively benign condition with manifestations limited to skin and subcutaneous tissue—is not just simply a skin disease in close to one-quarter of affected children, Dr. Francesco Zulian said at a congress on skin, rheumatism, and autoimmunity.

Investigations of a worldwide database of 727 patients have shown that 22.4% of patients have extracutaneous disease manifestations, said Dr. Zulian of the University of Padua (Italy).

Among patients with extracutaneous manifestations, 66% had the linear subtype of juvenile scleroderma, while 25% had the plaque subtype. An additional 7% had generalized morphea, and 2% had deep morphea. “The mean age of onset was 7 years, but we have 17 patients with onset in the first year of life and 6 with congenital lesions,” he said. There was a family history of autoimmune disease in 12%, and a recent history of trauma in 14%. Juvenile localized scleroderma still was not well recognized, and the mean delay in diagnosis was 18 months.

The most common extracutaneous manifestation was arthritis, reported in 12.1%. Neurologic involvement was seen in 4.4%, vascular involvement in 2.4%, and ocular involvement in 2.1%.

The arthritis often is seen on the same side of the body as the cutaneous lesion, which raises the possibility that linear bands of sclerosis spreading across joints could cause inflammation by local mechanisms (Arthritis Rheum. 2005;52:2873–81).

But the observation that articular involvement sometimes occurred on the opposite side “makes us suspect that some systemic inflammation was going on,” Dr. Zulian said.

Neurologic manifestations were seen primarily among children with linear scleroderma of the face. Accordingly, any child with this presentation should be evaluated with an electroencephalogram and CT or MRI, particularly because abnormalities on MRI were found in seven of the children who had no neurologic symptoms, he said.

Treatment of the condition was addressed in a separate session by Dr. Davide Meneghesso, one of Dr. Zulian's colleagues at the University of Padua.

“There is no universally accepted treatment,” Dr. Meneghesso said. Topical, oral, and parenteral steroids have been used, as has D-penicillamine, vitamin D, and nonsteroidal anti-inflammatory drugs. Various supportive treatments such as anticonvulsants also have been used in patients with extracutaneous complications (Rheumatology 2005 Dec. 20 [Epub ahead of print];doi 10.1093/rheumatology/kei251).

But now, a prospective trial evaluating methotrexate, 15 mg/m

Mean age of the patients was 8.3 years, mean disease duration was 49 months, and the female to male ratio was 2.8:1.0. Nineteen children had linear scleroderma and eight had generalized morphea, he said.

Only two patients did not respond to the treatment. The remaining 11 patients remained stable during 12 months of follow-up, he said. Histologic evaluation in 16 of the patients found improvements in inflammation and fibrosis in nine and stable disease in seven. Side effects were seen in 55% of patients, but none were severe.

Among children with extracutaneous manifestations of scleroderma, the linear subtype (left) was found in two-thirds. Generalized morphea (right) is much more uncommon. PHOTOS COURTESY DR. FRANCESCO ZULIAN

ABANO TERME, ITALY — Juvenile localized scleroderma—traditionally considered a relatively benign condition with manifestations limited to skin and subcutaneous tissue—is not just simply a skin disease in close to one-quarter of affected children, Dr. Francesco Zulian said at a congress on skin, rheumatism, and autoimmunity.

Investigations of a worldwide database of 727 patients have shown that 22.4% of patients have extracutaneous disease manifestations, said Dr. Zulian of the University of Padua (Italy).

Among patients with extracutaneous manifestations, 66% had the linear subtype of juvenile scleroderma, while 25% had the plaque subtype. An additional 7% had generalized morphea, and 2% had deep morphea. “The mean age of onset was 7 years, but we have 17 patients with onset in the first year of life and 6 with congenital lesions,” he said. There was a family history of autoimmune disease in 12%, and a recent history of trauma in 14%. Juvenile localized scleroderma still was not well recognized, and the mean delay in diagnosis was 18 months.

The most common extracutaneous manifestation was arthritis, reported in 12.1%. Neurologic involvement was seen in 4.4%, vascular involvement in 2.4%, and ocular involvement in 2.1%.

The arthritis often is seen on the same side of the body as the cutaneous lesion, which raises the possibility that linear bands of sclerosis spreading across joints could cause inflammation by local mechanisms (Arthritis Rheum. 2005;52:2873–81).

But the observation that articular involvement sometimes occurred on the opposite side “makes us suspect that some systemic inflammation was going on,” Dr. Zulian said.

Neurologic manifestations were seen primarily among children with linear scleroderma of the face. Accordingly, any child with this presentation should be evaluated with an electroencephalogram and CT or MRI, particularly because abnormalities on MRI were found in seven of the children who had no neurologic symptoms, he said.

Treatment of the condition was addressed in a separate session by Dr. Davide Meneghesso, one of Dr. Zulian's colleagues at the University of Padua.

