NYU Post-Graduate Medical School: Evidence-Based RA Therapy

NEW YORK – Among new medications under development for rheumatoid arthritis, oral Janus kinase inhibitors appear to be close to coming to market and have strong supportive clinical data, according to Dr. Martin Jan Bergman at a course sponsored by New York University.

Unlike most drugs for RA that affect extracellular cytokines, oral JAK inhibitors are small molecules that act to disrupt one of the intracellular signal pathways used by some cytokines to regulate immune and regulatory responses. Of this family of drugs, Pfizer’s tofacitinib primarily targets JAK3 (the JAK protein kinase that is most associated with inflammation), although it also overlaps to JAK1 and JAK2.

On Dec. 20, Pfizer announced that the Food and Drug Administration has accepted a New Drug Application for tofacitinib, formerly known as tasocitinib. About 1 month earlier, the European Medicines Agency had taken similar action, according to Pfizer.

According to Pfizer, nearly 5,000 patients with RA have undergone treatment in clinical trials of tofacitinib held at more than 350 sites in 35 countries worldwide. The data come primarily from the ORAL (Oral Rheumatoid Arthritis Phase III) trials, comprising five studies for which the data necessary for registration are complete, and one ongoing phase III trial. Two long-term, open-label extension studies are also ongoing.

During his presentation, Dr. Bergman reviewed data presented in 2001 at the annual European Congress of Rheumatology by Dr. Joel M. Kremer, head of the division of rheumatology at Albany (N.Y.) Medical College. Those data concerned the effects of tofacitinib in patients whose active RA had not responded to therapy with DMARDs (disease-modifying antirheumatic drugs). Patients received tofacitinib in doses of either 5 mg or 10 mg, in combination with background DMARDs. In this double-blind, placebo-controlled, randomized study of 792 patients, any patient in the placebo group who had not met the target efficacy response by 3 months was switched to tofacitinib 5 mg or 10 mg. All remaining placebo-treated patients were switched to tofacitinib by 6 months. At 6 months, 52.7% in those treated with tofacitinib 5 mg achieved ACR 20 (defined as 20% improvement on an American College of Rheumatology evaluation scale), as did 58.3% in those treated at the 10-mg dose, a response significantly greater than the placebo group. "Now we are starting to see levels that we see with [tumor necrosis factor] inhibitors," said Dr. Bergman of Drexel University in Philadelphia.

Dr. Kremer also found significant improvement on the DAS28-4 (ESR) – that is, the Disease Activity Score including a 28-joint count and the erythrocyte sedimentation rate – less than 2.6 for both doses of tofacitinib, as well as on the HAQ-DI (Health Assessment Questionnaire–Disability Index). "The minimally clinically important (MCI) difference for the HAQ-DI is 0.21 or 0.23; patients on tofacitinib had double the MCI improvement," noted Dr. Bergman, referring to the change of –0.46 for the 5-mg dose and –0.56 for the 10-mg dose (P less than .001, compared with placebo, for both differences). "What we see is very reassuring."

Dr. Bergman then highlighted some of data included in nine abstracts presented on tofacitinib at the 2011 annual meeting of the American College of Rheumatology. Dr. Roy M. Fleischmann of the University of Texas Southwestern Medical Center, Dallas, addressed the question of whether tofacitinib’s efficacy and safety hold up against the standard of care, such as a tumor necrosis factor (TNF) inhibitor (Arthritis Rheum. 2011;63[suppl.]:S153; abstract 408). In this 12-month trial, 717 patients were randomized to tofacitinib (5 mg or 10 mg twice daily), adalimumab (40-mg subcutaneous injections every 2 weeks), or placebo. "This was not a head-to-head trial, but rather comparability vs. placebo," commented Dr. Bergman. The results showed that tofacitinib 5 mg and 10 mg, as well as adalimumab, were statistically superior to placebo for all primary efficacy end points, and efficacy results for tofacitinib and adalimumab were numerically similar. "The ACR 20 responses (tofacitinib 5 mg, 51.5%; tofacitinib 10 mg, 52.6%; adalimumab, 47.2%) are very robust and comparable to the responses we see [with anti-TNFs] all the time," he added.

Tofacitinib also holds promise as a rescue therapy for RA patients with inadequate response to TNF inhibitors, as suggested by the results of a study by Dr. Gerd-Rüdiger Burmester of Charité Medical University Berlin (Arthritis Rheum. 2011;63[suppl.]:S279; abstract 718). In this 6-month study of 399 patients who were randomized to 5 mg or 10 mg of tofacitinib or placebo (or who were first treated with placebo and then given tofacitinib), rapid, significant and clinically meaningful improvements were noted in the signs and symptoms of RA (according to ACR 20/50/70 scores), physical functioning (per HAQ-DI scores) and disease activity (per DAS28-4 [ESR] scores less than 2.6). After looking at the ACR responses of the group that was initially given placebo and then 5-mg tofacitinib, Dr. Bergman commented that the 6-month ACR 20/50/70 responses (45.5, 28.79, and 10.6, respectively) were "identical to what we see with all of the rescue therapies currently available."

Interim results of a 24-month study regarding the effect of tofacitinib on radiographic progression were reported by Dr. Désirée van der Heijde of the department of rheumatology at Leiden (the Netherlands) University Medical Center (Arthritis Rheum. 2011;63[suppl.]:S1017-8; abstract 2592). The study included 797 patients with active RA who had a history of inadequate response to methotrexate and were on a stable dose of methotrexate. After 6 months of treatment, the mean change in the mTSS (modified Total Sharp Score) for tofacitinib 10 mg twice daily was 0.06, which was significantly lower (P less than .05) than placebo (mTSS, 0.47), indicating reduced progression of structural damage. The difference was not statistically significant for the 5-mg tofacitinib dose, in which the mTSS was 0.12.

In reviewing Dr. van der Heijde’s findings, Dr. Bergman questioned whether even a mean change of mTSS of 0.47 – on a scale of 0-400 – was clinically meaningful. At 12 months, the proportion of patients with no radiographic progression or no new erosions was greater in both tofacitinib groups, compared with placebo. "I don’t think we should make too much of these results, but I think the findings are reassuring that this oral medication has effects similar to the anti-TNFs," commented Dr. Bergman.

According to Dr. Bergman, more safety data are available for tofacitinib than for any other RA drug currently on the market, given its stage of development, especially as measured by patient-years. Two abstracts at the ACR annual meeting reported on long-term safety data, one summarizing pooled data from five randomized, double-blind, phase III studies, and two long-term, open-label extension studies (Arthritis Rheum. 2011;63[suppl.]:S153; abstract 409) and the other just from the same two long-term, open-label extension studies (Arthritis Rheum. 2011;63[suppl.]:S152-3; abstract 407). The former was an analysis by Dr. Stanley B. Cohen, a rheumatologist at the University of Texas, Dallas. It included 3,030 RA patients from the phase III trials and 3,227 from the long-term extensions, resulting in approximately 2,000 and 3,000 patient-years of exposure to tofacitinib. In the phase III studies, there were 12 deaths, with a death rate of 0.40% with tofacitinib (5 deaths caused by infections, and 2 with cardiovascular causes), and 8 deaths in the long-term extensions (3 from infections, and 1 with a cardiovascular cause), with a death rate of 0.62%; the rate for placebo was 0.15%. This rate was comparable with that reported for adalimumab (0.49%).

The rates of serious infections were 2% in the tofacitinib phase III studies, and 2.9% in the tofacitinib long-term extensions, compared with 1.5% for adalimumab. There was some indication in the long-term extension data that the higher dose was associated with more serious infections than was the lower dose. Whether tofacitinib was given as monotherapy or with background DMARDs did not change the infection rate. Opportunistic infections, including tuberculosis, were uncommon.

In the second analysis, based on data from the long-term extension studies and reported by Dr. Jürgen Wollenhaupt of the University of Hamburg (Germany), there were some adverse events to "keep an eye out for," commented Dr. Bergman. This report represented data on 3,227 patients who were treated for a total duration of 3,118 patient-years. Serious adverse events were reported in 10.5% of patients. Confirmed increases in creatinine (defined as greater than 33% from baseline) were found in 12.2% of patients. Decreased hemoglobin levels (greater than or equal to 2 g/dL or less than 8) were found in 2.5% of patients, and raised aminotransferase levels (defined as greater than three times the upper limit of normal) were found in 1.7% (alanine) and 1.1% (aspartate) of patients. A 15% persistent rise across all doses was seen in total cholesterol. Diarrhea may also be a problem for some patients.

