Nancy Walsh

BARCELONA — Significant improvements in disease activity were observed among lupus patients treated with belimumab in a new analysis of data from an earlier study using a combined response end point, Dr. Ellen Ginzler said at the annual European Congress of Rheumatology.

The analysis used an evidence-based combined response end point that has been developed to improve the assessment of responses to drug intervention in clinical trials for systemic lupus erythematosus. “The heterogeneity of lupus disease manifestations contributes to the difficulty of using a single index to adequately assess therapeutic response,” Dr. Ginzler explained.

Belimumab (LymphoStat-B) is a monoclonal antibody that binds with high specificity to B lymphocyte stimulator (BLyS), which, being a potent costimulator of B cells, is thought to play a role in B-cell-mediated autoimmunity.

In the original analysis of the study results, the primary end point—reduction in disease activity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) as modified for the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) at 24 weeks—was not met.

The study included 449 patients with lupus who were randomized to receive placebo or belimumab in doses of 1, 4, or 10 mg/kg on days 0, 14, 28, and then monthly for 52 weeks. The study continued in open-label fashion through week 76.

A subsequent analysis, however, determined that significant benefits were seen at 52 weeks among the 72% of patients who were serologically active at baseline, with titers of antinuclear antibody of 1:80 or greater and/or titers of anti-double-stranded (ds) DNA of 30 IU or greater (Arthritis Rheum. 2006;54[9]:S258).

Responses among this cohort have now been analyzed according to the new combined response end point, which defines efficacy as an improvement in SELENA-SLEDAI of four points or more and a British Isles Lupus Assessment Group (BILAG) score that reflects the number and severity of organ system flares.

The combined end point also reflects physician's global assessment and patient health-related quality of life as evaluated on the Short Form (SF)-36.

“Using this combined outcome efficacy measure, the response to belimumab therapy among patients who were serologically active at baseline was 46%, which is highly statistically significant at 52 weeks compared to a response rate of 29% with placebo,” said Dr. Ginzler, who is professor of medicine and chief of rheumatology, State University of New York, Brooklyn.

By week 76 the response rate had risen to 56%.

At baseline, the mean SELANA-SLEDAI score was 9.6. Patients in the active treatment groups had 29% and 38% reductions in SELENA-SLEDAI scores at weeks 52 and 76, respectively.

At week 52 the belimumab-treated patients had fewer shifts to worse scores in three of the eight BILAG organ systems: musculoskeletal, neurologic, and cardiovascular-respiratory.

Patients who were classified as responders on the composite end point also had greater reductions in activated B cells and anti-ds DNA antibodies, along with greater improvements in the SF-36.

Combining multiple disease activity measures into a response end point improved the assessment of variable disease activity and was predictive of biomarker and quality of life improvements, Dr. Ginzler said.

“This combined end point has now been accepted by regulatory authorities and is being used in two global phase III studies of belimumab that have recently begun enrollment,” she said.

The studies are being sponsored by Human Genome Sciences, Inc., the manufacturer of LymphoStat-B, and GlaxoSmithKline.

Dr. Ginzler has previously disclosed receiving research grants from Human Genome Sciences.

A single index cannot adequately assess treatment response in this heterogeneous disease. DR. GINZLER

BARCELONA — Significant improvements in disease activity were observed among lupus patients treated with belimumab in a new analysis of data from an earlier study using a combined response end point, Dr. Ellen Ginzler said at the annual European Congress of Rheumatology.

The analysis used an evidence-based combined response end point that has been developed to improve the assessment of responses to drug intervention in clinical trials for systemic lupus erythematosus. “The heterogeneity of lupus disease manifestations contributes to the difficulty of using a single index to adequately assess therapeutic response,” Dr. Ginzler explained.

Belimumab (LymphoStat-B) is a monoclonal antibody that binds with high specificity to B lymphocyte stimulator (BLyS), which, being a potent costimulator of B cells, is thought to play a role in B-cell-mediated autoimmunity.

In the original analysis of the study results, the primary end point—reduction in disease activity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) as modified for the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) at 24 weeks—was not met.

The study included 449 patients with lupus who were randomized to receive placebo or belimumab in doses of 1, 4, or 10 mg/kg on days 0, 14, 28, and then monthly for 52 weeks. The study continued in open-label fashion through week 76.

A subsequent analysis, however, determined that significant benefits were seen at 52 weeks among the 72% of patients who were serologically active at baseline, with titers of antinuclear antibody of 1:80 or greater and/or titers of anti-double-stranded (ds) DNA of 30 IU or greater (Arthritis Rheum. 2006;54[9]:S258).

Responses among this cohort have now been analyzed according to the new combined response end point, which defines efficacy as an improvement in SELENA-SLEDAI of four points or more and a British Isles Lupus Assessment Group (BILAG) score that reflects the number and severity of organ system flares.

The combined end point also reflects physician's global assessment and patient health-related quality of life as evaluated on the Short Form (SF)-36.

“Using this combined outcome efficacy measure, the response to belimumab therapy among patients who were serologically active at baseline was 46%, which is highly statistically significant at 52 weeks compared to a response rate of 29% with placebo,” said Dr. Ginzler, who is professor of medicine and chief of rheumatology, State University of New York, Brooklyn.

By week 76 the response rate had risen to 56%.

At baseline, the mean SELANA-SLEDAI score was 9.6. Patients in the active treatment groups had 29% and 38% reductions in SELENA-SLEDAI scores at weeks 52 and 76, respectively.

At week 52 the belimumab-treated patients had fewer shifts to worse scores in three of the eight BILAG organ systems: musculoskeletal, neurologic, and cardiovascular-respiratory.

Patients who were classified as responders on the composite end point also had greater reductions in activated B cells and anti-ds DNA antibodies, along with greater improvements in the SF-36.

Combining multiple disease activity measures into a response end point improved the assessment of variable disease activity and was predictive of biomarker and quality of life improvements, Dr. Ginzler said.

“This combined end point has now been accepted by regulatory authorities and is being used in two global phase III studies of belimumab that have recently begun enrollment,” she said.

The studies are being sponsored by Human Genome Sciences, Inc., the manufacturer of LymphoStat-B, and GlaxoSmithKline.

Dr. Ginzler has previously disclosed receiving research grants from Human Genome Sciences.

A single index cannot adequately assess treatment response in this heterogeneous disease. DR. GINZLER

BARCELONA — Significant improvements in disease activity were observed among lupus patients treated with belimumab in a new analysis of data from an earlier study using a combined response end point, Dr. Ellen Ginzler said at the annual European Congress of Rheumatology.

The analysis used an evidence-based combined response end point that has been developed to improve the assessment of responses to drug intervention in clinical trials for systemic lupus erythematosus. “The heterogeneity of lupus disease manifestations contributes to the difficulty of using a single index to adequately assess therapeutic response,” Dr. Ginzler explained.

Belimumab (LymphoStat-B) is a monoclonal antibody that binds with high specificity to B lymphocyte stimulator (BLyS), which, being a potent costimulator of B cells, is thought to play a role in B-cell-mediated autoimmunity.

In the original analysis of the study results, the primary end point—reduction in disease activity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) as modified for the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) at 24 weeks—was not met.

The study included 449 patients with lupus who were randomized to receive placebo or belimumab in doses of 1, 4, or 10 mg/kg on days 0, 14, 28, and then monthly for 52 weeks. The study continued in open-label fashion through week 76.

A subsequent analysis, however, determined that significant benefits were seen at 52 weeks among the 72% of patients who were serologically active at baseline, with titers of antinuclear antibody of 1:80 or greater and/or titers of anti-double-stranded (ds) DNA of 30 IU or greater (Arthritis Rheum. 2006;54[9]:S258).

Responses among this cohort have now been analyzed according to the new combined response end point, which defines efficacy as an improvement in SELENA-SLEDAI of four points or more and a British Isles Lupus Assessment Group (BILAG) score that reflects the number and severity of organ system flares.

The combined end point also reflects physician's global assessment and patient health-related quality of life as evaluated on the Short Form (SF)-36.

“Using this combined outcome efficacy measure, the response to belimumab therapy among patients who were serologically active at baseline was 46%, which is highly statistically significant at 52 weeks compared to a response rate of 29% with placebo,” said Dr. Ginzler, who is professor of medicine and chief of rheumatology, State University of New York, Brooklyn.

By week 76 the response rate had risen to 56%.

At baseline, the mean SELANA-SLEDAI score was 9.6. Patients in the active treatment groups had 29% and 38% reductions in SELENA-SLEDAI scores at weeks 52 and 76, respectively.

At week 52 the belimumab-treated patients had fewer shifts to worse scores in three of the eight BILAG organ systems: musculoskeletal, neurologic, and cardiovascular-respiratory.

Patients who were classified as responders on the composite end point also had greater reductions in activated B cells and anti-ds DNA antibodies, along with greater improvements in the SF-36.

Combining multiple disease activity measures into a response end point improved the assessment of variable disease activity and was predictive of biomarker and quality of life improvements, Dr. Ginzler said.

“This combined end point has now been accepted by regulatory authorities and is being used in two global phase III studies of belimumab that have recently begun enrollment,” she said.

The studies are being sponsored by Human Genome Sciences, Inc., the manufacturer of LymphoStat-B, and GlaxoSmithKline.

Dr. Ginzler has previously disclosed receiving research grants from Human Genome Sciences.

A single index cannot adequately assess treatment response in this heterogeneous disease. DR. GINZLER

BARCELONA – Treatment with tumor necrosis factor blocking drugs has been shown for the first time to improve mortality in rheumatoid arthritis, Dr. Lennart Jacobsson said at the annual European Congress of Rheumatology.

Patients with rheumatoid arthritis (RA) have an increased mortality, compared with the healthy general population, particularly from cardiovascular causes, and methotrexate treatment has been shown to confer a survival benefit. This benefit now has been extended to treatment with anti-tumor necrosis factor (TNF) drugs in a cohort of 921 Swedish patients enrolled in the South Swedish Arthritis Treatment Group register, said Dr. Jacobsson of the department of rheumatology, Malmö University Hospital.

They were compared with 1,016 patients with RA in the same area of Sweden who were not treated with anti-TNF drugs, and were found to have an adjusted hazard ratio (HR) of 0.65 for death after controlling for age, sex, disability, and baseline comorbidities. “There was a 35% risk reduction with treatment with anti-TNF therapy.”

There were 188 deaths in the combined groups during 7,077 patient-years. Of these, 63 deaths were in men during 1,817 patient-years, and 125 were in women during 5,260 patient-years. After controlling for age, disability, and comorbidity, mortality was significantly reduced in women treated with anti-TNF drugs, with an adjusted HR of 0.52, but not in men, whose adjusted HR was 0.95 (Ann. Rheum. Dis. 2007;66:670-5).

When the mortality rates in women who had RA with and without anti-TNF therapy were compared with those of the general Swedish female population, there was an increased risk of death of 70%-80% in those not treated with the drugs. “But in women with RA treated with anti-TNF therapy, the risk is comparable with that of women of the same age in the general Swedish population,” Dr. Jacobsson said. The lack of significance in men could reflect insufficient numbers or the men's higher baseline risk for death, he said.

There are numerous unanswered questions about the benefits of the TNF blocking drugs. “Is there a role for TNF inhibitors in non-RA groups to prevent cardiovascular events? Are the effects of TNF blockers additive to those of methotrexate? Preliminary data from our register indicate that this is the case,” he said.

This question of potentially additive cardiovascular benefits of TNF blockers and methotrexate was addressed in a separate presentation at the meeting.

Dr. Gurkirpal Singh of Stanford (Calif.) University performed a nested case-control study using data from Medi-Cal, the Medicare program for California. The patients with RA who received a TNF inhibitor, methotrexate, or other disease-modifying antirheumatic drugs (DMARDs) between January 1999 and June 2005 were included.

Among the 19,233 RA patients who were identified, 13,383 were taking methotrexate, 14,958 were on other DMARDs, and 4,943 were receiving a TNF inhibitor. During 74,006 patient-years of follow-up, there were 441 cases of acute myocardial infarction. Cases were risk set matched with four controls for age, gender, and date of MI.

