Nancy Walsh

NEW YORK — Increased understanding of the natural history and pathogenic cellular events associated with Takayasu arteritis has only begun to translate into improvements in treatment, and the condition remains exceedingly difficult to manage, according to Dr. Gary S. Hoffman, who has been following a cohort of these patients at the Cleveland Clinic since 1992.

Corticosteroids have long been the cornerstone of therapy for the granulomatous vasculitis first described by Japanese ophthalmologist Dr. Mikito Takayasu in 1908. The disease affects the aorta and its primary branches and can lead to segmental stenosis, occlusion, and aneurysm formation, but with high doses, almost all patients improve—temporarily.

Among the 30 patients in Dr. Hoffman's longitudinal cohort, 28 were able to achieve disease remission of any duration, but only 8 have had sustained remissions of 6 months or more and have been able to taper their steroids to 10 mg/day or less.

Relapses ultimately have been seen in 27 while steroids were being tapered, and 8 relapsed while on steroids plus two immunosuppressive agents, said Dr. Hoffman, who is Harold C. Schott professor of medicine at Case Western Reserve University, Cleveland, and founder of the Center for Vasculitis Care and Research at the Cleveland Clinic Foundation. “A further testimony to how ineffective our treatment has been is that half of the patients we followed required on average more than two surgical procedures,” he said.

“Initially, we were excited about the results with surgery, but when we looked at long-term follow-up, we found recurrences with 14 angioplasties and 16 vascular bypass/reconstruction procedures. The results were even worse with stents, which has led us to avoid conventional stenting,” Dr. Hoffman said at the Fourth International Conference on Giant Cell Arteritis and Polymyalgia Rheumatica.

One area that has seen improvement is long-term survival. In an earlier series from the National Institutes of Health, four patients died, while in the Cleveland Clinic series, there was one death. “I feel proud of our mortality data,” he said. However, in both of these cohorts, the rates of disability were “stunning,” with 25 patients in the Cleveland cohort and 44 patients in the NIH series being disabled (Ann. Intern. Med. 1994;120:919–29).

“And the mean age of these patients was only 26 years,” he said.

Clearly, better therapies are needed, and recent efforts have focused on potential roles for biologic agents. In a pilot study that included 15 patients with relapsing Takayasu arteritis, 14 patients improved with etanercept or infliximab and 10 achieved complete remission that persisted for up to 3 years without steroids (Arthritis Rheum. 2004;50:2296–304).

A total of 28 patients now have been treated with anti-tumor necrosis factor (TNF) drugs, most commonly infliximab, and long-term follow-up data are available on 20. Mean follow-up is 28 months, with the longest being 6.5 years. Steroid-free, long-term remissions have been seen in 12. Marked improvements have been seen in an additional six. Only two patients have been unable either to discontinue steroids or to cut them to less than 10 mg/day.

“We are encouraged by this open-label experience, and I think it's possible that anti-TNF therapy may be useful in the treatment of Takayasu arteritis,” Dr. Hoffman said at the meeting sponsored by the Hospital for Special Surgery.

But randomized, controlled trials are sorely needed, he added.

Another biologic agent that may prove helpful is the interleukin (IL)-6 inhibitor tocilizumab. Serum levels of the inflammatory cytokine IL-6 are elevated in this disorder and correlate with disease activity, and it is also strongly expressed in patients' affected aortic tissue.

Benefits were seen with tocilizumab in a recent case report of a 20-year-old woman with Takayasu arteritis and Crohn's disease whose disease activity could not be suppressed with high doses of corticosteroids plus multiple immunosuppressants. After a single 4-mg/kg dose of tocilizumab, her C-reactive protein level fell within a week from 126 mg/L to 26 mg/L, and by week 46, after 26 doses of the drug, her serum IL-6 level had decreased from 1,720 pg/mL to 114 pg/mL (Arthritis Rheum. 2008;58:1197–200).

Further experimental investigations include a trial of abatacept sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, expected to begin shortly, that will enroll 66 patients with Takayasu arteritis or giant cell arteritis.

Another possibility is fontolizumab, an anti-interferon-gamma antibody previously tested for Crohn's disease (Gut 2006;55:1131–7). “If it turns out that interferon-gamma is a key player in Takayasu arteritis I'll be interested to see what this drug would do,” Dr. Hoffman said.

Dr. Hoffman has previously disclosed having no conflicts of interest.

Mononuclear cells, left, infiltrated the aortic arch, leading to a 5.0-cm aneurysm, right. Corticosteroids have long been the cornerstone of therapy for Takayasu arteritis. Images courtesy Dr. Gary S. Hoffman

NEW YORK — Increased understanding of the natural history and pathogenic cellular events associated with Takayasu arteritis has only begun to translate into improvements in treatment, and the condition remains exceedingly difficult to manage, according to Dr. Gary S. Hoffman, who has been following a cohort of these patients at the Cleveland Clinic since 1992.

Corticosteroids have long been the cornerstone of therapy for the granulomatous vasculitis first described by Japanese ophthalmologist Dr. Mikito Takayasu in 1908. The disease affects the aorta and its primary branches and can lead to segmental stenosis, occlusion, and aneurysm formation, but with high doses, almost all patients improve—temporarily.

Among the 30 patients in Dr. Hoffman's longitudinal cohort, 28 were able to achieve disease remission of any duration, but only 8 have had sustained remissions of 6 months or more and have been able to taper their steroids to 10 mg/day or less.

Relapses ultimately have been seen in 27 while steroids were being tapered, and 8 relapsed while on steroids plus two immunosuppressive agents, said Dr. Hoffman, who is Harold C. Schott professor of medicine at Case Western Reserve University, Cleveland, and founder of the Center for Vasculitis Care and Research at the Cleveland Clinic Foundation. “A further testimony to how ineffective our treatment has been is that half of the patients we followed required on average more than two surgical procedures,” he said.

“Initially, we were excited about the results with surgery, but when we looked at long-term follow-up, we found recurrences with 14 angioplasties and 16 vascular bypass/reconstruction procedures. The results were even worse with stents, which has led us to avoid conventional stenting,” Dr. Hoffman said at the Fourth International Conference on Giant Cell Arteritis and Polymyalgia Rheumatica.

One area that has seen improvement is long-term survival. In an earlier series from the National Institutes of Health, four patients died, while in the Cleveland Clinic series, there was one death. “I feel proud of our mortality data,” he said. However, in both of these cohorts, the rates of disability were “stunning,” with 25 patients in the Cleveland cohort and 44 patients in the NIH series being disabled (Ann. Intern. Med. 1994;120:919–29).

“And the mean age of these patients was only 26 years,” he said.

Clearly, better therapies are needed, and recent efforts have focused on potential roles for biologic agents. In a pilot study that included 15 patients with relapsing Takayasu arteritis, 14 patients improved with etanercept or infliximab and 10 achieved complete remission that persisted for up to 3 years without steroids (Arthritis Rheum. 2004;50:2296–304).

A total of 28 patients now have been treated with anti-tumor necrosis factor (TNF) drugs, most commonly infliximab, and long-term follow-up data are available on 20. Mean follow-up is 28 months, with the longest being 6.5 years. Steroid-free, long-term remissions have been seen in 12. Marked improvements have been seen in an additional six. Only two patients have been unable either to discontinue steroids or to cut them to less than 10 mg/day.

“We are encouraged by this open-label experience, and I think it's possible that anti-TNF therapy may be useful in the treatment of Takayasu arteritis,” Dr. Hoffman said at the meeting sponsored by the Hospital for Special Surgery.

But randomized, controlled trials are sorely needed, he added.

Another biologic agent that may prove helpful is the interleukin (IL)-6 inhibitor tocilizumab. Serum levels of the inflammatory cytokine IL-6 are elevated in this disorder and correlate with disease activity, and it is also strongly expressed in patients' affected aortic tissue.

Benefits were seen with tocilizumab in a recent case report of a 20-year-old woman with Takayasu arteritis and Crohn's disease whose disease activity could not be suppressed with high doses of corticosteroids plus multiple immunosuppressants. After a single 4-mg/kg dose of tocilizumab, her C-reactive protein level fell within a week from 126 mg/L to 26 mg/L, and by week 46, after 26 doses of the drug, her serum IL-6 level had decreased from 1,720 pg/mL to 114 pg/mL (Arthritis Rheum. 2008;58:1197–200).

Further experimental investigations include a trial of abatacept sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, expected to begin shortly, that will enroll 66 patients with Takayasu arteritis or giant cell arteritis.

Another possibility is fontolizumab, an anti-interferon-gamma antibody previously tested for Crohn's disease (Gut 2006;55:1131–7). “If it turns out that interferon-gamma is a key player in Takayasu arteritis I'll be interested to see what this drug would do,” Dr. Hoffman said.

Dr. Hoffman has previously disclosed having no conflicts of interest.

Mononuclear cells, left, infiltrated the aortic arch, leading to a 5.0-cm aneurysm, right. Corticosteroids have long been the cornerstone of therapy for Takayasu arteritis. Images courtesy Dr. Gary S. Hoffman

NEW YORK — Increased understanding of the natural history and pathogenic cellular events associated with Takayasu arteritis has only begun to translate into improvements in treatment, and the condition remains exceedingly difficult to manage, according to Dr. Gary S. Hoffman, who has been following a cohort of these patients at the Cleveland Clinic since 1992.

Corticosteroids have long been the cornerstone of therapy for the granulomatous vasculitis first described by Japanese ophthalmologist Dr. Mikito Takayasu in 1908. The disease affects the aorta and its primary branches and can lead to segmental stenosis, occlusion, and aneurysm formation, but with high doses, almost all patients improve—temporarily.