“There is no universally accepted treatment,” Dr. Meneghesso said. Topical, oral, and parenteral steroids have been used, as has D-penicillamine, vitamin D, and nonsteroidal anti-inflammatory drugs. Various supportive treatments such as anticonvulsants also have been used in patients with extracutaneous complications (Rheumatology 2005 Dec. 20 [Epub ahead of print];doi 10.1093/rheumatology/kei251).

But now, a prospective trial evaluating methotrexate, 15 mg/m

Mean age of the patients was 8.3 years, mean disease duration was 49 months, and the female to male ratio was 2.8:1.0. Nineteen children had linear scleroderma and eight had generalized morphea, he said.

Only two patients did not respond to the treatment. The remaining 11 patients remained stable during 12 months of follow-up, he said. Histologic evaluation in 16 of the patients found improvements in inflammation and fibrosis in nine and stable disease in seven. Side effects were seen in 55% of patients, but none were severe.

Among children with extracutaneous manifestations of scleroderma, the linear subtype (left) was found in two-thirds. Generalized morphea (right) is much more uncommon. PHOTOS COURTESY DR. FRANCESCO ZULIAN

NEW YORK — Progress toward unraveling the complexities of the B cell and its role in autoimmunity continues, with identification of potential new therapeutic targets for lupus nephritis and early clinical investigations providing insights on what B-cell depletion does—and does not—do.

The most experience with B-cell depletion in lupus thus far is with rituximab. This drug selectively targets the intermediate-stage B cells, though not stem or plasma cells, and causes significant decreases in markers of T-cell activation. “The risk of infection is limited because IgG is conserved,” Dr. Gregg Silverman said at a rheumatology meeting sponsored by New York University.

A recent open study of rituximab that included 10 patients with biopsy-proven proliferative glomerulonephritis showed “very impressive” results, Dr. Silverman said. Patients received four weekly infusions of 375 mg/m

Another ongoing investigation involves the autoreactive B-cell survival factor BAFF (also known as BLyS). BAFF, a tumor necrosis factor, can be blocked a number of ways, such as through decoy receptors and with anti-BAFF monoclonal antibodies, explained Dr. Silverman, professor of medicine at the University of California, San Diego.

One anti-BAFF monoclonal antibody, belimumab (LymphoStat-B, Human Genome Sciences, Rockville, Md.) has been tested in a phase I trial that included 70 lupus patients, and found to be safe, with no clinically significant differences from placebo in adverse events. It also significantly reduced levels of circulating B cells and anti-double stranded (ds) DNA antibodies, which are seen in high titers in lupus nephritis. A phase II trial that includes 449 patients now has been initiated, according to the company's Web site.

Abetimus (LJP 394, Riquent, La Jolla Pharmaceutical Co., San Diego), an agent that induces tolerance in B cells against anti-ds-DNA antibodies was investigated in a 76-week blinded study that randomized 230 patients to 16 weekly doses of 100 mg of the active drug or placebo, then alternating 8-week drug holidays and 12 weekly doses of 50 mg of the drug or placebo.

In this trial the primary efficacy outcome—prevention or delay of subsequent renal flare in patients with a history of lupus renal disease—was not met (Arthritis Rheum. 2003;48:442–54). But an ad hoc retrospective analysis found that in the subset of patients with high levels of anti-ds-DNA antibodies there were 67% fewer renal flares and time to renal flare was longer. A new multicenter trial is planned that will test three different doses of abetimus, he said.

NEW YORK — Progress toward unraveling the complexities of the B cell and its role in autoimmunity continues, with identification of potential new therapeutic targets for lupus nephritis and early clinical investigations providing insights on what B-cell depletion does—and does not—do.

The most experience with B-cell depletion in lupus thus far is with rituximab. This drug selectively targets the intermediate-stage B cells, though not stem or plasma cells, and causes significant decreases in markers of T-cell activation. “The risk of infection is limited because IgG is conserved,” Dr. Gregg Silverman said at a rheumatology meeting sponsored by New York University.

A recent open study of rituximab that included 10 patients with biopsy-proven proliferative glomerulonephritis showed “very impressive” results, Dr. Silverman said. Patients received four weekly infusions of 375 mg/m

Another ongoing investigation involves the autoreactive B-cell survival factor BAFF (also known as BLyS). BAFF, a tumor necrosis factor, can be blocked a number of ways, such as through decoy receptors and with anti-BAFF monoclonal antibodies, explained Dr. Silverman, professor of medicine at the University of California, San Diego.

One anti-BAFF monoclonal antibody, belimumab (LymphoStat-B, Human Genome Sciences, Rockville, Md.) has been tested in a phase I trial that included 70 lupus patients, and found to be safe, with no clinically significant differences from placebo in adverse events. It also significantly reduced levels of circulating B cells and anti-double stranded (ds) DNA antibodies, which are seen in high titers in lupus nephritis. A phase II trial that includes 449 patients now has been initiated, according to the company's Web site.

