Diana Mahoney

COPENHAGEN — The anti-interleukin-6 receptor monoclonal antibody tocilizumab represents “a major breakthrough” in the treatment of systemic-onset juvenile idiopathic arthritis, according to Dr. Shumpei Yokota, speaking at the annual European Congress of Rheumatology.

New data from an open-label extension trial of patients with systemic juvenile idiopathic arthritis (sJIA) who previously participated in phase II and phase III trials of the biologic agent confirmed the results of the earlier studies; the data demonstrated significant improvement in clinical responses among children who were refractory to conventional therapy, reported Dr. Yokota, professor of pediatrics at Yokohama (Japan) City University.

In addition, the findings from the extension study showed that the “acceptable safety profile” of tocilizumab therapy is maintained up to 3 years, he said.

In the double-blind, withdrawal phase III trial reported last year, 56 children (aged 2-19 years) with sJIA who didn't respond to conventional treatment received three doses of tocilizumab (8 mg/kg every 2 weeks) during a 6-week, open-label lead-in phase.

Patients who achieved an American College of Rheumatology (ACR) Pediatric 30 response and had a C-reactive protein concentration (CRP) of less than 5 mg/dL were then either randomized to placebo or continued on tocilizumab treatment for a 12-week, double-blind phase.

Patients responding to tocilizumab during the double-blind phase of the study who needed further treatment were enrolled in an open-label extension phase for up to 3 years (Lancet 2008;371:998-1006).

“At the end of the open-label lead-in phase, ACR Pedi 30, 50, and 70 were achieved by 91%, 86%, and 68% patients, respectively,” Dr. Yokota said. Of the 43 patients who continued to the double-blind phase and were included in the efficacy analysis, significantly more patients in the tocilizumab group, compared with the placebo group, maintained an ACR Pedi 30 response and a CRP level less than 1.5 mg/dL (80% vs. 17%, respectively). By week 48 of the open-label extension phase, 100%, 95%, and 90% of the patients achieved ACR Pedi 30, 50, and 70, respectively, he said.

To evaluate the longer-term efficacy and safety of the treatment, Dr. Yokota and colleagues analyzed the outcomes of 67 patients who previously participated in the phase II and phase III trials who were eligible to receive tocilizumab.

“Safety end points included the incidence of serious adverse events and death, and efficacy end points were the ACR Pedi 30, Pedi 50, Pedi 70, and Pedi 90 criteria,” he said.

Of the 67 patients included in the 3-year analysis of continuous tocilizumab therapy, 9 patients discontinued treatment, including 4 who experienced serious adverse events, 4 who developed anti-tocilizumab antibodies, and 1 in whom the treatment was no longer effective, Dr. Yokota said.

The median duration of tocilizumab treatment was 185 weeks, he noted.

In the 3-year analysis, the overall rate of serious adverse events—including anaphylactic reaction, gastrointestinal hemorrhage, bronchitis, and gastroenteritis—was 35.5 per 100 patient-years, Dr. Yokota reported, noting that “there were no cases of opportunistic infections, malignancies, autoimmune diseases, or reported deaths.”

Among the frequently observed nonsevere adverse events were nasopharyngitis, upper respiratory tract infection, and gastroenteritis, he said.

Regarding efficacy, 96%, 96%, 88%, and 73% of patients, respectively, achieved ACR Pedi 30, 50, 70, and 90 by at week 168. “During the long-term treatment, 77% of them had reduced doses of corticosteroids at week 168 and tocilizumab was ceased in eight patients because of continuous remission,” said Dr. Yokota.

The findings indicate that tocilizumab produces “favorable levels of clinical improvements in the signs and symptoms of systemic juvenile idiopathic arthritis with acceptable safety” up to 3 years, Dr. Yokota concluded.

Dr. Yokota disclosed no financial conflicts of interest with respect to his presentation. Chugai Pharmaceutical Co. sponsored the phase III trial.

COPENHAGEN — The anti-interleukin-6 receptor monoclonal antibody tocilizumab represents “a major breakthrough” in the treatment of systemic-onset juvenile idiopathic arthritis, according to Dr. Shumpei Yokota, speaking at the annual European Congress of Rheumatology.

New data from an open-label extension trial of patients with systemic juvenile idiopathic arthritis (sJIA) who previously participated in phase II and phase III trials of the biologic agent confirmed the results of the earlier studies; the data demonstrated significant improvement in clinical responses among children who were refractory to conventional therapy, reported Dr. Yokota, professor of pediatrics at Yokohama (Japan) City University.

In addition, the findings from the extension study showed that the “acceptable safety profile” of tocilizumab therapy is maintained up to 3 years, he said.

In the double-blind, withdrawal phase III trial reported last year, 56 children (aged 2-19 years) with sJIA who didn't respond to conventional treatment received three doses of tocilizumab (8 mg/kg every 2 weeks) during a 6-week, open-label lead-in phase.

Patients who achieved an American College of Rheumatology (ACR) Pediatric 30 response and had a C-reactive protein concentration (CRP) of less than 5 mg/dL were then either randomized to placebo or continued on tocilizumab treatment for a 12-week, double-blind phase.

Patients responding to tocilizumab during the double-blind phase of the study who needed further treatment were enrolled in an open-label extension phase for up to 3 years (Lancet 2008;371:998-1006).

“At the end of the open-label lead-in phase, ACR Pedi 30, 50, and 70 were achieved by 91%, 86%, and 68% patients, respectively,” Dr. Yokota said. Of the 43 patients who continued to the double-blind phase and were included in the efficacy analysis, significantly more patients in the tocilizumab group, compared with the placebo group, maintained an ACR Pedi 30 response and a CRP level less than 1.5 mg/dL (80% vs. 17%, respectively). By week 48 of the open-label extension phase, 100%, 95%, and 90% of the patients achieved ACR Pedi 30, 50, and 70, respectively, he said.

To evaluate the longer-term efficacy and safety of the treatment, Dr. Yokota and colleagues analyzed the outcomes of 67 patients who previously participated in the phase II and phase III trials who were eligible to receive tocilizumab.

“Safety end points included the incidence of serious adverse events and death, and efficacy end points were the ACR Pedi 30, Pedi 50, Pedi 70, and Pedi 90 criteria,” he said.

Of the 67 patients included in the 3-year analysis of continuous tocilizumab therapy, 9 patients discontinued treatment, including 4 who experienced serious adverse events, 4 who developed anti-tocilizumab antibodies, and 1 in whom the treatment was no longer effective, Dr. Yokota said.

The median duration of tocilizumab treatment was 185 weeks, he noted.

In the 3-year analysis, the overall rate of serious adverse events—including anaphylactic reaction, gastrointestinal hemorrhage, bronchitis, and gastroenteritis—was 35.5 per 100 patient-years, Dr. Yokota reported, noting that “there were no cases of opportunistic infections, malignancies, autoimmune diseases, or reported deaths.”

Among the frequently observed nonsevere adverse events were nasopharyngitis, upper respiratory tract infection, and gastroenteritis, he said.

Regarding efficacy, 96%, 96%, 88%, and 73% of patients, respectively, achieved ACR Pedi 30, 50, 70, and 90 by at week 168. “During the long-term treatment, 77% of them had reduced doses of corticosteroids at week 168 and tocilizumab was ceased in eight patients because of continuous remission,” said Dr. Yokota.

The findings indicate that tocilizumab produces “favorable levels of clinical improvements in the signs and symptoms of systemic juvenile idiopathic arthritis with acceptable safety” up to 3 years, Dr. Yokota concluded.

Dr. Yokota disclosed no financial conflicts of interest with respect to his presentation. Chugai Pharmaceutical Co. sponsored the phase III trial.

COPENHAGEN — The anti-interleukin-6 receptor monoclonal antibody tocilizumab represents “a major breakthrough” in the treatment of systemic-onset juvenile idiopathic arthritis, according to Dr. Shumpei Yokota, speaking at the annual European Congress of Rheumatology.

New data from an open-label extension trial of patients with systemic juvenile idiopathic arthritis (sJIA) who previously participated in phase II and phase III trials of the biologic agent confirmed the results of the earlier studies; the data demonstrated significant improvement in clinical responses among children who were refractory to conventional therapy, reported Dr. Yokota, professor of pediatrics at Yokohama (Japan) City University.

In addition, the findings from the extension study showed that the “acceptable safety profile” of tocilizumab therapy is maintained up to 3 years, he said.

In the double-blind, withdrawal phase III trial reported last year, 56 children (aged 2-19 years) with sJIA who didn't respond to conventional treatment received three doses of tocilizumab (8 mg/kg every 2 weeks) during a 6-week, open-label lead-in phase.

Patients who achieved an American College of Rheumatology (ACR) Pediatric 30 response and had a C-reactive protein concentration (CRP) of less than 5 mg/dL were then either randomized to placebo or continued on tocilizumab treatment for a 12-week, double-blind phase.

Patients responding to tocilizumab during the double-blind phase of the study who needed further treatment were enrolled in an open-label extension phase for up to 3 years (Lancet 2008;371:998-1006).

“At the end of the open-label lead-in phase, ACR Pedi 30, 50, and 70 were achieved by 91%, 86%, and 68% patients, respectively,” Dr. Yokota said. Of the 43 patients who continued to the double-blind phase and were included in the efficacy analysis, significantly more patients in the tocilizumab group, compared with the placebo group, maintained an ACR Pedi 30 response and a CRP level less than 1.5 mg/dL (80% vs. 17%, respectively). By week 48 of the open-label extension phase, 100%, 95%, and 90% of the patients achieved ACR Pedi 30, 50, and 70, respectively, he said.

To evaluate the longer-term efficacy and safety of the treatment, Dr. Yokota and colleagues analyzed the outcomes of 67 patients who previously participated in the phase II and phase III trials who were eligible to receive tocilizumab.

“Safety end points included the incidence of serious adverse events and death, and efficacy end points were the ACR Pedi 30, Pedi 50, Pedi 70, and Pedi 90 criteria,” he said.

Of the 67 patients included in the 3-year analysis of continuous tocilizumab therapy, 9 patients discontinued treatment, including 4 who experienced serious adverse events, 4 who developed anti-tocilizumab antibodies, and 1 in whom the treatment was no longer effective, Dr. Yokota said.

The median duration of tocilizumab treatment was 185 weeks, he noted.

In the 3-year analysis, the overall rate of serious adverse events—including anaphylactic reaction, gastrointestinal hemorrhage, bronchitis, and gastroenteritis—was 35.5 per 100 patient-years, Dr. Yokota reported, noting that “there were no cases of opportunistic infections, malignancies, autoimmune diseases, or reported deaths.”

Among the frequently observed nonsevere adverse events were nasopharyngitis, upper respiratory tract infection, and gastroenteritis, he said.

Regarding efficacy, 96%, 96%, 88%, and 73% of patients, respectively, achieved ACR Pedi 30, 50, 70, and 90 by at week 168. “During the long-term treatment, 77% of them had reduced doses of corticosteroids at week 168 and tocilizumab was ceased in eight patients because of continuous remission,” said Dr. Yokota.

The findings indicate that tocilizumab produces “favorable levels of clinical improvements in the signs and symptoms of systemic juvenile idiopathic arthritis with acceptable safety” up to 3 years, Dr. Yokota concluded.

Dr. Yokota disclosed no financial conflicts of interest with respect to his presentation. Chugai Pharmaceutical Co. sponsored the phase III trial.

COPENHAGEN — Rheumatoid arthritis patients can safely undergo multiple courses of retreatment with the anti-CD20 monoclonal antibody rituximab without increasing their risk of serious adverse events, Dr. Ronald F. van Vollenhoven reported at the annual European Congress of Rheumatology.

Presenting the results of a pooled analysis of safety data representing 5,964 patient-years of rituximab exposure from retreatment populations in RA clinical trials, Dr. van Vollenhoven reported that rituximab remains well tolerated with a stable safety profile after up to five treatment courses. Specifically, “the rates of adverse events, serious adverse events, and infections remained stable following each course of treatment,” he said. The findings are particularly important because multiple courses of treatment are often needed to sustain the efficacy of rituximab, which is often used as a treatment of last resort after the failure of other therapies.

The pooled analysis, which included safety data from phase IIA, IIB, and III studies, included 2,579 RA patients who received multiple courses of rituximab. Of these, 1,926 patients received two or more treatment courses, 1,228 patients received three or more courses, 794 patients received four or more, and 282 received at least five courses, said Dr. van Vollenhoven, a rheumatologist at the Karolinska University Hospital in Stockholm. Of the 2,579 patients, 2,417 were followed for more than 1 year from start of treatment, whereas 1,198, 743, 564, and 109, respectively, were followed for more than 2, 3, 4, and 5 years, and 138 withdrew from the trials because of adverse events.

Based on the pooled analysis, the rates of any adverse event (reported per 100 patient-years) after treatment courses one through five, respectively, were 379, 313, 319, 329, and 330, and the respective rates per 100 patient-years of any serious adverse events were 18.3, 17.4, 16.6, 12.0, and 13.4.

“The most frequent adverse events were infusion-related reactions, which occurred in 25% of the patients for the first infusion of the first course, and decreased for subsequent infusions,” Dr. van Vollenhoven said. In all, “15 events in 14 patients were considered serious infusion-related reactions, with 10, 4, 0, 1, and 0 events occurring in courses one through five, respectively.”