Dr. Bergman serves as a consultant to Pfizer.

NEW YORK – Among new medications under development for rheumatoid arthritis, oral Janus kinase inhibitors appear to be close to coming to market and have strong supportive clinical data, according to Dr. Martin Jan Bergman at a course sponsored by New York University.

Unlike most drugs for RA that affect extracellular cytokines, oral JAK inhibitors are small molecules that act to disrupt one of the intracellular signal pathways used by some cytokines to regulate immune and regulatory responses. Of this family of drugs, Pfizer’s tofacitinib primarily targets JAK3 (the JAK protein kinase that is most associated with inflammation), although it also overlaps to JAK1 and JAK2.

On Dec. 20, Pfizer announced that the Food and Drug Administration has accepted a New Drug Application for tofacitinib, formerly known as tasocitinib. About 1 month earlier, the European Medicines Agency had taken similar action, according to Pfizer.

According to Pfizer, nearly 5,000 patients with RA have undergone treatment in clinical trials of tofacitinib held at more than 350 sites in 35 countries worldwide. The data come primarily from the ORAL (Oral Rheumatoid Arthritis Phase III) trials, comprising five studies for which the data necessary for registration are complete, and one ongoing phase III trial. Two long-term, open-label extension studies are also ongoing.

During his presentation, Dr. Bergman reviewed data presented in 2001 at the annual European Congress of Rheumatology by Dr. Joel M. Kremer, head of the division of rheumatology at Albany (N.Y.) Medical College. Those data concerned the effects of tofacitinib in patients whose active RA had not responded to therapy with DMARDs (disease-modifying antirheumatic drugs). Patients received tofacitinib in doses of either 5 mg or 10 mg, in combination with background DMARDs. In this double-blind, placebo-controlled, randomized study of 792 patients, any patient in the placebo group who had not met the target efficacy response by 3 months was switched to tofacitinib 5 mg or 10 mg. All remaining placebo-treated patients were switched to tofacitinib by 6 months. At 6 months, 52.7% in those treated with tofacitinib 5 mg achieved ACR 20 (defined as 20% improvement on an American College of Rheumatology evaluation scale), as did 58.3% in those treated at the 10-mg dose, a response significantly greater than the placebo group. "Now we are starting to see levels that we see with [tumor necrosis factor] inhibitors," said Dr. Bergman of Drexel University in Philadelphia.

Dr. Kremer also found significant improvement on the DAS28-4 (ESR) – that is, the Disease Activity Score including a 28-joint count and the erythrocyte sedimentation rate – less than 2.6 for both doses of tofacitinib, as well as on the HAQ-DI (Health Assessment Questionnaire–Disability Index). "The minimally clinically important (MCI) difference for the HAQ-DI is 0.21 or 0.23; patients on tofacitinib had double the MCI improvement," noted Dr. Bergman, referring to the change of –0.46 for the 5-mg dose and –0.56 for the 10-mg dose (P less than .001, compared with placebo, for both differences). "What we see is very reassuring."

Dr. Bergman then highlighted some of data included in nine abstracts presented on tofacitinib at the 2011 annual meeting of the American College of Rheumatology. Dr. Roy M. Fleischmann of the University of Texas Southwestern Medical Center, Dallas, addressed the question of whether tofacitinib’s efficacy and safety hold up against the standard of care, such as a tumor necrosis factor (TNF) inhibitor (Arthritis Rheum. 2011;63[suppl.]:S153; abstract 408). In this 12-month trial, 717 patients were randomized to tofacitinib (5 mg or 10 mg twice daily), adalimumab (40-mg subcutaneous injections every 2 weeks), or placebo. "This was not a head-to-head trial, but rather comparability vs. placebo," commented Dr. Bergman. The results showed that tofacitinib 5 mg and 10 mg, as well as adalimumab, were statistically superior to placebo for all primary efficacy end points, and efficacy results for tofacitinib and adalimumab were numerically similar. "The ACR 20 responses (tofacitinib 5 mg, 51.5%; tofacitinib 10 mg, 52.6%; adalimumab, 47.2%) are very robust and comparable to the responses we see [with anti-TNFs] all the time," he added.

Tofacitinib also holds promise as a rescue therapy for RA patients with inadequate response to TNF inhibitors, as suggested by the results of a study by Dr. Gerd-Rüdiger Burmester of Charité Medical University Berlin (Arthritis Rheum. 2011;63[suppl.]:S279; abstract 718). In this 6-month study of 399 patients who were randomized to 5 mg or 10 mg of tofacitinib or placebo (or who were first treated with placebo and then given tofacitinib), rapid, significant and clinically meaningful improvements were noted in the signs and symptoms of RA (according to ACR 20/50/70 scores), physical functioning (per HAQ-DI scores) and disease activity (per DAS28-4 [ESR] scores less than 2.6). After looking at the ACR responses of the group that was initially given placebo and then 5-mg tofacitinib, Dr. Bergman commented that the 6-month ACR 20/50/70 responses (45.5, 28.79, and 10.6, respectively) were "identical to what we see with all of the rescue therapies currently available."

Interim results of a 24-month study regarding the effect of tofacitinib on radiographic progression were reported by Dr. Désirée van der Heijde of the department of rheumatology at Leiden (the Netherlands) University Medical Center (Arthritis Rheum. 2011;63[suppl.]:S1017-8; abstract 2592). The study included 797 patients with active RA who had a history of inadequate response to methotrexate and were on a stable dose of methotrexate. After 6 months of treatment, the mean change in the mTSS (modified Total Sharp Score) for tofacitinib 10 mg twice daily was 0.06, which was significantly lower (P less than .05) than placebo (mTSS, 0.47), indicating reduced progression of structural damage. The difference was not statistically significant for the 5-mg tofacitinib dose, in which the mTSS was 0.12.

In reviewing Dr. van der Heijde’s findings, Dr. Bergman questioned whether even a mean change of mTSS of 0.47 – on a scale of 0-400 – was clinically meaningful. At 12 months, the proportion of patients with no radiographic progression or no new erosions was greater in both tofacitinib groups, compared with placebo. "I don’t think we should make too much of these results, but I think the findings are reassuring that this oral medication has effects similar to the anti-TNFs," commented Dr. Bergman.

According to Dr. Bergman, more safety data are available for tofacitinib than for any other RA drug currently on the market, given its stage of development, especially as measured by patient-years. Two abstracts at the ACR annual meeting reported on long-term safety data, one summarizing pooled data from five randomized, double-blind, phase III studies, and two long-term, open-label extension studies (Arthritis Rheum. 2011;63[suppl.]:S153; abstract 409) and the other just from the same two long-term, open-label extension studies (Arthritis Rheum. 2011;63[suppl.]:S152-3; abstract 407). The former was an analysis by Dr. Stanley B. Cohen, a rheumatologist at the University of Texas, Dallas. It included 3,030 RA patients from the phase III trials and 3,227 from the long-term extensions, resulting in approximately 2,000 and 3,000 patient-years of exposure to tofacitinib. In the phase III studies, there were 12 deaths, with a death rate of 0.40% with tofacitinib (5 deaths caused by infections, and 2 with cardiovascular causes), and 8 deaths in the long-term extensions (3 from infections, and 1 with a cardiovascular cause), with a death rate of 0.62%; the rate for placebo was 0.15%. This rate was comparable with that reported for adalimumab (0.49%).

The rates of serious infections were 2% in the tofacitinib phase III studies, and 2.9% in the tofacitinib long-term extensions, compared with 1.5% for adalimumab. There was some indication in the long-term extension data that the higher dose was associated with more serious infections than was the lower dose. Whether tofacitinib was given as monotherapy or with background DMARDs did not change the infection rate. Opportunistic infections, including tuberculosis, were uncommon.