Among the 30 patients in Dr. Hoffman's longitudinal cohort, 28 were able to achieve disease remission of any duration, but only 8 have had sustained remissions of 6 months or more and have been able to taper their steroids to 10 mg/day or less.

Relapses ultimately have been seen in 27 while steroids were being tapered, and 8 relapsed while on steroids plus two immunosuppressive agents, said Dr. Hoffman, who is Harold C. Schott professor of medicine at Case Western Reserve University, Cleveland, and founder of the Center for Vasculitis Care and Research at the Cleveland Clinic Foundation. “A further testimony to how ineffective our treatment has been is that half of the patients we followed required on average more than two surgical procedures,” he said.

“Initially, we were excited about the results with surgery, but when we looked at long-term follow-up, we found recurrences with 14 angioplasties and 16 vascular bypass/reconstruction procedures. The results were even worse with stents, which has led us to avoid conventional stenting,” Dr. Hoffman said at the Fourth International Conference on Giant Cell Arteritis and Polymyalgia Rheumatica.

One area that has seen improvement is long-term survival. In an earlier series from the National Institutes of Health, four patients died, while in the Cleveland Clinic series, there was one death. “I feel proud of our mortality data,” he said. However, in both of these cohorts, the rates of disability were “stunning,” with 25 patients in the Cleveland cohort and 44 patients in the NIH series being disabled (Ann. Intern. Med. 1994;120:919–29).

“And the mean age of these patients was only 26 years,” he said.

Clearly, better therapies are needed, and recent efforts have focused on potential roles for biologic agents. In a pilot study that included 15 patients with relapsing Takayasu arteritis, 14 patients improved with etanercept or infliximab and 10 achieved complete remission that persisted for up to 3 years without steroids (Arthritis Rheum. 2004;50:2296–304).

A total of 28 patients now have been treated with anti-tumor necrosis factor (TNF) drugs, most commonly infliximab, and long-term follow-up data are available on 20. Mean follow-up is 28 months, with the longest being 6.5 years. Steroid-free, long-term remissions have been seen in 12. Marked improvements have been seen in an additional six. Only two patients have been unable either to discontinue steroids or to cut them to less than 10 mg/day.

“We are encouraged by this open-label experience, and I think it's possible that anti-TNF therapy may be useful in the treatment of Takayasu arteritis,” Dr. Hoffman said at the meeting sponsored by the Hospital for Special Surgery.

But randomized, controlled trials are sorely needed, he added.

Another biologic agent that may prove helpful is the interleukin (IL)-6 inhibitor tocilizumab. Serum levels of the inflammatory cytokine IL-6 are elevated in this disorder and correlate with disease activity, and it is also strongly expressed in patients' affected aortic tissue.

Benefits were seen with tocilizumab in a recent case report of a 20-year-old woman with Takayasu arteritis and Crohn's disease whose disease activity could not be suppressed with high doses of corticosteroids plus multiple immunosuppressants. After a single 4-mg/kg dose of tocilizumab, her C-reactive protein level fell within a week from 126 mg/L to 26 mg/L, and by week 46, after 26 doses of the drug, her serum IL-6 level had decreased from 1,720 pg/mL to 114 pg/mL (Arthritis Rheum. 2008;58:1197–200).

Further experimental investigations include a trial of abatacept sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, expected to begin shortly, that will enroll 66 patients with Takayasu arteritis or giant cell arteritis.

Another possibility is fontolizumab, an anti-interferon-gamma antibody previously tested for Crohn's disease (Gut 2006;55:1131–7). “If it turns out that interferon-gamma is a key player in Takayasu arteritis I'll be interested to see what this drug would do,” Dr. Hoffman said.

Dr. Hoffman has previously disclosed having no conflicts of interest.

Mononuclear cells, left, infiltrated the aortic arch, leading to a 5.0-cm aneurysm, right. Corticosteroids have long been the cornerstone of therapy for Takayasu arteritis. Images courtesy Dr. Gary S. Hoffman

NEW YORK — Tumor necrosis factor inhibitors, given in conjunction with corticosteroids for recent onset giant cell arteritis or polymyalgia rheumatica, do not appear to confer a substantial benefit over treatment with steroids alone, judging from findings from recent studies.

Systemic corticosteroids represent the cornerstone of treatment for both giant cell arteritis (GCA) and the forme fruste of this large vessel vasculitis, polymyalgia rheumatica (PMR).

However, in the 50-year-and-older age group susceptible to these conditions, steroid-related toxicities such as osteoporotic fractures represent significant hazards.

Therefore, various types of adjunctive cytotoxic and anti-inflammatory drugs—most notably methotrexate—have been tried for potential roles as steroid-sparing agents. Results thus far have been disappointing. (See related story.)

More recently, the tumor necrosis factor (TNF) blocking agents have been investigated for use both as monotherapy and in conjunction with corticosteroids, according to Dr. Nicolo Pipitone of the Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.

The rationale for using TNF inhibitors lies in the fact that circulating levels of this cytokine are elevated in patients with GCA and PMR, and it is overexpressed in the temporal arteries of patients with GCA, Dr. Pipitone said at the Fourth International Conference on Giant Cell Arteritis and Polymyalgia Rheumatica.

Small early studies with infliximab initially seemed promising, with a few patients going into remission, so randomized trials were undertaken. For GCA, 44 patients with newly diagnosed disease were randomized to receive corticosteroids plus infliximab (5 mg/kg), or placebo at weeks 0, 2, 6, and every 8 weeks thereafter, with steroids being tapered within 6 months.

An interim analysis at week 22 found no difference between the groups in the proportions of patients who were relapse free, in time to first relapse, or in cumulative prednisone dose.

There was a trend for more infections in the infliximab group, with three serious infections, compared with one in the placebo group.

There also were six infusion reactions in the infliximab group and none in the control group. In the active treatment group, antibodies to infliximab developed in 27%, and antibodies to double-stranded DNA developed in 16% (Ann. Intern. Med. 2007;146:621–30). The study was discontinued prematurely, Dr. Pipitone said.

A second trial included 51 patients with newly diagnosed PMR who were randomized to receive corticosteroids plus 3 mg/kg infliximab or placebo at weeks 0, 2, 6, 14, and 22, with steroids being tapered over 16 weeks.

In this trial, again, the proportions of patients who were relapse free at 52 weeks did not differ between the two groups, and the investigators concluded that the treatment “does not substantially affect the course of polymyalgia rheumatica” (Ann. Intern. Med. 2007;146:631–9).

In contrast to these studies of new onset disease, however, benefits have been seen with TNF blockade in patients with refractory, long-standing disease.

In six of seven reported cases of refractory GCA, patients had a positive response to infliximab. Disease duration in these patients ranged from 1 to 5 years, and steroid dosages ranged from 7.5 mg/day to 40 mg/day. Among four of these patients, reported as a single case series, three were steroid free and in remission following three infusions of infliximab at 3 mg/kg (Arthritis Rheum. 2001;44:2933–5).

More recently, 17 patients with longstanding biopsy-proven GCA who were in remission on stable dosages of prednisone (10 mg/day or more) were randomized to etanercept or placebo, 25 mg twice weekly for 12 months. Prednisone was tapered according to a prearranged schedule but adjusted if flares occurred, and the primary end point was the ability to withdraw steroids at 12 months.

The primary end point was met by 50% of the etanercept-treated patients but by only 22% of the placebo-treated patients, Dr. Pipitone said at the meeting, which was sponsored by the Hospital for Special Surgery. A total of 50% of the etanercept group experienced a flare, as did 78% of the placebo group.

Although the numbers in this study were small and statistical significance was not reached, the findings do suggest that there may be some benefits in subsets of patients with longstanding, steroid-resistant GCA, Dr. Pipitone said.

An additional role for TNF blockade may be for patients who cannot tolerate or are unwilling to take corticosteroids. In a separate poster presentation at the meeting, Dr. Carlotta Nannini of Misericordia e Dolce Hospital, Prato, Italy, described three elderly women with biopsy-confirmed GCA.

Erythrocyte sedimentation rates (ESR) in the three patients were 78 mm/hour, 96 mm/hour, and 84 mm/hour, whereas C-reactive protein (CRP) levels were 8.3 mg/dL, 13.4 mg/dL, and 7.6 mg/dL.

All three had poorly controlled diabetes despite insulin therapy, with a mean fasting glucose level of 210 mg/dL; hypertension, with mean systolic and diastolic blood pressures of 180 mm Hg and 100 mm Hg; and severe osteoporosis with multiple vertebral fractures.

Despite the need for treatment, these patients declined steroid therapy because of their comorbidities, according to Dr. Nannini.

They did, however, consent to treatment with adalimumab (40 mg) every 2 weeks.

After 1 month of therapy, all three were in remission, with ESRs less than 20 mm/hour, CRPs less than 0.5 mg/dL, and no remaining musculoskeletal, cranial, or systemic symptoms.

After 6 months, the adalimumab dosage was reduced to 40 mg once monthly; after 12 months of therapy, the drug was discontinued in two of the three patients. They remain in remission 4 and 5 months later, whereas the third patient is completing 1 year of treatment with good response.

“Comorbidities such as diabetes, hypertension, and osteoporosis are very common among patients with GCA, highlighting the need for corticosteroid-sparing agents. … Our limited experience with adalimumab suggests that the drug may represent an effective alternative to corticosteroids in patients with GCA who had corticosteroid dose-limiting comorbidities,” she concluded.

Dr. Pipitone described these findings with adalimumab as “quite intriguing.” He added, however, “I don't think we can make a case for the use of TNF blockers in clinical practice, at least not at this stage.”

Neither Dr. Pipitone nor Dr. Nannini reported conflicts of interest.