Although the proportion of patients with below-normal IgM or IgG levels increased with the number of treatment courses, there were no significant differences by course in the rates of infections or serious infections, said Dr. van Vollenhoven. The overall serious infection rate per 100 patient-years was 4.26, which is consistent with observations in other RA cohorts, and there were no cases of tuberculosis, he noted.

“There was one case of progressive multifocal leukoencephalopathy [PML] reported in a patient who had previously received chemotherapy for oropharyngeal cancer,” Dr. van Vollenhoven said, but like other cases of PML that have been reported in the RA treatment literature, it is unclear whether the occurrence of the fatal reactivation of the JC virus in the central nervous system was related to the rituximab, to other drugs, to the prior cancer treatment, or to the patient's existing impaired immune response.

With respect to malignancy, the analysis showed rates comparable to malignancy rates observed in the general RA population, and there was no increased risk of malignancy with additional courses of treatment, he said.

“These [data], showing the same basic safety profile with retreatment that has been shown in clinical treatment trials, are important. We pride ourselves on the use of biologics and the ability to reach specific targets with treatment, but B-cell therapies, for all their effectiveness, may have long-term consequences that are hard to predict,” said Dr. van Vollenhoven. “It's important to have a good long-term safety system to evaluate retreatment with these drugs.”

Dr. van Vollenhoven disclosed having received financial support for research from Roche.

COPENHAGEN — Rheumatoid arthritis patients can safely undergo multiple courses of retreatment with the anti-CD20 monoclonal antibody rituximab without increasing their risk of serious adverse events, Dr. Ronald F. van Vollenhoven reported at the annual European Congress of Rheumatology.

Presenting the results of a pooled analysis of safety data representing 5,964 patient-years of rituximab exposure from retreatment populations in RA clinical trials, Dr. van Vollenhoven reported that rituximab remains well tolerated with a stable safety profile after up to five treatment courses. Specifically, “the rates of adverse events, serious adverse events, and infections remained stable following each course of treatment,” he said. The findings are particularly important because multiple courses of treatment are often needed to sustain the efficacy of rituximab, which is often used as a treatment of last resort after the failure of other therapies.

The pooled analysis, which included safety data from phase IIA, IIB, and III studies, included 2,579 RA patients who received multiple courses of rituximab. Of these, 1,926 patients received two or more treatment courses, 1,228 patients received three or more courses, 794 patients received four or more, and 282 received at least five courses, said Dr. van Vollenhoven, a rheumatologist at the Karolinska University Hospital in Stockholm. Of the 2,579 patients, 2,417 were followed for more than 1 year from start of treatment, whereas 1,198, 743, 564, and 109, respectively, were followed for more than 2, 3, 4, and 5 years, and 138 withdrew from the trials because of adverse events.

Based on the pooled analysis, the rates of any adverse event (reported per 100 patient-years) after treatment courses one through five, respectively, were 379, 313, 319, 329, and 330, and the respective rates per 100 patient-years of any serious adverse events were 18.3, 17.4, 16.6, 12.0, and 13.4.

“The most frequent adverse events were infusion-related reactions, which occurred in 25% of the patients for the first infusion of the first course, and decreased for subsequent infusions,” Dr. van Vollenhoven said. In all, “15 events in 14 patients were considered serious infusion-related reactions, with 10, 4, 0, 1, and 0 events occurring in courses one through five, respectively.”

Although the proportion of patients with below-normal IgM or IgG levels increased with the number of treatment courses, there were no significant differences by course in the rates of infections or serious infections, said Dr. van Vollenhoven. The overall serious infection rate per 100 patient-years was 4.26, which is consistent with observations in other RA cohorts, and there were no cases of tuberculosis, he noted.

“There was one case of progressive multifocal leukoencephalopathy [PML] reported in a patient who had previously received chemotherapy for oropharyngeal cancer,” Dr. van Vollenhoven said, but like other cases of PML that have been reported in the RA treatment literature, it is unclear whether the occurrence of the fatal reactivation of the JC virus in the central nervous system was related to the rituximab, to other drugs, to the prior cancer treatment, or to the patient's existing impaired immune response.

With respect to malignancy, the analysis showed rates comparable to malignancy rates observed in the general RA population, and there was no increased risk of malignancy with additional courses of treatment, he said.

“These [data], showing the same basic safety profile with retreatment that has been shown in clinical treatment trials, are important. We pride ourselves on the use of biologics and the ability to reach specific targets with treatment, but B-cell therapies, for all their effectiveness, may have long-term consequences that are hard to predict,” said Dr. van Vollenhoven. “It's important to have a good long-term safety system to evaluate retreatment with these drugs.”

Dr. van Vollenhoven disclosed having received financial support for research from Roche.

COPENHAGEN — Rheumatoid arthritis patients can safely undergo multiple courses of retreatment with the anti-CD20 monoclonal antibody rituximab without increasing their risk of serious adverse events, Dr. Ronald F. van Vollenhoven reported at the annual European Congress of Rheumatology.

Presenting the results of a pooled analysis of safety data representing 5,964 patient-years of rituximab exposure from retreatment populations in RA clinical trials, Dr. van Vollenhoven reported that rituximab remains well tolerated with a stable safety profile after up to five treatment courses. Specifically, “the rates of adverse events, serious adverse events, and infections remained stable following each course of treatment,” he said. The findings are particularly important because multiple courses of treatment are often needed to sustain the efficacy of rituximab, which is often used as a treatment of last resort after the failure of other therapies.

The pooled analysis, which included safety data from phase IIA, IIB, and III studies, included 2,579 RA patients who received multiple courses of rituximab. Of these, 1,926 patients received two or more treatment courses, 1,228 patients received three or more courses, 794 patients received four or more, and 282 received at least five courses, said Dr. van Vollenhoven, a rheumatologist at the Karolinska University Hospital in Stockholm. Of the 2,579 patients, 2,417 were followed for more than 1 year from start of treatment, whereas 1,198, 743, 564, and 109, respectively, were followed for more than 2, 3, 4, and 5 years, and 138 withdrew from the trials because of adverse events.

Based on the pooled analysis, the rates of any adverse event (reported per 100 patient-years) after treatment courses one through five, respectively, were 379, 313, 319, 329, and 330, and the respective rates per 100 patient-years of any serious adverse events were 18.3, 17.4, 16.6, 12.0, and 13.4.

“The most frequent adverse events were infusion-related reactions, which occurred in 25% of the patients for the first infusion of the first course, and decreased for subsequent infusions,” Dr. van Vollenhoven said. In all, “15 events in 14 patients were considered serious infusion-related reactions, with 10, 4, 0, 1, and 0 events occurring in courses one through five, respectively.”

Although the proportion of patients with below-normal IgM or IgG levels increased with the number of treatment courses, there were no significant differences by course in the rates of infections or serious infections, said Dr. van Vollenhoven. The overall serious infection rate per 100 patient-years was 4.26, which is consistent with observations in other RA cohorts, and there were no cases of tuberculosis, he noted.

“There was one case of progressive multifocal leukoencephalopathy [PML] reported in a patient who had previously received chemotherapy for oropharyngeal cancer,” Dr. van Vollenhoven said, but like other cases of PML that have been reported in the RA treatment literature, it is unclear whether the occurrence of the fatal reactivation of the JC virus in the central nervous system was related to the rituximab, to other drugs, to the prior cancer treatment, or to the patient's existing impaired immune response.

With respect to malignancy, the analysis showed rates comparable to malignancy rates observed in the general RA population, and there was no increased risk of malignancy with additional courses of treatment, he said.

“These [data], showing the same basic safety profile with retreatment that has been shown in clinical treatment trials, are important. We pride ourselves on the use of biologics and the ability to reach specific targets with treatment, but B-cell therapies, for all their effectiveness, may have long-term consequences that are hard to predict,” said Dr. van Vollenhoven. “It's important to have a good long-term safety system to evaluate retreatment with these drugs.”

Dr. van Vollenhoven disclosed having received financial support for research from Roche.

COPENHAGEN — Reduced responses to pneumococcal polysaccharide and neoantigen vaccination in rheumatoid arthritis patients who were treated with rituximab and methotrexate suggest that polysaccharide and primary immunizations should be administered before rituximab infusions to maximize their efficacy, Dr. Clifton O. Bingham III said at the annual European Congress of Rheumatology.

Presenting data from SIERRA (Study Investigating the Effects of Rituximab on Rheumatoid Arthritis Patients), Dr. Bingham, director of the rheumatology clinics at Johns Hopkins University in Baltimore, reported that relative to patients treated with methotrexate only, patients who were given rituximab plus methotrexate mount a comparable recall response to tetanus toxoid, a measure of retained immunity. Patients on combination therapy also showed preserved delayed-type hypersensitivity (DTH) responses to the Candida albicans skin test.

However, patients on combination therapy showed decreased responses to both the 23-valent pneumococcal polysaccharide vaccine (PPV23), which measures T cell-independent humoral responses, and the neoantigen keyhole limpet hemocyanin (KLH), which tests T cell-dependent primary humoral responses.

The multicenter trial included 103 patients with active RA who were stratified by age and randomized 2:1 to receive two 1,000-mg infusions of rituximab 14 days apart plus methotrexate, or methotrexate alone. Patients aged 18-65 years were included in the study if they had at least four swollen and five tender joints and had been on stable doses of methotrexate for more than 4 weeks, Dr. Bingham explained. Additionally, background corticosteroids were permitted “as long as the dose was less than 10 mg per day and stable for more than 4 weeks,” he said.

Individuals older than 65 years were excluded from the study “because of the known effect of aging on immune responses,” Dr. Bingham stated. Patients who received the pneumococcal vaccine within the previous 3 years, or the tetanus vaccine within the previous 5 years, and those with other uncontrolled concomitant medical illnesses or concurrent use of other disease-modifying antirheumatic drugs or biologics were also excluded, he said.

The methotrexate-only patients received the tetanus toxoid-adsorbed vaccine on day 1, the PPV23 at week 4, and KLH at weeks 8 and 9, whereas the rituximab group received the same vaccines in the same intervals beginning at week 24, Dr. Bingham said.

The C. albicans skin test was administered on day 1 to both groups and then again at week 12 in the methotrexate-only group and at week 24 in the rituximab group.

The study's primary end point was the proportion of patients with a fourfold increase in antitetanus IgG from prevaccination levels, measured 4 weeks after immunization, Dr. Bingham stated. Secondary end points included a twofold increase in tetanus toxoid titer; a twofold increase or an increase of more than one mcg/mL from prevaccination levels in immune response to the PPV23; postvaccination KLH titers; and postvaccination DTH reactions, based on a C. albicans skin test with a cutoff of 5 mm of induration, he said.

With respect to baseline demographics, the patients in both groups were similarly matched except for baseline steroid use and positive skin test at baseline, Dr. Bingham noted. Baseline steroid use was higher in the rituximab group (42%), compared with 19% in the methotrexate-only group, whereas the proportion of patients with a positive skin test was lower in the rituximab group (48%), compared with 71% in the methotrexate-only population, he said.

An evaluation of B cells in the rituximab group at the time of vaccine administration showed that “peripheral B-cell depletion was as expected,” Dr. Bingham said.

“At 24 weeks, when the tetanus toxoid was administered, 92% of the patients remained B cell depleted; at 28 weeks, when the pneumococcus vaccine was given, 89% were B cell depleted; and at 36 weeks, when the KLH was given, 76% of the patients were B cell depleted.”

Regarding the study end points, there was no significant difference between the methotrexate-only patients and the rituximab patients in their responses to the tetanus vaccine at either the fourfold or twofold titer increase thresholds, Dr. Bingham stated.

“What was striking, actually, is that even in patients treated with methotrexate only, the tetanus responses were somewhat low, with only 39% of the rituximab-treated group and 42% of the methotrexate-only group demonstrating a fourfold titer rise.”

Significantly fewer of the rituximab patients responded to at least one pneumococcal serotype of the PPV23 (57% vs. 82% of the methotrexate-only group) and to KLH (47% vs. 93%), said Dr. Bingham. “The mean titers were also lower in the rituximab-treated patients.”

Although many patients in the rituximab group were able to mount an immune response to the vaccinations, “it did appear that neoantigen responses to KLH and T cell-independent responses to pneumococcal polysaccharide vaccination were decreased,” according to Dr. Bingham.

The only significant predictor of vaccine response was IgG2 level at the time of immunization for tetanus, PPV23, and KLH vaccines, he said, noting that “age, methotrexate dose, concomitant corticosteroid use, diagnosis of diabetes mellitus, skin test anergy [less than 5-mm induration], IgM, IgA, total IgG, and IgG1, IgG3, and IgG4 subsets were not predictors of immunization response, nor did rituximab affect total IgG or IgG2 levels.”

Dr. Bingham has served as a consultant to Genentech Inc. and to Roche.

COPENHAGEN — Reduced responses to pneumococcal polysaccharide and neoantigen vaccination in rheumatoid arthritis patients who were treated with rituximab and methotrexate suggest that polysaccharide and primary immunizations should be administered before rituximab infusions to maximize their efficacy, Dr. Clifton O. Bingham III said at the annual European Congress of Rheumatology.