In the second analysis, based on data from the long-term extension studies and reported by Dr. Jürgen Wollenhaupt of the University of Hamburg (Germany), there were some adverse events to "keep an eye out for," commented Dr. Bergman. This report represented data on 3,227 patients who were treated for a total duration of 3,118 patient-years. Serious adverse events were reported in 10.5% of patients. Confirmed increases in creatinine (defined as greater than 33% from baseline) were found in 12.2% of patients. Decreased hemoglobin levels (greater than or equal to 2 g/dL or less than 8) were found in 2.5% of patients, and raised aminotransferase levels (defined as greater than three times the upper limit of normal) were found in 1.7% (alanine) and 1.1% (aspartate) of patients. A 15% persistent rise across all doses was seen in total cholesterol. Diarrhea may also be a problem for some patients.

Dr. Bergman serves as a consultant to Pfizer.

NEW YORK – Among new medications under development for rheumatoid arthritis, oral Janus kinase inhibitors appear to be close to coming to market and have strong supportive clinical data, according to Dr. Martin Jan Bergman at a course sponsored by New York University.

Unlike most drugs for RA that affect extracellular cytokines, oral JAK inhibitors are small molecules that act to disrupt one of the intracellular signal pathways used by some cytokines to regulate immune and regulatory responses. Of this family of drugs, Pfizer’s tofacitinib primarily targets JAK3 (the JAK protein kinase that is most associated with inflammation), although it also overlaps to JAK1 and JAK2.

On Dec. 20, Pfizer announced that the Food and Drug Administration has accepted a New Drug Application for tofacitinib, formerly known as tasocitinib. About 1 month earlier, the European Medicines Agency had taken similar action, according to Pfizer.

According to Pfizer, nearly 5,000 patients with RA have undergone treatment in clinical trials of tofacitinib held at more than 350 sites in 35 countries worldwide. The data come primarily from the ORAL (Oral Rheumatoid Arthritis Phase III) trials, comprising five studies for which the data necessary for registration are complete, and one ongoing phase III trial. Two long-term, open-label extension studies are also ongoing.

During his presentation, Dr. Bergman reviewed data presented in 2001 at the annual European Congress of Rheumatology by Dr. Joel M. Kremer, head of the division of rheumatology at Albany (N.Y.) Medical College. Those data concerned the effects of tofacitinib in patients whose active RA had not responded to therapy with DMARDs (disease-modifying antirheumatic drugs). Patients received tofacitinib in doses of either 5 mg or 10 mg, in combination with background DMARDs. In this double-blind, placebo-controlled, randomized study of 792 patients, any patient in the placebo group who had not met the target efficacy response by 3 months was switched to tofacitinib 5 mg or 10 mg. All remaining placebo-treated patients were switched to tofacitinib by 6 months. At 6 months, 52.7% in those treated with tofacitinib 5 mg achieved ACR 20 (defined as 20% improvement on an American College of Rheumatology evaluation scale), as did 58.3% in those treated at the 10-mg dose, a response significantly greater than the placebo group. "Now we are starting to see levels that we see with [tumor necrosis factor] inhibitors," said Dr. Bergman of Drexel University in Philadelphia.

Dr. Kremer also found significant improvement on the DAS28-4 (ESR) – that is, the Disease Activity Score including a 28-joint count and the erythrocyte sedimentation rate – less than 2.6 for both doses of tofacitinib, as well as on the HAQ-DI (Health Assessment Questionnaire–Disability Index). "The minimally clinically important (MCI) difference for the HAQ-DI is 0.21 or 0.23; patients on tofacitinib had double the MCI improvement," noted Dr. Bergman, referring to the change of –0.46 for the 5-mg dose and –0.56 for the 10-mg dose (P less than .001, compared with placebo, for both differences). "What we see is very reassuring."

Dr. Bergman then highlighted some of data included in nine abstracts presented on tofacitinib at the 2011 annual meeting of the American College of Rheumatology. Dr. Roy M. Fleischmann of the University of Texas Southwestern Medical Center, Dallas, addressed the question of whether tofacitinib’s efficacy and safety hold up against the standard of care, such as a tumor necrosis factor (TNF) inhibitor (Arthritis Rheum. 2011;63[suppl.]:S153; abstract 408). In this 12-month trial, 717 patients were randomized to tofacitinib (5 mg or 10 mg twice daily), adalimumab (40-mg subcutaneous injections every 2 weeks), or placebo. "This was not a head-to-head trial, but rather comparability vs. placebo," commented Dr. Bergman. The results showed that tofacitinib 5 mg and 10 mg, as well as adalimumab, were statistically superior to placebo for all primary efficacy end points, and efficacy results for tofacitinib and adalimumab were numerically similar. "The ACR 20 responses (tofacitinib 5 mg, 51.5%; tofacitinib 10 mg, 52.6%; adalimumab, 47.2%) are very robust and comparable to the responses we see [with anti-TNFs] all the time," he added.

Tofacitinib also holds promise as a rescue therapy for RA patients with inadequate response to TNF inhibitors, as suggested by the results of a study by Dr. Gerd-Rüdiger Burmester of Charité Medical University Berlin (Arthritis Rheum. 2011;63[suppl.]:S279; abstract 718). In this 6-month study of 399 patients who were randomized to 5 mg or 10 mg of tofacitinib or placebo (or who were first treated with placebo and then given tofacitinib), rapid, significant and clinically meaningful improvements were noted in the signs and symptoms of RA (according to ACR 20/50/70 scores), physical functioning (per HAQ-DI scores) and disease activity (per DAS28-4 [ESR] scores less than 2.6). After looking at the ACR responses of the group that was initially given placebo and then 5-mg tofacitinib, Dr. Bergman commented that the 6-month ACR 20/50/70 responses (45.5, 28.79, and 10.6, respectively) were "identical to what we see with all of the rescue therapies currently available."

Interim results of a 24-month study regarding the effect of tofacitinib on radiographic progression were reported by Dr. Désirée van der Heijde of the department of rheumatology at Leiden (the Netherlands) University Medical Center (Arthritis Rheum. 2011;63[suppl.]:S1017-8; abstract 2592). The study included 797 patients with active RA who had a history of inadequate response to methotrexate and were on a stable dose of methotrexate. After 6 months of treatment, the mean change in the mTSS (modified Total Sharp Score) for tofacitinib 10 mg twice daily was 0.06, which was significantly lower (P less than .05) than placebo (mTSS, 0.47), indicating reduced progression of structural damage. The difference was not statistically significant for the 5-mg tofacitinib dose, in which the mTSS was 0.12.

In reviewing Dr. van der Heijde’s findings, Dr. Bergman questioned whether even a mean change of mTSS of 0.47 – on a scale of 0-400 – was clinically meaningful. At 12 months, the proportion of patients with no radiographic progression or no new erosions was greater in both tofacitinib groups, compared with placebo. "I don’t think we should make too much of these results, but I think the findings are reassuring that this oral medication has effects similar to the anti-TNFs," commented Dr. Bergman.

According to Dr. Bergman, more safety data are available for tofacitinib than for any other RA drug currently on the market, given its stage of development, especially as measured by patient-years. Two abstracts at the ACR annual meeting reported on long-term safety data, one summarizing pooled data from five randomized, double-blind, phase III studies, and two long-term, open-label extension studies (Arthritis Rheum. 2011;63[suppl.]:S153; abstract 409) and the other just from the same two long-term, open-label extension studies (Arthritis Rheum. 2011;63[suppl.]:S152-3; abstract 407). The former was an analysis by Dr. Stanley B. Cohen, a rheumatologist at the University of Texas, Dallas. It included 3,030 RA patients from the phase III trials and 3,227 from the long-term extensions, resulting in approximately 2,000 and 3,000 patient-years of exposure to tofacitinib. In the phase III studies, there were 12 deaths, with a death rate of 0.40% with tofacitinib (5 deaths caused by infections, and 2 with cardiovascular causes), and 8 deaths in the long-term extensions (3 from infections, and 1 with a cardiovascular cause), with a death rate of 0.62%; the rate for placebo was 0.15%. This rate was comparable with that reported for adalimumab (0.49%).