Abetimus (LJP 394, Riquent, La Jolla Pharmaceutical Co., San Diego), an agent that induces tolerance in B cells against anti-ds-DNA antibodies was investigated in a 76-week blinded study that randomized 230 patients to 16 weekly doses of 100 mg of the active drug or placebo, then alternating 8-week drug holidays and 12 weekly doses of 50 mg of the drug or placebo.

In this trial the primary efficacy outcome—prevention or delay of subsequent renal flare in patients with a history of lupus renal disease—was not met (Arthritis Rheum. 2003;48:442–54). But an ad hoc retrospective analysis found that in the subset of patients with high levels of anti-ds-DNA antibodies there were 67% fewer renal flares and time to renal flare was longer. A new multicenter trial is planned that will test three different doses of abetimus, he said.

NEW YORK — Progress toward unraveling the complexities of the B cell and its role in autoimmunity continues, with identification of potential new therapeutic targets for lupus nephritis and early clinical investigations providing insights on what B-cell depletion does—and does not—do.

The most experience with B-cell depletion in lupus thus far is with rituximab. This drug selectively targets the intermediate-stage B cells, though not stem or plasma cells, and causes significant decreases in markers of T-cell activation. “The risk of infection is limited because IgG is conserved,” Dr. Gregg Silverman said at a rheumatology meeting sponsored by New York University.

A recent open study of rituximab that included 10 patients with biopsy-proven proliferative glomerulonephritis showed “very impressive” results, Dr. Silverman said. Patients received four weekly infusions of 375 mg/m

Another ongoing investigation involves the autoreactive B-cell survival factor BAFF (also known as BLyS). BAFF, a tumor necrosis factor, can be blocked a number of ways, such as through decoy receptors and with anti-BAFF monoclonal antibodies, explained Dr. Silverman, professor of medicine at the University of California, San Diego.

One anti-BAFF monoclonal antibody, belimumab (LymphoStat-B, Human Genome Sciences, Rockville, Md.) has been tested in a phase I trial that included 70 lupus patients, and found to be safe, with no clinically significant differences from placebo in adverse events. It also significantly reduced levels of circulating B cells and anti-double stranded (ds) DNA antibodies, which are seen in high titers in lupus nephritis. A phase II trial that includes 449 patients now has been initiated, according to the company's Web site.

Abetimus (LJP 394, Riquent, La Jolla Pharmaceutical Co., San Diego), an agent that induces tolerance in B cells against anti-ds-DNA antibodies was investigated in a 76-week blinded study that randomized 230 patients to 16 weekly doses of 100 mg of the active drug or placebo, then alternating 8-week drug holidays and 12 weekly doses of 50 mg of the drug or placebo.

In this trial the primary efficacy outcome—prevention or delay of subsequent renal flare in patients with a history of lupus renal disease—was not met (Arthritis Rheum. 2003;48:442–54). But an ad hoc retrospective analysis found that in the subset of patients with high levels of anti-ds-DNA antibodies there were 67% fewer renal flares and time to renal flare was longer. A new multicenter trial is planned that will test three different doses of abetimus, he said.

NEW YORK — Evidence is mounting that implicates the Epstein-Barr virus as the trigger that sets off the autoantibody production central to the pathogenesis of systemic lupus erythematosus, according to Dr. John B. Harley.

It has long been assumed that an etiologic agent from the environment would be required to initiate the production of the antinuclear antibodies that begin to appear in lupus patients' sera long before clinical disease develops. An association of lupus with Epstein-Barr virus (EBV) was first noted more than 3 decades ago, but the technical means of proving a connection was lacking, and the idea was set aside.

The EBV hypothesis was resurrected during the 1990s, however. Because almost all adults are infected with the virus—a hindrance to finding an epidemiologic connection—Dr. Harley and his colleagues investigated a group of 117 children and adolescents with lupus. Among patients aged 4–19 years, an infection rate of approximately 70% would be expected, and indeed, that was what was found among 153 controls, he said.

Among the lupus patients, however, 99% had seroconverted against EBV. “This was an odds ratio of 50,” Dr. Harley said at a rheumatology meeting sponsored by New York University.

Certain characteristics of the virus itself also lend credence to its etiologic probability. It infects B cells—B-cell dysregulation is prominent in lupus—and EBV itself can cause B-cell activation and autoantibody production. Among the antibodies that have been identified in patients with EBV-related mononucleosis are those targeting the Sm autoantigen, which otherwise is considered specific for lupus.

Infection is lifelong, providing continuous immune stimulation, and curiously, the virus also generates proteins that inhibit its own immune-mediated destruction, Dr. Harley said.