Presenting data from SIERRA (Study Investigating the Effects of Rituximab on Rheumatoid Arthritis Patients), Dr. Bingham, director of the rheumatology clinics at Johns Hopkins University in Baltimore, reported that relative to patients treated with methotrexate only, patients who were given rituximab plus methotrexate mount a comparable recall response to tetanus toxoid, a measure of retained immunity. Patients on combination therapy also showed preserved delayed-type hypersensitivity (DTH) responses to the Candida albicans skin test.

However, patients on combination therapy showed decreased responses to both the 23-valent pneumococcal polysaccharide vaccine (PPV23), which measures T cell-independent humoral responses, and the neoantigen keyhole limpet hemocyanin (KLH), which tests T cell-dependent primary humoral responses.

The multicenter trial included 103 patients with active RA who were stratified by age and randomized 2:1 to receive two 1,000-mg infusions of rituximab 14 days apart plus methotrexate, or methotrexate alone. Patients aged 18-65 years were included in the study if they had at least four swollen and five tender joints and had been on stable doses of methotrexate for more than 4 weeks, Dr. Bingham explained. Additionally, background corticosteroids were permitted “as long as the dose was less than 10 mg per day and stable for more than 4 weeks,” he said.

Individuals older than 65 years were excluded from the study “because of the known effect of aging on immune responses,” Dr. Bingham stated. Patients who received the pneumococcal vaccine within the previous 3 years, or the tetanus vaccine within the previous 5 years, and those with other uncontrolled concomitant medical illnesses or concurrent use of other disease-modifying antirheumatic drugs or biologics were also excluded, he said.

The methotrexate-only patients received the tetanus toxoid-adsorbed vaccine on day 1, the PPV23 at week 4, and KLH at weeks 8 and 9, whereas the rituximab group received the same vaccines in the same intervals beginning at week 24, Dr. Bingham said.

The C. albicans skin test was administered on day 1 to both groups and then again at week 12 in the methotrexate-only group and at week 24 in the rituximab group.

The study's primary end point was the proportion of patients with a fourfold increase in antitetanus IgG from prevaccination levels, measured 4 weeks after immunization, Dr. Bingham stated. Secondary end points included a twofold increase in tetanus toxoid titer; a twofold increase or an increase of more than one mcg/mL from prevaccination levels in immune response to the PPV23; postvaccination KLH titers; and postvaccination DTH reactions, based on a C. albicans skin test with a cutoff of 5 mm of induration, he said.

With respect to baseline demographics, the patients in both groups were similarly matched except for baseline steroid use and positive skin test at baseline, Dr. Bingham noted. Baseline steroid use was higher in the rituximab group (42%), compared with 19% in the methotrexate-only group, whereas the proportion of patients with a positive skin test was lower in the rituximab group (48%), compared with 71% in the methotrexate-only population, he said.

An evaluation of B cells in the rituximab group at the time of vaccine administration showed that “peripheral B-cell depletion was as expected,” Dr. Bingham said.

“At 24 weeks, when the tetanus toxoid was administered, 92% of the patients remained B cell depleted; at 28 weeks, when the pneumococcus vaccine was given, 89% were B cell depleted; and at 36 weeks, when the KLH was given, 76% of the patients were B cell depleted.”

Regarding the study end points, there was no significant difference between the methotrexate-only patients and the rituximab patients in their responses to the tetanus vaccine at either the fourfold or twofold titer increase thresholds, Dr. Bingham stated.

“What was striking, actually, is that even in patients treated with methotrexate only, the tetanus responses were somewhat low, with only 39% of the rituximab-treated group and 42% of the methotrexate-only group demonstrating a fourfold titer rise.”

Significantly fewer of the rituximab patients responded to at least one pneumococcal serotype of the PPV23 (57% vs. 82% of the methotrexate-only group) and to KLH (47% vs. 93%), said Dr. Bingham. “The mean titers were also lower in the rituximab-treated patients.”

Although many patients in the rituximab group were able to mount an immune response to the vaccinations, “it did appear that neoantigen responses to KLH and T cell-independent responses to pneumococcal polysaccharide vaccination were decreased,” according to Dr. Bingham.

The only significant predictor of vaccine response was IgG2 level at the time of immunization for tetanus, PPV23, and KLH vaccines, he said, noting that “age, methotrexate dose, concomitant corticosteroid use, diagnosis of diabetes mellitus, skin test anergy [less than 5-mm induration], IgM, IgA, total IgG, and IgG1, IgG3, and IgG4 subsets were not predictors of immunization response, nor did rituximab affect total IgG or IgG2 levels.”

Dr. Bingham has served as a consultant to Genentech Inc. and to Roche.

COPENHAGEN — Reduced responses to pneumococcal polysaccharide and neoantigen vaccination in rheumatoid arthritis patients who were treated with rituximab and methotrexate suggest that polysaccharide and primary immunizations should be administered before rituximab infusions to maximize their efficacy, Dr. Clifton O. Bingham III said at the annual European Congress of Rheumatology.

Presenting data from SIERRA (Study Investigating the Effects of Rituximab on Rheumatoid Arthritis Patients), Dr. Bingham, director of the rheumatology clinics at Johns Hopkins University in Baltimore, reported that relative to patients treated with methotrexate only, patients who were given rituximab plus methotrexate mount a comparable recall response to tetanus toxoid, a measure of retained immunity. Patients on combination therapy also showed preserved delayed-type hypersensitivity (DTH) responses to the Candida albicans skin test.

However, patients on combination therapy showed decreased responses to both the 23-valent pneumococcal polysaccharide vaccine (PPV23), which measures T cell-independent humoral responses, and the neoantigen keyhole limpet hemocyanin (KLH), which tests T cell-dependent primary humoral responses.

The multicenter trial included 103 patients with active RA who were stratified by age and randomized 2:1 to receive two 1,000-mg infusions of rituximab 14 days apart plus methotrexate, or methotrexate alone. Patients aged 18-65 years were included in the study if they had at least four swollen and five tender joints and had been on stable doses of methotrexate for more than 4 weeks, Dr. Bingham explained. Additionally, background corticosteroids were permitted “as long as the dose was less than 10 mg per day and stable for more than 4 weeks,” he said.

Individuals older than 65 years were excluded from the study “because of the known effect of aging on immune responses,” Dr. Bingham stated. Patients who received the pneumococcal vaccine within the previous 3 years, or the tetanus vaccine within the previous 5 years, and those with other uncontrolled concomitant medical illnesses or concurrent use of other disease-modifying antirheumatic drugs or biologics were also excluded, he said.

The methotrexate-only patients received the tetanus toxoid-adsorbed vaccine on day 1, the PPV23 at week 4, and KLH at weeks 8 and 9, whereas the rituximab group received the same vaccines in the same intervals beginning at week 24, Dr. Bingham said.

The C. albicans skin test was administered on day 1 to both groups and then again at week 12 in the methotrexate-only group and at week 24 in the rituximab group.

The study's primary end point was the proportion of patients with a fourfold increase in antitetanus IgG from prevaccination levels, measured 4 weeks after immunization, Dr. Bingham stated. Secondary end points included a twofold increase in tetanus toxoid titer; a twofold increase or an increase of more than one mcg/mL from prevaccination levels in immune response to the PPV23; postvaccination KLH titers; and postvaccination DTH reactions, based on a C. albicans skin test with a cutoff of 5 mm of induration, he said.

With respect to baseline demographics, the patients in both groups were similarly matched except for baseline steroid use and positive skin test at baseline, Dr. Bingham noted. Baseline steroid use was higher in the rituximab group (42%), compared with 19% in the methotrexate-only group, whereas the proportion of patients with a positive skin test was lower in the rituximab group (48%), compared with 71% in the methotrexate-only population, he said.

An evaluation of B cells in the rituximab group at the time of vaccine administration showed that “peripheral B-cell depletion was as expected,” Dr. Bingham said.

“At 24 weeks, when the tetanus toxoid was administered, 92% of the patients remained B cell depleted; at 28 weeks, when the pneumococcus vaccine was given, 89% were B cell depleted; and at 36 weeks, when the KLH was given, 76% of the patients were B cell depleted.”

Regarding the study end points, there was no significant difference between the methotrexate-only patients and the rituximab patients in their responses to the tetanus vaccine at either the fourfold or twofold titer increase thresholds, Dr. Bingham stated.

“What was striking, actually, is that even in patients treated with methotrexate only, the tetanus responses were somewhat low, with only 39% of the rituximab-treated group and 42% of the methotrexate-only group demonstrating a fourfold titer rise.”

Significantly fewer of the rituximab patients responded to at least one pneumococcal serotype of the PPV23 (57% vs. 82% of the methotrexate-only group) and to KLH (47% vs. 93%), said Dr. Bingham. “The mean titers were also lower in the rituximab-treated patients.”

Although many patients in the rituximab group were able to mount an immune response to the vaccinations, “it did appear that neoantigen responses to KLH and T cell-independent responses to pneumococcal polysaccharide vaccination were decreased,” according to Dr. Bingham.

The only significant predictor of vaccine response was IgG2 level at the time of immunization for tetanus, PPV23, and KLH vaccines, he said, noting that “age, methotrexate dose, concomitant corticosteroid use, diagnosis of diabetes mellitus, skin test anergy [less than 5-mm induration], IgM, IgA, total IgG, and IgG1, IgG3, and IgG4 subsets were not predictors of immunization response, nor did rituximab affect total IgG or IgG2 levels.”

Dr. Bingham has served as a consultant to Genentech Inc. and to Roche.

COPENHAGEN — New European League Against Rheumatism recommendations for monitoring systemic lupus erythematosus offer a road map for careful assessment of the multiple organ systems that the disease can attack.

The guidelines also distinguish among potentially reversible disease activity, disease-related organ damage, and health problems that are unrelated to the disease, Dr. Marta Mosca reported at the annual European Congress of Rheumatology.

The evidence-based recommendations “are designed specifically for use in clinical practice by rheumatologists and other clinicians caring for lupus patients,” said Dr. Mosca, a rheumatologist at the University of Pisa, Italy, and lead author of the recommendation paper.

The 10 recommendations include:

▸ Patient assessment. In addition to routine clinical practice, “the assessment of SLE patients must include an evaluation of disease activity with a validated index at each visit and an annual evaluation of organ damage,” said Dr. Mosca.

Additionally, general quality of life, as ascertained by patient history and by a 0-10 visual analog scale, comorbidities, and drug toxicity should be assessed at each visit.

▸ Cardiovascular risk factors. At the baseline visit, and at least once annually during follow-up, “ask patients about smoking, vascular events, physical activity, their use of oral contraceptives and/or hormonal therapies, and family history,” Dr. Mosca said.

Lipid profile and serum glucose measurement should be done at baseline and annually thereafter, as should examination of blood pressure and body mass index or waist circumference. “Dependent on the findings, a patient may require more regular follow-up for specific conditions,” she said.

▸ Other comorbidities. Individuals with lupus are at increased risk for certain comorbidities, in particular osteoporosis, said Dr. Mosca. “Corticosteroid medications can trigger bone loss; disease-associated pain and fatigue can lead to inactivity, further increasing the osteoporosis risk; and bone loss may occur as a direct result of the disease.”

The guidelines recommend assessing all SLE patients for adequate calcium and vitamin D intake, regular exercise, and smoking status.

SLE patients should be screened and followed for osteoporosis according to the guidelines for postmenopausal women, for patients on steroids, or for patients on any other drug that may interfere with bone mineral density, she said at the meeting.

Studies have also shown that SLE patients are at an increased risk for certain cancers, “yet lupus patients tend to undergo screening less often than do individuals in the general population,” possibly because lupus-related concerns may take precedence, said Dr. Mosca. The guidelines recommend cancer screening according to the guidelines for the general population.

“It's up to the clinicians who care for these patients to encourage appropriate screening,” she said.

▸ Infection risk. Lupus patients should be screened for HIV based on individual risk factors, and they should be screened for the hepatitis C and the hepatitis B viruses and for tuberculosis according to local guidelines before beginning immunosuppressive therapy, according to the recommendations.

During immunosuppressive therapy, selected SLE patients should be tested for cytomegalovirus infection, because it increases the degree of immunosuppression of cell-mediated immunity, Dr. Mosca said.

Because of the increased risk of infection in SLE, patients should receive only inactivated pneumococcal and influenzae vaccines, according to CDC guidelines for immunosuppressed patients, “preferably during periods of inactive disease,” she said.

▸ Frequency of assessment. The recommendations suggest patient assessments every 6-12 months for individuals with inactive disease, no organ damage, and no comorbidities. The treating clinician should emphasize prevention at the time of these assessments, Dr. Mosca said.

▸ Laboratory assessment. According to the guidelines, baseline laboratory assessment should include testing for anti-nuclear antibodies (ANA), anti-phospholipid (aPL) antibodies, Complement 3 (C3) and Complement 4 (C4), as well as the following autoantibodies: anti-double stranded DNA (anti-dsDNA), anti-Ro, anti-La, and anti-ribonuclear protein (RNP).

Prior to pregnancy, previously negative patients should be re-evaluated for aPL, anti-Ro, and anti-La antibodies. Prior to surgery, transplant, or the initiation of estrogen-containing treatments, or in the presence of a new neurologic or vascular event, previously negative patients should be tested for aPL, according to Dr. Mosca.

At 6- to 12-month intervals in patients with inactive disease, “we recommend performing a complete blood cell count, erythrocyte sedimentation rate, C-reactive protein, serum albumin, serum creatinine, and urinalysis,” she said. “Monitoring should be tailored to specific treatment drugs, when necessary.”