NEW YORK — Tumor necrosis factor inhibitors, given in conjunction with corticosteroids for recent onset giant cell arteritis or polymyalgia rheumatica, do not appear to confer a substantial benefit over treatment with steroids alone, judging from findings from recent studies.

Systemic corticosteroids represent the cornerstone of treatment for both giant cell arteritis (GCA) and the forme fruste of this large vessel vasculitis, polymyalgia rheumatica (PMR).

However, in the 50-year-and-older age group susceptible to these conditions, steroid-related toxicities such as osteoporotic fractures represent significant hazards.

Therefore, various types of adjunctive cytotoxic and anti-inflammatory drugs—most notably methotrexate—have been tried for potential roles as steroid-sparing agents. Results thus far have been disappointing. (See related story.)

More recently, the tumor necrosis factor (TNF) blocking agents have been investigated for use both as monotherapy and in conjunction with corticosteroids, according to Dr. Nicolo Pipitone of the Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.

The rationale for using TNF inhibitors lies in the fact that circulating levels of this cytokine are elevated in patients with GCA and PMR, and it is overexpressed in the temporal arteries of patients with GCA, Dr. Pipitone said at the Fourth International Conference on Giant Cell Arteritis and Polymyalgia Rheumatica.

Small early studies with infliximab initially seemed promising, with a few patients going into remission, so randomized trials were undertaken. For GCA, 44 patients with newly diagnosed disease were randomized to receive corticosteroids plus infliximab (5 mg/kg), or placebo at weeks 0, 2, 6, and every 8 weeks thereafter, with steroids being tapered within 6 months.

An interim analysis at week 22 found no difference between the groups in the proportions of patients who were relapse free, in time to first relapse, or in cumulative prednisone dose.

There was a trend for more infections in the infliximab group, with three serious infections, compared with one in the placebo group.

There also were six infusion reactions in the infliximab group and none in the control group. In the active treatment group, antibodies to infliximab developed in 27%, and antibodies to double-stranded DNA developed in 16% (Ann. Intern. Med. 2007;146:621–30). The study was discontinued prematurely, Dr. Pipitone said.

A second trial included 51 patients with newly diagnosed PMR who were randomized to receive corticosteroids plus 3 mg/kg infliximab or placebo at weeks 0, 2, 6, 14, and 22, with steroids being tapered over 16 weeks.

In this trial, again, the proportions of patients who were relapse free at 52 weeks did not differ between the two groups, and the investigators concluded that the treatment “does not substantially affect the course of polymyalgia rheumatica” (Ann. Intern. Med. 2007;146:631–9).

In contrast to these studies of new onset disease, however, benefits have been seen with TNF blockade in patients with refractory, long-standing disease.

In six of seven reported cases of refractory GCA, patients had a positive response to infliximab. Disease duration in these patients ranged from 1 to 5 years, and steroid dosages ranged from 7.5 mg/day to 40 mg/day. Among four of these patients, reported as a single case series, three were steroid free and in remission following three infusions of infliximab at 3 mg/kg (Arthritis Rheum. 2001;44:2933–5).

More recently, 17 patients with longstanding biopsy-proven GCA who were in remission on stable dosages of prednisone (10 mg/day or more) were randomized to etanercept or placebo, 25 mg twice weekly for 12 months. Prednisone was tapered according to a prearranged schedule but adjusted if flares occurred, and the primary end point was the ability to withdraw steroids at 12 months.

The primary end point was met by 50% of the etanercept-treated patients but by only 22% of the placebo-treated patients, Dr. Pipitone said at the meeting, which was sponsored by the Hospital for Special Surgery. A total of 50% of the etanercept group experienced a flare, as did 78% of the placebo group.

Although the numbers in this study were small and statistical significance was not reached, the findings do suggest that there may be some benefits in subsets of patients with longstanding, steroid-resistant GCA, Dr. Pipitone said.

An additional role for TNF blockade may be for patients who cannot tolerate or are unwilling to take corticosteroids. In a separate poster presentation at the meeting, Dr. Carlotta Nannini of Misericordia e Dolce Hospital, Prato, Italy, described three elderly women with biopsy-confirmed GCA.

Erythrocyte sedimentation rates (ESR) in the three patients were 78 mm/hour, 96 mm/hour, and 84 mm/hour, whereas C-reactive protein (CRP) levels were 8.3 mg/dL, 13.4 mg/dL, and 7.6 mg/dL.

All three had poorly controlled diabetes despite insulin therapy, with a mean fasting glucose level of 210 mg/dL; hypertension, with mean systolic and diastolic blood pressures of 180 mm Hg and 100 mm Hg; and severe osteoporosis with multiple vertebral fractures.

Despite the need for treatment, these patients declined steroid therapy because of their comorbidities, according to Dr. Nannini.

They did, however, consent to treatment with adalimumab (40 mg) every 2 weeks.

After 1 month of therapy, all three were in remission, with ESRs less than 20 mm/hour, CRPs less than 0.5 mg/dL, and no remaining musculoskeletal, cranial, or systemic symptoms.

After 6 months, the adalimumab dosage was reduced to 40 mg once monthly; after 12 months of therapy, the drug was discontinued in two of the three patients. They remain in remission 4 and 5 months later, whereas the third patient is completing 1 year of treatment with good response.

“Comorbidities such as diabetes, hypertension, and osteoporosis are very common among patients with GCA, highlighting the need for corticosteroid-sparing agents. … Our limited experience with adalimumab suggests that the drug may represent an effective alternative to corticosteroids in patients with GCA who had corticosteroid dose-limiting comorbidities,” she concluded.

Dr. Pipitone described these findings with adalimumab as “quite intriguing.” He added, however, “I don't think we can make a case for the use of TNF blockers in clinical practice, at least not at this stage.”

Neither Dr. Pipitone nor Dr. Nannini reported conflicts of interest.

NEW YORK — Tumor necrosis factor inhibitors, given in conjunction with corticosteroids for recent onset giant cell arteritis or polymyalgia rheumatica, do not appear to confer a substantial benefit over treatment with steroids alone, judging from findings from recent studies.

Systemic corticosteroids represent the cornerstone of treatment for both giant cell arteritis (GCA) and the forme fruste of this large vessel vasculitis, polymyalgia rheumatica (PMR).

However, in the 50-year-and-older age group susceptible to these conditions, steroid-related toxicities such as osteoporotic fractures represent significant hazards.

Therefore, various types of adjunctive cytotoxic and anti-inflammatory drugs—most notably methotrexate—have been tried for potential roles as steroid-sparing agents. Results thus far have been disappointing. (See related story.)

More recently, the tumor necrosis factor (TNF) blocking agents have been investigated for use both as monotherapy and in conjunction with corticosteroids, according to Dr. Nicolo Pipitone of the Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.

The rationale for using TNF inhibitors lies in the fact that circulating levels of this cytokine are elevated in patients with GCA and PMR, and it is overexpressed in the temporal arteries of patients with GCA, Dr. Pipitone said at the Fourth International Conference on Giant Cell Arteritis and Polymyalgia Rheumatica.

Small early studies with infliximab initially seemed promising, with a few patients going into remission, so randomized trials were undertaken. For GCA, 44 patients with newly diagnosed disease were randomized to receive corticosteroids plus infliximab (5 mg/kg), or placebo at weeks 0, 2, 6, and every 8 weeks thereafter, with steroids being tapered within 6 months.

An interim analysis at week 22 found no difference between the groups in the proportions of patients who were relapse free, in time to first relapse, or in cumulative prednisone dose.

There was a trend for more infections in the infliximab group, with three serious infections, compared with one in the placebo group.

There also were six infusion reactions in the infliximab group and none in the control group. In the active treatment group, antibodies to infliximab developed in 27%, and antibodies to double-stranded DNA developed in 16% (Ann. Intern. Med. 2007;146:621–30). The study was discontinued prematurely, Dr. Pipitone said.

A second trial included 51 patients with newly diagnosed PMR who were randomized to receive corticosteroids plus 3 mg/kg infliximab or placebo at weeks 0, 2, 6, 14, and 22, with steroids being tapered over 16 weeks.

In this trial, again, the proportions of patients who were relapse free at 52 weeks did not differ between the two groups, and the investigators concluded that the treatment “does not substantially affect the course of polymyalgia rheumatica” (Ann. Intern. Med. 2007;146:631–9).

In contrast to these studies of new onset disease, however, benefits have been seen with TNF blockade in patients with refractory, long-standing disease.

In six of seven reported cases of refractory GCA, patients had a positive response to infliximab. Disease duration in these patients ranged from 1 to 5 years, and steroid dosages ranged from 7.5 mg/day to 40 mg/day. Among four of these patients, reported as a single case series, three were steroid free and in remission following three infusions of infliximab at 3 mg/kg (Arthritis Rheum. 2001;44:2933–5).

More recently, 17 patients with longstanding biopsy-proven GCA who were in remission on stable dosages of prednisone (10 mg/day or more) were randomized to etanercept or placebo, 25 mg twice weekly for 12 months. Prednisone was tapered according to a prearranged schedule but adjusted if flares occurred, and the primary end point was the ability to withdraw steroids at 12 months.

The primary end point was met by 50% of the etanercept-treated patients but by only 22% of the placebo-treated patients, Dr. Pipitone said at the meeting, which was sponsored by the Hospital for Special Surgery. A total of 50% of the etanercept group experienced a flare, as did 78% of the placebo group.

Although the numbers in this study were small and statistical significance was not reached, the findings do suggest that there may be some benefits in subsets of patients with longstanding, steroid-resistant GCA, Dr. Pipitone said.