The rates of serious infections were 2% in the tofacitinib phase III studies, and 2.9% in the tofacitinib long-term extensions, compared with 1.5% for adalimumab. There was some indication in the long-term extension data that the higher dose was associated with more serious infections than was the lower dose. Whether tofacitinib was given as monotherapy or with background DMARDs did not change the infection rate. Opportunistic infections, including tuberculosis, were uncommon.

In the second analysis, based on data from the long-term extension studies and reported by Dr. Jürgen Wollenhaupt of the University of Hamburg (Germany), there were some adverse events to "keep an eye out for," commented Dr. Bergman. This report represented data on 3,227 patients who were treated for a total duration of 3,118 patient-years. Serious adverse events were reported in 10.5% of patients. Confirmed increases in creatinine (defined as greater than 33% from baseline) were found in 12.2% of patients. Decreased hemoglobin levels (greater than or equal to 2 g/dL or less than 8) were found in 2.5% of patients, and raised aminotransferase levels (defined as greater than three times the upper limit of normal) were found in 1.7% (alanine) and 1.1% (aspartate) of patients. A 15% persistent rise across all doses was seen in total cholesterol. Diarrhea may also be a problem for some patients.

Dr. Bergman serves as a consultant to Pfizer.

NEW YORK – Tocilizumab monotherapy is a viable alternative treatment for patients with moderate to severe rheumatoid arthritis who have not responded to methotrexate in use with the biologic, according to Dr. Yusuf Yazici, speaking at a meeting sponsored by New York University.

"One paradigm of RA treatment is that a biologic alone is equivalent to methotrexate alone, but that the combination is better. These data suggest that tocilizumab may possibly be used alone," said Dr. Yazici, director of the Seligman Center for Advanced Therapeutics and Behçet’s Syndrome Evaluation, Treatment, and Research Center at the NYU Hospital for Joint Diseases.

Data from the ACT-RAY trial, which was presented by Dr. Maxime Dougados, professor of rheumatology at René Descartes University, Cochin Hospital, Paris, at the 2011 annual meeting of the American College of Rheumatology, showed that the DAS28 remission rate was 35% for tocilizumab plus placebo, compared with 40% for tocilizumab plus methotrexate, a difference that was not statistically significant (P = .19; 95% confidence interval, 2.4%-13.7%).

There were also no significant differences among ACR 20/50/70/90 response rates between groups. For both groups, the onset of action was comparable, with 18.1% of the combination group and 15.2% of the tocilizumab monotherapy group achieving remission by week 8.

The ACT-RAY trial is a phase IIIb double-blind 2-year study of biologic-naive adults with moderate to severe active RA who were considered to be inadequate responders to methotrexate. Of the 556 patients enrolled, 279 were randomized to tocilizumab (8 mg/kg every 4 weeks) plus a stable dose of methotrexate and 277 received the same dose of tocilizumab plus placebo for 24 weeks. Radiographs taken of the hands and feet at baseline and 24 weeks were assessed for structural changes.

Secondary outcomes, such as progression of structural damage as measured by the Genant-modified Sharp score (GSS) and joint space narrowing score, also showed no significant differences between treatment groups. On several measures, including total GSS scores, the proportion of patients with no progression of structural damage was similar (for example, 65.3% for the combination treatment vs. 58.7% for tocilizumab monotherapy). Improvements from baseline on the Health-Assessment Questionnaire Disability Index and rheumatoid arthritis quality of life score were comparable.

As far as safety, rates of adverse events, serious adverse events, and serious infections per 100 patient-years were indistinguishable.

"There are other pieces of information pointing in the same direction, where for most of the outcome measures there was no difference between the groups; however, some favored the combination arm. None of the studies by themselves prove that monotherapy is as good as combination treatment, but the data provide information that tocilizumab monotherapy is a good option for some patients," said Dr Yazici.

"It would be good to do a study that looks at truly methotrexate-naive patients with early disease and see how tocilizumab monotherapy compares to methotrexate alone and a combination of tocilizumab with methotrexate.

"While the AMBITION study (Ann. Rheum. Dis. 2010;69:88-96) reported that tocilizumab monotherapy was better than methotrexate alone, one-third of patients had been on methotrexate before the trial but discontinued treatment. Those patients are not going to have as robust a response with methotrexate as those who are truly methotrexate naive."

Dr. Yazici also spoke about the results of the ACT-STAR study, a prospective, 24-week open label trial, which were presented at the 2011 annual meeting of the American College of Rheumatology by Dr. Michael E. Weinblatt, codirector of clinical rheumatology at the Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, Boston.

In this trial, the enrolled patients were inadequate responders to anti-tumor necrosis factor (anti-TNF) therapy. No significant differences were found on the ACR 20/50/70 among those treated with tocilizumab monotherapy (8 mg/kg, n = 129) and those who received a combination of tocilizumab plus a DMARD (those in the combination group received either tocilizumab 8 mg/kg throughout the trial (n = 221) while others began with a 4 mg/kg dose which then was raised to 8 mg/kg (n = 322)).

While the study concluded that tocilizumab monotherapy was similar to combination therapy, Dr. Yazici commented that the randomization process used was inadequate as this was an open label trial and the data needs to be interpreted with this in mind. He said, "However, all these studies suggest that there may be a role for tocilizumab monotherapy in patients who have had an inadequate response to methotrexate in the past."

Tocilizumab, a biologic that targets interleukin-6 receptors, was approved in the United States in January 2010 for the treatment of adults with moderate to severe, active RA who have had an inadequate response to one or more TNF inhibitors. Tocilizumab monotherapy could be particularly beneficial for those with RA who respond poorly to methotrexate or experience adverse effects from it.

Dr. Yazici serves as a consultant to Bristol-Myers Squibb and Genentech.

NEW YORK – Tocilizumab monotherapy is a viable alternative treatment for patients with moderate to severe rheumatoid arthritis who have not responded to methotrexate in use with the biologic, according to Dr. Yusuf Yazici, speaking at a meeting sponsored by New York University.

"One paradigm of RA treatment is that a biologic alone is equivalent to methotrexate alone, but that the combination is better. These data suggest that tocilizumab may possibly be used alone," said Dr. Yazici, director of the Seligman Center for Advanced Therapeutics and Behçet’s Syndrome Evaluation, Treatment, and Research Center at the NYU Hospital for Joint Diseases.

Data from the ACT-RAY trial, which was presented by Dr. Maxime Dougados, professor of rheumatology at René Descartes University, Cochin Hospital, Paris, at the 2011 annual meeting of the American College of Rheumatology, showed that the DAS28 remission rate was 35% for tocilizumab plus placebo, compared with 40% for tocilizumab plus methotrexate, a difference that was not statistically significant (P = .19; 95% confidence interval, 2.4%-13.7%).

There were also no significant differences among ACR 20/50/70/90 response rates between groups. For both groups, the onset of action was comparable, with 18.1% of the combination group and 15.2% of the tocilizumab monotherapy group achieving remission by week 8.

The ACT-RAY trial is a phase IIIb double-blind 2-year study of biologic-naive adults with moderate to severe active RA who were considered to be inadequate responders to methotrexate. Of the 556 patients enrolled, 279 were randomized to tocilizumab (8 mg/kg every 4 weeks) plus a stable dose of methotrexate and 277 received the same dose of tocilizumab plus placebo for 24 weeks. Radiographs taken of the hands and feet at baseline and 24 weeks were assessed for structural changes.

Secondary outcomes, such as progression of structural damage as measured by the Genant-modified Sharp score (GSS) and joint space narrowing score, also showed no significant differences between treatment groups. On several measures, including total GSS scores, the proportion of patients with no progression of structural damage was similar (for example, 65.3% for the combination treatment vs. 58.7% for tocilizumab monotherapy). Improvements from baseline on the Health-Assessment Questionnaire Disability Index and rheumatoid arthritis quality of life score were comparable.

As far as safety, rates of adverse events, serious adverse events, and serious infections per 100 patient-years were indistinguishable.

"There are other pieces of information pointing in the same direction, where for most of the outcome measures there was no difference between the groups; however, some favored the combination arm. None of the studies by themselves prove that monotherapy is as good as combination treatment, but the data provide information that tocilizumab monotherapy is a good option for some patients," said Dr Yazici.