▸ Mucocutaneous involvement. “Mucocutaneous lesions should be characterized, according to existing classification systems, as to whether they may be lupus-specific, lupus nonspecific, lupus mimickers, or drug related,” Dr. Mosca reported. “All lesions should be assessed for activity and damage using validated indexes.”

▸ Kidney involvement. Monitoring recommendations in this domain depend on kidney status.

“Patients with persistently abnormal urinalysis or creatinine should have a urine protein/creatinine ratio or 24-hour proteinuria [test], urine microscopy, renal ultrasound, and be considered for biopsy referral,” Dr. Mosca said. “Patients with established nephropathy should have urine protein/creatinine ratio or 24-hour proteinuria [test], immunological studies [C3, C4, anti-dsDNA], and urine microscopy at least every 3 months for the first 2-3 years; and patients with established chronic kidney disease should be followed according to the National Kidney Foundation guidelines for chronic kidney disease.”

▸ Neuropsychological manifestations. Although the rate of neurocognitive impairment in SLE is high, “monitoring neurocognitive status is difficult because there are no standardized assessment tools for this population,” Dr. Mosca stated.

All SLE patients should be monitored for neuropsychological symptoms using a focused history. Additionally, “cognitive impairment may be assessed by evaluating memory, attention, concentration, and word finding difficulties; and if there is suspicion of cognitive impairment, the patient should be referred to a specialist for a more detailed assessment,” she said.

▸ Eye assessment. Eye damage in patients with lupus varies from minor problems to severe retinopathy. A small percentage of lupus patients develop scleritis, retinal vasculitis, cotton wool spots at the back of the eyeball, or retinal bleeding and swelling of the optic disc.

According to the guidelines, patients on steroids or antimalarial drugs should undergo a baseline eye examination according to standard recommendations.

Annual follow-up eye exams are recommended in selected patients taking steroids and those at high risk for eye problems.

“In patients taking antimalarial drugs who are low risk for eye problems, no further testing is required until after 5 years from baseline, at which point yearly examinations are recommended,” Dr. Mosca said.

In addition to facilitating good clinical practice, the recommendations for monitoring SLE are expected to “improve the quality control of care for lupus patients and to standardize the collection and comparison of data in observational studies,” Dr. Mosca concluded.

The recommendations, which are expected to be published in the Annals of Rheumatic Disease later this year, were developed by an expert panel using a three-staged consensus approach comprising a discussion of relevant categories, a comprehensive literature review and level of evidence assessment, and the integration of the evidence with expert opinion, said Dr. Mosca.

She reported having no financial conflicts of interest to disclose.

COPENHAGEN — New European League Against Rheumatism recommendations for monitoring systemic lupus erythematosus offer a road map for careful assessment of the multiple organ systems that the disease can attack.

The guidelines also distinguish among potentially reversible disease activity, disease-related organ damage, and health problems that are unrelated to the disease, Dr. Marta Mosca reported at the annual European Congress of Rheumatology.

The evidence-based recommendations “are designed specifically for use in clinical practice by rheumatologists and other clinicians caring for lupus patients,” said Dr. Mosca, a rheumatologist at the University of Pisa, Italy, and lead author of the recommendation paper.

The 10 recommendations include:

▸ Patient assessment. In addition to routine clinical practice, “the assessment of SLE patients must include an evaluation of disease activity with a validated index at each visit and an annual evaluation of organ damage,” said Dr. Mosca.

Additionally, general quality of life, as ascertained by patient history and by a 0-10 visual analog scale, comorbidities, and drug toxicity should be assessed at each visit.

▸ Cardiovascular risk factors. At the baseline visit, and at least once annually during follow-up, “ask patients about smoking, vascular events, physical activity, their use of oral contraceptives and/or hormonal therapies, and family history,” Dr. Mosca said.

Lipid profile and serum glucose measurement should be done at baseline and annually thereafter, as should examination of blood pressure and body mass index or waist circumference. “Dependent on the findings, a patient may require more regular follow-up for specific conditions,” she said.

▸ Other comorbidities. Individuals with lupus are at increased risk for certain comorbidities, in particular osteoporosis, said Dr. Mosca. “Corticosteroid medications can trigger bone loss; disease-associated pain and fatigue can lead to inactivity, further increasing the osteoporosis risk; and bone loss may occur as a direct result of the disease.”

The guidelines recommend assessing all SLE patients for adequate calcium and vitamin D intake, regular exercise, and smoking status.

SLE patients should be screened and followed for osteoporosis according to the guidelines for postmenopausal women, for patients on steroids, or for patients on any other drug that may interfere with bone mineral density, she said at the meeting.

Studies have also shown that SLE patients are at an increased risk for certain cancers, “yet lupus patients tend to undergo screening less often than do individuals in the general population,” possibly because lupus-related concerns may take precedence, said Dr. Mosca. The guidelines recommend cancer screening according to the guidelines for the general population.

“It's up to the clinicians who care for these patients to encourage appropriate screening,” she said.

▸ Infection risk. Lupus patients should be screened for HIV based on individual risk factors, and they should be screened for the hepatitis C and the hepatitis B viruses and for tuberculosis according to local guidelines before beginning immunosuppressive therapy, according to the recommendations.

During immunosuppressive therapy, selected SLE patients should be tested for cytomegalovirus infection, because it increases the degree of immunosuppression of cell-mediated immunity, Dr. Mosca said.

Because of the increased risk of infection in SLE, patients should receive only inactivated pneumococcal and influenzae vaccines, according to CDC guidelines for immunosuppressed patients, “preferably during periods of inactive disease,” she said.

▸ Frequency of assessment. The recommendations suggest patient assessments every 6-12 months for individuals with inactive disease, no organ damage, and no comorbidities. The treating clinician should emphasize prevention at the time of these assessments, Dr. Mosca said.

▸ Laboratory assessment. According to the guidelines, baseline laboratory assessment should include testing for anti-nuclear antibodies (ANA), anti-phospholipid (aPL) antibodies, Complement 3 (C3) and Complement 4 (C4), as well as the following autoantibodies: anti-double stranded DNA (anti-dsDNA), anti-Ro, anti-La, and anti-ribonuclear protein (RNP).

Prior to pregnancy, previously negative patients should be re-evaluated for aPL, anti-Ro, and anti-La antibodies. Prior to surgery, transplant, or the initiation of estrogen-containing treatments, or in the presence of a new neurologic or vascular event, previously negative patients should be tested for aPL, according to Dr. Mosca.

At 6- to 12-month intervals in patients with inactive disease, “we recommend performing a complete blood cell count, erythrocyte sedimentation rate, C-reactive protein, serum albumin, serum creatinine, and urinalysis,” she said. “Monitoring should be tailored to specific treatment drugs, when necessary.”

▸ Mucocutaneous involvement. “Mucocutaneous lesions should be characterized, according to existing classification systems, as to whether they may be lupus-specific, lupus nonspecific, lupus mimickers, or drug related,” Dr. Mosca reported. “All lesions should be assessed for activity and damage using validated indexes.”

▸ Kidney involvement. Monitoring recommendations in this domain depend on kidney status.

“Patients with persistently abnormal urinalysis or creatinine should have a urine protein/creatinine ratio or 24-hour proteinuria [test], urine microscopy, renal ultrasound, and be considered for biopsy referral,” Dr. Mosca said. “Patients with established nephropathy should have urine protein/creatinine ratio or 24-hour proteinuria [test], immunological studies [C3, C4, anti-dsDNA], and urine microscopy at least every 3 months for the first 2-3 years; and patients with established chronic kidney disease should be followed according to the National Kidney Foundation guidelines for chronic kidney disease.”

▸ Neuropsychological manifestations. Although the rate of neurocognitive impairment in SLE is high, “monitoring neurocognitive status is difficult because there are no standardized assessment tools for this population,” Dr. Mosca stated.

All SLE patients should be monitored for neuropsychological symptoms using a focused history. Additionally, “cognitive impairment may be assessed by evaluating memory, attention, concentration, and word finding difficulties; and if there is suspicion of cognitive impairment, the patient should be referred to a specialist for a more detailed assessment,” she said.

▸ Eye assessment. Eye damage in patients with lupus varies from minor problems to severe retinopathy. A small percentage of lupus patients develop scleritis, retinal vasculitis, cotton wool spots at the back of the eyeball, or retinal bleeding and swelling of the optic disc.

According to the guidelines, patients on steroids or antimalarial drugs should undergo a baseline eye examination according to standard recommendations.

Annual follow-up eye exams are recommended in selected patients taking steroids and those at high risk for eye problems.

“In patients taking antimalarial drugs who are low risk for eye problems, no further testing is required until after 5 years from baseline, at which point yearly examinations are recommended,” Dr. Mosca said.

In addition to facilitating good clinical practice, the recommendations for monitoring SLE are expected to “improve the quality control of care for lupus patients and to standardize the collection and comparison of data in observational studies,” Dr. Mosca concluded.

The recommendations, which are expected to be published in the Annals of Rheumatic Disease later this year, were developed by an expert panel using a three-staged consensus approach comprising a discussion of relevant categories, a comprehensive literature review and level of evidence assessment, and the integration of the evidence with expert opinion, said Dr. Mosca.

She reported having no financial conflicts of interest to disclose.

COPENHAGEN — New European League Against Rheumatism recommendations for monitoring systemic lupus erythematosus offer a road map for careful assessment of the multiple organ systems that the disease can attack.

The guidelines also distinguish among potentially reversible disease activity, disease-related organ damage, and health problems that are unrelated to the disease, Dr. Marta Mosca reported at the annual European Congress of Rheumatology.

The evidence-based recommendations “are designed specifically for use in clinical practice by rheumatologists and other clinicians caring for lupus patients,” said Dr. Mosca, a rheumatologist at the University of Pisa, Italy, and lead author of the recommendation paper.

The 10 recommendations include:

▸ Patient assessment. In addition to routine clinical practice, “the assessment of SLE patients must include an evaluation of disease activity with a validated index at each visit and an annual evaluation of organ damage,” said Dr. Mosca.

Additionally, general quality of life, as ascertained by patient history and by a 0-10 visual analog scale, comorbidities, and drug toxicity should be assessed at each visit.

▸ Cardiovascular risk factors. At the baseline visit, and at least once annually during follow-up, “ask patients about smoking, vascular events, physical activity, their use of oral contraceptives and/or hormonal therapies, and family history,” Dr. Mosca said.

Lipid profile and serum glucose measurement should be done at baseline and annually thereafter, as should examination of blood pressure and body mass index or waist circumference. “Dependent on the findings, a patient may require more regular follow-up for specific conditions,” she said.

▸ Other comorbidities. Individuals with lupus are at increased risk for certain comorbidities, in particular osteoporosis, said Dr. Mosca. “Corticosteroid medications can trigger bone loss; disease-associated pain and fatigue can lead to inactivity, further increasing the osteoporosis risk; and bone loss may occur as a direct result of the disease.”

The guidelines recommend assessing all SLE patients for adequate calcium and vitamin D intake, regular exercise, and smoking status.

SLE patients should be screened and followed for osteoporosis according to the guidelines for postmenopausal women, for patients on steroids, or for patients on any other drug that may interfere with bone mineral density, she said at the meeting.

Studies have also shown that SLE patients are at an increased risk for certain cancers, “yet lupus patients tend to undergo screening less often than do individuals in the general population,” possibly because lupus-related concerns may take precedence, said Dr. Mosca. The guidelines recommend cancer screening according to the guidelines for the general population.

“It's up to the clinicians who care for these patients to encourage appropriate screening,” she said.

▸ Infection risk. Lupus patients should be screened for HIV based on individual risk factors, and they should be screened for the hepatitis C and the hepatitis B viruses and for tuberculosis according to local guidelines before beginning immunosuppressive therapy, according to the recommendations.

During immunosuppressive therapy, selected SLE patients should be tested for cytomegalovirus infection, because it increases the degree of immunosuppression of cell-mediated immunity, Dr. Mosca said.

Because of the increased risk of infection in SLE, patients should receive only inactivated pneumococcal and influenzae vaccines, according to CDC guidelines for immunosuppressed patients, “preferably during periods of inactive disease,” she said.

▸ Frequency of assessment. The recommendations suggest patient assessments every 6-12 months for individuals with inactive disease, no organ damage, and no comorbidities. The treating clinician should emphasize prevention at the time of these assessments, Dr. Mosca said.

▸ Laboratory assessment. According to the guidelines, baseline laboratory assessment should include testing for anti-nuclear antibodies (ANA), anti-phospholipid (aPL) antibodies, Complement 3 (C3) and Complement 4 (C4), as well as the following autoantibodies: anti-double stranded DNA (anti-dsDNA), anti-Ro, anti-La, and anti-ribonuclear protein (RNP).

Prior to pregnancy, previously negative patients should be re-evaluated for aPL, anti-Ro, and anti-La antibodies. Prior to surgery, transplant, or the initiation of estrogen-containing treatments, or in the presence of a new neurologic or vascular event, previously negative patients should be tested for aPL, according to Dr. Mosca.

At 6- to 12-month intervals in patients with inactive disease, “we recommend performing a complete blood cell count, erythrocyte sedimentation rate, C-reactive protein, serum albumin, serum creatinine, and urinalysis,” she said. “Monitoring should be tailored to specific treatment drugs, when necessary.”