Current exposure to TNF inhibitors, as monotherapy or in combination with methotrexate or other DMARDs, was compared with methotrexate monotherapy, and all analyses were adjusted for multiple potentially confounding risk factors including surrogate variables for smoking and dyslipidemia. Analysis revealed that combination TNF inhibitor-methotrexate treatment significantly reduced the risk of acute MI, compared with methotrexate monotherapy, with an adjusted relative risk (RR) of 0.20, Dr. Singh reported.

No statistical differences were seen when combination TNF inhibitor-methotrexate therapy was compared with TNF blocking monotherapy (RR 1.17), when compared with anti-TNF therapy combined with other DMARDs (RR 1.78), or for other DMARD therapies without methotrexate (RR 0.88). Combined TNF inhibitor-methotrexate therapy is associated with a reduction in the risk of acute MI by 80%, compared with methotrexate monotherapy in patients with RA, Dr. Singh concluded.

BARCELONA – Treatment with tumor necrosis factor blocking drugs has been shown for the first time to improve mortality in rheumatoid arthritis, Dr. Lennart Jacobsson said at the annual European Congress of Rheumatology.

Patients with rheumatoid arthritis (RA) have an increased mortality, compared with the healthy general population, particularly from cardiovascular causes, and methotrexate treatment has been shown to confer a survival benefit. This benefit now has been extended to treatment with anti-tumor necrosis factor (TNF) drugs in a cohort of 921 Swedish patients enrolled in the South Swedish Arthritis Treatment Group register, said Dr. Jacobsson of the department of rheumatology, Malmö University Hospital.

They were compared with 1,016 patients with RA in the same area of Sweden who were not treated with anti-TNF drugs, and were found to have an adjusted hazard ratio (HR) of 0.65 for death after controlling for age, sex, disability, and baseline comorbidities. “There was a 35% risk reduction with treatment with anti-TNF therapy.”

There were 188 deaths in the combined groups during 7,077 patient-years. Of these, 63 deaths were in men during 1,817 patient-years, and 125 were in women during 5,260 patient-years. After controlling for age, disability, and comorbidity, mortality was significantly reduced in women treated with anti-TNF drugs, with an adjusted HR of 0.52, but not in men, whose adjusted HR was 0.95 (Ann. Rheum. Dis. 2007;66:670-5).

When the mortality rates in women who had RA with and without anti-TNF therapy were compared with those of the general Swedish female population, there was an increased risk of death of 70%-80% in those not treated with the drugs. “But in women with RA treated with anti-TNF therapy, the risk is comparable with that of women of the same age in the general Swedish population,” Dr. Jacobsson said. The lack of significance in men could reflect insufficient numbers or the men's higher baseline risk for death, he said.

There are numerous unanswered questions about the benefits of the TNF blocking drugs. “Is there a role for TNF inhibitors in non-RA groups to prevent cardiovascular events? Are the effects of TNF blockers additive to those of methotrexate? Preliminary data from our register indicate that this is the case,” he said.

This question of potentially additive cardiovascular benefits of TNF blockers and methotrexate was addressed in a separate presentation at the meeting.

Dr. Gurkirpal Singh of Stanford (Calif.) University performed a nested case-control study using data from Medi-Cal, the Medicare program for California. The patients with RA who received a TNF inhibitor, methotrexate, or other disease-modifying antirheumatic drugs (DMARDs) between January 1999 and June 2005 were included.

Among the 19,233 RA patients who were identified, 13,383 were taking methotrexate, 14,958 were on other DMARDs, and 4,943 were receiving a TNF inhibitor. During 74,006 patient-years of follow-up, there were 441 cases of acute myocardial infarction. Cases were risk set matched with four controls for age, gender, and date of MI.

Current exposure to TNF inhibitors, as monotherapy or in combination with methotrexate or other DMARDs, was compared with methotrexate monotherapy, and all analyses were adjusted for multiple potentially confounding risk factors including surrogate variables for smoking and dyslipidemia. Analysis revealed that combination TNF inhibitor-methotrexate treatment significantly reduced the risk of acute MI, compared with methotrexate monotherapy, with an adjusted relative risk (RR) of 0.20, Dr. Singh reported.

No statistical differences were seen when combination TNF inhibitor-methotrexate therapy was compared with TNF blocking monotherapy (RR 1.17), when compared with anti-TNF therapy combined with other DMARDs (RR 1.78), or for other DMARD therapies without methotrexate (RR 0.88). Combined TNF inhibitor-methotrexate therapy is associated with a reduction in the risk of acute MI by 80%, compared with methotrexate monotherapy in patients with RA, Dr. Singh concluded.

BARCELONA – Treatment with tumor necrosis factor blocking drugs has been shown for the first time to improve mortality in rheumatoid arthritis, Dr. Lennart Jacobsson said at the annual European Congress of Rheumatology.

Patients with rheumatoid arthritis (RA) have an increased mortality, compared with the healthy general population, particularly from cardiovascular causes, and methotrexate treatment has been shown to confer a survival benefit. This benefit now has been extended to treatment with anti-tumor necrosis factor (TNF) drugs in a cohort of 921 Swedish patients enrolled in the South Swedish Arthritis Treatment Group register, said Dr. Jacobsson of the department of rheumatology, Malmö University Hospital.

They were compared with 1,016 patients with RA in the same area of Sweden who were not treated with anti-TNF drugs, and were found to have an adjusted hazard ratio (HR) of 0.65 for death after controlling for age, sex, disability, and baseline comorbidities. “There was a 35% risk reduction with treatment with anti-TNF therapy.”

There were 188 deaths in the combined groups during 7,077 patient-years. Of these, 63 deaths were in men during 1,817 patient-years, and 125 were in women during 5,260 patient-years. After controlling for age, disability, and comorbidity, mortality was significantly reduced in women treated with anti-TNF drugs, with an adjusted HR of 0.52, but not in men, whose adjusted HR was 0.95 (Ann. Rheum. Dis. 2007;66:670-5).

When the mortality rates in women who had RA with and without anti-TNF therapy were compared with those of the general Swedish female population, there was an increased risk of death of 70%-80% in those not treated with the drugs. “But in women with RA treated with anti-TNF therapy, the risk is comparable with that of women of the same age in the general Swedish population,” Dr. Jacobsson said. The lack of significance in men could reflect insufficient numbers or the men's higher baseline risk for death, he said.

There are numerous unanswered questions about the benefits of the TNF blocking drugs. “Is there a role for TNF inhibitors in non-RA groups to prevent cardiovascular events? Are the effects of TNF blockers additive to those of methotrexate? Preliminary data from our register indicate that this is the case,” he said.

This question of potentially additive cardiovascular benefits of TNF blockers and methotrexate was addressed in a separate presentation at the meeting.

Dr. Gurkirpal Singh of Stanford (Calif.) University performed a nested case-control study using data from Medi-Cal, the Medicare program for California. The patients with RA who received a TNF inhibitor, methotrexate, or other disease-modifying antirheumatic drugs (DMARDs) between January 1999 and June 2005 were included.

Among the 19,233 RA patients who were identified, 13,383 were taking methotrexate, 14,958 were on other DMARDs, and 4,943 were receiving a TNF inhibitor. During 74,006 patient-years of follow-up, there were 441 cases of acute myocardial infarction. Cases were risk set matched with four controls for age, gender, and date of MI.

Current exposure to TNF inhibitors, as monotherapy or in combination with methotrexate or other DMARDs, was compared with methotrexate monotherapy, and all analyses were adjusted for multiple potentially confounding risk factors including surrogate variables for smoking and dyslipidemia. Analysis revealed that combination TNF inhibitor-methotrexate treatment significantly reduced the risk of acute MI, compared with methotrexate monotherapy, with an adjusted relative risk (RR) of 0.20, Dr. Singh reported.

No statistical differences were seen when combination TNF inhibitor-methotrexate therapy was compared with TNF blocking monotherapy (RR 1.17), when compared with anti-TNF therapy combined with other DMARDs (RR 1.78), or for other DMARD therapies without methotrexate (RR 0.88). Combined TNF inhibitor-methotrexate therapy is associated with a reduction in the risk of acute MI by 80%, compared with methotrexate monotherapy in patients with RA, Dr. Singh concluded.

VIENNA – Adult patients who are diagnosed with dermatomyositis should have a thorough work-up for malignancy because they are at heightened risk for various cancers, Dr. Ralph M. Trueb said at the 16th Congress of the European Academy of Dermatology and Venereology.

About 15%-30% of patients with this inflammatory autoimmune disorder will develop cancer, with the risk being most prominent early in the course of disease. Most reported malignancies are carcinomas rather than sarcomas or lymphomas, said Dr. Trueb of the University Hospital of Zurich.

The work-up should include a chest radiograph, Pap smear, and breast and rectal examinations, and should be repeated at regular intervals, he said.

Patients are also at risk for potentially life-threatening organ involvement. The lung is involved in 40% of these patients, with the development of aspiration pneumonia, interstitial fibrosis, and respiratory insufficiency. The joints, gastrointestinal tract, and cardiovascular system also can be affected. More than one-fourth of patients have arthritis, and electrocardiogram abnormalities are present in half of patients.

The condition also may be limited to the skin or muscles. The skin lesions typical of dermatomyositis can be classified as pathognomonic, characteristic, or compatible, Dr. Trueb said.

Pathognomonic findings include Gottron's papules, which are slightly elevated violaceous papules located over the joints of the hands, as well as over the ankles, knees, and elbows, and Gottron's sign, which refers to the erythematous plaques that spare the interphalangeal spaces.

“It's important to note that, while the skin lesions in dermatomyositis can resemble those seen in lupus, they are located over the joints in dermatomyositis and primarily between the joints in lupus,” he said.

Characteristic skin findings include a heliotrope periorbital rash with or without associated periorbital edema; the “shawl sign,” which is a symmetrical macular violaceous erythema at the nape of the neck and around the shoulders; and scalp involvement, including alopecia.

Compatible findings include poikiloderma, especially in long-standing disease, and calcinosis.

Muscle manifestations include progressive weakness, electromyographic changes, and elevations of muscle enzymes such as creatine kinase. “Patients lose the ability to raise their arms for hair grooming or shaving,” Dr. Trueb said. They may subsequently become unable to climb stairs, to rise from a sitting position, or to walk unaided. Patients with severe muscle involvement have a poor prognosis, he said.

First-line treatment remains high-dose oral corticosteroids, but this is evolving, with increasing reports of the use of intravenous immunoglobulin (IVIg) and the biologic drugs, he said.

In one series, eight patients with dermatomyositis or poly-myositis who had not responded to corticosteroids, IVIg, and immunosuppressants received a tumor necrosis factor inhibitor. Six of the eight showed improvements in muscle strength and fatigue and marked reductions in creatine kinase (Ann. Rheum. Dis. 2006;65:1233-6).

The B-cell-depleting monoclonal antibody rituximab also has now been used in a small number of patients with refractory disease. In an open-label pilot study that included six patients who each received four infusions of rituximab, muscle strength improved 36%-113% over baseline, beginning as early as 12 weeks after the initial infusion (Arthritis Rheum. 2005;52:601-7).

In a more recent report describing three patients whose cutaneous lesions responded well to rituximab, researchers from Australia suggested a possible mechanism by which this drug might act in dermatomyositis. They noted that B lymphocytes are not present in the skin lesions in this disorder, and that T cells predominate in areas of skin changes. They suggested that the drug may affect T cells as well as B cells, possibly through downstream effects on costimulatory molecules that inhibit activation and development of T helper type 1 cell dominance (J. Am. Acad. Dermatol. 2007;56:148-53).

VIENNA – Adult patients who are diagnosed with dermatomyositis should have a thorough work-up for malignancy because they are at heightened risk for various cancers, Dr. Ralph M. Trueb said at the 16th Congress of the European Academy of Dermatology and Venereology.

About 15%-30% of patients with this inflammatory autoimmune disorder will develop cancer, with the risk being most prominent early in the course of disease. Most reported malignancies are carcinomas rather than sarcomas or lymphomas, said Dr. Trueb of the University Hospital of Zurich.

The work-up should include a chest radiograph, Pap smear, and breast and rectal examinations, and should be repeated at regular intervals, he said.

Patients are also at risk for potentially life-threatening organ involvement. The lung is involved in 40% of these patients, with the development of aspiration pneumonia, interstitial fibrosis, and respiratory insufficiency. The joints, gastrointestinal tract, and cardiovascular system also can be affected. More than one-fourth of patients have arthritis, and electrocardiogram abnormalities are present in half of patients.