"It would be good to do a study that looks at truly methotrexate-naive patients with early disease and see how tocilizumab monotherapy compares to methotrexate alone and a combination of tocilizumab with methotrexate.

"While the AMBITION study (Ann. Rheum. Dis. 2010;69:88-96) reported that tocilizumab monotherapy was better than methotrexate alone, one-third of patients had been on methotrexate before the trial but discontinued treatment. Those patients are not going to have as robust a response with methotrexate as those who are truly methotrexate naive."

Dr. Yazici also spoke about the results of the ACT-STAR study, a prospective, 24-week open label trial, which were presented at the 2011 annual meeting of the American College of Rheumatology by Dr. Michael E. Weinblatt, codirector of clinical rheumatology at the Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, Boston.

In this trial, the enrolled patients were inadequate responders to anti-tumor necrosis factor (anti-TNF) therapy. No significant differences were found on the ACR 20/50/70 among those treated with tocilizumab monotherapy (8 mg/kg, n = 129) and those who received a combination of tocilizumab plus a DMARD (those in the combination group received either tocilizumab 8 mg/kg throughout the trial (n = 221) while others began with a 4 mg/kg dose which then was raised to 8 mg/kg (n = 322)).

While the study concluded that tocilizumab monotherapy was similar to combination therapy, Dr. Yazici commented that the randomization process used was inadequate as this was an open label trial and the data needs to be interpreted with this in mind. He said, "However, all these studies suggest that there may be a role for tocilizumab monotherapy in patients who have had an inadequate response to methotrexate in the past."

Tocilizumab, a biologic that targets interleukin-6 receptors, was approved in the United States in January 2010 for the treatment of adults with moderate to severe, active RA who have had an inadequate response to one or more TNF inhibitors. Tocilizumab monotherapy could be particularly beneficial for those with RA who respond poorly to methotrexate or experience adverse effects from it.

Dr. Yazici serves as a consultant to Bristol-Myers Squibb and Genentech.

NEW YORK – Tocilizumab monotherapy is a viable alternative treatment for patients with moderate to severe rheumatoid arthritis who have not responded to methotrexate in use with the biologic, according to Dr. Yusuf Yazici, speaking at a meeting sponsored by New York University.

"One paradigm of RA treatment is that a biologic alone is equivalent to methotrexate alone, but that the combination is better. These data suggest that tocilizumab may possibly be used alone," said Dr. Yazici, director of the Seligman Center for Advanced Therapeutics and Behçet’s Syndrome Evaluation, Treatment, and Research Center at the NYU Hospital for Joint Diseases.

Data from the ACT-RAY trial, which was presented by Dr. Maxime Dougados, professor of rheumatology at René Descartes University, Cochin Hospital, Paris, at the 2011 annual meeting of the American College of Rheumatology, showed that the DAS28 remission rate was 35% for tocilizumab plus placebo, compared with 40% for tocilizumab plus methotrexate, a difference that was not statistically significant (P = .19; 95% confidence interval, 2.4%-13.7%).

There were also no significant differences among ACR 20/50/70/90 response rates between groups. For both groups, the onset of action was comparable, with 18.1% of the combination group and 15.2% of the tocilizumab monotherapy group achieving remission by week 8.

The ACT-RAY trial is a phase IIIb double-blind 2-year study of biologic-naive adults with moderate to severe active RA who were considered to be inadequate responders to methotrexate. Of the 556 patients enrolled, 279 were randomized to tocilizumab (8 mg/kg every 4 weeks) plus a stable dose of methotrexate and 277 received the same dose of tocilizumab plus placebo for 24 weeks. Radiographs taken of the hands and feet at baseline and 24 weeks were assessed for structural changes.

Secondary outcomes, such as progression of structural damage as measured by the Genant-modified Sharp score (GSS) and joint space narrowing score, also showed no significant differences between treatment groups. On several measures, including total GSS scores, the proportion of patients with no progression of structural damage was similar (for example, 65.3% for the combination treatment vs. 58.7% for tocilizumab monotherapy). Improvements from baseline on the Health-Assessment Questionnaire Disability Index and rheumatoid arthritis quality of life score were comparable.

As far as safety, rates of adverse events, serious adverse events, and serious infections per 100 patient-years were indistinguishable.

"There are other pieces of information pointing in the same direction, where for most of the outcome measures there was no difference between the groups; however, some favored the combination arm. None of the studies by themselves prove that monotherapy is as good as combination treatment, but the data provide information that tocilizumab monotherapy is a good option for some patients," said Dr Yazici.

"It would be good to do a study that looks at truly methotrexate-naive patients with early disease and see how tocilizumab monotherapy compares to methotrexate alone and a combination of tocilizumab with methotrexate.

"While the AMBITION study (Ann. Rheum. Dis. 2010;69:88-96) reported that tocilizumab monotherapy was better than methotrexate alone, one-third of patients had been on methotrexate before the trial but discontinued treatment. Those patients are not going to have as robust a response with methotrexate as those who are truly methotrexate naive."

Dr. Yazici also spoke about the results of the ACT-STAR study, a prospective, 24-week open label trial, which were presented at the 2011 annual meeting of the American College of Rheumatology by Dr. Michael E. Weinblatt, codirector of clinical rheumatology at the Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, Boston.

In this trial, the enrolled patients were inadequate responders to anti-tumor necrosis factor (anti-TNF) therapy. No significant differences were found on the ACR 20/50/70 among those treated with tocilizumab monotherapy (8 mg/kg, n = 129) and those who received a combination of tocilizumab plus a DMARD (those in the combination group received either tocilizumab 8 mg/kg throughout the trial (n = 221) while others began with a 4 mg/kg dose which then was raised to 8 mg/kg (n = 322)).

While the study concluded that tocilizumab monotherapy was similar to combination therapy, Dr. Yazici commented that the randomization process used was inadequate as this was an open label trial and the data needs to be interpreted with this in mind. He said, "However, all these studies suggest that there may be a role for tocilizumab monotherapy in patients who have had an inadequate response to methotrexate in the past."

Tocilizumab, a biologic that targets interleukin-6 receptors, was approved in the United States in January 2010 for the treatment of adults with moderate to severe, active RA who have had an inadequate response to one or more TNF inhibitors. Tocilizumab monotherapy could be particularly beneficial for those with RA who respond poorly to methotrexate or experience adverse effects from it.

Dr. Yazici serves as a consultant to Bristol-Myers Squibb and Genentech.

NEW YORK – Recent data indicate that the subcutaneous formulation of abatacept is comparable in safety to the intravenous formulation in the management of rheumatoid arthritis, according to Dr. Yusuf Yazici, who spoke at "The ‘Tightrope’ of RA Therapy" course sponsored by New York University.

"For the first time, we have a biologic that is available in both infusible and injectable versions, giving patients an option of using one or the other," said Dr. Yazici, director of the Seligman Center for Advanced Therapeutics at New York University.

The subcutaneous formulation of abatacept became commercially available in September 2011.

Safety data were presented as part of the phase IIIb, double-blind, 6-month ACQUIRE (Abatacept Comparison of Sub(Qu)cutaneous vs. Intravenous in Inadequate Responders to Methotrexate) registration trial of subcutaneous abatacept. That study, however, included fewer than 700 patients with rheumatoid arthritis (RA) in both the subcutaneous and intravenous arms (Arthritis Rheum. 2011;63:2854-64). Injection site reactions, including hematoma, pruritus, and erythema, were found in 2.6% of the subcutaneous group and 2.5% of the intravenous group. Serious infections were reported in 0.7% of the subcutaneous group and 1.4% of the intravenous group, said Dr. Yazici, who also is with the Behcet’s Syndrome Evaluation, Treatment, and Research Center at New York University.

A study presented at the 2011 EULAR (European League Against Rheumatism) annual congress by Dr. Rieke Alten, of the University of Medicine in Berlin, provided data on the long-term safety of subcutaneous abatacept. The study included pooled safety data from five clinical trials on 1,879 RA patients who had up to 4.5 years of exposure, representing 3,086 patient-years of use. The subcutaneous formulation was found to produce effects generally consistent with those of the intravenous formulation. Mean duration of exposure was 20 months in the subcutaneous group, compared with 36 months for the intravenous group. Data on the safety of the intravenous formulation came from an integrated safety analysis from the abatacept RA clinical trial program, which included 4,149 patients with 12,132 patient-years of exposure. These data were presented at the 2010 annual meeting of the American College of Rheumatology.