▸ Mucocutaneous involvement. “Mucocutaneous lesions should be characterized, according to existing classification systems, as to whether they may be lupus-specific, lupus nonspecific, lupus mimickers, or drug related,” Dr. Mosca reported. “All lesions should be assessed for activity and damage using validated indexes.”

▸ Kidney involvement. Monitoring recommendations in this domain depend on kidney status.

“Patients with persistently abnormal urinalysis or creatinine should have a urine protein/creatinine ratio or 24-hour proteinuria [test], urine microscopy, renal ultrasound, and be considered for biopsy referral,” Dr. Mosca said. “Patients with established nephropathy should have urine protein/creatinine ratio or 24-hour proteinuria [test], immunological studies [C3, C4, anti-dsDNA], and urine microscopy at least every 3 months for the first 2-3 years; and patients with established chronic kidney disease should be followed according to the National Kidney Foundation guidelines for chronic kidney disease.”

▸ Neuropsychological manifestations. Although the rate of neurocognitive impairment in SLE is high, “monitoring neurocognitive status is difficult because there are no standardized assessment tools for this population,” Dr. Mosca stated.

All SLE patients should be monitored for neuropsychological symptoms using a focused history. Additionally, “cognitive impairment may be assessed by evaluating memory, attention, concentration, and word finding difficulties; and if there is suspicion of cognitive impairment, the patient should be referred to a specialist for a more detailed assessment,” she said.

▸ Eye assessment. Eye damage in patients with lupus varies from minor problems to severe retinopathy. A small percentage of lupus patients develop scleritis, retinal vasculitis, cotton wool spots at the back of the eyeball, or retinal bleeding and swelling of the optic disc.

According to the guidelines, patients on steroids or antimalarial drugs should undergo a baseline eye examination according to standard recommendations.

Annual follow-up eye exams are recommended in selected patients taking steroids and those at high risk for eye problems.

“In patients taking antimalarial drugs who are low risk for eye problems, no further testing is required until after 5 years from baseline, at which point yearly examinations are recommended,” Dr. Mosca said.

In addition to facilitating good clinical practice, the recommendations for monitoring SLE are expected to “improve the quality control of care for lupus patients and to standardize the collection and comparison of data in observational studies,” Dr. Mosca concluded.

The recommendations, which are expected to be published in the Annals of Rheumatic Disease later this year, were developed by an expert panel using a three-staged consensus approach comprising a discussion of relevant categories, a comprehensive literature review and level of evidence assessment, and the integration of the evidence with expert opinion, said Dr. Mosca.

She reported having no financial conflicts of interest to disclose.

BOSTON — The high prevalence of vitamin D deficiency found in a cohort of healthy children in a sunny Southwestern climate has prompted a call by the study's investigators for generalized routine screening of vitamin D levels among all children.

In a study designed to assess vitamin D levels in children living in a region with year-round sunshine and to compare vitamin D levels in children with vague musculoskeletal pain with those of children without pain, Dr. Elizabeth A. Szalay and her colleagues at the University of New Mexico Hospital in Albuquerque retrospectively studied the serum 25-hydroxyvitamin D (25[OH]D) levels of 77 healthy children who were seen for musculoskeletal pain but who lacked a concrete diagnosis to explain their pain (pain group). They also prospectively obtained serum 25(OH)D levels from 35 healthy children without pain.

The study included healthy children aged 2-16 years who were freely ambulatory and could play outside as they chose. It excluded children with any endocrinopathy and those taking medications that affect vitamin D metabolism, such as steroids or bisphosphonates, Dr. Szalay said in a poster presented at the annual meeting of the Pediatric Orthopaedic Society of North America.

The study population (mean age, 9 years) included 66 girls and 46 boys, and was primarily Hispanic (59) and white (37). The average 25-hydroxyvitamin D levels for the pain and control groups were not statistically different, at 28 ng/mL and 31 ng/mL, Dr. Szalay reported, nor did the vitamin D levels vary by month of the year.

Based on the collective data, the mean 25(OH)D level was 29 ng/mL. "While there is no consensus on optimal serum vitamin D levels in children, optimal calcium absorption is seen between 40 and 100 ng/mL," Dr. Szalay said. "Vitamin D deficiency is defined by most experts as a [25-hydroxyvitamin D] level less than 20 ng/mL."

Only 13% of the children had vitamin D levels in the optimal range, while 33% had levels from 30 to 39 ng/mL, 35% had levels from 20 to 29 ng/mL, 16% had levels from 10 to 19 ng/mL, and 3% had levels less than 10 ng/mL—the level at which rachitic changes may occur.

"This is an alarming trend, especially because the location—with its Southern latitude—had been thought to be ideal for adequate vitamin D levels," said Dr. Szalay. Despite the abundant sun exposure and lack of chronic illness, "the percentage of children with suboptimal vitamin D levels was significantly greater than that demonstrated among healthy teens studied in the 2002 Third National Health and Nutrition Examination Survey."

The findings seem to suggest that modern lifestyles, even among children living in sun-rich regions, may be taking an ever greater toll on pediatric vitamin D levels and indirectly on pediatric bone health, said Dr. Szalay. "Increasing childhood obesity, declining dairy intake, increased time using computers and video games, decreased outdoor activity, and increased sunscreen usage may be contributing factors impairing availability to vitamin D, which is essential for normal calcium metabolism and bone mineralization."

Dr. Szalay reported having no financial conflicts with respect to this presentation.

BOSTON — The high prevalence of vitamin D deficiency found in a cohort of healthy children in a sunny Southwestern climate has prompted a call by the study's investigators for generalized routine screening of vitamin D levels among all children.

In a study designed to assess vitamin D levels in children living in a region with year-round sunshine and to compare vitamin D levels in children with vague musculoskeletal pain with those of children without pain, Dr. Elizabeth A. Szalay and her colleagues at the University of New Mexico Hospital in Albuquerque retrospectively studied the serum 25-hydroxyvitamin D (25[OH]D) levels of 77 healthy children who were seen for musculoskeletal pain but who lacked a concrete diagnosis to explain their pain (pain group). They also prospectively obtained serum 25(OH)D levels from 35 healthy children without pain.

The study included healthy children aged 2-16 years who were freely ambulatory and could play outside as they chose. It excluded children with any endocrinopathy and those taking medications that affect vitamin D metabolism, such as steroids or bisphosphonates, Dr. Szalay said in a poster presented at the annual meeting of the Pediatric Orthopaedic Society of North America.

The study population (mean age, 9 years) included 66 girls and 46 boys, and was primarily Hispanic (59) and white (37). The average 25-hydroxyvitamin D levels for the pain and control groups were not statistically different, at 28 ng/mL and 31 ng/mL, Dr. Szalay reported, nor did the vitamin D levels vary by month of the year.

Based on the collective data, the mean 25(OH)D level was 29 ng/mL. "While there is no consensus on optimal serum vitamin D levels in children, optimal calcium absorption is seen between 40 and 100 ng/mL," Dr. Szalay said. "Vitamin D deficiency is defined by most experts as a [25-hydroxyvitamin D] level less than 20 ng/mL."

Only 13% of the children had vitamin D levels in the optimal range, while 33% had levels from 30 to 39 ng/mL, 35% had levels from 20 to 29 ng/mL, 16% had levels from 10 to 19 ng/mL, and 3% had levels less than 10 ng/mL—the level at which rachitic changes may occur.

"This is an alarming trend, especially because the location—with its Southern latitude—had been thought to be ideal for adequate vitamin D levels," said Dr. Szalay. Despite the abundant sun exposure and lack of chronic illness, "the percentage of children with suboptimal vitamin D levels was significantly greater than that demonstrated among healthy teens studied in the 2002 Third National Health and Nutrition Examination Survey."

The findings seem to suggest that modern lifestyles, even among children living in sun-rich regions, may be taking an ever greater toll on pediatric vitamin D levels and indirectly on pediatric bone health, said Dr. Szalay. "Increasing childhood obesity, declining dairy intake, increased time using computers and video games, decreased outdoor activity, and increased sunscreen usage may be contributing factors impairing availability to vitamin D, which is essential for normal calcium metabolism and bone mineralization."

Dr. Szalay reported having no financial conflicts with respect to this presentation.

BOSTON — The high prevalence of vitamin D deficiency found in a cohort of healthy children in a sunny Southwestern climate has prompted a call by the study's investigators for generalized routine screening of vitamin D levels among all children.

In a study designed to assess vitamin D levels in children living in a region with year-round sunshine and to compare vitamin D levels in children with vague musculoskeletal pain with those of children without pain, Dr. Elizabeth A. Szalay and her colleagues at the University of New Mexico Hospital in Albuquerque retrospectively studied the serum 25-hydroxyvitamin D (25[OH]D) levels of 77 healthy children who were seen for musculoskeletal pain but who lacked a concrete diagnosis to explain their pain (pain group). They also prospectively obtained serum 25(OH)D levels from 35 healthy children without pain.

The study included healthy children aged 2-16 years who were freely ambulatory and could play outside as they chose. It excluded children with any endocrinopathy and those taking medications that affect vitamin D metabolism, such as steroids or bisphosphonates, Dr. Szalay said in a poster presented at the annual meeting of the Pediatric Orthopaedic Society of North America.

The study population (mean age, 9 years) included 66 girls and 46 boys, and was primarily Hispanic (59) and white (37). The average 25-hydroxyvitamin D levels for the pain and control groups were not statistically different, at 28 ng/mL and 31 ng/mL, Dr. Szalay reported, nor did the vitamin D levels vary by month of the year.

Based on the collective data, the mean 25(OH)D level was 29 ng/mL. "While there is no consensus on optimal serum vitamin D levels in children, optimal calcium absorption is seen between 40 and 100 ng/mL," Dr. Szalay said. "Vitamin D deficiency is defined by most experts as a [25-hydroxyvitamin D] level less than 20 ng/mL."

Only 13% of the children had vitamin D levels in the optimal range, while 33% had levels from 30 to 39 ng/mL, 35% had levels from 20 to 29 ng/mL, 16% had levels from 10 to 19 ng/mL, and 3% had levels less than 10 ng/mL—the level at which rachitic changes may occur.

"This is an alarming trend, especially because the location—with its Southern latitude—had been thought to be ideal for adequate vitamin D levels," said Dr. Szalay. Despite the abundant sun exposure and lack of chronic illness, "the percentage of children with suboptimal vitamin D levels was significantly greater than that demonstrated among healthy teens studied in the 2002 Third National Health and Nutrition Examination Survey."

The findings seem to suggest that modern lifestyles, even among children living in sun-rich regions, may be taking an ever greater toll on pediatric vitamin D levels and indirectly on pediatric bone health, said Dr. Szalay. "Increasing childhood obesity, declining dairy intake, increased time using computers and video games, decreased outdoor activity, and increased sunscreen usage may be contributing factors impairing availability to vitamin D, which is essential for normal calcium metabolism and bone mineralization."

Dr. Szalay reported having no financial conflicts with respect to this presentation.

COPENHAGEN — Rheumatoid arthritis patients who do not respond to initial treatment with rituximab can be re-treated successfully with a second course of the B-cell-depleting, monoclonal anti-CD20 antibody after 6 months, Dr. Edward Vital reported at the European Congress of Rheumatology.

The findings are particularly important because rituximab is often used as a treatment of last resort after the failure of other therapies, such as anti-tumor necrosis factor agents and methotrexate, “and approximately one-third of patients fail to achieve an adequate response to initial treatment with the drug,” said Dr. Vital of the Leeds Institute of Molecular Medicine at the University of Leeds (England).

Although it had previously been presumed that RA patients who failed initial rituximab therapy had B-cell-independent disease, the new data suggest that is not the case, said Dr. Vital.

To determine whether nonresponders to initial rituximab therapy might have disease that is potentially still amenable to B-cell-depletion therapy, and to assess the impact of re-treatment, Dr. Vital and his colleagues assessed the B-cell status and treatment response of 104 RA patients treated with standard doses of rituximab. All of the patients were positive for rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies. Of the 104 patients, 38 did not respond to initial therapy, based on change in clinical status as measured by Disease Activity Score 28 and EULAR criteria.

A comparison of baseline blood and synovial B-cell parameters showed no difference in erythrocyte sedimentation rates or C reactive protein levels between nonresponders and responders. But nonresponders had significantly higher numbers of memory and pre-plasma cells at baseline, along with more synovial B cells, Dr. Vital reported. Additionally, using highly sensitive rare-event fluorescence-activated cell sorting (RE-FACS), the investigators identified incomplete B-cell depletion in 90% of the treatment nonresponders, he said.

Of the nonresponders, 25 underwent re-treatment 6 months later, “when their B-cell numbers were significantly lower than they were at baseline of their first treatment cycle,” Dr. Vital reported. Among the re-treated patients, 72% responded clinically (defined as a moderate or better EULAR response) to the therapy at 6 months. Of these, 32% had a good response and 16% were in remission—response rates that are comparable to those observed among treatment-naive patients, he said.

The findings have had an immediate impact on clinical practice at the Leeds Teaching Hospitals. “From these results, we have immediately changed our practice regarding how we treat these patients. Now all patients who fail the first cycle of rituximab get a second cycle of treatment,” Dr. Vital said.

“The next question to consider is whether patients who have predictors of poor response could be treated more intensively from the outset, possibly with a different dose of rituximab, which is something we are currently investigating,” he noted. Dr. Vital disclosed a financial relationship with Roche, which provided free study drugs for 45 patients. The study was funded by the U.K. National Institute for Health Research.