The condition also may be limited to the skin or muscles. The skin lesions typical of dermatomyositis can be classified as pathognomonic, characteristic, or compatible, Dr. Trueb said.

Pathognomonic findings include Gottron's papules, which are slightly elevated violaceous papules located over the joints of the hands, as well as over the ankles, knees, and elbows, and Gottron's sign, which refers to the erythematous plaques that spare the interphalangeal spaces.

“It's important to note that, while the skin lesions in dermatomyositis can resemble those seen in lupus, they are located over the joints in dermatomyositis and primarily between the joints in lupus,” he said.

Characteristic skin findings include a heliotrope periorbital rash with or without associated periorbital edema; the “shawl sign,” which is a symmetrical macular violaceous erythema at the nape of the neck and around the shoulders; and scalp involvement, including alopecia.

Compatible findings include poikiloderma, especially in long-standing disease, and calcinosis.

Muscle manifestations include progressive weakness, electromyographic changes, and elevations of muscle enzymes such as creatine kinase. “Patients lose the ability to raise their arms for hair grooming or shaving,” Dr. Trueb said. They may subsequently become unable to climb stairs, to rise from a sitting position, or to walk unaided. Patients with severe muscle involvement have a poor prognosis, he said.

First-line treatment remains high-dose oral corticosteroids, but this is evolving, with increasing reports of the use of intravenous immunoglobulin (IVIg) and the biologic drugs, he said.

In one series, eight patients with dermatomyositis or poly-myositis who had not responded to corticosteroids, IVIg, and immunosuppressants received a tumor necrosis factor inhibitor. Six of the eight showed improvements in muscle strength and fatigue and marked reductions in creatine kinase (Ann. Rheum. Dis. 2006;65:1233-6).

The B-cell-depleting monoclonal antibody rituximab also has now been used in a small number of patients with refractory disease. In an open-label pilot study that included six patients who each received four infusions of rituximab, muscle strength improved 36%-113% over baseline, beginning as early as 12 weeks after the initial infusion (Arthritis Rheum. 2005;52:601-7).

In a more recent report describing three patients whose cutaneous lesions responded well to rituximab, researchers from Australia suggested a possible mechanism by which this drug might act in dermatomyositis. They noted that B lymphocytes are not present in the skin lesions in this disorder, and that T cells predominate in areas of skin changes. They suggested that the drug may affect T cells as well as B cells, possibly through downstream effects on costimulatory molecules that inhibit activation and development of T helper type 1 cell dominance (J. Am. Acad. Dermatol. 2007;56:148-53).

VIENNA – Adult patients who are diagnosed with dermatomyositis should have a thorough work-up for malignancy because they are at heightened risk for various cancers, Dr. Ralph M. Trueb said at the 16th Congress of the European Academy of Dermatology and Venereology.

About 15%-30% of patients with this inflammatory autoimmune disorder will develop cancer, with the risk being most prominent early in the course of disease. Most reported malignancies are carcinomas rather than sarcomas or lymphomas, said Dr. Trueb of the University Hospital of Zurich.

The work-up should include a chest radiograph, Pap smear, and breast and rectal examinations, and should be repeated at regular intervals, he said.

Patients are also at risk for potentially life-threatening organ involvement. The lung is involved in 40% of these patients, with the development of aspiration pneumonia, interstitial fibrosis, and respiratory insufficiency. The joints, gastrointestinal tract, and cardiovascular system also can be affected. More than one-fourth of patients have arthritis, and electrocardiogram abnormalities are present in half of patients.

The condition also may be limited to the skin or muscles. The skin lesions typical of dermatomyositis can be classified as pathognomonic, characteristic, or compatible, Dr. Trueb said.

Pathognomonic findings include Gottron's papules, which are slightly elevated violaceous papules located over the joints of the hands, as well as over the ankles, knees, and elbows, and Gottron's sign, which refers to the erythematous plaques that spare the interphalangeal spaces.

“It's important to note that, while the skin lesions in dermatomyositis can resemble those seen in lupus, they are located over the joints in dermatomyositis and primarily between the joints in lupus,” he said.

Characteristic skin findings include a heliotrope periorbital rash with or without associated periorbital edema; the “shawl sign,” which is a symmetrical macular violaceous erythema at the nape of the neck and around the shoulders; and scalp involvement, including alopecia.

Compatible findings include poikiloderma, especially in long-standing disease, and calcinosis.

Muscle manifestations include progressive weakness, electromyographic changes, and elevations of muscle enzymes such as creatine kinase. “Patients lose the ability to raise their arms for hair grooming or shaving,” Dr. Trueb said. They may subsequently become unable to climb stairs, to rise from a sitting position, or to walk unaided. Patients with severe muscle involvement have a poor prognosis, he said.

First-line treatment remains high-dose oral corticosteroids, but this is evolving, with increasing reports of the use of intravenous immunoglobulin (IVIg) and the biologic drugs, he said.

In one series, eight patients with dermatomyositis or poly-myositis who had not responded to corticosteroids, IVIg, and immunosuppressants received a tumor necrosis factor inhibitor. Six of the eight showed improvements in muscle strength and fatigue and marked reductions in creatine kinase (Ann. Rheum. Dis. 2006;65:1233-6).

The B-cell-depleting monoclonal antibody rituximab also has now been used in a small number of patients with refractory disease. In an open-label pilot study that included six patients who each received four infusions of rituximab, muscle strength improved 36%-113% over baseline, beginning as early as 12 weeks after the initial infusion (Arthritis Rheum. 2005;52:601-7).

In a more recent report describing three patients whose cutaneous lesions responded well to rituximab, researchers from Australia suggested a possible mechanism by which this drug might act in dermatomyositis. They noted that B lymphocytes are not present in the skin lesions in this disorder, and that T cells predominate in areas of skin changes. They suggested that the drug may affect T cells as well as B cells, possibly through downstream effects on costimulatory molecules that inhibit activation and development of T helper type 1 cell dominance (J. Am. Acad. Dermatol. 2007;56:148-53).

VIENNA — Early results with biologic therapy for systemic lupus erythematosus show promise, but the results of controlled trials are needed before these drugs can be widely used in lupus, according to Dr. Martin Aringer of the department of rheumatology, Medical University of Vienna.

The complexity of lupus provides multiple potential targets for biologic response modifiers, including the B cell, which is quantitatively and functionally abnormal in lupus; the interface between B cells and T cells; and various cytokines involved in the inflammatory response, Dr. Aringer said at the 16th Congress of the European Academy of Dermatology and Venereology.

B cell-depleting therapies being evaluated in lupus include monoclonal antibodies against the surface antigens CD20 (rituximab) and CD22 (epratuzumab).

The first study of rituximab in lupus was an open-label trial that included 17 patients with longstanding, clinically active disease. Mean age was 37 years, prednisone dosage was 13 mg/day, and Systemic Lupus Activity Measure (SLAM) score was 8.8.

Patients received either a single infusion of 100 mg/m

A total of 11 patients achieved B-cell depletion, and in these patients SLAM scores improved significantly, with improvements persisting for 12 months (Arthritis Rheum. 2004;50:2580–9).

Only three patients showed a decline in autoantibody levels, which suggests that the role of B cells in lupus is autoantibody independent, Dr. Aringer said.

In another study that included six patients with refractory disease, rituximab was given as two infusions of 500 mg along with two infusions of 750 mg of cyclophosphamide and high-dose corticosteroids. One patient was lost to follow-up, but the remaining five all improved clinically and serologically, with decreases in anti-double-stranded DNA antibodies, erythrocyte sedimentation rate, and urinary protein-to-creatinine ratio (Arthritis Rheum. 2002;46:2673–7).

“B-cell depletion does seem to be one way to check autoimmunity,” Dr. Aringer said. “Either way is probably fine, with rituximab alone or in combination with cyclophosphamide. It's not clear which is better,” he said. This may be an option for patients who do not respond to other therapies, but controlled data are lacking at this point, he said.

B-cell immunotherapy using epratuzumab was evaluated in an open-label study that included 14 patients with moderately active lupus. After receiving four doses of 360 mg/m

“We can also target the contact between T cells and antigen-presenting B cells with the costimulatory blocker abatacept,” he said. “We don't yet have published human experience with this, but we have spectacular mouse data on the combination of abatacept and cyclophosphamide—better than anything that was used before in this mouse model,” he said. Two human trials are ongoing, one with the combination and the other with abatacept alone. “We will know very soon if this works.”

“Finally, our focus in the last couple of years has been on targeting the downstream inflammatory response using tumor necrosis factor blockade,” he said.

Despite the fact that tumor necrosis factor (TNF) is very high in the serum of patients with lupus and correlates with several measures of disease activity, the widely available tumor necrosis factor-α blockers have not been given much consideration in lupus.

One reason for this is that approximately 15% of patients with rheumatoid arthritis and Crohn's disease being treated with these drugs develop anti-double-stranded DNA and anticardiolipin antibodies, and some develop drug-induced lupus, according to Dr. Aringer. Also, some mouse models have suggested worsening of nephritis, although others have demonstrated delay in disease.

Despite this controversy, but with the reassuring observation that the antibodies clear on withdrawal of the drug, Dr. Aringer and his colleagues performed the first open-label trial of infliximab in lupus.

Six patients each received four infusions of 300 mg of infliximab on day 0 and at weeks 2, 6, and 10 in addition to immunosuppression with methotrexate or azathioprine.

Global disease activity decreased in all patients during the treatment period, and there were no flares in a follow-up period of 52 weeks, he said.

In the three patients who had arthritis, there was rapid improvement with no swollen joints being seen during treatment, although symptoms returned about 8 weeks after the final infusion (Arthritis Rheum. 2004;50:3161–9).

There was an increase in anti-double-stranded DNA antibodies in four patients, and one patient developed antiphospholipid and anticardiolipin antibodies and a deep venous thrombosis. “This was the only immunologic adverse event we saw,” he said.

Marked improvements were seen in longstanding proteinuria among all four patients with nephritis, with a decrease of 60% or more within a few weeks. “More than 3 years later these patients continue to have very low level proteinuria. We can't explain this, but we think it's important,” he said.

A larger, controlled trial of infliximab is now underway, he said.

VIENNA — Early results with biologic therapy for systemic lupus erythematosus show promise, but the results of controlled trials are needed before these drugs can be widely used in lupus, according to Dr. Martin Aringer of the department of rheumatology, Medical University of Vienna.

The complexity of lupus provides multiple potential targets for biologic response modifiers, including the B cell, which is quantitatively and functionally abnormal in lupus; the interface between B cells and T cells; and various cytokines involved in the inflammatory response, Dr. Aringer said at the 16th Congress of the European Academy of Dermatology and Venereology.

B cell-depleting therapies being evaluated in lupus include monoclonal antibodies against the surface antigens CD20 (rituximab) and CD22 (epratuzumab).

The first study of rituximab in lupus was an open-label trial that included 17 patients with longstanding, clinically active disease. Mean age was 37 years, prednisone dosage was 13 mg/day, and Systemic Lupus Activity Measure (SLAM) score was 8.8.

Patients received either a single infusion of 100 mg/m

A total of 11 patients achieved B-cell depletion, and in these patients SLAM scores improved significantly, with improvements persisting for 12 months (Arthritis Rheum. 2004;50:2580–9).

Only three patients showed a decline in autoantibody levels, which suggests that the role of B cells in lupus is autoantibody independent, Dr. Aringer said.

In another study that included six patients with refractory disease, rituximab was given as two infusions of 500 mg along with two infusions of 750 mg of cyclophosphamide and high-dose corticosteroids. One patient was lost to follow-up, but the remaining five all improved clinically and serologically, with decreases in anti-double-stranded DNA antibodies, erythrocyte sedimentation rate, and urinary protein-to-creatinine ratio (Arthritis Rheum. 2002;46:2673–7).

“B-cell depletion does seem to be one way to check autoimmunity,” Dr. Aringer said. “Either way is probably fine, with rituximab alone or in combination with cyclophosphamide. It's not clear which is better,” he said. This may be an option for patients who do not respond to other therapies, but controlled data are lacking at this point, he said.

B-cell immunotherapy using epratuzumab was evaluated in an open-label study that included 14 patients with moderately active lupus. After receiving four doses of 360 mg/m

“We can also target the contact between T cells and antigen-presenting B cells with the costimulatory blocker abatacept,” he said. “We don't yet have published human experience with this, but we have spectacular mouse data on the combination of abatacept and cyclophosphamide—better than anything that was used before in this mouse model,” he said. Two human trials are ongoing, one with the combination and the other with abatacept alone. “We will know very soon if this works.”