An additional role for TNF blockade may be for patients who cannot tolerate or are unwilling to take corticosteroids. In a separate poster presentation at the meeting, Dr. Carlotta Nannini of Misericordia e Dolce Hospital, Prato, Italy, described three elderly women with biopsy-confirmed GCA.

Erythrocyte sedimentation rates (ESR) in the three patients were 78 mm/hour, 96 mm/hour, and 84 mm/hour, whereas C-reactive protein (CRP) levels were 8.3 mg/dL, 13.4 mg/dL, and 7.6 mg/dL.

All three had poorly controlled diabetes despite insulin therapy, with a mean fasting glucose level of 210 mg/dL; hypertension, with mean systolic and diastolic blood pressures of 180 mm Hg and 100 mm Hg; and severe osteoporosis with multiple vertebral fractures.

Despite the need for treatment, these patients declined steroid therapy because of their comorbidities, according to Dr. Nannini.

They did, however, consent to treatment with adalimumab (40 mg) every 2 weeks.

After 1 month of therapy, all three were in remission, with ESRs less than 20 mm/hour, CRPs less than 0.5 mg/dL, and no remaining musculoskeletal, cranial, or systemic symptoms.

After 6 months, the adalimumab dosage was reduced to 40 mg once monthly; after 12 months of therapy, the drug was discontinued in two of the three patients. They remain in remission 4 and 5 months later, whereas the third patient is completing 1 year of treatment with good response.

“Comorbidities such as diabetes, hypertension, and osteoporosis are very common among patients with GCA, highlighting the need for corticosteroid-sparing agents. … Our limited experience with adalimumab suggests that the drug may represent an effective alternative to corticosteroids in patients with GCA who had corticosteroid dose-limiting comorbidities,” she concluded.

Dr. Pipitone described these findings with adalimumab as “quite intriguing.” He added, however, “I don't think we can make a case for the use of TNF blockers in clinical practice, at least not at this stage.”

Neither Dr. Pipitone nor Dr. Nannini reported conflicts of interest.

Joint distraction, a surgical technique that involves the placement of an external fixation frame around a degenerated joint, may help postpone the need for total knee replacement in young patients with severe osteoarthritis.

The cartilage in end-stage OA is severely damaged, with fissuring; altered chondrocyte distribution and death; and a significant loss of extracellular matrix constituents. These changes in cartilage are accompanied by characteristic changes in periarticular bone and soft tissue. All these structural changes mean severe pain and functional limitations for patients, who typically rate their pain with a score of 80% out of a maximum of 100%, according to Dr. Floris P.J.G. Lafeber, of the University Medical Center Utrecht (the Netherlands).

The standard treatment for these patients is total knee replacement. However, “Total knee prostheses don't last forever,” Dr. Lafeber said. “They last on average 15 years, so if you have one placed at age 60 you are likely to need a replacement at 75, which is complicated and expensive, and the results are often disappointing. And then if you need another at age 90 the difficulties are really serious,” he said, adding that in the Netherlands, approximately 1,000 total knee prostheses are placed each year in patients younger than 60.

“This is a major socioeconomic problem and will only grow with the aging of the population,” he said.

The rationale for joint distraction lies in the hypothesis that osteoarthritic cartilage is capable of self-repair if the joint is unloaded and chondrocyte nutrition is maintained. Pins are drilled through the soft tissue and bone just above and below the joint, and when the frame is in place the distance between the cartilaginous surfaces of the joint is increased by 5 mm. This transfers the load and stresses on cartilage away from the joint, eliminating further wear and tear. Then, springs within the distraction frame cause changes to occur in fluid pressure in the joint, with increases during loading and normalization with unloading. This continuous change in fluid pressure is important for the cartilage, because chondrocytes depend on synovial flow for nutrition, Dr. Lafeber explained.

The loading onto the frame also results in periarticular osteopenia, which in turn permits the sclerotic, osteoarthritic bone to become more flexible and the mineral content to normalize once the frame is removed. Furthermore, the periarticular bone turnover results in the release of multiple growth factors that can help repair the cartilage.

In collaboration with his center's orthopedic department, Dr. Lafeber and his colleagues in the department of rheumatology and clinical immunology began exploring this technique in a proof-of-concept study with ankle distraction. Although ankle OA is much less common than knee OA, in the case of failure an arthrodesis could be performed without much risk, he said.

A total of 73 patients underwent ankle distraction for 3 months, with the result that pain scores—rated at an average of 75% of 100%—fell to 20%, while scores for function and clinical condition rose from 25% at baseline to 80%. Some of these patients now have been followed for as long as 10 years, with continuing benefits.

They next did a feasibility study that included three patients with knee OA, and found similar results on pain and function scores as well as on stiffness scores. They then undertook a larger prospective study in which 19 patients with severe knee OA (mean age, 48 years) have been treated with 2-month periods of distraction. Thus far, six have been followed for up to 2 years. Functional ability and clinical condition, poor at the onset with scores of 39% and 32%, respectively, increased to 82% and 81%.

Serum and urinary biomarkers of cartilage turnover were measured throughout a 12-month follow-up. During the distraction phase there was an enormous turnover, with elevations of markers of both synthesis and breakdown, but after the distraction phase there was a gradual decrease of breakdown markers and an increase in the markers of synthesis, indicating repair of the cartilage, Dr. Lafeber said.

Imaging studies also demonstrated improvements. In seven patients who have been followed for more than 12 months, joint space width shown on x-rays increased from slightly greater than 2.5 mm to more than 3.5 mm. “And on MRI studies done after 1 year and read in a blinded fashion in collaboration with Prof. Felix Eckstein, who is one of the leading researchers in this field, the amount of subchondral bone covered with cartilage was shown to have increased by 40%, cartilage volume increased by 50%, and cartilage thickness over the bone increased by 5%,” Dr. Lafeber said.

The overall conclusion is that joint distraction is clinically very effective in young patients with end-stage knee arthritis, with cartilage repair presumably responsible for the clinical benefit, he said. However, more prolonged follow-up is needed.

Some of the ankle patients have had a second distraction, but whether this will be feasible and advisable in the knee patients remains to be seen, because the follow-up is too short.

“It may be possible, and of course we hope [that] it's not just a delay before joint replacement, but that we can really cure the joint. That's only wishful thinking so far, though,” he said.

Dr. Lafeber acknowledged that his study was not placebo controlled.

“Of course it would be better to have a good control, which in this case would be placement of the complete frame but without the distraction,” he said.

Currently, however, they are offering this treatment only to patients with end-stage OA who otherwise would be considered for joint replacement. “We cannot ethically allow these patients to go without any treatment for 2 years,” he said.

Moreover, with benefits persisting for up to 10 years for the ankle patients, placebo effects are hardly likely to still be in play. “Maybe for the first year, because these patients are seeing their physicians more frequently than they would otherwise, but certainly after several years the placebo effect would have vanished,” he said.

This knee has OA at baseline on x-ray (top). Cartilage repaired itself after 2 years of treatment (bottom). Distraction may alleviate the need for total knee arthroplasty. Photos courtesy Dr. Floris P.J.G. Lafeber

Biomarkers of bone breakdown and synthesis increase during distraction. Courtesy Dr. Floris P.J.G. Lafeber

Iowa's Experience With Ankle OA

Ankle distraction also has been performed and is being evaluated in a randomized study led by Dr. Annunziato Amendola of the University of Iowa, Iowa City.

The study, funded by the National Institutes of Health, prospectively enrolled about 40 patients with posttraumatic OA of the ankle. They used the same ankle distraction technique as did Dr. Lafeber's group, but patients were randomized to distraction alone or with the addition of continuous passive joint motion.

Patients have been evaluated clinically and radiographically, and with a special three-dimensional CT scanning technique to look at cartilage regeneration.

All but three patients have now undergone 2- and 3-year evaluations, and the results thus far have been comparable to the results they have had in Utrecht in terms of relief of pain, according to Dr. Amendola. Additional improvements have been seen over time, and patients in the motion group did significantly better at every time point than did the non-motion group.

“I think this is quite an intriguing technique,” Dr. Amendola said.

Joint distraction, a surgical technique that involves the placement of an external fixation frame around a degenerated joint, may help postpone the need for total knee replacement in young patients with severe osteoarthritis.

The cartilage in end-stage OA is severely damaged, with fissuring; altered chondrocyte distribution and death; and a significant loss of extracellular matrix constituents. These changes in cartilage are accompanied by characteristic changes in periarticular bone and soft tissue. All these structural changes mean severe pain and functional limitations for patients, who typically rate their pain with a score of 80% out of a maximum of 100%, according to Dr. Floris P.J.G. Lafeber, of the University Medical Center Utrecht (the Netherlands).

The standard treatment for these patients is total knee replacement. However, “Total knee prostheses don't last forever,” Dr. Lafeber said. “They last on average 15 years, so if you have one placed at age 60 you are likely to need a replacement at 75, which is complicated and expensive, and the results are often disappointing. And then if you need another at age 90 the difficulties are really serious,” he said, adding that in the Netherlands, approximately 1,000 total knee prostheses are placed each year in patients younger than 60.

“This is a major socioeconomic problem and will only grow with the aging of the population,” he said.

The rationale for joint distraction lies in the hypothesis that osteoarthritic cartilage is capable of self-repair if the joint is unloaded and chondrocyte nutrition is maintained. Pins are drilled through the soft tissue and bone just above and below the joint, and when the frame is in place the distance between the cartilaginous surfaces of the joint is increased by 5 mm. This transfers the load and stresses on cartilage away from the joint, eliminating further wear and tear. Then, springs within the distraction frame cause changes to occur in fluid pressure in the joint, with increases during loading and normalization with unloading. This continuous change in fluid pressure is important for the cartilage, because chondrocytes depend on synovial flow for nutrition, Dr. Lafeber explained.