In lupus, it is the host response to the virus that is the crucial aberrant factor, rather than the virus itself, said Dr. Harley, professor of immunology and medicine, University of Oklahoma Health Sciences Center, Oklahoma City. An alteration in humoral response to Epstein-Barr nuclear antigen 1 (EBNA-1) appears to be involved, and in describing his findings in the pediatric cohort, Dr. Harley explained the altered response: “In the present study, lupus patients were shown to make higher concentrations of antibody against the fragments encompassing the amino and carboxyl ends of EBNA-1, while normal EBV-positive controls actually made higher levels of antibody against the middle fragment than did lupus patients” (Arthritis Rheum. 2006;54:360–8).

Further evidence has come from molecular techniques including epitope mapping and peptide sequencing. The first anti-Sm autoantibodies that appear in lupus patients' sera bind to a structure known as PPPGMRPP that cross-reacts with a similar peptide, PPPGRRP, on EBNA-1, Dr. Harley explained. A similar capability has been identified with anti-Ro antibodies, and the generation of cross-reacting antibodies to Sm or Ro may be the “central and critical step that defines the onset of lupus-specific autoimmunity,” he said. This critical step involving cross-reactive antibodies is then followed by epitope spreading and, ultimately, clinical disease.

Moreover, proof of the principle that a viral structure could generate autoimmunity was demonstrated by immunization of rabbits with the PPPGMRPP peptide. Following immunization, the animals went on to develop proteinuria, thrombocytopenia, elevated antinuclear antibody titers, and anti-double-stranded DNA antibodies (Nat. Med. 2005;11:85–9).

Dr. Harley's group also is focusing on the genetics of autoimmunity, and the Arthritis and Immunology Research Program, which he heads, at the Oklahoma Medical Research Foundation in Oklahoma City maintains a registry and repository of multiplex lupus families that is available for academic work. The registry can be accessed at http://lupus.omrf.org

NEW YORK — Evidence is mounting that implicates the Epstein-Barr virus as the trigger that sets off the autoantibody production central to the pathogenesis of systemic lupus erythematosus, according to Dr. John B. Harley.

It has long been assumed that an etiologic agent from the environment would be required to initiate the production of the antinuclear antibodies that begin to appear in lupus patients' sera long before clinical disease develops. An association of lupus with Epstein-Barr virus (EBV) was first noted more than 3 decades ago, but the technical means of proving a connection was lacking, and the idea was set aside.

The EBV hypothesis was resurrected during the 1990s, however. Because almost all adults are infected with the virus—a hindrance to finding an epidemiologic connection—Dr. Harley and his colleagues investigated a group of 117 children and adolescents with lupus. Among patients aged 4–19 years, an infection rate of approximately 70% would be expected, and indeed, that was what was found among 153 controls, he said.

Among the lupus patients, however, 99% had seroconverted against EBV. “This was an odds ratio of 50,” Dr. Harley said at a rheumatology meeting sponsored by New York University.

Certain characteristics of the virus itself also lend credence to its etiologic probability. It infects B cells—B-cell dysregulation is prominent in lupus—and EBV itself can cause B-cell activation and autoantibody production. Among the antibodies that have been identified in patients with EBV-related mononucleosis are those targeting the Sm autoantigen, which otherwise is considered specific for lupus.

Infection is lifelong, providing continuous immune stimulation, and curiously, the virus also generates proteins that inhibit its own immune-mediated destruction, Dr. Harley said.

In lupus, it is the host response to the virus that is the crucial aberrant factor, rather than the virus itself, said Dr. Harley, professor of immunology and medicine, University of Oklahoma Health Sciences Center, Oklahoma City. An alteration in humoral response to Epstein-Barr nuclear antigen 1 (EBNA-1) appears to be involved, and in describing his findings in the pediatric cohort, Dr. Harley explained the altered response: “In the present study, lupus patients were shown to make higher concentrations of antibody against the fragments encompassing the amino and carboxyl ends of EBNA-1, while normal EBV-positive controls actually made higher levels of antibody against the middle fragment than did lupus patients” (Arthritis Rheum. 2006;54:360–8).

Further evidence has come from molecular techniques including epitope mapping and peptide sequencing. The first anti-Sm autoantibodies that appear in lupus patients' sera bind to a structure known as PPPGMRPP that cross-reacts with a similar peptide, PPPGRRP, on EBNA-1, Dr. Harley explained. A similar capability has been identified with anti-Ro antibodies, and the generation of cross-reacting antibodies to Sm or Ro may be the “central and critical step that defines the onset of lupus-specific autoimmunity,” he said. This critical step involving cross-reactive antibodies is then followed by epitope spreading and, ultimately, clinical disease.

Moreover, proof of the principle that a viral structure could generate autoimmunity was demonstrated by immunization of rabbits with the PPPGMRPP peptide. Following immunization, the animals went on to develop proteinuria, thrombocytopenia, elevated antinuclear antibody titers, and anti-double-stranded DNA antibodies (Nat. Med. 2005;11:85–9).