Dr. Alten found the incidence rate for death to be 0.55 events/100 patient-years in the subcutaneous group, compared with 0.60 in the intravenous group. The incidence rate for serious adverse events was 9.53 in the subcutaneous group vs. 14.61 in the intravenous group, and did not increase with increasing abatacept exposure over time. The incidence of injection site reactions in the subcutaneous group was 2.22, and more than 95% of reactions were mild.

As far as serious infections, the incidence rates of the most common ones after subcutaneous injections were 0.36 for pneumonia (vs. 0.46 in the intravenous group), 0.10 for lobar pneumonia (vs. 0.11), 0.10 for herpes zoster (vs. 0.03), and 0.03 (vs. 0.03) for tuberculosis. The incidence rates for malignancies, excluding nonmelanoma skin cancer, were 0.68 in patients receiving subcutaneous abatacept and 0.73 in the intravenous group. The incidence rates for autoimmune events, including psoriasis and Sjögren’s syndrome, were 1.28 with subcutaneous administration and 1.99 with intravenous use.

Unlike the intravenous formulation, subcutaneous abatacept can be self-administered, allowing patients to forego trips to the physician’s office for infusions – a benefit for those who have busy schedules or transportation limitations. Diabetics may prefer the subcutaneous formulation because it does not contain maltose, which can interfere with the accuracy of blood sugar readings. On the other hand, some patients may be anxious about self-injection or unwilling to take the time to secure their own supplies (such as bandages, alcohol swabs, cotton balls, and puncture-resistant containers for syringes) or prepare the syringes, which must be kept cool before use and then warmed before injection; they may prefer the monthly infusions given at the doctor’s office.

The label’s product information for abatacept recommends a single intravenous infusion as a loading dose (based on body weight) preceding the first 125-mg subcutaneous injection. Dr. Yazici reviewed recent data that challenged that recommendation. These findings come from a study by Dr. Peter T. Nash of the University of Queensland, Brisbane, that were presented at the 2011 EULAR congress. The study involved a comparison of open-label data from two phase III trials that showed comparable improvements with subcutaneous abatacept, with or without an intravenous loading dose, on physical function, as assessed by the Health Assessment Questionnaire–Disease Index, and disease activity, as assessed by the Disease Activity Score 28/C-reactive protein.

Dr. Yazici serves as a consultant to Bristol-Myers Squibb and Genentech. Dr. Alten receives grant or research support from, is a consultant for, or is on the speakers bureau of Abbott Laboratories, Bristol-Myers Squibb, Horizon Pharma, Merck Pharma GmbH, Nitec Pharma GmbH, Norvartis Pharmaceuticals, Roche, and Wyeth Pharmaceuticals.

NEW YORK – Recent data indicate that the subcutaneous formulation of abatacept is comparable in safety to the intravenous formulation in the management of rheumatoid arthritis, according to Dr. Yusuf Yazici, who spoke at "The ‘Tightrope’ of RA Therapy" course sponsored by New York University.

"For the first time, we have a biologic that is available in both infusible and injectable versions, giving patients an option of using one or the other," said Dr. Yazici, director of the Seligman Center for Advanced Therapeutics at New York University.

The subcutaneous formulation of abatacept became commercially available in September 2011.

Safety data were presented as part of the phase IIIb, double-blind, 6-month ACQUIRE (Abatacept Comparison of Sub(Qu)cutaneous vs. Intravenous in Inadequate Responders to Methotrexate) registration trial of subcutaneous abatacept. That study, however, included fewer than 700 patients with rheumatoid arthritis (RA) in both the subcutaneous and intravenous arms (Arthritis Rheum. 2011;63:2854-64). Injection site reactions, including hematoma, pruritus, and erythema, were found in 2.6% of the subcutaneous group and 2.5% of the intravenous group. Serious infections were reported in 0.7% of the subcutaneous group and 1.4% of the intravenous group, said Dr. Yazici, who also is with the Behcet’s Syndrome Evaluation, Treatment, and Research Center at New York University.

A study presented at the 2011 EULAR (European League Against Rheumatism) annual congress by Dr. Rieke Alten, of the University of Medicine in Berlin, provided data on the long-term safety of subcutaneous abatacept. The study included pooled safety data from five clinical trials on 1,879 RA patients who had up to 4.5 years of exposure, representing 3,086 patient-years of use. The subcutaneous formulation was found to produce effects generally consistent with those of the intravenous formulation. Mean duration of exposure was 20 months in the subcutaneous group, compared with 36 months for the intravenous group. Data on the safety of the intravenous formulation came from an integrated safety analysis from the abatacept RA clinical trial program, which included 4,149 patients with 12,132 patient-years of exposure. These data were presented at the 2010 annual meeting of the American College of Rheumatology.

Dr. Alten found the incidence rate for death to be 0.55 events/100 patient-years in the subcutaneous group, compared with 0.60 in the intravenous group. The incidence rate for serious adverse events was 9.53 in the subcutaneous group vs. 14.61 in the intravenous group, and did not increase with increasing abatacept exposure over time. The incidence of injection site reactions in the subcutaneous group was 2.22, and more than 95% of reactions were mild.

As far as serious infections, the incidence rates of the most common ones after subcutaneous injections were 0.36 for pneumonia (vs. 0.46 in the intravenous group), 0.10 for lobar pneumonia (vs. 0.11), 0.10 for herpes zoster (vs. 0.03), and 0.03 (vs. 0.03) for tuberculosis. The incidence rates for malignancies, excluding nonmelanoma skin cancer, were 0.68 in patients receiving subcutaneous abatacept and 0.73 in the intravenous group. The incidence rates for autoimmune events, including psoriasis and Sjögren’s syndrome, were 1.28 with subcutaneous administration and 1.99 with intravenous use.

Unlike the intravenous formulation, subcutaneous abatacept can be self-administered, allowing patients to forego trips to the physician’s office for infusions – a benefit for those who have busy schedules or transportation limitations. Diabetics may prefer the subcutaneous formulation because it does not contain maltose, which can interfere with the accuracy of blood sugar readings. On the other hand, some patients may be anxious about self-injection or unwilling to take the time to secure their own supplies (such as bandages, alcohol swabs, cotton balls, and puncture-resistant containers for syringes) or prepare the syringes, which must be kept cool before use and then warmed before injection; they may prefer the monthly infusions given at the doctor’s office.

The label’s product information for abatacept recommends a single intravenous infusion as a loading dose (based on body weight) preceding the first 125-mg subcutaneous injection. Dr. Yazici reviewed recent data that challenged that recommendation. These findings come from a study by Dr. Peter T. Nash of the University of Queensland, Brisbane, that were presented at the 2011 EULAR congress. The study involved a comparison of open-label data from two phase III trials that showed comparable improvements with subcutaneous abatacept, with or without an intravenous loading dose, on physical function, as assessed by the Health Assessment Questionnaire–Disease Index, and disease activity, as assessed by the Disease Activity Score 28/C-reactive protein.

Dr. Yazici serves as a consultant to Bristol-Myers Squibb and Genentech. Dr. Alten receives grant or research support from, is a consultant for, or is on the speakers bureau of Abbott Laboratories, Bristol-Myers Squibb, Horizon Pharma, Merck Pharma GmbH, Nitec Pharma GmbH, Norvartis Pharmaceuticals, Roche, and Wyeth Pharmaceuticals.

NEW YORK – Recent data indicate that the subcutaneous formulation of abatacept is comparable in safety to the intravenous formulation in the management of rheumatoid arthritis, according to Dr. Yusuf Yazici, who spoke at "The ‘Tightrope’ of RA Therapy" course sponsored by New York University.

"For the first time, we have a biologic that is available in both infusible and injectable versions, giving patients an option of using one or the other," said Dr. Yazici, director of the Seligman Center for Advanced Therapeutics at New York University.

The subcutaneous formulation of abatacept became commercially available in September 2011.