The loading onto the frame also results in periarticular osteopenia, which in turn permits the sclerotic, osteoarthritic bone to become more flexible and the mineral content to normalize once the frame is removed. Furthermore, the periarticular bone turnover results in the release of multiple growth factors that can help repair the cartilage.

In collaboration with his center's orthopedic department, Dr. Lafeber and his colleagues in the department of rheumatology and clinical immunology began exploring this technique in a proof-of-concept study with ankle distraction. Although ankle OA is much less common than knee OA, in the case of failure an arthrodesis could be performed without much risk, he said.

A total of 73 patients underwent ankle distraction for 3 months, with the result that pain scores—rated at an average of 75% of 100%—fell to 20%, while scores for function and clinical condition rose from 25% at baseline to 80%. Some of these patients now have been followed for as long as 10 years, with continuing benefits.

They next did a feasibility study that included three patients with knee OA, and found similar results on pain and function scores as well as on stiffness scores. They then undertook a larger prospective study in which 19 patients with severe knee OA (mean age, 48 years) have been treated with 2-month periods of distraction. Thus far, six have been followed for up to 2 years. Functional ability and clinical condition, poor at the onset with scores of 39% and 32%, respectively, increased to 82% and 81%.

Serum and urinary biomarkers of cartilage turnover were measured throughout a 12-month follow-up. During the distraction phase there was an enormous turnover, with elevations of markers of both synthesis and breakdown, but after the distraction phase there was a gradual decrease of breakdown markers and an increase in the markers of synthesis, indicating repair of the cartilage, Dr. Lafeber said.

Imaging studies also demonstrated improvements. In seven patients who have been followed for more than 12 months, joint space width shown on x-rays increased from slightly greater than 2.5 mm to more than 3.5 mm. “And on MRI studies done after 1 year and read in a blinded fashion in collaboration with Prof. Felix Eckstein, who is one of the leading researchers in this field, the amount of subchondral bone covered with cartilage was shown to have increased by 40%, cartilage volume increased by 50%, and cartilage thickness over the bone increased by 5%,” Dr. Lafeber said.

The overall conclusion is that joint distraction is clinically very effective in young patients with end-stage knee arthritis, with cartilage repair presumably responsible for the clinical benefit, he said. However, more prolonged follow-up is needed.

Some of the ankle patients have had a second distraction, but whether this will be feasible and advisable in the knee patients remains to be seen, because the follow-up is too short.

“It may be possible, and of course we hope [that] it's not just a delay before joint replacement, but that we can really cure the joint. That's only wishful thinking so far, though,” he said.

Dr. Lafeber acknowledged that his study was not placebo controlled.

“Of course it would be better to have a good control, which in this case would be placement of the complete frame but without the distraction,” he said.

Currently, however, they are offering this treatment only to patients with end-stage OA who otherwise would be considered for joint replacement. “We cannot ethically allow these patients to go without any treatment for 2 years,” he said.

Moreover, with benefits persisting for up to 10 years for the ankle patients, placebo effects are hardly likely to still be in play. “Maybe for the first year, because these patients are seeing their physicians more frequently than they would otherwise, but certainly after several years the placebo effect would have vanished,” he said.

This knee has OA at baseline on x-ray (top). Cartilage repaired itself after 2 years of treatment (bottom). Distraction may alleviate the need for total knee arthroplasty. Photos courtesy Dr. Floris P.J.G. Lafeber

Biomarkers of bone breakdown and synthesis increase during distraction. Courtesy Dr. Floris P.J.G. Lafeber

Iowa's Experience With Ankle OA

Ankle distraction also has been performed and is being evaluated in a randomized study led by Dr. Annunziato Amendola of the University of Iowa, Iowa City.

The study, funded by the National Institutes of Health, prospectively enrolled about 40 patients with posttraumatic OA of the ankle. They used the same ankle distraction technique as did Dr. Lafeber's group, but patients were randomized to distraction alone or with the addition of continuous passive joint motion.

Patients have been evaluated clinically and radiographically, and with a special three-dimensional CT scanning technique to look at cartilage regeneration.

All but three patients have now undergone 2- and 3-year evaluations, and the results thus far have been comparable to the results they have had in Utrecht in terms of relief of pain, according to Dr. Amendola. Additional improvements have been seen over time, and patients in the motion group did significantly better at every time point than did the non-motion group.

“I think this is quite an intriguing technique,” Dr. Amendola said.

Joint distraction, a surgical technique that involves the placement of an external fixation frame around a degenerated joint, may help postpone the need for total knee replacement in young patients with severe osteoarthritis.

The cartilage in end-stage OA is severely damaged, with fissuring; altered chondrocyte distribution and death; and a significant loss of extracellular matrix constituents. These changes in cartilage are accompanied by characteristic changes in periarticular bone and soft tissue. All these structural changes mean severe pain and functional limitations for patients, who typically rate their pain with a score of 80% out of a maximum of 100%, according to Dr. Floris P.J.G. Lafeber, of the University Medical Center Utrecht (the Netherlands).

The standard treatment for these patients is total knee replacement. However, “Total knee prostheses don't last forever,” Dr. Lafeber said. “They last on average 15 years, so if you have one placed at age 60 you are likely to need a replacement at 75, which is complicated and expensive, and the results are often disappointing. And then if you need another at age 90 the difficulties are really serious,” he said, adding that in the Netherlands, approximately 1,000 total knee prostheses are placed each year in patients younger than 60.

“This is a major socioeconomic problem and will only grow with the aging of the population,” he said.

The rationale for joint distraction lies in the hypothesis that osteoarthritic cartilage is capable of self-repair if the joint is unloaded and chondrocyte nutrition is maintained. Pins are drilled through the soft tissue and bone just above and below the joint, and when the frame is in place the distance between the cartilaginous surfaces of the joint is increased by 5 mm. This transfers the load and stresses on cartilage away from the joint, eliminating further wear and tear. Then, springs within the distraction frame cause changes to occur in fluid pressure in the joint, with increases during loading and normalization with unloading. This continuous change in fluid pressure is important for the cartilage, because chondrocytes depend on synovial flow for nutrition, Dr. Lafeber explained.

The loading onto the frame also results in periarticular osteopenia, which in turn permits the sclerotic, osteoarthritic bone to become more flexible and the mineral content to normalize once the frame is removed. Furthermore, the periarticular bone turnover results in the release of multiple growth factors that can help repair the cartilage.

In collaboration with his center's orthopedic department, Dr. Lafeber and his colleagues in the department of rheumatology and clinical immunology began exploring this technique in a proof-of-concept study with ankle distraction. Although ankle OA is much less common than knee OA, in the case of failure an arthrodesis could be performed without much risk, he said.

A total of 73 patients underwent ankle distraction for 3 months, with the result that pain scores—rated at an average of 75% of 100%—fell to 20%, while scores for function and clinical condition rose from 25% at baseline to 80%. Some of these patients now have been followed for as long as 10 years, with continuing benefits.

They next did a feasibility study that included three patients with knee OA, and found similar results on pain and function scores as well as on stiffness scores. They then undertook a larger prospective study in which 19 patients with severe knee OA (mean age, 48 years) have been treated with 2-month periods of distraction. Thus far, six have been followed for up to 2 years. Functional ability and clinical condition, poor at the onset with scores of 39% and 32%, respectively, increased to 82% and 81%.

Serum and urinary biomarkers of cartilage turnover were measured throughout a 12-month follow-up. During the distraction phase there was an enormous turnover, with elevations of markers of both synthesis and breakdown, but after the distraction phase there was a gradual decrease of breakdown markers and an increase in the markers of synthesis, indicating repair of the cartilage, Dr. Lafeber said.

Imaging studies also demonstrated improvements. In seven patients who have been followed for more than 12 months, joint space width shown on x-rays increased from slightly greater than 2.5 mm to more than 3.5 mm. “And on MRI studies done after 1 year and read in a blinded fashion in collaboration with Prof. Felix Eckstein, who is one of the leading researchers in this field, the amount of subchondral bone covered with cartilage was shown to have increased by 40%, cartilage volume increased by 50%, and cartilage thickness over the bone increased by 5%,” Dr. Lafeber said.

The overall conclusion is that joint distraction is clinically very effective in young patients with end-stage knee arthritis, with cartilage repair presumably responsible for the clinical benefit, he said. However, more prolonged follow-up is needed.

Some of the ankle patients have had a second distraction, but whether this will be feasible and advisable in the knee patients remains to be seen, because the follow-up is too short.

“It may be possible, and of course we hope [that] it's not just a delay before joint replacement, but that we can really cure the joint. That's only wishful thinking so far, though,” he said.

Dr. Lafeber acknowledged that his study was not placebo controlled.

“Of course it would be better to have a good control, which in this case would be placement of the complete frame but without the distraction,” he said.

Currently, however, they are offering this treatment only to patients with end-stage OA who otherwise would be considered for joint replacement. “We cannot ethically allow these patients to go without any treatment for 2 years,” he said.

Moreover, with benefits persisting for up to 10 years for the ankle patients, placebo effects are hardly likely to still be in play. “Maybe for the first year, because these patients are seeing their physicians more frequently than they would otherwise, but certainly after several years the placebo effect would have vanished,” he said.

This knee has OA at baseline on x-ray (top). Cartilage repaired itself after 2 years of treatment (bottom). Distraction may alleviate the need for total knee arthroplasty. Photos courtesy Dr. Floris P.J.G. Lafeber

Biomarkers of bone breakdown and synthesis increase during distraction. Courtesy Dr. Floris P.J.G. Lafeber

Iowa's Experience With Ankle OA

Ankle distraction also has been performed and is being evaluated in a randomized study led by Dr. Annunziato Amendola of the University of Iowa, Iowa City.