Dr. Harley's group also is focusing on the genetics of autoimmunity, and the Arthritis and Immunology Research Program, which he heads, at the Oklahoma Medical Research Foundation in Oklahoma City maintains a registry and repository of multiplex lupus families that is available for academic work. The registry can be accessed at http://lupus.omrf.org

NEW YORK — Evidence is mounting that implicates the Epstein-Barr virus as the trigger that sets off the autoantibody production central to the pathogenesis of systemic lupus erythematosus, according to Dr. John B. Harley.

It has long been assumed that an etiologic agent from the environment would be required to initiate the production of the antinuclear antibodies that begin to appear in lupus patients' sera long before clinical disease develops. An association of lupus with Epstein-Barr virus (EBV) was first noted more than 3 decades ago, but the technical means of proving a connection was lacking, and the idea was set aside.

The EBV hypothesis was resurrected during the 1990s, however. Because almost all adults are infected with the virus—a hindrance to finding an epidemiologic connection—Dr. Harley and his colleagues investigated a group of 117 children and adolescents with lupus. Among patients aged 4–19 years, an infection rate of approximately 70% would be expected, and indeed, that was what was found among 153 controls, he said.

Among the lupus patients, however, 99% had seroconverted against EBV. “This was an odds ratio of 50,” Dr. Harley said at a rheumatology meeting sponsored by New York University.

Certain characteristics of the virus itself also lend credence to its etiologic probability. It infects B cells—B-cell dysregulation is prominent in lupus—and EBV itself can cause B-cell activation and autoantibody production. Among the antibodies that have been identified in patients with EBV-related mononucleosis are those targeting the Sm autoantigen, which otherwise is considered specific for lupus.

Infection is lifelong, providing continuous immune stimulation, and curiously, the virus also generates proteins that inhibit its own immune-mediated destruction, Dr. Harley said.

In lupus, it is the host response to the virus that is the crucial aberrant factor, rather than the virus itself, said Dr. Harley, professor of immunology and medicine, University of Oklahoma Health Sciences Center, Oklahoma City. An alteration in humoral response to Epstein-Barr nuclear antigen 1 (EBNA-1) appears to be involved, and in describing his findings in the pediatric cohort, Dr. Harley explained the altered response: “In the present study, lupus patients were shown to make higher concentrations of antibody against the fragments encompassing the amino and carboxyl ends of EBNA-1, while normal EBV-positive controls actually made higher levels of antibody against the middle fragment than did lupus patients” (Arthritis Rheum. 2006;54:360–8).

Further evidence has come from molecular techniques including epitope mapping and peptide sequencing. The first anti-Sm autoantibodies that appear in lupus patients' sera bind to a structure known as PPPGMRPP that cross-reacts with a similar peptide, PPPGRRP, on EBNA-1, Dr. Harley explained. A similar capability has been identified with anti-Ro antibodies, and the generation of cross-reacting antibodies to Sm or Ro may be the “central and critical step that defines the onset of lupus-specific autoimmunity,” he said. This critical step involving cross-reactive antibodies is then followed by epitope spreading and, ultimately, clinical disease.

Moreover, proof of the principle that a viral structure could generate autoimmunity was demonstrated by immunization of rabbits with the PPPGMRPP peptide. Following immunization, the animals went on to develop proteinuria, thrombocytopenia, elevated antinuclear antibody titers, and anti-double-stranded DNA antibodies (Nat. Med. 2005;11:85–9).

Dr. Harley's group also is focusing on the genetics of autoimmunity, and the Arthritis and Immunology Research Program, which he heads, at the Oklahoma Medical Research Foundation in Oklahoma City maintains a registry and repository of multiplex lupus families that is available for academic work. The registry can be accessed at http://lupus.omrf.org

Laboratory evaluation revealed leukocytosis, with 10%–28% eosinophils, anemia, and an elevated erythrocyte sedimentation rate. Histology findings included hyperkeratosis, irregular acanthosis, and a mixed inflammatory infiltrate of lymphocytes, plasmocytes, and numerous eosinophils. Thrombosis of small vessels in the dermis and edema of the vessel walls was also noted.

Immunohistochemical staining of tissue specimens from this patient revealed the presence of CD43-positive and CD4-positive cells, as well as CD8-negative and CD20-negative lymphocytes.

No cause for her eosinophilia could be identified, despite a meticulous search. Reactive eosinophilia, which can occur with parasitic infections, and clonal disorders of the bone marrow associated with eosinophilia, (e.g., various types of leukemia), were ruled out. The diagnosis therefore was idiopathic hypereosinophilia syndrome.

Some investigators have proposed that idiopathic hypereosinophilia syndrome is a Th2-mediated disease characterized by clonal expansion of a T-cell population able to produce interleukin (IL)-5 and IL-4. Pathogenic T cells—usually CD3 negative, CD4 positive—display an aberrant surface phenotype.