“Finally, our focus in the last couple of years has been on targeting the downstream inflammatory response using tumor necrosis factor blockade,” he said.

Despite the fact that tumor necrosis factor (TNF) is very high in the serum of patients with lupus and correlates with several measures of disease activity, the widely available tumor necrosis factor-α blockers have not been given much consideration in lupus.

One reason for this is that approximately 15% of patients with rheumatoid arthritis and Crohn's disease being treated with these drugs develop anti-double-stranded DNA and anticardiolipin antibodies, and some develop drug-induced lupus, according to Dr. Aringer. Also, some mouse models have suggested worsening of nephritis, although others have demonstrated delay in disease.

Despite this controversy, but with the reassuring observation that the antibodies clear on withdrawal of the drug, Dr. Aringer and his colleagues performed the first open-label trial of infliximab in lupus.

Six patients each received four infusions of 300 mg of infliximab on day 0 and at weeks 2, 6, and 10 in addition to immunosuppression with methotrexate or azathioprine.

Global disease activity decreased in all patients during the treatment period, and there were no flares in a follow-up period of 52 weeks, he said.

In the three patients who had arthritis, there was rapid improvement with no swollen joints being seen during treatment, although symptoms returned about 8 weeks after the final infusion (Arthritis Rheum. 2004;50:3161–9).

There was an increase in anti-double-stranded DNA antibodies in four patients, and one patient developed antiphospholipid and anticardiolipin antibodies and a deep venous thrombosis. “This was the only immunologic adverse event we saw,” he said.

Marked improvements were seen in longstanding proteinuria among all four patients with nephritis, with a decrease of 60% or more within a few weeks. “More than 3 years later these patients continue to have very low level proteinuria. We can't explain this, but we think it's important,” he said.

A larger, controlled trial of infliximab is now underway, he said.

VIENNA — Early results with biologic therapy for systemic lupus erythematosus show promise, but the results of controlled trials are needed before these drugs can be widely used in lupus, according to Dr. Martin Aringer of the department of rheumatology, Medical University of Vienna.

The complexity of lupus provides multiple potential targets for biologic response modifiers, including the B cell, which is quantitatively and functionally abnormal in lupus; the interface between B cells and T cells; and various cytokines involved in the inflammatory response, Dr. Aringer said at the 16th Congress of the European Academy of Dermatology and Venereology.

B cell-depleting therapies being evaluated in lupus include monoclonal antibodies against the surface antigens CD20 (rituximab) and CD22 (epratuzumab).

The first study of rituximab in lupus was an open-label trial that included 17 patients with longstanding, clinically active disease. Mean age was 37 years, prednisone dosage was 13 mg/day, and Systemic Lupus Activity Measure (SLAM) score was 8.8.

Patients received either a single infusion of 100 mg/m

A total of 11 patients achieved B-cell depletion, and in these patients SLAM scores improved significantly, with improvements persisting for 12 months (Arthritis Rheum. 2004;50:2580–9).

Only three patients showed a decline in autoantibody levels, which suggests that the role of B cells in lupus is autoantibody independent, Dr. Aringer said.

In another study that included six patients with refractory disease, rituximab was given as two infusions of 500 mg along with two infusions of 750 mg of cyclophosphamide and high-dose corticosteroids. One patient was lost to follow-up, but the remaining five all improved clinically and serologically, with decreases in anti-double-stranded DNA antibodies, erythrocyte sedimentation rate, and urinary protein-to-creatinine ratio (Arthritis Rheum. 2002;46:2673–7).

“B-cell depletion does seem to be one way to check autoimmunity,” Dr. Aringer said. “Either way is probably fine, with rituximab alone or in combination with cyclophosphamide. It's not clear which is better,” he said. This may be an option for patients who do not respond to other therapies, but controlled data are lacking at this point, he said.

B-cell immunotherapy using epratuzumab was evaluated in an open-label study that included 14 patients with moderately active lupus. After receiving four doses of 360 mg/m

“We can also target the contact between T cells and antigen-presenting B cells with the costimulatory blocker abatacept,” he said. “We don't yet have published human experience with this, but we have spectacular mouse data on the combination of abatacept and cyclophosphamide—better than anything that was used before in this mouse model,” he said. Two human trials are ongoing, one with the combination and the other with abatacept alone. “We will know very soon if this works.”

“Finally, our focus in the last couple of years has been on targeting the downstream inflammatory response using tumor necrosis factor blockade,” he said.

Despite the fact that tumor necrosis factor (TNF) is very high in the serum of patients with lupus and correlates with several measures of disease activity, the widely available tumor necrosis factor-α blockers have not been given much consideration in lupus.

One reason for this is that approximately 15% of patients with rheumatoid arthritis and Crohn's disease being treated with these drugs develop anti-double-stranded DNA and anticardiolipin antibodies, and some develop drug-induced lupus, according to Dr. Aringer. Also, some mouse models have suggested worsening of nephritis, although others have demonstrated delay in disease.

Despite this controversy, but with the reassuring observation that the antibodies clear on withdrawal of the drug, Dr. Aringer and his colleagues performed the first open-label trial of infliximab in lupus.

Six patients each received four infusions of 300 mg of infliximab on day 0 and at weeks 2, 6, and 10 in addition to immunosuppression with methotrexate or azathioprine.

Global disease activity decreased in all patients during the treatment period, and there were no flares in a follow-up period of 52 weeks, he said.

In the three patients who had arthritis, there was rapid improvement with no swollen joints being seen during treatment, although symptoms returned about 8 weeks after the final infusion (Arthritis Rheum. 2004;50:3161–9).

There was an increase in anti-double-stranded DNA antibodies in four patients, and one patient developed antiphospholipid and anticardiolipin antibodies and a deep venous thrombosis. “This was the only immunologic adverse event we saw,” he said.

Marked improvements were seen in longstanding proteinuria among all four patients with nephritis, with a decrease of 60% or more within a few weeks. “More than 3 years later these patients continue to have very low level proteinuria. We can't explain this, but we think it's important,” he said.

A larger, controlled trial of infliximab is now underway, he said.

BARCELONA — The first evidence-based recommendations issued by the European League Against Rheumatism for the management of systemic sclerosis address the current and future challenges in the treatment of this clinically heterogeneous condition.

The preliminary recommendations, which are based on research evidence, expert opinion, and clinical experience, have been formulated by a EULAR task force that included experts in systemic sclerosis from Europe, the United States, and Japan, according to Dr. Marco Matucci-Cerinic, professor of rheumatology and medicine at the University of Florence (Italy).

The recommendations include treatment considerations for digital vasculopathy and disease manifestations in the lung, skin, kidney, and gastrointestinal tract. They were summarized by Dr. Matucci-Cerinic at the annual European Congress of Rheumatology as follows:

▸ Vasculopathy. Among the first-line therapies recommended for reducing the frequency and severity of attacks of scleroderma-associated Raynaud's phenomenon are calcium channel blockers. Significant clinical benefits for these drugs were demonstrated in a meta-analysis that included six small trials (Arthritis Rheum. 2001;44:1841–7).

Prostacyclins, particularly iloprost, also are recommended for vasculopathy. Two randomized clinical trials have demonstrated benefits for these agents in the treatment of Raynaud's phenomenon and for healing digital ulcers.

A third recommendation for scleroderma-associated vasculopathy involves the use of endothelin receptor antagonists such as bosentan. Two large studies found that bosentan can prevent the development of new digital ulcers and improve hand function, although it did not affect healing of ulcers.

▸ Pulmonary arterial hypertension. Bosentan and another endothelin receptor antagonist, sitaxsentan, are strongly recommended for the treatment of pulmonary arterial hypertension, Dr. Matucci-Cerinic said. Also recommended is the phosphodiesterase inhibitor sildenafil, which improved exercise capacity and functional class in a high-quality clinical trial, he said. Epoprostenol is another agent that can be considered a feasible treatment for severe pulmonary arterial hypertension in systemic sclerosis.

▸ Interstitial lung disease. Two randomized controlled trials published in recent years form the basis of a recommendation favoring the use of cyclophosphamide in patients with scleroderma-associated interstitial lung disease despite the potential toxicity of this treatment.

▸ Renal crisis. “We all know that ACE inhibitors are helpful in renal crisis, but there are no randomized controlled trials,” Dr. Matucci-Cerinic said. Despite this lack of evidence, the expert recommendation is that angiotensin-converting enzyme inhibitors should be given.

With regard to corticosteroids, these drugs clearly are associated with a high risk of renal crisis in patients with systemic sclerosis. If they are used, patients should be very carefully monitored for blood pressure and kidney function, he said.

▸ Skin involvement. Two randomized clinical trials provided evidence for the use of methotrexate to alleviate the cutaneous manifestations of scleroderma, particularly in early diffuse disease.

▸ Gastrointestinal manifestations. Thus far there have been no randomized trials evaluating therapies for the various gastrointestinal disorders associated with systemic sclerosis. “Nonetheless, expert opinion tells us that we should be employing drugs such as proton-pump inhibitors, prokinetic agents, and antibiotics for bacterial overgrowth,” he said.

▸ Research agenda. Because many gaps and uncertainties remain in the understanding and treatment of systemic sclerosis, a research agenda was also established, Dr. Matucci-Cerinic said. Among the concerns that were identified as warranting further investigation and analysis were the safety and efficacy of long-term cyclophosphamide and mycophenolate mofetil and the use of sildenafil for Raynaud's phenomenon. Evidence for the safety and efficacy of ACE inhibitors in renal crisis also should be pursued, and clearer guidelines on their use should be developed.

Another member of the guidelines task force, Dr. Daniel E. Furst, said in an interview that these guidelines combine what is clear from the medical literature with experience from experts and patient representatives. “While these recommendations are preliminary and undoubtedly will change as more data become available, they are a good first step toward helping rheumatologists treat systemic sclerosis,” said Dr. Furst, who is Carl M. Pearson professor of medicine and director of the Rheumatology Clinical Research Center, University of California, Los Angeles.

BARCELONA — The first evidence-based recommendations issued by the European League Against Rheumatism for the management of systemic sclerosis address the current and future challenges in the treatment of this clinically heterogeneous condition.

The preliminary recommendations, which are based on research evidence, expert opinion, and clinical experience, have been formulated by a EULAR task force that included experts in systemic sclerosis from Europe, the United States, and Japan, according to Dr. Marco Matucci-Cerinic, professor of rheumatology and medicine at the University of Florence (Italy).

The recommendations include treatment considerations for digital vasculopathy and disease manifestations in the lung, skin, kidney, and gastrointestinal tract. They were summarized by Dr. Matucci-Cerinic at the annual European Congress of Rheumatology as follows:

▸ Vasculopathy. Among the first-line therapies recommended for reducing the frequency and severity of attacks of scleroderma-associated Raynaud's phenomenon are calcium channel blockers. Significant clinical benefits for these drugs were demonstrated in a meta-analysis that included six small trials (Arthritis Rheum. 2001;44:1841–7).

Prostacyclins, particularly iloprost, also are recommended for vasculopathy. Two randomized clinical trials have demonstrated benefits for these agents in the treatment of Raynaud's phenomenon and for healing digital ulcers.

A third recommendation for scleroderma-associated vasculopathy involves the use of endothelin receptor antagonists such as bosentan. Two large studies found that bosentan can prevent the development of new digital ulcers and improve hand function, although it did not affect healing of ulcers.

▸ Pulmonary arterial hypertension. Bosentan and another endothelin receptor antagonist, sitaxsentan, are strongly recommended for the treatment of pulmonary arterial hypertension, Dr. Matucci-Cerinic said. Also recommended is the phosphodiesterase inhibitor sildenafil, which improved exercise capacity and functional class in a high-quality clinical trial, he said. Epoprostenol is another agent that can be considered a feasible treatment for severe pulmonary arterial hypertension in systemic sclerosis.

▸ Interstitial lung disease. Two randomized controlled trials published in recent years form the basis of a recommendation favoring the use of cyclophosphamide in patients with scleroderma-associated interstitial lung disease despite the potential toxicity of this treatment.