Safety data were presented as part of the phase IIIb, double-blind, 6-month ACQUIRE (Abatacept Comparison of Sub(Qu)cutaneous vs. Intravenous in Inadequate Responders to Methotrexate) registration trial of subcutaneous abatacept. That study, however, included fewer than 700 patients with rheumatoid arthritis (RA) in both the subcutaneous and intravenous arms (Arthritis Rheum. 2011;63:2854-64). Injection site reactions, including hematoma, pruritus, and erythema, were found in 2.6% of the subcutaneous group and 2.5% of the intravenous group. Serious infections were reported in 0.7% of the subcutaneous group and 1.4% of the intravenous group, said Dr. Yazici, who also is with the Behcet’s Syndrome Evaluation, Treatment, and Research Center at New York University.

A study presented at the 2011 EULAR (European League Against Rheumatism) annual congress by Dr. Rieke Alten, of the University of Medicine in Berlin, provided data on the long-term safety of subcutaneous abatacept. The study included pooled safety data from five clinical trials on 1,879 RA patients who had up to 4.5 years of exposure, representing 3,086 patient-years of use. The subcutaneous formulation was found to produce effects generally consistent with those of the intravenous formulation. Mean duration of exposure was 20 months in the subcutaneous group, compared with 36 months for the intravenous group. Data on the safety of the intravenous formulation came from an integrated safety analysis from the abatacept RA clinical trial program, which included 4,149 patients with 12,132 patient-years of exposure. These data were presented at the 2010 annual meeting of the American College of Rheumatology.

Dr. Alten found the incidence rate for death to be 0.55 events/100 patient-years in the subcutaneous group, compared with 0.60 in the intravenous group. The incidence rate for serious adverse events was 9.53 in the subcutaneous group vs. 14.61 in the intravenous group, and did not increase with increasing abatacept exposure over time. The incidence of injection site reactions in the subcutaneous group was 2.22, and more than 95% of reactions were mild.

As far as serious infections, the incidence rates of the most common ones after subcutaneous injections were 0.36 for pneumonia (vs. 0.46 in the intravenous group), 0.10 for lobar pneumonia (vs. 0.11), 0.10 for herpes zoster (vs. 0.03), and 0.03 (vs. 0.03) for tuberculosis. The incidence rates for malignancies, excluding nonmelanoma skin cancer, were 0.68 in patients receiving subcutaneous abatacept and 0.73 in the intravenous group. The incidence rates for autoimmune events, including psoriasis and Sjögren’s syndrome, were 1.28 with subcutaneous administration and 1.99 with intravenous use.

Unlike the intravenous formulation, subcutaneous abatacept can be self-administered, allowing patients to forego trips to the physician’s office for infusions – a benefit for those who have busy schedules or transportation limitations. Diabetics may prefer the subcutaneous formulation because it does not contain maltose, which can interfere with the accuracy of blood sugar readings. On the other hand, some patients may be anxious about self-injection or unwilling to take the time to secure their own supplies (such as bandages, alcohol swabs, cotton balls, and puncture-resistant containers for syringes) or prepare the syringes, which must be kept cool before use and then warmed before injection; they may prefer the monthly infusions given at the doctor’s office.

The label’s product information for abatacept recommends a single intravenous infusion as a loading dose (based on body weight) preceding the first 125-mg subcutaneous injection. Dr. Yazici reviewed recent data that challenged that recommendation. These findings come from a study by Dr. Peter T. Nash of the University of Queensland, Brisbane, that were presented at the 2011 EULAR congress. The study involved a comparison of open-label data from two phase III trials that showed comparable improvements with subcutaneous abatacept, with or without an intravenous loading dose, on physical function, as assessed by the Health Assessment Questionnaire–Disease Index, and disease activity, as assessed by the Disease Activity Score 28/C-reactive protein.

Dr. Yazici serves as a consultant to Bristol-Myers Squibb and Genentech. Dr. Alten receives grant or research support from, is a consultant for, or is on the speakers bureau of Abbott Laboratories, Bristol-Myers Squibb, Horizon Pharma, Merck Pharma GmbH, Nitec Pharma GmbH, Norvartis Pharmaceuticals, Roche, and Wyeth Pharmaceuticals.

NEW YORK – The low levels of immunoglobulin G seen in a group of patients receiving rituximab for rheumatoid arthritis were associated with a twofold increased risk of serious infections, judging from the results of a 5-year prospective French register of 2,000 patients, according to Dr. Yusuf Yazici.

“These results give us one piece of evidence to support what investigators have long suspected: Low IgG levels may increase risk of infections,” said Dr. Yazici, director of the Seligman Center for Advanced Therapeutics and Behçet’s Syndrome Evaluation, Treatment, and Research Center at the New York University Hospital for Joint Diseases.*

Of the risk factors investigated by Dr. Jacques-Eric Gottenberg of the Strasbourg (France) University Hospital and his associates, only low serum IgG levels – not gamma globulin or immunoglobulin M (IgM) levels – were associated with serious infections in rheumatoid arthritis (RA) patients treated with rituximab, according to Dr. Yazici. This finding suggests that serum IgG levels in particular should be checked before each new cycle of rituximab and that the risk/benefit ratio of rituximab should be carefully assessed for those with low IgG levels. A therapy other than rituximab should be considered for patients with low immunoglobulin G (IgG) levels who already have a severe infection or severe comorbidities, according to Dr. Gottenberg’s findings.

The French AIR (Autoimmunity and Rituximab) Registry is a 5-year, prospective, multicenter study begun in 2006 that prospectively collects data on patients treated with rituximab on and off label for refractory arthritides. It is thought to be the largest prospective study, based on a national registry, focusing on severe infections in RA patients treated with rituximab in a clinical setting. Many patients have comorbidities, such as cancer, chronic lung disease, cardiac insufficiency, or diabetes. A nationwide initiative, most patients were registered from rheumatology departments while less than 10% originated from internal medicine departments. The 88 centers who participated in the register write more than 85% of all rituximab prescriptions in France for nonhematologic, nononcologic indications.

"You can’t suppress IgG levels forever without expecting some increase in infections."

Since this was a noninterventional study, no laboratory exams were required either at baseline or after rituximab treatment. Even though immunoglobulin levels are not routinely assessed during rituximab therapy, of the 2000 patients with RA included in the AIR Registry, gamma globulin, IgM, or IgG levels after rituximab treatment had been collected in almost 60% of enrolled patients. Of those who had undergone these analyses, 15.5% had low levels of serum gamma globulin less than 6 g/L), 26.6% had low levels of IgM less than 0.5 g/L) and 12.1% had low IgG levels (less than 6 g/L).

The authors looked at the rates of serious infections (defined as an infection occurring during the 12 months following each infusion of rituximab that required hospitalization and/or intravenous antibiotics and/or resulted in death) in patients with normal and low levels of gamma globulin, IgM, or IgG. Univariate analysis adjusted according to follow-up duration revealed that only low IgG levels after rituximab were associated with a significantly increased risk of serious infections, with almost a twofold increase in risk (odds ratio, 1.99; 95% confidence interval, 1.2-3.3; P = .008). No significant effects were found for low levels of gamma globulin (OR, 1.5; 95% CI, 0.9-2.5; P = .09) or IgM (OR, 1.5; 95% CI, 0.9-2.3; P = .08).

In a multivariate analysis, when the researchers adjusted for older age, previous cancer, or serious or recurrent infections, only low IgG after rituximab remained associated with serious infections. In published work, Dr. Gottenberg reported that chronic lung disease and/or cardiac insufficiency and extraarticular involvement also rendered RA patients treated with rituximab more prone to severe infections (Arthritis Rheum. 2010;62[9]:2625-32).

For all measures serious infections were more frequent in those with lower levels of immunologic indices. For instance, 13.5% of patients with low gamma globulin levels after rituximab had serious infections, compared with 8.8% of those with normal gamma globulin levels. Rates of serious infection, as indicated by the ratio of low to normal levels for IgM, were 11.8%:8.1% while the rates for IgG were 15.1%:8.2%.

Dr. Yazici serves as a consultant to Bristol-Myers Squibb and Genentech. Dr. Gottenberg reported a relevant financial relationship with Roche.

* Clarification: This story was updated on 12/12/2011.