The clinical presentation is heterogeneous and includes myeloproliferative and lymphocytic variants. In the more aggressive myeloid variant, patients can have chromosomal abnormalities, hepatosplenomegaly, cardiac complications, and myeloid malignancies. The prognosis is poor, said Dr. Mira Kadurina of the Military Medical Academy in Sofia, Bulgaria.

The lymphocytic variant may be a primitive lymphoid disorder characterized by nonmalignant expansion of an IL-5-producing T cell population. Cutaneous manifestations can include pruritus, eczema, erythroderma, andurticaria.

She was treated with prednisone, 60 mg/day, which was gradually tapered to 15 mg/day over a month's time. After treatment was withdrawn, she again developed disseminated, erythematous, pruritic lesions, this time involving the hands and feet. The fingers became painful, cyanotic, and swollen, initially after exposure to cold. A painful ulcer appeared on the third finger of the right hand.

Raynaud's phenomenon, identified by capillaroscopy, was an unusual cutaneous complication of the idiopathic hypereosinophilia syndrome in this patient, Dr. Kadurina wrote.

The administration of methylprednisolone, 60 mg/day, and pentoxifylline, 800 mg/day, led to a remission; the corticosteroid dosage was tapered to 5 mg/day over 45 days.

During 3 months of follow-up, no new lesions appeared, the vasoconstriction of the patient's hands disappeared, and the finger ulcer healed.

One explanation for the development of Raynaud's phenomenon and digital gangrene, in association with hypereosinophilia, is that major basic protein and eosinophil cationic proteins located within the eosinophil granule matrix contributed to the formation of microthrombi.

Efforts continue to further explicate the pathogenesis. “Future progress in unveiling variants of the syndrome is likely to consign to history the term idiopathic, replacing it with an array of well-defined hematologic disorders,” Dr. Kadurina wrote.

DR. KADURINA reported this case as a poster at the 14th Congress of the European Academy of Dermatology and Venereology.

Laboratory evaluation revealed leukocytosis, with 10%–28% eosinophils, anemia, and an elevated erythrocyte sedimentation rate. Histology findings included hyperkeratosis, irregular acanthosis, and a mixed inflammatory infiltrate of lymphocytes, plasmocytes, and numerous eosinophils. Thrombosis of small vessels in the dermis and edema of the vessel walls was also noted.

Immunohistochemical staining of tissue specimens from this patient revealed the presence of CD43-positive and CD4-positive cells, as well as CD8-negative and CD20-negative lymphocytes.

No cause for her eosinophilia could be identified, despite a meticulous search. Reactive eosinophilia, which can occur with parasitic infections, and clonal disorders of the bone marrow associated with eosinophilia, (e.g., various types of leukemia), were ruled out. The diagnosis therefore was idiopathic hypereosinophilia syndrome.

Some investigators have proposed that idiopathic hypereosinophilia syndrome is a Th2-mediated disease characterized by clonal expansion of a T-cell population able to produce interleukin (IL)-5 and IL-4. Pathogenic T cells—usually CD3 negative, CD4 positive—display an aberrant surface phenotype.

The clinical presentation is heterogeneous and includes myeloproliferative and lymphocytic variants. In the more aggressive myeloid variant, patients can have chromosomal abnormalities, hepatosplenomegaly, cardiac complications, and myeloid malignancies. The prognosis is poor, said Dr. Mira Kadurina of the Military Medical Academy in Sofia, Bulgaria.

The lymphocytic variant may be a primitive lymphoid disorder characterized by nonmalignant expansion of an IL-5-producing T cell population. Cutaneous manifestations can include pruritus, eczema, erythroderma, andurticaria.

She was treated with prednisone, 60 mg/day, which was gradually tapered to 15 mg/day over a month's time. After treatment was withdrawn, she again developed disseminated, erythematous, pruritic lesions, this time involving the hands and feet. The fingers became painful, cyanotic, and swollen, initially after exposure to cold. A painful ulcer appeared on the third finger of the right hand.

Raynaud's phenomenon, identified by capillaroscopy, was an unusual cutaneous complication of the idiopathic hypereosinophilia syndrome in this patient, Dr. Kadurina wrote.

The administration of methylprednisolone, 60 mg/day, and pentoxifylline, 800 mg/day, led to a remission; the corticosteroid dosage was tapered to 5 mg/day over 45 days.

During 3 months of follow-up, no new lesions appeared, the vasoconstriction of the patient's hands disappeared, and the finger ulcer healed.

One explanation for the development of Raynaud's phenomenon and digital gangrene, in association with hypereosinophilia, is that major basic protein and eosinophil cationic proteins located within the eosinophil granule matrix contributed to the formation of microthrombi.

Efforts continue to further explicate the pathogenesis. “Future progress in unveiling variants of the syndrome is likely to consign to history the term idiopathic, replacing it with an array of well-defined hematologic disorders,” Dr. Kadurina wrote.