▸ Renal crisis. “We all know that ACE inhibitors are helpful in renal crisis, but there are no randomized controlled trials,” Dr. Matucci-Cerinic said. Despite this lack of evidence, the expert recommendation is that angiotensin-converting enzyme inhibitors should be given.

With regard to corticosteroids, these drugs clearly are associated with a high risk of renal crisis in patients with systemic sclerosis. If they are used, patients should be very carefully monitored for blood pressure and kidney function, he said.

▸ Skin involvement. Two randomized clinical trials provided evidence for the use of methotrexate to alleviate the cutaneous manifestations of scleroderma, particularly in early diffuse disease.

▸ Gastrointestinal manifestations. Thus far there have been no randomized trials evaluating therapies for the various gastrointestinal disorders associated with systemic sclerosis. “Nonetheless, expert opinion tells us that we should be employing drugs such as proton-pump inhibitors, prokinetic agents, and antibiotics for bacterial overgrowth,” he said.

▸ Research agenda. Because many gaps and uncertainties remain in the understanding and treatment of systemic sclerosis, a research agenda was also established, Dr. Matucci-Cerinic said. Among the concerns that were identified as warranting further investigation and analysis were the safety and efficacy of long-term cyclophosphamide and mycophenolate mofetil and the use of sildenafil for Raynaud's phenomenon. Evidence for the safety and efficacy of ACE inhibitors in renal crisis also should be pursued, and clearer guidelines on their use should be developed.

Another member of the guidelines task force, Dr. Daniel E. Furst, said in an interview that these guidelines combine what is clear from the medical literature with experience from experts and patient representatives. “While these recommendations are preliminary and undoubtedly will change as more data become available, they are a good first step toward helping rheumatologists treat systemic sclerosis,” said Dr. Furst, who is Carl M. Pearson professor of medicine and director of the Rheumatology Clinical Research Center, University of California, Los Angeles.

BARCELONA — The first evidence-based recommendations issued by the European League Against Rheumatism for the management of systemic sclerosis address the current and future challenges in the treatment of this clinically heterogeneous condition.

The preliminary recommendations, which are based on research evidence, expert opinion, and clinical experience, have been formulated by a EULAR task force that included experts in systemic sclerosis from Europe, the United States, and Japan, according to Dr. Marco Matucci-Cerinic, professor of rheumatology and medicine at the University of Florence (Italy).

The recommendations include treatment considerations for digital vasculopathy and disease manifestations in the lung, skin, kidney, and gastrointestinal tract. They were summarized by Dr. Matucci-Cerinic at the annual European Congress of Rheumatology as follows:

▸ Vasculopathy. Among the first-line therapies recommended for reducing the frequency and severity of attacks of scleroderma-associated Raynaud's phenomenon are calcium channel blockers. Significant clinical benefits for these drugs were demonstrated in a meta-analysis that included six small trials (Arthritis Rheum. 2001;44:1841–7).

Prostacyclins, particularly iloprost, also are recommended for vasculopathy. Two randomized clinical trials have demonstrated benefits for these agents in the treatment of Raynaud's phenomenon and for healing digital ulcers.

A third recommendation for scleroderma-associated vasculopathy involves the use of endothelin receptor antagonists such as bosentan. Two large studies found that bosentan can prevent the development of new digital ulcers and improve hand function, although it did not affect healing of ulcers.

▸ Pulmonary arterial hypertension. Bosentan and another endothelin receptor antagonist, sitaxsentan, are strongly recommended for the treatment of pulmonary arterial hypertension, Dr. Matucci-Cerinic said. Also recommended is the phosphodiesterase inhibitor sildenafil, which improved exercise capacity and functional class in a high-quality clinical trial, he said. Epoprostenol is another agent that can be considered a feasible treatment for severe pulmonary arterial hypertension in systemic sclerosis.

▸ Interstitial lung disease. Two randomized controlled trials published in recent years form the basis of a recommendation favoring the use of cyclophosphamide in patients with scleroderma-associated interstitial lung disease despite the potential toxicity of this treatment.

▸ Renal crisis. “We all know that ACE inhibitors are helpful in renal crisis, but there are no randomized controlled trials,” Dr. Matucci-Cerinic said. Despite this lack of evidence, the expert recommendation is that angiotensin-converting enzyme inhibitors should be given.

With regard to corticosteroids, these drugs clearly are associated with a high risk of renal crisis in patients with systemic sclerosis. If they are used, patients should be very carefully monitored for blood pressure and kidney function, he said.

▸ Skin involvement. Two randomized clinical trials provided evidence for the use of methotrexate to alleviate the cutaneous manifestations of scleroderma, particularly in early diffuse disease.

▸ Gastrointestinal manifestations. Thus far there have been no randomized trials evaluating therapies for the various gastrointestinal disorders associated with systemic sclerosis. “Nonetheless, expert opinion tells us that we should be employing drugs such as proton-pump inhibitors, prokinetic agents, and antibiotics for bacterial overgrowth,” he said.

▸ Research agenda. Because many gaps and uncertainties remain in the understanding and treatment of systemic sclerosis, a research agenda was also established, Dr. Matucci-Cerinic said. Among the concerns that were identified as warranting further investigation and analysis were the safety and efficacy of long-term cyclophosphamide and mycophenolate mofetil and the use of sildenafil for Raynaud's phenomenon. Evidence for the safety and efficacy of ACE inhibitors in renal crisis also should be pursued, and clearer guidelines on their use should be developed.

Another member of the guidelines task force, Dr. Daniel E. Furst, said in an interview that these guidelines combine what is clear from the medical literature with experience from experts and patient representatives. “While these recommendations are preliminary and undoubtedly will change as more data become available, they are a good first step toward helping rheumatologists treat systemic sclerosis,” said Dr. Furst, who is Carl M. Pearson professor of medicine and director of the Rheumatology Clinical Research Center, University of California, Los Angeles.

VIENNA — Prurigo pigmentosa should be included in the differential diagnosis of hyperpigmentary disorders among patients worldwide, Dr. Hiroshi Shimizu reported at the 16th Congress of the European Academy of Dermatology and Venereology.

This condition, first described by Dr. Masaji Nagashima in 1971, is characterized by pruritic urticarial papules and papulovesicles arranged in a reticular pattern and distributed symmetrically on the back, neck, and chest. The lesions evolve over the course of several days, leaving behind distinctive pigmentation in a netlike, reticular-shaped pattern (J. Dermatol. 1978;5:61–7).

Dr. Shimizu was the first to report prurigo pigmentosa in the major English-language literature; he and his colleagues noted that nearly 100 cases had been seen in Japan but that the condition remained little known outside of that country (J. Am. Acad. Dermatol. 1985;12:165–9).

Approximately 700 cases have now been reported in Japan, and during recent years the condition has also been identified in patients of various races and from numerous countries, including the United Kingdom, Spain, Italy, Turkey, Iran, and Korea.

The majority of cases occur in young women, with more than 70% being seen among patients aged 11–20 years, said Dr. Shimizu, who is professor and chairman, department of dermatology, Hokkaido University School of Medicine, Sapporo, Japan.

Histopathologic findings depend on the stage of the lesion. In the early papular phase, numerous neutrophils can be seen in the epidermis, whereas in a fully developed lesion both neutrophils and lymphocytes are present, accompanied by spongiosis and vesiculation, he said. Histopathologic findings in the late pigmented lesion include a predominance of lymphocytes and melanophages and a lichenoid tissue reaction.

The differential diagnosis includes pigmented contact dermatitis, confluent and reticulated papillomatosis, leukocytoclastic vasculitis, and acute lupus erythematosus.

In Japan, the gold standard of treatment is minocycline or dapsone, both of which inhibit the migration and function of neutrophils. “Dapsone works somewhat more quickly than minocycline, but its recurrence rate is rather high,” Dr. Shimizu said. The usual starting dose of dapsone for adults is 50–75 mg/day, and for minocycline, 200 mg/day. “If one does not work, you can try the other, and if both do not work, your diagnosis may be wrong,” he said.

The etiology and pathogenesis of prurigo pigmentosa remain unknown, although some investigators have speculated on a possible metabolic influence because cases have been reported in patients with diabetes and in association with fasting, dieting, and ketosis (J. Am. Acad. Dermatol. 1996;34:509–11). “But we really don't know yet. I think an exogenous factor must be involved,” he said.

The condition involves pruritic urticarial papules and papulovesicles arranged in a reticular pattern. Courtesy Dr. Hiroshi Shimizu

VIENNA — Prurigo pigmentosa should be included in the differential diagnosis of hyperpigmentary disorders among patients worldwide, Dr. Hiroshi Shimizu reported at the 16th Congress of the European Academy of Dermatology and Venereology.

This condition, first described by Dr. Masaji Nagashima in 1971, is characterized by pruritic urticarial papules and papulovesicles arranged in a reticular pattern and distributed symmetrically on the back, neck, and chest. The lesions evolve over the course of several days, leaving behind distinctive pigmentation in a netlike, reticular-shaped pattern (J. Dermatol. 1978;5:61–7).

Dr. Shimizu was the first to report prurigo pigmentosa in the major English-language literature; he and his colleagues noted that nearly 100 cases had been seen in Japan but that the condition remained little known outside of that country (J. Am. Acad. Dermatol. 1985;12:165–9).

Approximately 700 cases have now been reported in Japan, and during recent years the condition has also been identified in patients of various races and from numerous countries, including the United Kingdom, Spain, Italy, Turkey, Iran, and Korea.

The majority of cases occur in young women, with more than 70% being seen among patients aged 11–20 years, said Dr. Shimizu, who is professor and chairman, department of dermatology, Hokkaido University School of Medicine, Sapporo, Japan.

Histopathologic findings depend on the stage of the lesion. In the early papular phase, numerous neutrophils can be seen in the epidermis, whereas in a fully developed lesion both neutrophils and lymphocytes are present, accompanied by spongiosis and vesiculation, he said. Histopathologic findings in the late pigmented lesion include a predominance of lymphocytes and melanophages and a lichenoid tissue reaction.

The differential diagnosis includes pigmented contact dermatitis, confluent and reticulated papillomatosis, leukocytoclastic vasculitis, and acute lupus erythematosus.

In Japan, the gold standard of treatment is minocycline or dapsone, both of which inhibit the migration and function of neutrophils. “Dapsone works somewhat more quickly than minocycline, but its recurrence rate is rather high,” Dr. Shimizu said. The usual starting dose of dapsone for adults is 50–75 mg/day, and for minocycline, 200 mg/day. “If one does not work, you can try the other, and if both do not work, your diagnosis may be wrong,” he said.

The etiology and pathogenesis of prurigo pigmentosa remain unknown, although some investigators have speculated on a possible metabolic influence because cases have been reported in patients with diabetes and in association with fasting, dieting, and ketosis (J. Am. Acad. Dermatol. 1996;34:509–11). “But we really don't know yet. I think an exogenous factor must be involved,” he said.

The condition involves pruritic urticarial papules and papulovesicles arranged in a reticular pattern. Courtesy Dr. Hiroshi Shimizu

VIENNA — Prurigo pigmentosa should be included in the differential diagnosis of hyperpigmentary disorders among patients worldwide, Dr. Hiroshi Shimizu reported at the 16th Congress of the European Academy of Dermatology and Venereology.

This condition, first described by Dr. Masaji Nagashima in 1971, is characterized by pruritic urticarial papules and papulovesicles arranged in a reticular pattern and distributed symmetrically on the back, neck, and chest. The lesions evolve over the course of several days, leaving behind distinctive pigmentation in a netlike, reticular-shaped pattern (J. Dermatol. 1978;5:61–7).

Dr. Shimizu was the first to report prurigo pigmentosa in the major English-language literature; he and his colleagues noted that nearly 100 cases had been seen in Japan but that the condition remained little known outside of that country (J. Am. Acad. Dermatol. 1985;12:165–9).

Approximately 700 cases have now been reported in Japan, and during recent years the condition has also been identified in patients of various races and from numerous countries, including the United Kingdom, Spain, Italy, Turkey, Iran, and Korea.

The majority of cases occur in young women, with more than 70% being seen among patients aged 11–20 years, said Dr. Shimizu, who is professor and chairman, department of dermatology, Hokkaido University School of Medicine, Sapporo, Japan.