To watch an interview of Dr. Vital, go to www.youtube.com/watch?v=YfEX2UxSlps

COPENHAGEN — Rheumatoid arthritis patients who do not respond to initial treatment with rituximab can be re-treated successfully with a second course of the B-cell-depleting, monoclonal anti-CD20 antibody after 6 months, Dr. Edward Vital reported at the European Congress of Rheumatology.

The findings are particularly important because rituximab is often used as a treatment of last resort after the failure of other therapies, such as anti-tumor necrosis factor agents and methotrexate, “and approximately one-third of patients fail to achieve an adequate response to initial treatment with the drug,” said Dr. Vital of the Leeds Institute of Molecular Medicine at the University of Leeds (England).

Although it had previously been presumed that RA patients who failed initial rituximab therapy had B-cell-independent disease, the new data suggest that is not the case, said Dr. Vital.

To determine whether nonresponders to initial rituximab therapy might have disease that is potentially still amenable to B-cell-depletion therapy, and to assess the impact of re-treatment, Dr. Vital and his colleagues assessed the B-cell status and treatment response of 104 RA patients treated with standard doses of rituximab. All of the patients were positive for rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies. Of the 104 patients, 38 did not respond to initial therapy, based on change in clinical status as measured by Disease Activity Score 28 and EULAR criteria.

A comparison of baseline blood and synovial B-cell parameters showed no difference in erythrocyte sedimentation rates or C reactive protein levels between nonresponders and responders. But nonresponders had significantly higher numbers of memory and pre-plasma cells at baseline, along with more synovial B cells, Dr. Vital reported. Additionally, using highly sensitive rare-event fluorescence-activated cell sorting (RE-FACS), the investigators identified incomplete B-cell depletion in 90% of the treatment nonresponders, he said.

Of the nonresponders, 25 underwent re-treatment 6 months later, “when their B-cell numbers were significantly lower than they were at baseline of their first treatment cycle,” Dr. Vital reported. Among the re-treated patients, 72% responded clinically (defined as a moderate or better EULAR response) to the therapy at 6 months. Of these, 32% had a good response and 16% were in remission—response rates that are comparable to those observed among treatment-naive patients, he said.

The findings have had an immediate impact on clinical practice at the Leeds Teaching Hospitals. “From these results, we have immediately changed our practice regarding how we treat these patients. Now all patients who fail the first cycle of rituximab get a second cycle of treatment,” Dr. Vital said.

“The next question to consider is whether patients who have predictors of poor response could be treated more intensively from the outset, possibly with a different dose of rituximab, which is something we are currently investigating,” he noted. Dr. Vital disclosed a financial relationship with Roche, which provided free study drugs for 45 patients. The study was funded by the U.K. National Institute for Health Research.

To watch an interview of Dr. Vital, go to www.youtube.com/watch?v=YfEX2UxSlps

COPENHAGEN — Rheumatoid arthritis patients who do not respond to initial treatment with rituximab can be re-treated successfully with a second course of the B-cell-depleting, monoclonal anti-CD20 antibody after 6 months, Dr. Edward Vital reported at the European Congress of Rheumatology.

The findings are particularly important because rituximab is often used as a treatment of last resort after the failure of other therapies, such as anti-tumor necrosis factor agents and methotrexate, “and approximately one-third of patients fail to achieve an adequate response to initial treatment with the drug,” said Dr. Vital of the Leeds Institute of Molecular Medicine at the University of Leeds (England).

Although it had previously been presumed that RA patients who failed initial rituximab therapy had B-cell-independent disease, the new data suggest that is not the case, said Dr. Vital.

To determine whether nonresponders to initial rituximab therapy might have disease that is potentially still amenable to B-cell-depletion therapy, and to assess the impact of re-treatment, Dr. Vital and his colleagues assessed the B-cell status and treatment response of 104 RA patients treated with standard doses of rituximab. All of the patients were positive for rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies. Of the 104 patients, 38 did not respond to initial therapy, based on change in clinical status as measured by Disease Activity Score 28 and EULAR criteria.

A comparison of baseline blood and synovial B-cell parameters showed no difference in erythrocyte sedimentation rates or C reactive protein levels between nonresponders and responders. But nonresponders had significantly higher numbers of memory and pre-plasma cells at baseline, along with more synovial B cells, Dr. Vital reported. Additionally, using highly sensitive rare-event fluorescence-activated cell sorting (RE-FACS), the investigators identified incomplete B-cell depletion in 90% of the treatment nonresponders, he said.

Of the nonresponders, 25 underwent re-treatment 6 months later, “when their B-cell numbers were significantly lower than they were at baseline of their first treatment cycle,” Dr. Vital reported. Among the re-treated patients, 72% responded clinically (defined as a moderate or better EULAR response) to the therapy at 6 months. Of these, 32% had a good response and 16% were in remission—response rates that are comparable to those observed among treatment-naive patients, he said.

The findings have had an immediate impact on clinical practice at the Leeds Teaching Hospitals. “From these results, we have immediately changed our practice regarding how we treat these patients. Now all patients who fail the first cycle of rituximab get a second cycle of treatment,” Dr. Vital said.

“The next question to consider is whether patients who have predictors of poor response could be treated more intensively from the outset, possibly with a different dose of rituximab, which is something we are currently investigating,” he noted. Dr. Vital disclosed a financial relationship with Roche, which provided free study drugs for 45 patients. The study was funded by the U.K. National Institute for Health Research.

To watch an interview of Dr. Vital, go to www.youtube.com/watch?v=YfEX2UxSlps

COPENHAGEN — The addition of tocilizumab to methotrexate therapy is a promising new option for rheumatoid arthritis patients who do not fully respond to treatment with the disease-modifying antirheumatic drug alone, Dr. Joel M. Kremer said at the annual European Congress on Rheumatology.

Dr. Kremer, director of research at the Center for Rheumatology LLC in Albany, N.Y., presented 1-year data from the international LITHE (Tocilizumab Safety and the Prevention of Structural Joint Damage) study showing that the anti-interleukin-6 monoclonal antibody inhibits structural joint damage and improves physical function and clinical disease activity, compared with methotrexate alone.

The randomized, double-blind, placebo-controlled LITHE study, which was sponsored by Roche, enrolled 1,196 patients with moderate to severe rheumatoid arthritis who had an inadequate response to methotrexate. Patients were randomized to receive a 4-mg/kg or 8-mg/kg infusion of tocilizumab (Actemra) every 4 weeks in combination with stable doses of methotrexate or methotrexate/placebo. The study's primary end points included ACR 20 response at 24 weeks and change from baseline in Genant-modified Total Sharp Score (GmTSS) and physical function at 52 weeks, measured by area under the curve (AUC) of change from baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI), Dr. Kremer explained.

At 24 weeks, ACR 20 response was achieved by 56% and 51%, respectively, in the tocilizumab 8-mg and 4-mg combination therapy groups, compared with 27% of the methotrexate-only group, Dr. Kremer said, noting that significantly more patients in both combination therapy groups achieved ARC 20/50/70 responses at week 52.

Also at 52 weeks, there were significantly more patients in the combination therapy groups without radiographic progression from baseline, compared with the methotrexate-only group. Total GmTSS change from baseline for the tocilizumab (8 mg)/methotrexate, the tocilizumab (4 mg)/methotrexate, and the methotrexate-only groups were 0.29, 0.34 and 1.13, respectively. The respective percentages of patients achieving no progression in GmTSS were 85%, 81%, and 67%, Dr. Kremer said. The HAQ-DI AUC changes from baseline adjusted mean scores were −144.1, −128.4 and −58.1, respectively. At 24 and 52 weeks, the DAS28 (Disease Activity Score based on 28 joints) clinical remission scores were significantly greater in the combination therapy groups, compared with the methotrexate-only group. In both combination therapy groups, the DAS28 remission rate increased from week 24 to week 52, indicating an increasing magnitude of clinical benefit over time, he said.

“Tocilizumab represents a new approach to treating severe arthritis, but as always, the decision to use a particular biologic agent is not cast in stone” Dr. Kremer said in an interview. “There will always be patients in any busy practice who have tried and failed the multiple agents previously available.” In these patients, he said, “trying a new mechanism of action, while watching carefully for the emergence of side effects, is reasonable.”

In particular, patients must be monitored for abnormalities in transaminase enzymes, which would require an adjustment in the dose of either medication, Dr. Kremer said. In the event of significant increases in lipid levels in a patient with underlying risk factors for cardiovascular disease, strong consideration should be given to the initiation of a statin agent, he said.

Dr. Kremer, who is also the founder and president of CORRONA (Consortium of Rheumatology Researchers of North America), disclosed that he has received grants for clinical research from—and has served as a consultant for—Abbott Laboratories, Amgen Inc., Bristol-Myers Squibb Co., Centocor Inc., Genentech Inc., and Roche.

COPENHAGEN — The addition of tocilizumab to methotrexate therapy is a promising new option for rheumatoid arthritis patients who do not fully respond to treatment with the disease-modifying antirheumatic drug alone, Dr. Joel M. Kremer said at the annual European Congress on Rheumatology.

Dr. Kremer, director of research at the Center for Rheumatology LLC in Albany, N.Y., presented 1-year data from the international LITHE (Tocilizumab Safety and the Prevention of Structural Joint Damage) study showing that the anti-interleukin-6 monoclonal antibody inhibits structural joint damage and improves physical function and clinical disease activity, compared with methotrexate alone.

The randomized, double-blind, placebo-controlled LITHE study, which was sponsored by Roche, enrolled 1,196 patients with moderate to severe rheumatoid arthritis who had an inadequate response to methotrexate. Patients were randomized to receive a 4-mg/kg or 8-mg/kg infusion of tocilizumab (Actemra) every 4 weeks in combination with stable doses of methotrexate or methotrexate/placebo. The study's primary end points included ACR 20 response at 24 weeks and change from baseline in Genant-modified Total Sharp Score (GmTSS) and physical function at 52 weeks, measured by area under the curve (AUC) of change from baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI), Dr. Kremer explained.

At 24 weeks, ACR 20 response was achieved by 56% and 51%, respectively, in the tocilizumab 8-mg and 4-mg combination therapy groups, compared with 27% of the methotrexate-only group, Dr. Kremer said, noting that significantly more patients in both combination therapy groups achieved ARC 20/50/70 responses at week 52.

Also at 52 weeks, there were significantly more patients in the combination therapy groups without radiographic progression from baseline, compared with the methotrexate-only group. Total GmTSS change from baseline for the tocilizumab (8 mg)/methotrexate, the tocilizumab (4 mg)/methotrexate, and the methotrexate-only groups were 0.29, 0.34 and 1.13, respectively. The respective percentages of patients achieving no progression in GmTSS were 85%, 81%, and 67%, Dr. Kremer said. The HAQ-DI AUC changes from baseline adjusted mean scores were −144.1, −128.4 and −58.1, respectively. At 24 and 52 weeks, the DAS28 (Disease Activity Score based on 28 joints) clinical remission scores were significantly greater in the combination therapy groups, compared with the methotrexate-only group. In both combination therapy groups, the DAS28 remission rate increased from week 24 to week 52, indicating an increasing magnitude of clinical benefit over time, he said.

“Tocilizumab represents a new approach to treating severe arthritis, but as always, the decision to use a particular biologic agent is not cast in stone” Dr. Kremer said in an interview. “There will always be patients in any busy practice who have tried and failed the multiple agents previously available.” In these patients, he said, “trying a new mechanism of action, while watching carefully for the emergence of side effects, is reasonable.”

In particular, patients must be monitored for abnormalities in transaminase enzymes, which would require an adjustment in the dose of either medication, Dr. Kremer said. In the event of significant increases in lipid levels in a patient with underlying risk factors for cardiovascular disease, strong consideration should be given to the initiation of a statin agent, he said.

Dr. Kremer, who is also the founder and president of CORRONA (Consortium of Rheumatology Researchers of North America), disclosed that he has received grants for clinical research from—and has served as a consultant for—Abbott Laboratories, Amgen Inc., Bristol-Myers Squibb Co., Centocor Inc., Genentech Inc., and Roche.

COPENHAGEN — The addition of tocilizumab to methotrexate therapy is a promising new option for rheumatoid arthritis patients who do not fully respond to treatment with the disease-modifying antirheumatic drug alone, Dr. Joel M. Kremer said at the annual European Congress on Rheumatology.

Dr. Kremer, director of research at the Center for Rheumatology LLC in Albany, N.Y., presented 1-year data from the international LITHE (Tocilizumab Safety and the Prevention of Structural Joint Damage) study showing that the anti-interleukin-6 monoclonal antibody inhibits structural joint damage and improves physical function and clinical disease activity, compared with methotrexate alone.

The randomized, double-blind, placebo-controlled LITHE study, which was sponsored by Roche, enrolled 1,196 patients with moderate to severe rheumatoid arthritis who had an inadequate response to methotrexate. Patients were randomized to receive a 4-mg/kg or 8-mg/kg infusion of tocilizumab (Actemra) every 4 weeks in combination with stable doses of methotrexate or methotrexate/placebo. The study's primary end points included ACR 20 response at 24 weeks and change from baseline in Genant-modified Total Sharp Score (GmTSS) and physical function at 52 weeks, measured by area under the curve (AUC) of change from baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI), Dr. Kremer explained.