DR. KADURINA reported this case as a poster at the 14th Congress of the European Academy of Dermatology and Venereology.

Laboratory evaluation revealed leukocytosis, with 10%–28% eosinophils, anemia, and an elevated erythrocyte sedimentation rate. Histology findings included hyperkeratosis, irregular acanthosis, and a mixed inflammatory infiltrate of lymphocytes, plasmocytes, and numerous eosinophils. Thrombosis of small vessels in the dermis and edema of the vessel walls was also noted.

Immunohistochemical staining of tissue specimens from this patient revealed the presence of CD43-positive and CD4-positive cells, as well as CD8-negative and CD20-negative lymphocytes.

No cause for her eosinophilia could be identified, despite a meticulous search. Reactive eosinophilia, which can occur with parasitic infections, and clonal disorders of the bone marrow associated with eosinophilia, (e.g., various types of leukemia), were ruled out. The diagnosis therefore was idiopathic hypereosinophilia syndrome.

Some investigators have proposed that idiopathic hypereosinophilia syndrome is a Th2-mediated disease characterized by clonal expansion of a T-cell population able to produce interleukin (IL)-5 and IL-4. Pathogenic T cells—usually CD3 negative, CD4 positive—display an aberrant surface phenotype.

The clinical presentation is heterogeneous and includes myeloproliferative and lymphocytic variants. In the more aggressive myeloid variant, patients can have chromosomal abnormalities, hepatosplenomegaly, cardiac complications, and myeloid malignancies. The prognosis is poor, said Dr. Mira Kadurina of the Military Medical Academy in Sofia, Bulgaria.

The lymphocytic variant may be a primitive lymphoid disorder characterized by nonmalignant expansion of an IL-5-producing T cell population. Cutaneous manifestations can include pruritus, eczema, erythroderma, andurticaria.

She was treated with prednisone, 60 mg/day, which was gradually tapered to 15 mg/day over a month's time. After treatment was withdrawn, she again developed disseminated, erythematous, pruritic lesions, this time involving the hands and feet. The fingers became painful, cyanotic, and swollen, initially after exposure to cold. A painful ulcer appeared on the third finger of the right hand.

Raynaud's phenomenon, identified by capillaroscopy, was an unusual cutaneous complication of the idiopathic hypereosinophilia syndrome in this patient, Dr. Kadurina wrote.

The administration of methylprednisolone, 60 mg/day, and pentoxifylline, 800 mg/day, led to a remission; the corticosteroid dosage was tapered to 5 mg/day over 45 days.

During 3 months of follow-up, no new lesions appeared, the vasoconstriction of the patient's hands disappeared, and the finger ulcer healed.

One explanation for the development of Raynaud's phenomenon and digital gangrene, in association with hypereosinophilia, is that major basic protein and eosinophil cationic proteins located within the eosinophil granule matrix contributed to the formation of microthrombi.

Efforts continue to further explicate the pathogenesis. “Future progress in unveiling variants of the syndrome is likely to consign to history the term idiopathic, replacing it with an array of well-defined hematologic disorders,” Dr. Kadurina wrote.

DR. KADURINA reported this case as a poster at the 14th Congress of the European Academy of Dermatology and Venereology.

LAS VEGAS — An inhaled formulation of amphotericin B in clinical development may answer the unmet need for antifungal prophylaxis in immunocompromised patients, said Michael J. Weickert, Ph.D.

Regimens that protect against bacterial, viral, and yeast infections are widely used for patients undergoing chemotherapy to prepare for bone marrow or stem cell transplantation, prevent rejection of a solid organ transplant, treat hematologic malignancy, or control graft vs. host disease.

These patients—about 150,000 in the United States and Europe—remain susceptible to infections with molds such as Aspergillus fumigatus, and mortality is high, reportedly between 44% and 87%.

To meet the need for antifungal prophylaxis, a dry powder aerosol formulation of amphotericin B has been developed, and a multidose clinical study is underway, said Dr. Weickert, who is an employee of and shareholder in Nektar Therapeutics, the manufacturer.

The powder is packed into a capsule that is inserted into a small pulmonary delivery device. The drug is delivered to the lungs during a single inhalation. The particles, which have the same aerodynamic properties as fungal spores, distribute to the same sites that the spores would if inhaled, Dr. Weickert explained at a meeting on fungal infections sponsored by Imedex.

In the regimens being tested, a loading dose is given on day zero that would achieve a concentration of the drug in the lung many times higher than the minimum inhibitory concentration (MIC) required during the early, high-risk period for colonization and infection with Aspergillus.

The loading dose is followed by a lower maintenance dose that is self-administered at weekly intervals to maintain an adequate MIC long term, he said.