Histopathologic findings depend on the stage of the lesion. In the early papular phase, numerous neutrophils can be seen in the epidermis, whereas in a fully developed lesion both neutrophils and lymphocytes are present, accompanied by spongiosis and vesiculation, he said. Histopathologic findings in the late pigmented lesion include a predominance of lymphocytes and melanophages and a lichenoid tissue reaction.

The differential diagnosis includes pigmented contact dermatitis, confluent and reticulated papillomatosis, leukocytoclastic vasculitis, and acute lupus erythematosus.

In Japan, the gold standard of treatment is minocycline or dapsone, both of which inhibit the migration and function of neutrophils. “Dapsone works somewhat more quickly than minocycline, but its recurrence rate is rather high,” Dr. Shimizu said. The usual starting dose of dapsone for adults is 50–75 mg/day, and for minocycline, 200 mg/day. “If one does not work, you can try the other, and if both do not work, your diagnosis may be wrong,” he said.

The etiology and pathogenesis of prurigo pigmentosa remain unknown, although some investigators have speculated on a possible metabolic influence because cases have been reported in patients with diabetes and in association with fasting, dieting, and ketosis (J. Am. Acad. Dermatol. 1996;34:509–11). “But we really don't know yet. I think an exogenous factor must be involved,” he said.

The condition involves pruritic urticarial papules and papulovesicles arranged in a reticular pattern. Courtesy Dr. Hiroshi Shimizu

BARCELONA — The risk of reactivation of herpesvirus infection is increased among patients with rheumatoid arthritis who are treated with the anti-tumor necrosis factor agents, and especially with the monoclonal antibodies infliximab and adalimumab, Dr. Anja Strangfeld said at the annual European Congress of Rheumatology.

“An increased risk of bacterial infections during treatment with the TNF-blocking drugs is well documented, but less attention has been paid to viral infection and reactivation in this regard, so we analyzed data from the German biologics register to ascertain the incidence and risk factors for reactivation of herpesvirus infection,” said Dr. Strangfeld, who is an epidemiologist with the German Rheumatism Research Center, Berlin.

Among the patients enrolled in the registry as of June 2006, 1,132 had received etanercept, 563 infliximab, and 1,155 adalimumab.

Among these patients, 160 cases of herpes in 144 patients were reported, with 84 cases being herpes zoster and 76 being herpes simplex, she said.

Of note, 15 of the cases of herpes zoster were serious, with 13 being the rare multidermatomal form. An additional two were serious ophthalmic herpes; this results when the virus, which remains latent and lifelong in the sensory ganglia, reactivates in the geniculate ganglion.

The incidence of zoster reactivation among patients being treated with infliximab, adalimumab, and etanercept was compared with rates among control RA patients receiving conventional disease-modifying antirheumatic drugs, and was found to be higher rates among the biologic-treated patients overall. (See box.)

“We also analyzed the rates for the TNF blockers according to their molecular type, because previous analyses of rates of tuberculosis reactivation found differences in rates among patients receiving the monoclonal antibodies infliximab and adalimumab, compared with those receiving the receptor fusion protein etanercept,” she said.

Higher rates were seen for the monoclonal antibodies than for etanercept, and particularly for the serious multidermatomal and ophthalmic infections, she noted.

Analysis of risk factors for reactivation identified higher risk for increasing age (hazard ratio 1.24) and for increased duration of disease (HR 1.10).

Drug exposure also influenced risk. Prednisone in daily doses of 10 mg or more was associated with a higher risk (HR 3.53) than were doses less than 5 mg (HR 2.4).

On multivariate analysis, exposure to any TNF blocker was associated with a higher risk (HR 1.77), compared with patients in the control group. A significantly higher twofold risk was seen for infliximab and adalimumab (HR 1.96) but not for etanercept (HR 1.51).

“We therefore concluded that prednisone and anti-TNF use increased the risk for herpes reactivation, and that the risk is higher with treatment with the monoclonal antibodies, which may be due to a different mode of action,” she said.

The study was supported by a joint unconditional grant from Wyeth Pharma GmbH, Essex Pharma GmbH, Amgen GmbH, and Abbott GmbH.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — The risk of reactivation of herpesvirus infection is increased among patients with rheumatoid arthritis who are treated with the anti-tumor necrosis factor agents, and especially with the monoclonal antibodies infliximab and adalimumab, Dr. Anja Strangfeld said at the annual European Congress of Rheumatology.

“An increased risk of bacterial infections during treatment with the TNF-blocking drugs is well documented, but less attention has been paid to viral infection and reactivation in this regard, so we analyzed data from the German biologics register to ascertain the incidence and risk factors for reactivation of herpesvirus infection,” said Dr. Strangfeld, who is an epidemiologist with the German Rheumatism Research Center, Berlin.

Among the patients enrolled in the registry as of June 2006, 1,132 had received etanercept, 563 infliximab, and 1,155 adalimumab.

Among these patients, 160 cases of herpes in 144 patients were reported, with 84 cases being herpes zoster and 76 being herpes simplex, she said.

Of note, 15 of the cases of herpes zoster were serious, with 13 being the rare multidermatomal form. An additional two were serious ophthalmic herpes; this results when the virus, which remains latent and lifelong in the sensory ganglia, reactivates in the geniculate ganglion.

The incidence of zoster reactivation among patients being treated with infliximab, adalimumab, and etanercept was compared with rates among control RA patients receiving conventional disease-modifying antirheumatic drugs, and was found to be higher rates among the biologic-treated patients overall. (See box.)

“We also analyzed the rates for the TNF blockers according to their molecular type, because previous analyses of rates of tuberculosis reactivation found differences in rates among patients receiving the monoclonal antibodies infliximab and adalimumab, compared with those receiving the receptor fusion protein etanercept,” she said.

Higher rates were seen for the monoclonal antibodies than for etanercept, and particularly for the serious multidermatomal and ophthalmic infections, she noted.

Analysis of risk factors for reactivation identified higher risk for increasing age (hazard ratio 1.24) and for increased duration of disease (HR 1.10).

Drug exposure also influenced risk. Prednisone in daily doses of 10 mg or more was associated with a higher risk (HR 3.53) than were doses less than 5 mg (HR 2.4).

On multivariate analysis, exposure to any TNF blocker was associated with a higher risk (HR 1.77), compared with patients in the control group. A significantly higher twofold risk was seen for infliximab and adalimumab (HR 1.96) but not for etanercept (HR 1.51).

“We therefore concluded that prednisone and anti-TNF use increased the risk for herpes reactivation, and that the risk is higher with treatment with the monoclonal antibodies, which may be due to a different mode of action,” she said.

The study was supported by a joint unconditional grant from Wyeth Pharma GmbH, Essex Pharma GmbH, Amgen GmbH, and Abbott GmbH.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — The risk of reactivation of herpesvirus infection is increased among patients with rheumatoid arthritis who are treated with the anti-tumor necrosis factor agents, and especially with the monoclonal antibodies infliximab and adalimumab, Dr. Anja Strangfeld said at the annual European Congress of Rheumatology.

“An increased risk of bacterial infections during treatment with the TNF-blocking drugs is well documented, but less attention has been paid to viral infection and reactivation in this regard, so we analyzed data from the German biologics register to ascertain the incidence and risk factors for reactivation of herpesvirus infection,” said Dr. Strangfeld, who is an epidemiologist with the German Rheumatism Research Center, Berlin.

Among the patients enrolled in the registry as of June 2006, 1,132 had received etanercept, 563 infliximab, and 1,155 adalimumab.

Among these patients, 160 cases of herpes in 144 patients were reported, with 84 cases being herpes zoster and 76 being herpes simplex, she said.

Of note, 15 of the cases of herpes zoster were serious, with 13 being the rare multidermatomal form. An additional two were serious ophthalmic herpes; this results when the virus, which remains latent and lifelong in the sensory ganglia, reactivates in the geniculate ganglion.

The incidence of zoster reactivation among patients being treated with infliximab, adalimumab, and etanercept was compared with rates among control RA patients receiving conventional disease-modifying antirheumatic drugs, and was found to be higher rates among the biologic-treated patients overall. (See box.)

“We also analyzed the rates for the TNF blockers according to their molecular type, because previous analyses of rates of tuberculosis reactivation found differences in rates among patients receiving the monoclonal antibodies infliximab and adalimumab, compared with those receiving the receptor fusion protein etanercept,” she said.

Higher rates were seen for the monoclonal antibodies than for etanercept, and particularly for the serious multidermatomal and ophthalmic infections, she noted.

Analysis of risk factors for reactivation identified higher risk for increasing age (hazard ratio 1.24) and for increased duration of disease (HR 1.10).

Drug exposure also influenced risk. Prednisone in daily doses of 10 mg or more was associated with a higher risk (HR 3.53) than were doses less than 5 mg (HR 2.4).

On multivariate analysis, exposure to any TNF blocker was associated with a higher risk (HR 1.77), compared with patients in the control group. A significantly higher twofold risk was seen for infliximab and adalimumab (HR 1.96) but not for etanercept (HR 1.51).

“We therefore concluded that prednisone and anti-TNF use increased the risk for herpes reactivation, and that the risk is higher with treatment with the monoclonal antibodies, which may be due to a different mode of action,” she said.

The study was supported by a joint unconditional grant from Wyeth Pharma GmbH, Essex Pharma GmbH, Amgen GmbH, and Abbott GmbH.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — Statin therapy may ameliorate the vascular dysfunction that can lead to Raynaud's phenomenon and digital ulcers in systemic sclerosis, Dr. Anna Abou-Raya said at the annual European Congress of Rheumatology.

Systemic sclerosis is characterized by widespread vascular pathology, with initial events involving endothelial cell damage, loss of normal vasodilatory mediators, and excessive vasoconstriction. Within 4 years of diagnosis, up to 65% of patients have digital ulcers, which are painful and disabling and can be associated with infection, gangrene, and amputation, Dr. Abou-Raya said. Effective treatment remains elusive for many patients.

Aside from their well-documented lipid-lowering properties, statins display pleiotropic effects including effects on endothelial function that may be of benefit in slowing or preventing vascular damage.

“The appearance of endothelial cell abnormalities can be considered the crucial, and maybe the initial event in the pathogenesis of systemic sclerosis,” Dr. Abou-Raya said.

“Furthermore, endothelial activation and damage are primary events not only at the initiation but throughout the course of disease,” she added.

To evaluate the potential for statin therapy to retard or prevent vascular damage in systemic sclerosis, Dr. Abou-Raya and associates undertook a controlled study that randomized 40 patients with persistent Raynaud's phenomenon to receive atorvastatin, 40 mg/day, or placebo for 4 months.

The mean age of the patients was 49.7 years, and the mean duration of Raynaud's phenomenon was 8 years. The mean number of digital ulcers existing at baseline was 3.3, and all of the patients fulfilled the American College of Rheumatology criteria for having systemic sclerosis with Raynaud's phenomenon, despite ongoing vasodilator therapy.

Exclusion criteria included diabetes; hypercholesterolemia; hypertension; and cardiac, hepatic, and renal disease.

A mean of 1.6 new ulcers developed in patients in the statin group, compared with a mean of 2.5 new ulcers in the placebo group, which was a statistically significant difference, said Dr. Abou-Raya of the department of rheumatology at the University of Alexandria, Egypt.

Patients were also evaluated for functional status, with statistically significant improvements being seen on the modified Scleroderma Health Assessment Questionnaire Disability Index and on visual analog scale scores for pain and for physician global assessment.

Moreover, biomarkers of endothelial damage, such as intercellular adhesion molecule 1 (ICAM-1) and sE-selectin, as well as acute phase reactants, also improved significantly among patients in the atorvastatin group, Dr. Abou-Raya reported.

The drug was well tolerated, and there were no study dropouts.

The results of this study suggest statins can be beneficial in alleviating vascular dysfunction and improving patient functioning in systemic sclerosis.

“These drugs are relatively inexpensive, even in developing countries, and with our very limited therapeutic arsenal, any drug that leads to any improvement is a welcome addition,” saidDr. Abou-Raya.

Larger studies will be needed to confirm these results, she added.

BARCELONA — Statin therapy may ameliorate the vascular dysfunction that can lead to Raynaud's phenomenon and digital ulcers in systemic sclerosis, Dr. Anna Abou-Raya said at the annual European Congress of Rheumatology.