At 24 weeks, ACR 20 response was achieved by 56% and 51%, respectively, in the tocilizumab 8-mg and 4-mg combination therapy groups, compared with 27% of the methotrexate-only group, Dr. Kremer said, noting that significantly more patients in both combination therapy groups achieved ARC 20/50/70 responses at week 52.

Also at 52 weeks, there were significantly more patients in the combination therapy groups without radiographic progression from baseline, compared with the methotrexate-only group. Total GmTSS change from baseline for the tocilizumab (8 mg)/methotrexate, the tocilizumab (4 mg)/methotrexate, and the methotrexate-only groups were 0.29, 0.34 and 1.13, respectively. The respective percentages of patients achieving no progression in GmTSS were 85%, 81%, and 67%, Dr. Kremer said. The HAQ-DI AUC changes from baseline adjusted mean scores were −144.1, −128.4 and −58.1, respectively. At 24 and 52 weeks, the DAS28 (Disease Activity Score based on 28 joints) clinical remission scores were significantly greater in the combination therapy groups, compared with the methotrexate-only group. In both combination therapy groups, the DAS28 remission rate increased from week 24 to week 52, indicating an increasing magnitude of clinical benefit over time, he said.

“Tocilizumab represents a new approach to treating severe arthritis, but as always, the decision to use a particular biologic agent is not cast in stone” Dr. Kremer said in an interview. “There will always be patients in any busy practice who have tried and failed the multiple agents previously available.” In these patients, he said, “trying a new mechanism of action, while watching carefully for the emergence of side effects, is reasonable.”

In particular, patients must be monitored for abnormalities in transaminase enzymes, which would require an adjustment in the dose of either medication, Dr. Kremer said. In the event of significant increases in lipid levels in a patient with underlying risk factors for cardiovascular disease, strong consideration should be given to the initiation of a statin agent, he said.

Dr. Kremer, who is also the founder and president of CORRONA (Consortium of Rheumatology Researchers of North America), disclosed that he has received grants for clinical research from—and has served as a consultant for—Abbott Laboratories, Amgen Inc., Bristol-Myers Squibb Co., Centocor Inc., Genentech Inc., and Roche.

BOSTON — The high prevalence of vitamin D deficiency found in a cohort of healthy children in a sunny Southwestern climate has prompted a call by the study's investigators for generalized routine screening of vitamin D levels among all children.

In a study designed to assess vitamin D levels in children living in a region with year-round sunshine and to compare vitamin D levels in children with vague musculoskeletal pain with those of children without pain, Dr. Elizabeth A. Szalay and her colleagues at the University of New Mexico Hospital in Albuquerque retrospectively studied the serum 25-hydroxyvitamin D (25[OH]D) levels of 77 healthy children who were seen for musculoskeletal pain but who lacked a concrete diagnosis to explain their pain (pain group). They also prospectively obtained serum 25(OH)D levels from 35 healthy children without pain.

The study included healthy children aged 2-16 years old who were freely ambulatory and could play outside as they chose. It excluded children with any endocrinopathy and those taking medications that affect vitamin D metabolism, Dr. Szalay said at the annual meeting of the Pediatric Orthopaedic Society of North America.

The study population (mean age, 9 years) included 66 girls and 46 boys, and was primarily Hispanic (59) and white (37). The average 25-hydroxyvitamin D levels for the pain and control groups were not statistically different, at 28 ng/mL and 31 ng/mL.

The mean 25(OH)D level was 29 ng/mL. “While there is no consensus on optimal serum vitamin D levels in children, optimal calcium absorption is seen between 40 and 100 ng/mL,” she said. “Vitamin D deficiency is defined by most experts as a [25-hydroxyvitamin D] level less than 20 ng/mL.”

Collectively, only 13% of the children had vitamin D levels in the optimal range, while 33% had levels from 30 to 39 ng/mL, 35% had levels from 20 to 29 ng/mL, 16% had levels from 10 to 19 ng/mL, and 3% had levels less than 10 ng/mL—the level at which rachitic changes may occur.

The findings seem to suggest that modern lifestyles, even among children living in sun-rich regions, may be taking an ever greater toll on pediatric vitamin D levels and indirectly on pediatric bone health, said Dr. Szalay.

“Concern over hypovitaminosis D in children is warranted and routine screening should, at the very least, be considered,” said Dr. Szalay, who reported having no conflicts of interest.

BOSTON — The high prevalence of vitamin D deficiency found in a cohort of healthy children in a sunny Southwestern climate has prompted a call by the study's investigators for generalized routine screening of vitamin D levels among all children.

In a study designed to assess vitamin D levels in children living in a region with year-round sunshine and to compare vitamin D levels in children with vague musculoskeletal pain with those of children without pain, Dr. Elizabeth A. Szalay and her colleagues at the University of New Mexico Hospital in Albuquerque retrospectively studied the serum 25-hydroxyvitamin D (25[OH]D) levels of 77 healthy children who were seen for musculoskeletal pain but who lacked a concrete diagnosis to explain their pain (pain group). They also prospectively obtained serum 25(OH)D levels from 35 healthy children without pain.

The study included healthy children aged 2-16 years old who were freely ambulatory and could play outside as they chose. It excluded children with any endocrinopathy and those taking medications that affect vitamin D metabolism, Dr. Szalay said at the annual meeting of the Pediatric Orthopaedic Society of North America.

The study population (mean age, 9 years) included 66 girls and 46 boys, and was primarily Hispanic (59) and white (37). The average 25-hydroxyvitamin D levels for the pain and control groups were not statistically different, at 28 ng/mL and 31 ng/mL.

The mean 25(OH)D level was 29 ng/mL. “While there is no consensus on optimal serum vitamin D levels in children, optimal calcium absorption is seen between 40 and 100 ng/mL,” she said. “Vitamin D deficiency is defined by most experts as a [25-hydroxyvitamin D] level less than 20 ng/mL.”

Collectively, only 13% of the children had vitamin D levels in the optimal range, while 33% had levels from 30 to 39 ng/mL, 35% had levels from 20 to 29 ng/mL, 16% had levels from 10 to 19 ng/mL, and 3% had levels less than 10 ng/mL—the level at which rachitic changes may occur.

The findings seem to suggest that modern lifestyles, even among children living in sun-rich regions, may be taking an ever greater toll on pediatric vitamin D levels and indirectly on pediatric bone health, said Dr. Szalay.

“Concern over hypovitaminosis D in children is warranted and routine screening should, at the very least, be considered,” said Dr. Szalay, who reported having no conflicts of interest.

BOSTON — The high prevalence of vitamin D deficiency found in a cohort of healthy children in a sunny Southwestern climate has prompted a call by the study's investigators for generalized routine screening of vitamin D levels among all children.

In a study designed to assess vitamin D levels in children living in a region with year-round sunshine and to compare vitamin D levels in children with vague musculoskeletal pain with those of children without pain, Dr. Elizabeth A. Szalay and her colleagues at the University of New Mexico Hospital in Albuquerque retrospectively studied the serum 25-hydroxyvitamin D (25[OH]D) levels of 77 healthy children who were seen for musculoskeletal pain but who lacked a concrete diagnosis to explain their pain (pain group). They also prospectively obtained serum 25(OH)D levels from 35 healthy children without pain.

The study included healthy children aged 2-16 years old who were freely ambulatory and could play outside as they chose. It excluded children with any endocrinopathy and those taking medications that affect vitamin D metabolism, Dr. Szalay said at the annual meeting of the Pediatric Orthopaedic Society of North America.

The study population (mean age, 9 years) included 66 girls and 46 boys, and was primarily Hispanic (59) and white (37). The average 25-hydroxyvitamin D levels for the pain and control groups were not statistically different, at 28 ng/mL and 31 ng/mL.

The mean 25(OH)D level was 29 ng/mL. “While there is no consensus on optimal serum vitamin D levels in children, optimal calcium absorption is seen between 40 and 100 ng/mL,” she said. “Vitamin D deficiency is defined by most experts as a [25-hydroxyvitamin D] level less than 20 ng/mL.”

Collectively, only 13% of the children had vitamin D levels in the optimal range, while 33% had levels from 30 to 39 ng/mL, 35% had levels from 20 to 29 ng/mL, 16% had levels from 10 to 19 ng/mL, and 3% had levels less than 10 ng/mL—the level at which rachitic changes may occur.

The findings seem to suggest that modern lifestyles, even among children living in sun-rich regions, may be taking an ever greater toll on pediatric vitamin D levels and indirectly on pediatric bone health, said Dr. Szalay.

“Concern over hypovitaminosis D in children is warranted and routine screening should, at the very least, be considered,” said Dr. Szalay, who reported having no conflicts of interest.

BOSTON — The incidence of steroid-induced osteonecrosis is significantly lower in childhood systemic lupus erythematosus than in adults with the disease, according to the findings of a prospective MRI study.

Additionally, among pediatric patients, age of lupus onset is an independent risk factor for the degenerative bone condition, Dr. Junichi Nakamura reported at the annual meeting of the Pediatric Orthopaedic Society of North America.

Characterized by the death of bone marrow and trabecular bone as a result of disruption of blood supply to the bone, osteonecrosis is a well-known complication of systemic lupus erythematosus (SLE) and is often associated with steroid therapy, yet the incidence of steroid-induced osteonecrosis in childhood SLE has not been well established, according to Dr. Nakamura of Chiba (Japan) Children's Hospital.

To assess the relative incidence of the condition in children and adults and to determine associated risk factors in children, Dr. Nakamura and his colleagues prospectively studied 169 patients, including 43 with childhood lupus (aged younger than 20 years at time of diagnosis) and 126 adults with the disease. All the patients fulfilled the 1982 revised American College of Rheumatology criteria for SLE, and all underwent MRI of the knee and hip when steroid therapy was initiated and again after at least 1 year of steroid therapy. The mean follow-up period was 7.8 years, and the follow-up rate was 100%, he said.

In total, 676 joint MRIs were analyzed, including initial and follow-up knee and hip MRIs for each adult and childhood SLE patient, Dr. Nakamura said. “The incidence of osteonecrosis was significantly lower in the childhood SLE group than the adults [31% and 41%, respectively].” During the follow-up period, osteonecrosis developed in 20 hips and 33 knees of 20 childhood SLE patients, and in 95 hips and 112 knees of 74 adult SLE patients, he reported.

Among the childhood SLE patients, age at SLE onset, highest dose of corticosteroid per day, and highest dose of corticosteroid per weight per day were compared between those who did and did not develop osteonecrosis, Dr. Nakamura said. The mean age of SLE onset in the osteonecrosis group was 17.2 years, compared with 13.3 years in the nonosteonecrosis group, representing a significant difference. The highest corticosteroid dose per day and the highest dose per weight per day were statistically similar between the two groups, he said.

In logistic regression analysis, “the incidence of osteonecrosis was significantly lower at the younger age of initial steroid treatment,” said Dr. Nakamura. “The odds ratio for osteonecrosis associated with older age of onset was 1.31.”

In the childhood SLE group, “osteonecrosis never developed before 14 years of age,” said Dr. Nakamura. “The youngest patients with osteonecrosis included a 14.9-year-old with osteonecrosis in the hip and a 15.5-year-old with osteonecrosis in the knee.”

Although the findings should be replicated in a larger investigation, clinicians should be cognizant of the potential increased risk of osteonecrosis in children diagnosed with SLE at a later age, in order to optimize screening and management, Dr. Nakamura concluded.

Dr. Nakamura had no conflicts of interest to disclose with respect to his presentation.

T1 (left) and STIR MRI (right) show osteonecrosis of the femoral head in a 14.9-year-old with systemic lupus erythematosus—the youngest SLE patient in the study with evidence of osteonecrosis. The growth plates of the femoral heads have already closed. Images courtesy Dr. Junichi Nakamura

BOSTON — The incidence of steroid-induced osteonecrosis is significantly lower in childhood systemic lupus erythematosus than in adults with the disease, according to the findings of a prospective MRI study.

Additionally, among pediatric patients, age of lupus onset is an independent risk factor for the degenerative bone condition, Dr. Junichi Nakamura reported at the annual meeting of the Pediatric Orthopaedic Society of North America.

Characterized by the death of bone marrow and trabecular bone as a result of disruption of blood supply to the bone, osteonecrosis is a well-known complication of systemic lupus erythematosus (SLE) and is often associated with steroid therapy, yet the incidence of steroid-induced osteonecrosis in childhood SLE has not been well established, according to Dr. Nakamura of Chiba (Japan) Children's Hospital.

To assess the relative incidence of the condition in children and adults and to determine associated risk factors in children, Dr. Nakamura and his colleagues prospectively studied 169 patients, including 43 with childhood lupus (aged younger than 20 years at time of diagnosis) and 126 adults with the disease. All the patients fulfilled the 1982 revised American College of Rheumatology criteria for SLE, and all underwent MRI of the knee and hip when steroid therapy was initiated and again after at least 1 year of steroid therapy. The mean follow-up period was 7.8 years, and the follow-up rate was 100%, he said.

In total, 676 joint MRIs were analyzed, including initial and follow-up knee and hip MRIs for each adult and childhood SLE patient, Dr. Nakamura said. “The incidence of osteonecrosis was significantly lower in the childhood SLE group than the adults [31% and 41%, respectively].” During the follow-up period, osteonecrosis developed in 20 hips and 33 knees of 20 childhood SLE patients, and in 95 hips and 112 knees of 74 adult SLE patients, he reported.