The study, funded by the National Institutes of Health, prospectively enrolled about 40 patients with posttraumatic OA of the ankle. They used the same ankle distraction technique as did Dr. Lafeber's group, but patients were randomized to distraction alone or with the addition of continuous passive joint motion.

Patients have been evaluated clinically and radiographically, and with a special three-dimensional CT scanning technique to look at cartilage regeneration.

All but three patients have now undergone 2- and 3-year evaluations, and the results thus far have been comparable to the results they have had in Utrecht in terms of relief of pain, according to Dr. Amendola. Additional improvements have been seen over time, and patients in the motion group did significantly better at every time point than did the non-motion group.

“I think this is quite an intriguing technique,” Dr. Amendola said.

PARIS — Factors that predict which patients with rheumatoid arthritis will achieve and maintain stable remission following treatment with traditional disease-modifying drugs include low body mass index, low erythrocyte sedimentation rate levels, and absence of anti-cyclic citrullinated peptide antibody at baseline.

“In light of the fact that remission is increasingly becoming an attainable goal in rheumatoid arthritis treatment, it would be useful to be able to predict which patients are likely to achieve remission in the long run, and so to be able to avoid overly aggressive treatment and the associated side effects,” Dr. Diane van der Woude said at the annual European Congress of Rheumatology.

Although some factors have been identified that predict the achievement of very low disease activity with biologic agents, little is known about the characteristics and predictive factors of patients who are treated with less aggressive, conventional disease-modifying antirheumatic drugs (DMARDs), said Dr. van der Woude of the department of rheumatology at Leiden (the Netherlands) University Medical Center.

Dr. van der Woude and colleagues analyzed clinical, laboratory, and genetic data from patients enrolled in an inception cohort at the Leiden Early Arthritis Clinic between 1993 and 2003.

Among more than 1,900 patients referred to the clinic, 454 were diagnosed with RA and treated with chloroquine, sulfasalazine, or methotrexate, she said.

Sustained remission, defined as the absence of synovitis for longer than 1 year without the use of DMARDs, was achieved by 69 of these patients (15%) with an average follow-up of 8 years.

Six patients who had originally been discharged from the clinic because of remission experienced a recurrence of synovitis and were excluded from the remission group.

Univariate analysis revealed that the following factors were significantly associated with less likelihood of achieving DMARD-free remission: positive family history (hazard ratio 0.56); high body mass index (HR 0.90); long duration of symptoms at presentation (HR 0.93); smoking (HR 0.55); and the presence of IgM rheumatoid factor (HR 0.17), anti-cyclic citrullinated peptide (CCP) antibodies (HR 0.09), and shared epitope alleles (HR 0.47).

Multivariate analysis identified older age, low body mass index, low erythrocyte sedimentation rate, short duration of symptoms, nonsmoking status, and the absence of anti-CCP antibodies as being independent predictors for achieving DMARD-free remission, she said.

These findings demonstrate that “several clinical factors that are routinely assessed in clinical practice are robust predictors of achieving stable remission,” Dr. van der Woude said.

PARIS — Factors that predict which patients with rheumatoid arthritis will achieve and maintain stable remission following treatment with traditional disease-modifying drugs include low body mass index, low erythrocyte sedimentation rate levels, and absence of anti-cyclic citrullinated peptide antibody at baseline.

“In light of the fact that remission is increasingly becoming an attainable goal in rheumatoid arthritis treatment, it would be useful to be able to predict which patients are likely to achieve remission in the long run, and so to be able to avoid overly aggressive treatment and the associated side effects,” Dr. Diane van der Woude said at the annual European Congress of Rheumatology.

Although some factors have been identified that predict the achievement of very low disease activity with biologic agents, little is known about the characteristics and predictive factors of patients who are treated with less aggressive, conventional disease-modifying antirheumatic drugs (DMARDs), said Dr. van der Woude of the department of rheumatology at Leiden (the Netherlands) University Medical Center.

Dr. van der Woude and colleagues analyzed clinical, laboratory, and genetic data from patients enrolled in an inception cohort at the Leiden Early Arthritis Clinic between 1993 and 2003.

Among more than 1,900 patients referred to the clinic, 454 were diagnosed with RA and treated with chloroquine, sulfasalazine, or methotrexate, she said.

Sustained remission, defined as the absence of synovitis for longer than 1 year without the use of DMARDs, was achieved by 69 of these patients (15%) with an average follow-up of 8 years.

Six patients who had originally been discharged from the clinic because of remission experienced a recurrence of synovitis and were excluded from the remission group.

Univariate analysis revealed that the following factors were significantly associated with less likelihood of achieving DMARD-free remission: positive family history (hazard ratio 0.56); high body mass index (HR 0.90); long duration of symptoms at presentation (HR 0.93); smoking (HR 0.55); and the presence of IgM rheumatoid factor (HR 0.17), anti-cyclic citrullinated peptide (CCP) antibodies (HR 0.09), and shared epitope alleles (HR 0.47).

Multivariate analysis identified older age, low body mass index, low erythrocyte sedimentation rate, short duration of symptoms, nonsmoking status, and the absence of anti-CCP antibodies as being independent predictors for achieving DMARD-free remission, she said.

These findings demonstrate that “several clinical factors that are routinely assessed in clinical practice are robust predictors of achieving stable remission,” Dr. van der Woude said.

PARIS — Factors that predict which patients with rheumatoid arthritis will achieve and maintain stable remission following treatment with traditional disease-modifying drugs include low body mass index, low erythrocyte sedimentation rate levels, and absence of anti-cyclic citrullinated peptide antibody at baseline.

“In light of the fact that remission is increasingly becoming an attainable goal in rheumatoid arthritis treatment, it would be useful to be able to predict which patients are likely to achieve remission in the long run, and so to be able to avoid overly aggressive treatment and the associated side effects,” Dr. Diane van der Woude said at the annual European Congress of Rheumatology.

Although some factors have been identified that predict the achievement of very low disease activity with biologic agents, little is known about the characteristics and predictive factors of patients who are treated with less aggressive, conventional disease-modifying antirheumatic drugs (DMARDs), said Dr. van der Woude of the department of rheumatology at Leiden (the Netherlands) University Medical Center.

Dr. van der Woude and colleagues analyzed clinical, laboratory, and genetic data from patients enrolled in an inception cohort at the Leiden Early Arthritis Clinic between 1993 and 2003.

Among more than 1,900 patients referred to the clinic, 454 were diagnosed with RA and treated with chloroquine, sulfasalazine, or methotrexate, she said.

Sustained remission, defined as the absence of synovitis for longer than 1 year without the use of DMARDs, was achieved by 69 of these patients (15%) with an average follow-up of 8 years.

Six patients who had originally been discharged from the clinic because of remission experienced a recurrence of synovitis and were excluded from the remission group.

Univariate analysis revealed that the following factors were significantly associated with less likelihood of achieving DMARD-free remission: positive family history (hazard ratio 0.56); high body mass index (HR 0.90); long duration of symptoms at presentation (HR 0.93); smoking (HR 0.55); and the presence of IgM rheumatoid factor (HR 0.17), anti-cyclic citrullinated peptide (CCP) antibodies (HR 0.09), and shared epitope alleles (HR 0.47).

Multivariate analysis identified older age, low body mass index, low erythrocyte sedimentation rate, short duration of symptoms, nonsmoking status, and the absence of anti-CCP antibodies as being independent predictors for achieving DMARD-free remission, she said.

These findings demonstrate that “several clinical factors that are routinely assessed in clinical practice are robust predictors of achieving stable remission,” Dr. van der Woude said.

PARIS — The addition of infliximab to intensive combination disease-modifying therapy in early rheumatoid arthritis resulted in higher rates of remission and no radiographic progression at 2 years in a placebo-controlled trial of 100 patients.

Combination therapy with methotrexate, sulfasalazine, and hydroxychloroquine plus prednisone has previously been shown to be associated with a remission rate of 37% in patients with early RA, Dr. Marjatta Leirisalo-Repo said at the annual European Congress of Rheumatology.

In the current trial of 100 patients with RA of less than 1 year's duration, the patients were randomized to the regimen in the Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial plus infliximab or placebo, to determine whether the addition of the tumor necrosis factor (TNF)-blocking agent would increase remission rates.

The intensive, remission-targeted FIN-RACo regimen includes individually tailored doses of methotrexate, up to 25 mg/wk, and sulfasalazine, at a maximum of 2 g/day, along with fixed doses of hydroxychloroquine (35 mg/kg per week) and prednisone (7.5 mg/day).

In addition to the combination disease-modifying antirheumatic drug (DMARD) regimen, patients received placebo or infliximab in doses of 3 mg/kg at weeks 4, 6, 10, 18, and 26, and were followed for 2 years.

At baseline, patients had active disease, said Dr. Leirisalo-Repo of the division of rheumatology at Helsinki University Central Hospital. The patients' mean age was 46 years, and the median duration of their symptoms was 4 months; 68% of the patients were rheumatoid factor positive, and 67% were female. The mean number of swollen joints was 15, the mean number of tender joints was 20, the mean erythrocyte sedimentation rate was 33 mm/hr, and the mean Health Assessment Questionnaire (HAQ) score was 1.

At 24 months, the remission rate was 53% among patients receiving the combination plus placebo regimen and 70% in the combination plus infliximab group. Sustained remission out to 24 months was seen in 31% and 40% of those in the placebo and infliximab groups, respectively.

“Patients in the infliximab group had an overall odds ratio of 2.24 for reaching remission,” Dr. Leirisalo-Repo said.