Systemic sclerosis is characterized by widespread vascular pathology, with initial events involving endothelial cell damage, loss of normal vasodilatory mediators, and excessive vasoconstriction. Within 4 years of diagnosis, up to 65% of patients have digital ulcers, which are painful and disabling and can be associated with infection, gangrene, and amputation, Dr. Abou-Raya said. Effective treatment remains elusive for many patients.

Aside from their well-documented lipid-lowering properties, statins display pleiotropic effects including effects on endothelial function that may be of benefit in slowing or preventing vascular damage.

“The appearance of endothelial cell abnormalities can be considered the crucial, and maybe the initial event in the pathogenesis of systemic sclerosis,” Dr. Abou-Raya said.

“Furthermore, endothelial activation and damage are primary events not only at the initiation but throughout the course of disease,” she added.

To evaluate the potential for statin therapy to retard or prevent vascular damage in systemic sclerosis, Dr. Abou-Raya and associates undertook a controlled study that randomized 40 patients with persistent Raynaud's phenomenon to receive atorvastatin, 40 mg/day, or placebo for 4 months.

The mean age of the patients was 49.7 years, and the mean duration of Raynaud's phenomenon was 8 years. The mean number of digital ulcers existing at baseline was 3.3, and all of the patients fulfilled the American College of Rheumatology criteria for having systemic sclerosis with Raynaud's phenomenon, despite ongoing vasodilator therapy.

Exclusion criteria included diabetes; hypercholesterolemia; hypertension; and cardiac, hepatic, and renal disease.

A mean of 1.6 new ulcers developed in patients in the statin group, compared with a mean of 2.5 new ulcers in the placebo group, which was a statistically significant difference, said Dr. Abou-Raya of the department of rheumatology at the University of Alexandria, Egypt.

Patients were also evaluated for functional status, with statistically significant improvements being seen on the modified Scleroderma Health Assessment Questionnaire Disability Index and on visual analog scale scores for pain and for physician global assessment.

Moreover, biomarkers of endothelial damage, such as intercellular adhesion molecule 1 (ICAM-1) and sE-selectin, as well as acute phase reactants, also improved significantly among patients in the atorvastatin group, Dr. Abou-Raya reported.

The drug was well tolerated, and there were no study dropouts.

The results of this study suggest statins can be beneficial in alleviating vascular dysfunction and improving patient functioning in systemic sclerosis.

“These drugs are relatively inexpensive, even in developing countries, and with our very limited therapeutic arsenal, any drug that leads to any improvement is a welcome addition,” saidDr. Abou-Raya.

Larger studies will be needed to confirm these results, she added.

BARCELONA — Statin therapy may ameliorate the vascular dysfunction that can lead to Raynaud's phenomenon and digital ulcers in systemic sclerosis, Dr. Anna Abou-Raya said at the annual European Congress of Rheumatology.

Systemic sclerosis is characterized by widespread vascular pathology, with initial events involving endothelial cell damage, loss of normal vasodilatory mediators, and excessive vasoconstriction. Within 4 years of diagnosis, up to 65% of patients have digital ulcers, which are painful and disabling and can be associated with infection, gangrene, and amputation, Dr. Abou-Raya said. Effective treatment remains elusive for many patients.

Aside from their well-documented lipid-lowering properties, statins display pleiotropic effects including effects on endothelial function that may be of benefit in slowing or preventing vascular damage.

“The appearance of endothelial cell abnormalities can be considered the crucial, and maybe the initial event in the pathogenesis of systemic sclerosis,” Dr. Abou-Raya said.

“Furthermore, endothelial activation and damage are primary events not only at the initiation but throughout the course of disease,” she added.

To evaluate the potential for statin therapy to retard or prevent vascular damage in systemic sclerosis, Dr. Abou-Raya and associates undertook a controlled study that randomized 40 patients with persistent Raynaud's phenomenon to receive atorvastatin, 40 mg/day, or placebo for 4 months.

The mean age of the patients was 49.7 years, and the mean duration of Raynaud's phenomenon was 8 years. The mean number of digital ulcers existing at baseline was 3.3, and all of the patients fulfilled the American College of Rheumatology criteria for having systemic sclerosis with Raynaud's phenomenon, despite ongoing vasodilator therapy.

Exclusion criteria included diabetes; hypercholesterolemia; hypertension; and cardiac, hepatic, and renal disease.

A mean of 1.6 new ulcers developed in patients in the statin group, compared with a mean of 2.5 new ulcers in the placebo group, which was a statistically significant difference, said Dr. Abou-Raya of the department of rheumatology at the University of Alexandria, Egypt.

Patients were also evaluated for functional status, with statistically significant improvements being seen on the modified Scleroderma Health Assessment Questionnaire Disability Index and on visual analog scale scores for pain and for physician global assessment.

Moreover, biomarkers of endothelial damage, such as intercellular adhesion molecule 1 (ICAM-1) and sE-selectin, as well as acute phase reactants, also improved significantly among patients in the atorvastatin group, Dr. Abou-Raya reported.

The drug was well tolerated, and there were no study dropouts.

The results of this study suggest statins can be beneficial in alleviating vascular dysfunction and improving patient functioning in systemic sclerosis.

“These drugs are relatively inexpensive, even in developing countries, and with our very limited therapeutic arsenal, any drug that leads to any improvement is a welcome addition,” saidDr. Abou-Raya.

Larger studies will be needed to confirm these results, she added.

NEW YORK — Physicians should never feel guilty about overdiagnosing and overtreating possible Kawasaki disease, Dr. Jeffrey R. Starke said at a meeting sponsored by the American College of Emergency Physicians.

“If you look at the risk-benefit ratio of treatment versus the complications if we don't treat, it's clear we should err on the side of overtreatment, especially in children younger than 12 months who are at high risk for developing severe coronary artery abnormalities,” Dr. Starke stated.

These youngest patients also are more likely to present with incomplete Kawasaki disease, and this diagnosis should be considered in any infant younger than 6 months with fever persisting for more than 6 days who has evidence of systemic inflammation that cannot be otherwise explained.

The diagnosis of incomplete Kawasaki disease also should be considered in children with unexplained fever for more than 5 days who have two or three, rather than four, of the principal clinical features of Kawasaki disease (see box below).

In such a patient, if the C-reactive protein is 3 mg/dL or greater and/or the erythrocyte sedimentation rate is 40 mm/hour or more, supplemental laboratory criteria should be obtained.

If three or more of the supplemental laboratory criteria are present, the child should have an echocardiogram and treatment should begin.

If there are fewer than three of the supplemental laboratory criteria, an echocardiogram is in order.

If the echocardiogram shows evidence of cardiac abnormalities, start treatment. If it is negative and the fever abates, Kawasaki disease is unlikely.

But if it persists, repeat the echo and arrange for a consultation with an infectious disease or rheumatology expert, said Dr. Starke, vice chairman of pediatrics at Baylor College of Medicine, Houston.

Another reason for instituting treatment, even if the diagnosis is incomplete or uncertain, is that the standard treatment with intravenous immunoglobulin (IVIG), 2 g/kg as a single infusion, is quite safe.

“It's expensive, but the complication rate is pretty darn low,” he said.

On occasion, treatment can even begin before an echocardiogram is done.

“In my hospital, it's virtually impossible to get an echo between Friday afternoon and Monday morning, and if we are convinced the child has Kawasaki disease, we'll go ahead and give the IVIG and get the echo later,” he said.

Aspirin also is routinely given, even though a recent Cochrane review found insufficient evidence supporting this practice (Cochrane Database Syst. Rev. 2006;doi:10.1002/14651858.CD004175.pub2).

“I don't know of a single infectious disease expert or rheumatologist who doesn't still use aspirin in addition to IVIG in the treatment of Kawasaki disease,” Dr. Starke commented.

High aspirin doses of 80–100 mg/kg per day should be given initially. Some clinicians continue the high dose for 14 days and then reduce the dose to 3–5 mg/kg per day, while other pratitioners maintain the high dose only until 24–48 hours after the patient defervesces, and then switch to the low dose for 2 months for antiplatelet effects.

There have been no trials suggesting the superiority of either approach, he noted. Nor is there convincing evidence for adding corticosteroids to the treatment regimen, although data suggest some clinical benefit.

In a recent prospective randomized trial that included 178 patients with Kawasaki disease, children who received prednisolone in conjunction with IVIG had a shorter duration of fever and a faster fall in C-reactive protein, but there was no difference in coronary artery dilation at 1 month (J. Pediatr. 2006;149:336–41), Dr. Starke noted

If the fever persists or returns more than 36 hours after completion of the IVIG infusion, a second dose can be given. “But be patient. It's very common for kids to continue to run a fever the day after you give the IVIG dose, even as other symptoms are improving,” Dr. Starke advised. Most patients respond very well to that second dose, he added.

The Criteria for Kawasaki Disease

Diagnostic Criteria

Fever greater than 39°C for 5 days, plus four of the following:

▸ Conjunctivitis, usually bulbar and bilateral.

▸ Mucous membrane changes, such as redness and cracking.

▸ Rash, either generalized or local.

▸ Enlarged cervical lymph nodes, usually unilateral and nontender.

▸ Peripheral changes, such as swelling or peeling.

Incomplete Kawasaki Supplemental Laboratory Criteria

▸ Albumin 3 g/dL or less.

▸ Anemia for age.

▸ Elevation of alanine aminotransferase.

▸ Platelets 450,000/mcL or more after 7 days.

▸ White blood cell count 15,000/mcL or higher.

▸ Urine white blood cell count 10/HPF (high power field) or more.

Sources: Dr. Starke; Circulation 2004;110:2747–71

NEW YORK — Physicians should never feel guilty about overdiagnosing and overtreating possible Kawasaki disease, Dr. Jeffrey R. Starke said at a meeting sponsored by the American College of Emergency Physicians.

“If you look at the risk-benefit ratio of treatment versus the complications if we don't treat, it's clear we should err on the side of overtreatment, especially in children younger than 12 months who are at high risk for developing severe coronary artery abnormalities,” Dr. Starke stated.

These youngest patients also are more likely to present with incomplete Kawasaki disease, and this diagnosis should be considered in any infant younger than 6 months with fever persisting for more than 6 days who has evidence of systemic inflammation that cannot be otherwise explained.

The diagnosis of incomplete Kawasaki disease also should be considered in children with unexplained fever for more than 5 days who have two or three, rather than four, of the principal clinical features of Kawasaki disease (see box below).

In such a patient, if the C-reactive protein is 3 mg/dL or greater and/or the erythrocyte sedimentation rate is 40 mm/hour or more, supplemental laboratory criteria should be obtained.

If three or more of the supplemental laboratory criteria are present, the child should have an echocardiogram and treatment should begin.

If there are fewer than three of the supplemental laboratory criteria, an echocardiogram is in order.

If the echocardiogram shows evidence of cardiac abnormalities, start treatment. If it is negative and the fever abates, Kawasaki disease is unlikely.

But if it persists, repeat the echo and arrange for a consultation with an infectious disease or rheumatology expert, said Dr. Starke, vice chairman of pediatrics at Baylor College of Medicine, Houston.

Another reason for instituting treatment, even if the diagnosis is incomplete or uncertain, is that the standard treatment with intravenous immunoglobulin (IVIG), 2 g/kg as a single infusion, is quite safe.

“It's expensive, but the complication rate is pretty darn low,” he said.

On occasion, treatment can even begin before an echocardiogram is done.

“In my hospital, it's virtually impossible to get an echo between Friday afternoon and Monday morning, and if we are convinced the child has Kawasaki disease, we'll go ahead and give the IVIG and get the echo later,” he said.

Aspirin also is routinely given, even though a recent Cochrane review found insufficient evidence supporting this practice (Cochrane Database Syst. Rev. 2006;doi:10.1002/14651858.CD004175.pub2).

“I don't know of a single infectious disease expert or rheumatologist who doesn't still use aspirin in addition to IVIG in the treatment of Kawasaki disease,” Dr. Starke commented.

High aspirin doses of 80–100 mg/kg per day should be given initially. Some clinicians continue the high dose for 14 days and then reduce the dose to 3–5 mg/kg per day, while other pratitioners maintain the high dose only until 24–48 hours after the patient defervesces, and then switch to the low dose for 2 months for antiplatelet effects.

There have been no trials suggesting the superiority of either approach, he noted. Nor is there convincing evidence for adding corticosteroids to the treatment regimen, although data suggest some clinical benefit.