Systemic levels of the drug are expected to be very low, and the hope is that the toxicities that have long prevented the use of intravenous amphotericin B prophylactically will be avoided, he said.

The drug has been tested in doses of 5 mg, 10 mg, and 25 mg. For the 25-mg dose, the peak systemic level of the drug was 20 ng/mL, which is about 2% of the level generally regarded as the threshold of toxicity for amphotericin B, Dr. Weickert said.

Adverse events, such as cough, headache, and taste distortions, were not serious. “In general [amphotericin B] has been very well tolerated,” he said.

The product received orphan drug designation on Dec. 15, 2005, and a phase III trial is expected to begin within the next year.

LAS VEGAS — An inhaled formulation of amphotericin B in clinical development may answer the unmet need for antifungal prophylaxis in immunocompromised patients, said Michael J. Weickert, Ph.D.

Regimens that protect against bacterial, viral, and yeast infections are widely used for patients undergoing chemotherapy to prepare for bone marrow or stem cell transplantation, prevent rejection of a solid organ transplant, treat hematologic malignancy, or control graft vs. host disease.

These patients—about 150,000 in the United States and Europe—remain susceptible to infections with molds such as Aspergillus fumigatus, and mortality is high, reportedly between 44% and 87%.

To meet the need for antifungal prophylaxis, a dry powder aerosol formulation of amphotericin B has been developed, and a multidose clinical study is underway, said Dr. Weickert, who is an employee of and shareholder in Nektar Therapeutics, the manufacturer.

The powder is packed into a capsule that is inserted into a small pulmonary delivery device. The drug is delivered to the lungs during a single inhalation. The particles, which have the same aerodynamic properties as fungal spores, distribute to the same sites that the spores would if inhaled, Dr. Weickert explained at a meeting on fungal infections sponsored by Imedex.

In the regimens being tested, a loading dose is given on day zero that would achieve a concentration of the drug in the lung many times higher than the minimum inhibitory concentration (MIC) required during the early, high-risk period for colonization and infection with Aspergillus.

The loading dose is followed by a lower maintenance dose that is self-administered at weekly intervals to maintain an adequate MIC long term, he said.

Systemic levels of the drug are expected to be very low, and the hope is that the toxicities that have long prevented the use of intravenous amphotericin B prophylactically will be avoided, he said.

The drug has been tested in doses of 5 mg, 10 mg, and 25 mg. For the 25-mg dose, the peak systemic level of the drug was 20 ng/mL, which is about 2% of the level generally regarded as the threshold of toxicity for amphotericin B, Dr. Weickert said.

Adverse events, such as cough, headache, and taste distortions, were not serious. “In general [amphotericin B] has been very well tolerated,” he said.

The product received orphan drug designation on Dec. 15, 2005, and a phase III trial is expected to begin within the next year.

LAS VEGAS — An inhaled formulation of amphotericin B in clinical development may answer the unmet need for antifungal prophylaxis in immunocompromised patients, said Michael J. Weickert, Ph.D.

Regimens that protect against bacterial, viral, and yeast infections are widely used for patients undergoing chemotherapy to prepare for bone marrow or stem cell transplantation, prevent rejection of a solid organ transplant, treat hematologic malignancy, or control graft vs. host disease.

These patients—about 150,000 in the United States and Europe—remain susceptible to infections with molds such as Aspergillus fumigatus, and mortality is high, reportedly between 44% and 87%.

To meet the need for antifungal prophylaxis, a dry powder aerosol formulation of amphotericin B has been developed, and a multidose clinical study is underway, said Dr. Weickert, who is an employee of and shareholder in Nektar Therapeutics, the manufacturer.

The powder is packed into a capsule that is inserted into a small pulmonary delivery device. The drug is delivered to the lungs during a single inhalation. The particles, which have the same aerodynamic properties as fungal spores, distribute to the same sites that the spores would if inhaled, Dr. Weickert explained at a meeting on fungal infections sponsored by Imedex.

In the regimens being tested, a loading dose is given on day zero that would achieve a concentration of the drug in the lung many times higher than the minimum inhibitory concentration (MIC) required during the early, high-risk period for colonization and infection with Aspergillus.

The loading dose is followed by a lower maintenance dose that is self-administered at weekly intervals to maintain an adequate MIC long term, he said.

Systemic levels of the drug are expected to be very low, and the hope is that the toxicities that have long prevented the use of intravenous amphotericin B prophylactically will be avoided, he said.

The drug has been tested in doses of 5 mg, 10 mg, and 25 mg. For the 25-mg dose, the peak systemic level of the drug was 20 ng/mL, which is about 2% of the level generally regarded as the threshold of toxicity for amphotericin B, Dr. Weickert said.

Adverse events, such as cough, headache, and taste distortions, were not serious. “In general [amphotericin B] has been very well tolerated,” he said.

The product received orphan drug designation on Dec. 15, 2005, and a phase III trial is expected to begin within the next year.