NEW YORK – The low levels of immunoglobulin G seen in a group of patients receiving rituximab for rheumatoid arthritis were associated with a twofold increased risk of serious infections, judging from the results of a 5-year prospective French register of 2,000 patients, according to Dr. Yusuf Yazici.

“These results give us one piece of evidence to support what investigators have long suspected: Low IgG levels may increase risk of infections,” said Dr. Yazici, director of the Seligman Center for Advanced Therapeutics and Behçet’s Syndrome Evaluation, Treatment, and Research Center at the New York University Hospital for Joint Diseases.*

Of the risk factors investigated by Dr. Jacques-Eric Gottenberg of the Strasbourg (France) University Hospital and his associates, only low serum IgG levels – not gamma globulin or immunoglobulin M (IgM) levels – were associated with serious infections in rheumatoid arthritis (RA) patients treated with rituximab, according to Dr. Yazici. This finding suggests that serum IgG levels in particular should be checked before each new cycle of rituximab and that the risk/benefit ratio of rituximab should be carefully assessed for those with low IgG levels. A therapy other than rituximab should be considered for patients with low immunoglobulin G (IgG) levels who already have a severe infection or severe comorbidities, according to Dr. Gottenberg’s findings.

The French AIR (Autoimmunity and Rituximab) Registry is a 5-year, prospective, multicenter study begun in 2006 that prospectively collects data on patients treated with rituximab on and off label for refractory arthritides. It is thought to be the largest prospective study, based on a national registry, focusing on severe infections in RA patients treated with rituximab in a clinical setting. Many patients have comorbidities, such as cancer, chronic lung disease, cardiac insufficiency, or diabetes. A nationwide initiative, most patients were registered from rheumatology departments while less than 10% originated from internal medicine departments. The 88 centers who participated in the register write more than 85% of all rituximab prescriptions in France for nonhematologic, nononcologic indications.

"You can’t suppress IgG levels forever without expecting some increase in infections."

Since this was a noninterventional study, no laboratory exams were required either at baseline or after rituximab treatment. Even though immunoglobulin levels are not routinely assessed during rituximab therapy, of the 2000 patients with RA included in the AIR Registry, gamma globulin, IgM, or IgG levels after rituximab treatment had been collected in almost 60% of enrolled patients. Of those who had undergone these analyses, 15.5% had low levels of serum gamma globulin less than 6 g/L), 26.6% had low levels of IgM less than 0.5 g/L) and 12.1% had low IgG levels (less than 6 g/L).

The authors looked at the rates of serious infections (defined as an infection occurring during the 12 months following each infusion of rituximab that required hospitalization and/or intravenous antibiotics and/or resulted in death) in patients with normal and low levels of gamma globulin, IgM, or IgG. Univariate analysis adjusted according to follow-up duration revealed that only low IgG levels after rituximab were associated with a significantly increased risk of serious infections, with almost a twofold increase in risk (odds ratio, 1.99; 95% confidence interval, 1.2-3.3; P = .008). No significant effects were found for low levels of gamma globulin (OR, 1.5; 95% CI, 0.9-2.5; P = .09) or IgM (OR, 1.5; 95% CI, 0.9-2.3; P = .08).

In a multivariate analysis, when the researchers adjusted for older age, previous cancer, or serious or recurrent infections, only low IgG after rituximab remained associated with serious infections. In published work, Dr. Gottenberg reported that chronic lung disease and/or cardiac insufficiency and extraarticular involvement also rendered RA patients treated with rituximab more prone to severe infections (Arthritis Rheum. 2010;62[9]:2625-32).

For all measures serious infections were more frequent in those with lower levels of immunologic indices. For instance, 13.5% of patients with low gamma globulin levels after rituximab had serious infections, compared with 8.8% of those with normal gamma globulin levels. Rates of serious infection, as indicated by the ratio of low to normal levels for IgM, were 11.8%:8.1% while the rates for IgG were 15.1%:8.2%.

Dr. Yazici serves as a consultant to Bristol-Myers Squibb and Genentech. Dr. Gottenberg reported a relevant financial relationship with Roche.

* Clarification: This story was updated on 12/12/2011.

NEW YORK – The low levels of immunoglobulin G seen in a group of patients receiving rituximab for rheumatoid arthritis were associated with a twofold increased risk of serious infections, judging from the results of a 5-year prospective French register of 2,000 patients, according to Dr. Yusuf Yazici.

“These results give us one piece of evidence to support what investigators have long suspected: Low IgG levels may increase risk of infections,” said Dr. Yazici, director of the Seligman Center for Advanced Therapeutics and Behçet’s Syndrome Evaluation, Treatment, and Research Center at the New York University Hospital for Joint Diseases.*

Of the risk factors investigated by Dr. Jacques-Eric Gottenberg of the Strasbourg (France) University Hospital and his associates, only low serum IgG levels – not gamma globulin or immunoglobulin M (IgM) levels – were associated with serious infections in rheumatoid arthritis (RA) patients treated with rituximab, according to Dr. Yazici. This finding suggests that serum IgG levels in particular should be checked before each new cycle of rituximab and that the risk/benefit ratio of rituximab should be carefully assessed for those with low IgG levels. A therapy other than rituximab should be considered for patients with low immunoglobulin G (IgG) levels who already have a severe infection or severe comorbidities, according to Dr. Gottenberg’s findings.

The French AIR (Autoimmunity and Rituximab) Registry is a 5-year, prospective, multicenter study begun in 2006 that prospectively collects data on patients treated with rituximab on and off label for refractory arthritides. It is thought to be the largest prospective study, based on a national registry, focusing on severe infections in RA patients treated with rituximab in a clinical setting. Many patients have comorbidities, such as cancer, chronic lung disease, cardiac insufficiency, or diabetes. A nationwide initiative, most patients were registered from rheumatology departments while less than 10% originated from internal medicine departments. The 88 centers who participated in the register write more than 85% of all rituximab prescriptions in France for nonhematologic, nononcologic indications.

"You can’t suppress IgG levels forever without expecting some increase in infections."

Since this was a noninterventional study, no laboratory exams were required either at baseline or after rituximab treatment. Even though immunoglobulin levels are not routinely assessed during rituximab therapy, of the 2000 patients with RA included in the AIR Registry, gamma globulin, IgM, or IgG levels after rituximab treatment had been collected in almost 60% of enrolled patients. Of those who had undergone these analyses, 15.5% had low levels of serum gamma globulin less than 6 g/L), 26.6% had low levels of IgM less than 0.5 g/L) and 12.1% had low IgG levels (less than 6 g/L).

The authors looked at the rates of serious infections (defined as an infection occurring during the 12 months following each infusion of rituximab that required hospitalization and/or intravenous antibiotics and/or resulted in death) in patients with normal and low levels of gamma globulin, IgM, or IgG. Univariate analysis adjusted according to follow-up duration revealed that only low IgG levels after rituximab were associated with a significantly increased risk of serious infections, with almost a twofold increase in risk (odds ratio, 1.99; 95% confidence interval, 1.2-3.3; P = .008). No significant effects were found for low levels of gamma globulin (OR, 1.5; 95% CI, 0.9-2.5; P = .09) or IgM (OR, 1.5; 95% CI, 0.9-2.3; P = .08).

In a multivariate analysis, when the researchers adjusted for older age, previous cancer, or serious or recurrent infections, only low IgG after rituximab remained associated with serious infections. In published work, Dr. Gottenberg reported that chronic lung disease and/or cardiac insufficiency and extraarticular involvement also rendered RA patients treated with rituximab more prone to severe infections (Arthritis Rheum. 2010;62[9]:2625-32).

For all measures serious infections were more frequent in those with lower levels of immunologic indices. For instance, 13.5% of patients with low gamma globulin levels after rituximab had serious infections, compared with 8.8% of those with normal gamma globulin levels. Rates of serious infection, as indicated by the ratio of low to normal levels for IgM, were 11.8%:8.1% while the rates for IgG were 15.1%:8.2%.

Dr. Yazici serves as a consultant to Bristol-Myers Squibb and Genentech. Dr. Gottenberg reported a relevant financial relationship with Roche.

* Clarification: This story was updated on 12/12/2011.