Among the childhood SLE patients, age at SLE onset, highest dose of corticosteroid per day, and highest dose of corticosteroid per weight per day were compared between those who did and did not develop osteonecrosis, Dr. Nakamura said. The mean age of SLE onset in the osteonecrosis group was 17.2 years, compared with 13.3 years in the nonosteonecrosis group, representing a significant difference. The highest corticosteroid dose per day and the highest dose per weight per day were statistically similar between the two groups, he said.

In logistic regression analysis, “the incidence of osteonecrosis was significantly lower at the younger age of initial steroid treatment,” said Dr. Nakamura. “The odds ratio for osteonecrosis associated with older age of onset was 1.31.”

In the childhood SLE group, “osteonecrosis never developed before 14 years of age,” said Dr. Nakamura. “The youngest patients with osteonecrosis included a 14.9-year-old with osteonecrosis in the hip and a 15.5-year-old with osteonecrosis in the knee.”

Although the findings should be replicated in a larger investigation, clinicians should be cognizant of the potential increased risk of osteonecrosis in children diagnosed with SLE at a later age, in order to optimize screening and management, Dr. Nakamura concluded.

Dr. Nakamura had no conflicts of interest to disclose with respect to his presentation.

T1 (left) and STIR MRI (right) show osteonecrosis of the femoral head in a 14.9-year-old with systemic lupus erythematosus—the youngest SLE patient in the study with evidence of osteonecrosis. The growth plates of the femoral heads have already closed. Images courtesy Dr. Junichi Nakamura

BOSTON — The incidence of steroid-induced osteonecrosis is significantly lower in childhood systemic lupus erythematosus than in adults with the disease, according to the findings of a prospective MRI study.

Additionally, among pediatric patients, age of lupus onset is an independent risk factor for the degenerative bone condition, Dr. Junichi Nakamura reported at the annual meeting of the Pediatric Orthopaedic Society of North America.

Characterized by the death of bone marrow and trabecular bone as a result of disruption of blood supply to the bone, osteonecrosis is a well-known complication of systemic lupus erythematosus (SLE) and is often associated with steroid therapy, yet the incidence of steroid-induced osteonecrosis in childhood SLE has not been well established, according to Dr. Nakamura of Chiba (Japan) Children's Hospital.

To assess the relative incidence of the condition in children and adults and to determine associated risk factors in children, Dr. Nakamura and his colleagues prospectively studied 169 patients, including 43 with childhood lupus (aged younger than 20 years at time of diagnosis) and 126 adults with the disease. All the patients fulfilled the 1982 revised American College of Rheumatology criteria for SLE, and all underwent MRI of the knee and hip when steroid therapy was initiated and again after at least 1 year of steroid therapy. The mean follow-up period was 7.8 years, and the follow-up rate was 100%, he said.

In total, 676 joint MRIs were analyzed, including initial and follow-up knee and hip MRIs for each adult and childhood SLE patient, Dr. Nakamura said. “The incidence of osteonecrosis was significantly lower in the childhood SLE group than the adults [31% and 41%, respectively].” During the follow-up period, osteonecrosis developed in 20 hips and 33 knees of 20 childhood SLE patients, and in 95 hips and 112 knees of 74 adult SLE patients, he reported.

Among the childhood SLE patients, age at SLE onset, highest dose of corticosteroid per day, and highest dose of corticosteroid per weight per day were compared between those who did and did not develop osteonecrosis, Dr. Nakamura said. The mean age of SLE onset in the osteonecrosis group was 17.2 years, compared with 13.3 years in the nonosteonecrosis group, representing a significant difference. The highest corticosteroid dose per day and the highest dose per weight per day were statistically similar between the two groups, he said.

In logistic regression analysis, “the incidence of osteonecrosis was significantly lower at the younger age of initial steroid treatment,” said Dr. Nakamura. “The odds ratio for osteonecrosis associated with older age of onset was 1.31.”

In the childhood SLE group, “osteonecrosis never developed before 14 years of age,” said Dr. Nakamura. “The youngest patients with osteonecrosis included a 14.9-year-old with osteonecrosis in the hip and a 15.5-year-old with osteonecrosis in the knee.”

Although the findings should be replicated in a larger investigation, clinicians should be cognizant of the potential increased risk of osteonecrosis in children diagnosed with SLE at a later age, in order to optimize screening and management, Dr. Nakamura concluded.

Dr. Nakamura had no conflicts of interest to disclose with respect to his presentation.

T1 (left) and STIR MRI (right) show osteonecrosis of the femoral head in a 14.9-year-old with systemic lupus erythematosus—the youngest SLE patient in the study with evidence of osteonecrosis. The growth plates of the femoral heads have already closed. Images courtesy Dr. Junichi Nakamura

Pediatric psoriatic arthropathy requires more than combinations of topical medicines, according to Dr. Kelly M. Cordoro.

Among children with psoriasis, those who present with psoriatic arthropathy; severe, rapidly evolving, and debilitating generalized plaque; or pustular psoriasis represent a challenging subset, management of which “requires immediate response with the utilization of systemic medications that are neither well studied nor [Food and Drug Administration] approved for this indication in children,” said Dr. Cordoro of the department of dermatology at the University of California, San Francisco, who discussed such medications in a presentation at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

Targeted therapies that are aimed at specific components of the inflammatory cascade, such as anti-tumor necrosis factor agents, are widely used in adults with psoriasis and psoriatic arthritis. Although none of the three TNF antagonists that have received FDA approval for adult psoriasis (etanercept, infliximab, and adalimumab) has been approved for pediatric psoriasis, off-label use of these agents has demonstrated some promise in children with severe disease, Dr. Cordoro said in an interview.

“Etanercept has the most significant published literature, and the fact that the drug has received FDA approval for use in children for other indications [ankylosing spondylitis and psoriatic arthropathy for children aged 2 years and older, and juvenile rheumatoid arthritis in children aged 4 years and older] substantiates recommendations for its use in the pediatric psoriasis population,” she said. A recent, randomized controlled trial showed that etanercept can safely and effectively reduce disease severity in children and adolescents aged 4-17 years who have moderate to severe plaque psoriasis (N. Engl. J. Med. 2008;358:241-51).

Biologic agents have also been used in the treatment of children with generalized pustular psoriasis, a serious and rare form of the disease that can be fatal. “Systemic retinoids, cyclosporine, and methotrexate are considered standard therapy, but the use of TNF agents for this indication in children is based on several isolated cases reporting beneficial use in adults with severe forms of pustular psoriasis,” Dr. Cordoro said. “Infliximab is the most widely reported agent, but etanercept and adalimumab also have been reported as successful in children with this form of psoriasis.”

“Biologic agents represent an excellent choice for well-selected children who have contraindications to the use of phototherapy or other conventional systemic agents for severe psoriasis,” said Dr. Cordoro.

With respect to drug safety, “critical evaluation of the potential risk of the anti-TNF agents in children with psoriasis is difficult because of the small number of children treated and the short follow-up period, and enthusiasm for the efficacy, short-term safety, and ease of use of these agents in children is reasonably tempered by concerns about the risk of infection, lymphoma, demyelinating disorders, and cost,” Dr. Cordoro said. Even so, “because the known side effect profiles of traditional systemic agents used for severe psoriasis in children [including methotrexate, cyclosporine, and acitretin] are unacceptable, the documented benefits of the TNF inhibitors in children affected by severe, debilitating psoriasis create a therapeutic niche for these agents.”

Dr. Cordoro reported having no conflicts of interest with respect to her presentation. SDEF and this news organization are owned by Elsevier.

Pediatric psoriatic arthropathy requires more than combinations of topical medicines, according to Dr. Kelly M. Cordoro.

Among children with psoriasis, those who present with psoriatic arthropathy; severe, rapidly evolving, and debilitating generalized plaque; or pustular psoriasis represent a challenging subset, management of which “requires immediate response with the utilization of systemic medications that are neither well studied nor [Food and Drug Administration] approved for this indication in children,” said Dr. Cordoro of the department of dermatology at the University of California, San Francisco, who discussed such medications in a presentation at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

Targeted therapies that are aimed at specific components of the inflammatory cascade, such as anti-tumor necrosis factor agents, are widely used in adults with psoriasis and psoriatic arthritis. Although none of the three TNF antagonists that have received FDA approval for adult psoriasis (etanercept, infliximab, and adalimumab) has been approved for pediatric psoriasis, off-label use of these agents has demonstrated some promise in children with severe disease, Dr. Cordoro said in an interview.

“Etanercept has the most significant published literature, and the fact that the drug has received FDA approval for use in children for other indications [ankylosing spondylitis and psoriatic arthropathy for children aged 2 years and older, and juvenile rheumatoid arthritis in children aged 4 years and older] substantiates recommendations for its use in the pediatric psoriasis population,” she said. A recent, randomized controlled trial showed that etanercept can safely and effectively reduce disease severity in children and adolescents aged 4-17 years who have moderate to severe plaque psoriasis (N. Engl. J. Med. 2008;358:241-51).

Biologic agents have also been used in the treatment of children with generalized pustular psoriasis, a serious and rare form of the disease that can be fatal. “Systemic retinoids, cyclosporine, and methotrexate are considered standard therapy, but the use of TNF agents for this indication in children is based on several isolated cases reporting beneficial use in adults with severe forms of pustular psoriasis,” Dr. Cordoro said. “Infliximab is the most widely reported agent, but etanercept and adalimumab also have been reported as successful in children with this form of psoriasis.”

“Biologic agents represent an excellent choice for well-selected children who have contraindications to the use of phototherapy or other conventional systemic agents for severe psoriasis,” said Dr. Cordoro.

With respect to drug safety, “critical evaluation of the potential risk of the anti-TNF agents in children with psoriasis is difficult because of the small number of children treated and the short follow-up period, and enthusiasm for the efficacy, short-term safety, and ease of use of these agents in children is reasonably tempered by concerns about the risk of infection, lymphoma, demyelinating disorders, and cost,” Dr. Cordoro said. Even so, “because the known side effect profiles of traditional systemic agents used for severe psoriasis in children [including methotrexate, cyclosporine, and acitretin] are unacceptable, the documented benefits of the TNF inhibitors in children affected by severe, debilitating psoriasis create a therapeutic niche for these agents.”

Dr. Cordoro reported having no conflicts of interest with respect to her presentation. SDEF and this news organization are owned by Elsevier.

Pediatric psoriatic arthropathy requires more than combinations of topical medicines, according to Dr. Kelly M. Cordoro.

Among children with psoriasis, those who present with psoriatic arthropathy; severe, rapidly evolving, and debilitating generalized plaque; or pustular psoriasis represent a challenging subset, management of which “requires immediate response with the utilization of systemic medications that are neither well studied nor [Food and Drug Administration] approved for this indication in children,” said Dr. Cordoro of the department of dermatology at the University of California, San Francisco, who discussed such medications in a presentation at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

Targeted therapies that are aimed at specific components of the inflammatory cascade, such as anti-tumor necrosis factor agents, are widely used in adults with psoriasis and psoriatic arthritis. Although none of the three TNF antagonists that have received FDA approval for adult psoriasis (etanercept, infliximab, and adalimumab) has been approved for pediatric psoriasis, off-label use of these agents has demonstrated some promise in children with severe disease, Dr. Cordoro said in an interview.

“Etanercept has the most significant published literature, and the fact that the drug has received FDA approval for use in children for other indications [ankylosing spondylitis and psoriatic arthropathy for children aged 2 years and older, and juvenile rheumatoid arthritis in children aged 4 years and older] substantiates recommendations for its use in the pediatric psoriasis population,” she said. A recent, randomized controlled trial showed that etanercept can safely and effectively reduce disease severity in children and adolescents aged 4-17 years who have moderate to severe plaque psoriasis (N. Engl. J. Med. 2008;358:241-51).

Biologic agents have also been used in the treatment of children with generalized pustular psoriasis, a serious and rare form of the disease that can be fatal. “Systemic retinoids, cyclosporine, and methotrexate are considered standard therapy, but the use of TNF agents for this indication in children is based on several isolated cases reporting beneficial use in adults with severe forms of pustular psoriasis,” Dr. Cordoro said. “Infliximab is the most widely reported agent, but etanercept and adalimumab also have been reported as successful in children with this form of psoriasis.”

“Biologic agents represent an excellent choice for well-selected children who have contraindications to the use of phototherapy or other conventional systemic agents for severe psoriasis,” said Dr. Cordoro.

With respect to drug safety, “critical evaluation of the potential risk of the anti-TNF agents in children with psoriasis is difficult because of the small number of children treated and the short follow-up period, and enthusiasm for the efficacy, short-term safety, and ease of use of these agents in children is reasonably tempered by concerns about the risk of infection, lymphoma, demyelinating disorders, and cost,” Dr. Cordoro said. Even so, “because the known side effect profiles of traditional systemic agents used for severe psoriasis in children [including methotrexate, cyclosporine, and acitretin] are unacceptable, the documented benefits of the TNF inhibitors in children affected by severe, debilitating psoriasis create a therapeutic niche for these agents.”

Dr. Cordoro reported having no conflicts of interest with respect to her presentation. SDEF and this news organization are owned by Elsevier.