The median total Sharp/van der Heijde score was 0 at baseline in both groups. At 2 years, the score was 1.4 in the placebo group compared with 0.2 in the infliximab group, suggesting that there had been almost no radiographic progression in the infliximab group, she said.

Dr. Leirisalo-Repo disclosed that she has received research grants from Schering-Plough Finland and consulting fees from Centocor Inc., and that she holds nonremunerative positions of influence with Abbott Laboratories, Bristol-Myers Squibb Co., and Roche.

PARIS — The addition of infliximab to intensive combination disease-modifying therapy in early rheumatoid arthritis resulted in higher rates of remission and no radiographic progression at 2 years in a placebo-controlled trial of 100 patients.

Combination therapy with methotrexate, sulfasalazine, and hydroxychloroquine plus prednisone has previously been shown to be associated with a remission rate of 37% in patients with early RA, Dr. Marjatta Leirisalo-Repo said at the annual European Congress of Rheumatology.

In the current trial of 100 patients with RA of less than 1 year's duration, the patients were randomized to the regimen in the Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial plus infliximab or placebo, to determine whether the addition of the tumor necrosis factor (TNF)-blocking agent would increase remission rates.

The intensive, remission-targeted FIN-RACo regimen includes individually tailored doses of methotrexate, up to 25 mg/wk, and sulfasalazine, at a maximum of 2 g/day, along with fixed doses of hydroxychloroquine (35 mg/kg per week) and prednisone (7.5 mg/day).

In addition to the combination disease-modifying antirheumatic drug (DMARD) regimen, patients received placebo or infliximab in doses of 3 mg/kg at weeks 4, 6, 10, 18, and 26, and were followed for 2 years.

At baseline, patients had active disease, said Dr. Leirisalo-Repo of the division of rheumatology at Helsinki University Central Hospital. The patients' mean age was 46 years, and the median duration of their symptoms was 4 months; 68% of the patients were rheumatoid factor positive, and 67% were female. The mean number of swollen joints was 15, the mean number of tender joints was 20, the mean erythrocyte sedimentation rate was 33 mm/hr, and the mean Health Assessment Questionnaire (HAQ) score was 1.

At 24 months, the remission rate was 53% among patients receiving the combination plus placebo regimen and 70% in the combination plus infliximab group. Sustained remission out to 24 months was seen in 31% and 40% of those in the placebo and infliximab groups, respectively.

“Patients in the infliximab group had an overall odds ratio of 2.24 for reaching remission,” Dr. Leirisalo-Repo said.

The median total Sharp/van der Heijde score was 0 at baseline in both groups. At 2 years, the score was 1.4 in the placebo group compared with 0.2 in the infliximab group, suggesting that there had been almost no radiographic progression in the infliximab group, she said.

Dr. Leirisalo-Repo disclosed that she has received research grants from Schering-Plough Finland and consulting fees from Centocor Inc., and that she holds nonremunerative positions of influence with Abbott Laboratories, Bristol-Myers Squibb Co., and Roche.

PARIS — The addition of infliximab to intensive combination disease-modifying therapy in early rheumatoid arthritis resulted in higher rates of remission and no radiographic progression at 2 years in a placebo-controlled trial of 100 patients.

Combination therapy with methotrexate, sulfasalazine, and hydroxychloroquine plus prednisone has previously been shown to be associated with a remission rate of 37% in patients with early RA, Dr. Marjatta Leirisalo-Repo said at the annual European Congress of Rheumatology.

In the current trial of 100 patients with RA of less than 1 year's duration, the patients were randomized to the regimen in the Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial plus infliximab or placebo, to determine whether the addition of the tumor necrosis factor (TNF)-blocking agent would increase remission rates.

The intensive, remission-targeted FIN-RACo regimen includes individually tailored doses of methotrexate, up to 25 mg/wk, and sulfasalazine, at a maximum of 2 g/day, along with fixed doses of hydroxychloroquine (35 mg/kg per week) and prednisone (7.5 mg/day).

In addition to the combination disease-modifying antirheumatic drug (DMARD) regimen, patients received placebo or infliximab in doses of 3 mg/kg at weeks 4, 6, 10, 18, and 26, and were followed for 2 years.

At baseline, patients had active disease, said Dr. Leirisalo-Repo of the division of rheumatology at Helsinki University Central Hospital. The patients' mean age was 46 years, and the median duration of their symptoms was 4 months; 68% of the patients were rheumatoid factor positive, and 67% were female. The mean number of swollen joints was 15, the mean number of tender joints was 20, the mean erythrocyte sedimentation rate was 33 mm/hr, and the mean Health Assessment Questionnaire (HAQ) score was 1.

At 24 months, the remission rate was 53% among patients receiving the combination plus placebo regimen and 70% in the combination plus infliximab group. Sustained remission out to 24 months was seen in 31% and 40% of those in the placebo and infliximab groups, respectively.

“Patients in the infliximab group had an overall odds ratio of 2.24 for reaching remission,” Dr. Leirisalo-Repo said.

The median total Sharp/van der Heijde score was 0 at baseline in both groups. At 2 years, the score was 1.4 in the placebo group compared with 0.2 in the infliximab group, suggesting that there had been almost no radiographic progression in the infliximab group, she said.

Dr. Leirisalo-Repo disclosed that she has received research grants from Schering-Plough Finland and consulting fees from Centocor Inc., and that she holds nonremunerative positions of influence with Abbott Laboratories, Bristol-Myers Squibb Co., and Roche.

A 1-hour plasma glucose concentration higher than 155 mg/dL measured during an oral glucose tolerance test, plus the presence of the metabolic syndrome, strongly predicts future risk for type 2 diabetes in subjects with normal glucose tolerance, according to the results of a large population-based epidemiologic study.

Reliable models for identifying people at risk for the development of type 2 diabetes are essential, because lifestyle changes and pharmacologic interventions can reduce the likelihood that the disease will develop, according to the study, which was published in Diabetes Care.

The researchers used a classification tree model that can stratify risk for nondiabetics with risk factors such as obesity, dyslipidemia, and hypertension based on their 1-hour glucose concentration. The model was previously demonstrated to be a better predictor for future type 2 diabetes than fasting plasma glucose or the 2-hour plasma glucose concentration, according to Dr. Muhammad A. Abdul-Ghani and colleagues in the divisions of diabetes and epidemiology, University of Texas Health Science Center at San Antonio.

They tested the model in a study population of 1,611 adults from the population-based San Antonio Heart Study. All patients had oral glucose tolerance tests at baseline and again at follow-up, 7–8 years later.

None had diabetes at baseline, but 90 had impaired fasting glucose (IFG), 220 had impaired glucose tolerance (IGT), and 51 of the 220 with IGT also had IFG and were designated as having combined glucose intolerance (CGI).

During the 7- to 8-year follow-up period, the conversion rate to diabetes was 5% for those who had normal glucose tolerance at baseline, 26.1% for those with IFG, 30.9% for those with IGT, and 82.3% for those with CGI.

Patients were partitioned in the classification tree according to whether their 1-hour plasma glucose concentration was above or below 155 mg/dL, and stratified as being at low risk for future diabetes, with an annual risk below 0.5%; at intermediate risk, with an annual risk of 1–2%; or at high risk, with an annual risk greater than 4%.

Analysis revealed that in patients with normal glucose tolerance, the annual risk for future type 2 diabetes was significantly higher, at 2.2%, in those whose 1-hour plasma glucose concentration was higher than 155 mg/dL, than for those with concentrations below this level, whose risk was 0.39% per year.

For those with normal glucose tolerance whose glucose concentration was higher than 155 mg/dL and who also had metabolic syndrome, the annual risk was very high, at 4.3%.

Their odds ratio for developing diabetes, at 15.2, is double that of patients with IGT whose 1-hour plasma glucose is below 155 mg/dL. “This group of high-risk individuals [with normal glucose tolerance] could benefit from an intervention program employing diet, exercise, and pharmacotherapy (metformin) to reduce future risk for diabetes,” Dr. Abdul-Ghani and colleagues wrote (Diabetes Care 2008;31:1650–5).

The investigators also noted that their model is better at predicting risk than is the American Diabetes Association criteria of IGT or IFG. “About 17% of normal glucose-tolerant subjects, who have immediate and high risk for future type 2 diabetes and who were identified with the 1-h plasma glucose plus metabolic syndrome, would have been missed with the American Diabetes Association criteria alone,” they wrote.

A 1-hour plasma glucose concentration higher than 155 mg/dL measured during an oral glucose tolerance test, plus the presence of the metabolic syndrome, strongly predicts future risk for type 2 diabetes in subjects with normal glucose tolerance, according to the results of a large population-based epidemiologic study.

Reliable models for identifying people at risk for the development of type 2 diabetes are essential, because lifestyle changes and pharmacologic interventions can reduce the likelihood that the disease will develop, according to the study, which was published in Diabetes Care.

The researchers used a classification tree model that can stratify risk for nondiabetics with risk factors such as obesity, dyslipidemia, and hypertension based on their 1-hour glucose concentration. The model was previously demonstrated to be a better predictor for future type 2 diabetes than fasting plasma glucose or the 2-hour plasma glucose concentration, according to Dr. Muhammad A. Abdul-Ghani and colleagues in the divisions of diabetes and epidemiology, University of Texas Health Science Center at San Antonio.

They tested the model in a study population of 1,611 adults from the population-based San Antonio Heart Study. All patients had oral glucose tolerance tests at baseline and again at follow-up, 7–8 years later.

None had diabetes at baseline, but 90 had impaired fasting glucose (IFG), 220 had impaired glucose tolerance (IGT), and 51 of the 220 with IGT also had IFG and were designated as having combined glucose intolerance (CGI).