In a recent prospective randomized trial that included 178 patients with Kawasaki disease, children who received prednisolone in conjunction with IVIG had a shorter duration of fever and a faster fall in C-reactive protein, but there was no difference in coronary artery dilation at 1 month (J. Pediatr. 2006;149:336–41), Dr. Starke noted

If the fever persists or returns more than 36 hours after completion of the IVIG infusion, a second dose can be given. “But be patient. It's very common for kids to continue to run a fever the day after you give the IVIG dose, even as other symptoms are improving,” Dr. Starke advised. Most patients respond very well to that second dose, he added.

The Criteria for Kawasaki Disease

Diagnostic Criteria

Fever greater than 39°C for 5 days, plus four of the following:

▸ Conjunctivitis, usually bulbar and bilateral.

▸ Mucous membrane changes, such as redness and cracking.

▸ Rash, either generalized or local.

▸ Enlarged cervical lymph nodes, usually unilateral and nontender.

▸ Peripheral changes, such as swelling or peeling.

Incomplete Kawasaki Supplemental Laboratory Criteria

▸ Albumin 3 g/dL or less.

▸ Anemia for age.

▸ Elevation of alanine aminotransferase.

▸ Platelets 450,000/mcL or more after 7 days.

▸ White blood cell count 15,000/mcL or higher.

▸ Urine white blood cell count 10/HPF (high power field) or more.

Sources: Dr. Starke; Circulation 2004;110:2747–71

NEW YORK — Physicians should never feel guilty about overdiagnosing and overtreating possible Kawasaki disease, Dr. Jeffrey R. Starke said at a meeting sponsored by the American College of Emergency Physicians.

“If you look at the risk-benefit ratio of treatment versus the complications if we don't treat, it's clear we should err on the side of overtreatment, especially in children younger than 12 months who are at high risk for developing severe coronary artery abnormalities,” Dr. Starke stated.

These youngest patients also are more likely to present with incomplete Kawasaki disease, and this diagnosis should be considered in any infant younger than 6 months with fever persisting for more than 6 days who has evidence of systemic inflammation that cannot be otherwise explained.

The diagnosis of incomplete Kawasaki disease also should be considered in children with unexplained fever for more than 5 days who have two or three, rather than four, of the principal clinical features of Kawasaki disease (see box below).

In such a patient, if the C-reactive protein is 3 mg/dL or greater and/or the erythrocyte sedimentation rate is 40 mm/hour or more, supplemental laboratory criteria should be obtained.

If three or more of the supplemental laboratory criteria are present, the child should have an echocardiogram and treatment should begin.

If there are fewer than three of the supplemental laboratory criteria, an echocardiogram is in order.

If the echocardiogram shows evidence of cardiac abnormalities, start treatment. If it is negative and the fever abates, Kawasaki disease is unlikely.

But if it persists, repeat the echo and arrange for a consultation with an infectious disease or rheumatology expert, said Dr. Starke, vice chairman of pediatrics at Baylor College of Medicine, Houston.

Another reason for instituting treatment, even if the diagnosis is incomplete or uncertain, is that the standard treatment with intravenous immunoglobulin (IVIG), 2 g/kg as a single infusion, is quite safe.

“It's expensive, but the complication rate is pretty darn low,” he said.

On occasion, treatment can even begin before an echocardiogram is done.

“In my hospital, it's virtually impossible to get an echo between Friday afternoon and Monday morning, and if we are convinced the child has Kawasaki disease, we'll go ahead and give the IVIG and get the echo later,” he said.

Aspirin also is routinely given, even though a recent Cochrane review found insufficient evidence supporting this practice (Cochrane Database Syst. Rev. 2006;doi:10.1002/14651858.CD004175.pub2).

“I don't know of a single infectious disease expert or rheumatologist who doesn't still use aspirin in addition to IVIG in the treatment of Kawasaki disease,” Dr. Starke commented.

High aspirin doses of 80–100 mg/kg per day should be given initially. Some clinicians continue the high dose for 14 days and then reduce the dose to 3–5 mg/kg per day, while other pratitioners maintain the high dose only until 24–48 hours after the patient defervesces, and then switch to the low dose for 2 months for antiplatelet effects.

There have been no trials suggesting the superiority of either approach, he noted. Nor is there convincing evidence for adding corticosteroids to the treatment regimen, although data suggest some clinical benefit.

In a recent prospective randomized trial that included 178 patients with Kawasaki disease, children who received prednisolone in conjunction with IVIG had a shorter duration of fever and a faster fall in C-reactive protein, but there was no difference in coronary artery dilation at 1 month (J. Pediatr. 2006;149:336–41), Dr. Starke noted

If the fever persists or returns more than 36 hours after completion of the IVIG infusion, a second dose can be given. “But be patient. It's very common for kids to continue to run a fever the day after you give the IVIG dose, even as other symptoms are improving,” Dr. Starke advised. Most patients respond very well to that second dose, he added.

The Criteria for Kawasaki Disease

Diagnostic Criteria

Fever greater than 39°C for 5 days, plus four of the following:

▸ Conjunctivitis, usually bulbar and bilateral.

▸ Mucous membrane changes, such as redness and cracking.

▸ Rash, either generalized or local.

▸ Enlarged cervical lymph nodes, usually unilateral and nontender.

▸ Peripheral changes, such as swelling or peeling.

Incomplete Kawasaki Supplemental Laboratory Criteria

▸ Albumin 3 g/dL or less.

▸ Anemia for age.

▸ Elevation of alanine aminotransferase.

▸ Platelets 450,000/mcL or more after 7 days.

▸ White blood cell count 15,000/mcL or higher.

▸ Urine white blood cell count 10/HPF (high power field) or more.

Sources: Dr. Starke; Circulation 2004;110:2747–71

CHICAGO — The diagnosis of intussusception requires a high index of suspicion. In a recent retrospective review, only 22% of patients presented with the classic triad of emesis, pain, and hematochezia, and if a palpable mass is added to this constellation of signs and symptoms, only 6% met the diagnostic criteria, Dr. Alan P. Ladd said at the annual meeting of the Central Surgical Association.

Delay in presentation decreases the likelihood of successful radiologic reduction of intussusception and increases the chance that surgical intervention will be needed, he added.

The use of ultrasonography has reduced the morbidity of enema reduction in children with this still-common disorder. Reported success rates for enema reduction remain disparate, however, ranging from 42% to 95%, with better results occurring at hospitals with admission rates of 10,000 children per year. “We wanted to look at the trends for contemporary management at our hospital, which has 11,000 admissions each year,” he said.

During 1990 through 2004, 244 children were admitted with a diagnosis of intussusception, said Dr. Ladd of the Riley Hospital for Children and Indiana University, both in Indianapolis.

A retrospective review showed 162 were boys, 68% were young- er than 1 year old, and 86% had ileocolic intussusception. The most common presenting symptoms were emesis, seen in 81% of patients; hematochezia (61%); and abdominal pain (59%).

Either air- or liquid-contrasted enemas were performed in 190 children, with an overall success rate of 46%, he said. Air-contrasted enemas were more successful than liquid-contrasted enemas (54% vs. 34%, respectively).

A significantly greater success rate of 59% was seen in patients who presented within 24 hours after symptom onset, compared with a success rate of 36% seen in those who presented later.

A total of 155 patients required surgical intervention. Those who presented more than 24 hours after symptom onset had a greater risk of needing surgical intervention (relative risk 1.6) and of requiring bowel resection (RR 2.25). Of 42 patients who had a repeated attempt at reduction after a failed attempt at another hospital, 48% were successful. “Prior outside attempts at reduction did not preclude the possibility of radiologic success,” he said.

There was a recurrence rate of 5%; median time of occurrence was 3 weeks later. All were diagnosed radiologically and successfully reduced. There were no complications during the radiologic procedures, and postoperative complications were primarily infection. Two patients died after presenting in shock.

A combination contrast and air enema shows intussusception in the lumen. Courtesy Dr. Alan P. Ladd

CHICAGO — The diagnosis of intussusception requires a high index of suspicion. In a recent retrospective review, only 22% of patients presented with the classic triad of emesis, pain, and hematochezia, and if a palpable mass is added to this constellation of signs and symptoms, only 6% met the diagnostic criteria, Dr. Alan P. Ladd said at the annual meeting of the Central Surgical Association.

Delay in presentation decreases the likelihood of successful radiologic reduction of intussusception and increases the chance that surgical intervention will be needed, he added.

The use of ultrasonography has reduced the morbidity of enema reduction in children with this still-common disorder. Reported success rates for enema reduction remain disparate, however, ranging from 42% to 95%, with better results occurring at hospitals with admission rates of 10,000 children per year. “We wanted to look at the trends for contemporary management at our hospital, which has 11,000 admissions each year,” he said.

During 1990 through 2004, 244 children were admitted with a diagnosis of intussusception, said Dr. Ladd of the Riley Hospital for Children and Indiana University, both in Indianapolis.

A retrospective review showed 162 were boys, 68% were young- er than 1 year old, and 86% had ileocolic intussusception. The most common presenting symptoms were emesis, seen in 81% of patients; hematochezia (61%); and abdominal pain (59%).

Either air- or liquid-contrasted enemas were performed in 190 children, with an overall success rate of 46%, he said. Air-contrasted enemas were more successful than liquid-contrasted enemas (54% vs. 34%, respectively).

A significantly greater success rate of 59% was seen in patients who presented within 24 hours after symptom onset, compared with a success rate of 36% seen in those who presented later.

A total of 155 patients required surgical intervention. Those who presented more than 24 hours after symptom onset had a greater risk of needing surgical intervention (relative risk 1.6) and of requiring bowel resection (RR 2.25). Of 42 patients who had a repeated attempt at reduction after a failed attempt at another hospital, 48% were successful. “Prior outside attempts at reduction did not preclude the possibility of radiologic success,” he said.

There was a recurrence rate of 5%; median time of occurrence was 3 weeks later. All were diagnosed radiologically and successfully reduced. There were no complications during the radiologic procedures, and postoperative complications were primarily infection. Two patients died after presenting in shock.

A combination contrast and air enema shows intussusception in the lumen. Courtesy Dr. Alan P. Ladd

CHICAGO — The diagnosis of intussusception requires a high index of suspicion. In a recent retrospective review, only 22% of patients presented with the classic triad of emesis, pain, and hematochezia, and if a palpable mass is added to this constellation of signs and symptoms, only 6% met the diagnostic criteria, Dr. Alan P. Ladd said at the annual meeting of the Central Surgical Association.

Delay in presentation decreases the likelihood of successful radiologic reduction of intussusception and increases the chance that surgical intervention will be needed, he added.

The use of ultrasonography has reduced the morbidity of enema reduction in children with this still-common disorder. Reported success rates for enema reduction remain disparate, however, ranging from 42% to 95%, with better results occurring at hospitals with admission rates of 10,000 children per year. “We wanted to look at the trends for contemporary management at our hospital, which has 11,000 admissions each year,” he said.

During 1990 through 2004, 244 children were admitted with a diagnosis of intussusception, said Dr. Ladd of the Riley Hospital for Children and Indiana University, both in Indianapolis.

A retrospective review showed 162 were boys, 68% were young- er than 1 year old, and 86% had ileocolic intussusception. The most common presenting symptoms were emesis, seen in 81% of patients; hematochezia (61%); and abdominal pain (59%).

Either air- or liquid-contrasted enemas were performed in 190 children, with an overall success rate of 46%, he said. Air-contrasted enemas were more successful than liquid-contrasted enemas (54% vs. 34%, respectively).

A significantly greater success rate of 59% was seen in patients who presented within 24 hours after symptom onset, compared with a success rate of 36% seen in those who presented later.

A total of 155 patients required surgical intervention. Those who presented more than 24 hours after symptom onset had a greater risk of needing surgical intervention (relative risk 1.6) and of requiring bowel resection (RR 2.25). Of 42 patients who had a repeated attempt at reduction after a failed attempt at another hospital, 48% were successful. “Prior outside attempts at reduction did not preclude the possibility of radiologic success,” he said.

There was a recurrence rate of 5%; median time of occurrence was 3 weeks later. All were diagnosed radiologically and successfully reduced. There were no complications during the radiologic procedures, and postoperative complications were primarily infection. Two patients died after presenting in shock.

A combination contrast and air enema shows intussusception in the lumen. Courtesy Dr. Alan P. Ladd