During the 7- to 8-year follow-up period, the conversion rate to diabetes was 5% for those who had normal glucose tolerance at baseline, 26.1% for those with IFG, 30.9% for those with IGT, and 82.3% for those with CGI.

Patients were partitioned in the classification tree according to whether their 1-hour plasma glucose concentration was above or below 155 mg/dL, and stratified as being at low risk for future diabetes, with an annual risk below 0.5%; at intermediate risk, with an annual risk of 1–2%; or at high risk, with an annual risk greater than 4%.

Analysis revealed that in patients with normal glucose tolerance, the annual risk for future type 2 diabetes was significantly higher, at 2.2%, in those whose 1-hour plasma glucose concentration was higher than 155 mg/dL, than for those with concentrations below this level, whose risk was 0.39% per year.

For those with normal glucose tolerance whose glucose concentration was higher than 155 mg/dL and who also had metabolic syndrome, the annual risk was very high, at 4.3%.

Their odds ratio for developing diabetes, at 15.2, is double that of patients with IGT whose 1-hour plasma glucose is below 155 mg/dL. “This group of high-risk individuals [with normal glucose tolerance] could benefit from an intervention program employing diet, exercise, and pharmacotherapy (metformin) to reduce future risk for diabetes,” Dr. Abdul-Ghani and colleagues wrote (Diabetes Care 2008;31:1650–5).

The investigators also noted that their model is better at predicting risk than is the American Diabetes Association criteria of IGT or IFG. “About 17% of normal glucose-tolerant subjects, who have immediate and high risk for future type 2 diabetes and who were identified with the 1-h plasma glucose plus metabolic syndrome, would have been missed with the American Diabetes Association criteria alone,” they wrote.

A 1-hour plasma glucose concentration higher than 155 mg/dL measured during an oral glucose tolerance test, plus the presence of the metabolic syndrome, strongly predicts future risk for type 2 diabetes in subjects with normal glucose tolerance, according to the results of a large population-based epidemiologic study.

Reliable models for identifying people at risk for the development of type 2 diabetes are essential, because lifestyle changes and pharmacologic interventions can reduce the likelihood that the disease will develop, according to the study, which was published in Diabetes Care.

The researchers used a classification tree model that can stratify risk for nondiabetics with risk factors such as obesity, dyslipidemia, and hypertension based on their 1-hour glucose concentration. The model was previously demonstrated to be a better predictor for future type 2 diabetes than fasting plasma glucose or the 2-hour plasma glucose concentration, according to Dr. Muhammad A. Abdul-Ghani and colleagues in the divisions of diabetes and epidemiology, University of Texas Health Science Center at San Antonio.

They tested the model in a study population of 1,611 adults from the population-based San Antonio Heart Study. All patients had oral glucose tolerance tests at baseline and again at follow-up, 7–8 years later.

None had diabetes at baseline, but 90 had impaired fasting glucose (IFG), 220 had impaired glucose tolerance (IGT), and 51 of the 220 with IGT also had IFG and were designated as having combined glucose intolerance (CGI).

During the 7- to 8-year follow-up period, the conversion rate to diabetes was 5% for those who had normal glucose tolerance at baseline, 26.1% for those with IFG, 30.9% for those with IGT, and 82.3% for those with CGI.

Patients were partitioned in the classification tree according to whether their 1-hour plasma glucose concentration was above or below 155 mg/dL, and stratified as being at low risk for future diabetes, with an annual risk below 0.5%; at intermediate risk, with an annual risk of 1–2%; or at high risk, with an annual risk greater than 4%.

Analysis revealed that in patients with normal glucose tolerance, the annual risk for future type 2 diabetes was significantly higher, at 2.2%, in those whose 1-hour plasma glucose concentration was higher than 155 mg/dL, than for those with concentrations below this level, whose risk was 0.39% per year.

For those with normal glucose tolerance whose glucose concentration was higher than 155 mg/dL and who also had metabolic syndrome, the annual risk was very high, at 4.3%.

Their odds ratio for developing diabetes, at 15.2, is double that of patients with IGT whose 1-hour plasma glucose is below 155 mg/dL. “This group of high-risk individuals [with normal glucose tolerance] could benefit from an intervention program employing diet, exercise, and pharmacotherapy (metformin) to reduce future risk for diabetes,” Dr. Abdul-Ghani and colleagues wrote (Diabetes Care 2008;31:1650–5).

The investigators also noted that their model is better at predicting risk than is the American Diabetes Association criteria of IGT or IFG. “About 17% of normal glucose-tolerant subjects, who have immediate and high risk for future type 2 diabetes and who were identified with the 1-h plasma glucose plus metabolic syndrome, would have been missed with the American Diabetes Association criteria alone,” they wrote.

The epidemic of immune diseases that swept through the developed world during the 20th century may have resulted from a disruption in the delicate balance achieved throughout evolution between humans and certain parasitic fellow travelers, according to Dr. Joel V. Weinstock.

Diseases such as inflammatory bowel disease (IBD) were rare before the 1920s, when public health efforts began making significant strides in cleaning up the water supply, modernizing sewage treatment, and improving farming practices. While these efforts clearly had major benefits in curtailing or eliminating exposure to many disease-causing pathogens, they also had the unintended consequence of removing exposure to beneficial or even necessary organisms.

“People today live very differently than they did throughout history. People used to live close to the soil, without indoor plumbing, often with direct exposure to animals,” said Dr. Weinstock, professor of medicine, Tufts Medical Center and Tufts University Sackler School of Graduate Biomedical Sciences, Boston.

The result was near universal colonization with helminths, which are complex wormlike animals that inhabit the gastrointestinal tract of mammals. Like the myriad bacteria also found in the gut performing important tasks such as producing vitamins and aiding in digestion, some helminths can cause disease in the host but many are relatively harmless and, in fact, are important regulators of our immune systems.

“We have known for many years that helminths exert a powerful effect on immunity in the host, primarily by inducing the regulatory arm of the immune system, which is important in reigning in the effector 'fight and kill' arm of the immune system,” he said. The regulatory arm hones and shapes the immune response to bacteria, viruses, and parasites, quelling the effects of the effector arm so as to prevent needless tissue damage.

At least one rheumatologist was skeptical. “This is an interesting theory—but just that. We need more documentation,” said Dr. Roy D. Altman, professor of medicine, rheumatology, and immunology at the University of California, Los Angeles, in an interview. “In addition, longevity increases with the elimination of parasites. It may be that people are living longer and this allows them to get immune diseases like rheumatoid arthritis.”

When other researchers were investigating possible environmental causes for the increase in these diseases, such as exposure to food dyes or from vaccinations, Dr. Weinstock took a different approach, looking for something in the environment that had been protective and had been lost. “It occurred to us that the deworming of the population—a major public health project early in the 20th century—took place at the same time as the incidence of immunologic diseases really took off,” he said.

Moreover, diseases such as asthma, IBD, rheumatoid arthritis, and multiple sclerosis remain uncommon in less-developed parts of the world where helminthic colonization is still widespread.

Because Dr. Weinstock is a gastroenterologist with a special interest in immunology, his subsequent investigations in animals and humans have focused on IBD.

In a pilot study of 29 adult patients with longstanding, refractory Crohn's disease, patients were given a drink containing 2,500 specially prepared ova of Trichuris suis, the pig whipworm, every 3 weeks for 24 weeks. Ingestion of this helminth, which is similar to the human whipworm, causes a short-term colonization in the human gastrointestinal tract.

By the 12th week, 22 patients (76%) had responded to the treatment, with a decrease in the Crohn's disease activity index (CDAI) of more than 100 points or below 150, and 19 patients (66%) were in remission, with a CDAI below 150. At the 24th week, 23 patients (79%) were responders and 21 (72%) were in remission (Gut 2005;54:87-90).

In a subsequent double-blind trial that enrolled 54 adult patients with ulcerative colitis, participants received 2,500 T. suis ova in a liquid drink or a placebo drink every 2 weeks for 12 weeks.

Favorable responses, with decreases in the ulcerative colitis disease activity index of 4 or more points on an index ranging from 0 to 12, were seen in 13 patients receiving the active treatment (43%) compared with 4 receiving placebo (17%).

Similar findings have been shown in several other autoimmune conditions. Prospective data have shown that children with helminths are less likely to develop allergies, and disease has been arrested in patients with multiple sclerosis following helminth colonization.

Dr. Weinstock believes that helminths and human hosts evolved to the benefit of both over millennia. Petrified human stool many thousands of years old has been found to contain helminth eggs, and autopsies of mummies have found traces of helminths. The frozen iceman Ötzi, found in the northern Italian Alps in 1991 where he had lain buried in a glacier since 3300 B.C., had T. trichiura in his gut.

“We are teeming with life, and we really are part of the environment. When we try to separate ourselves from the environment and exposures to these organisms, we leave ourselves predisposed to disease,” he said.

Dr. Weinstock is not advocating a return to 19th-century hygiene. Rather, he and other researchers are working to characterize more fully the interaction of helminths with the immune system and to identify factors responsible for the beneficial exposures so they can be reintroduced at an appropriate time early in life, when the immune system is developing. Clinical studies in IBD, asthma, rhinoconjunctivitis, and multiple sclerosis are underway and more are planned, and one helminth-derived medication, ASP1002, is under review by the Food and Drug Administration.

“There has been a revolution in our thinking,” Dr. Weinstock said. “We have learned that we are not insulated from the world around us.”

Helminth colonization appeared beneficial in Crohn's disease and other disorders. Courtesy Dr. Joel V. Weinstock

The epidemic of immune diseases that swept through the developed world during the 20th century may have resulted from a disruption in the delicate balance achieved throughout evolution between humans and certain parasitic fellow travelers, according to Dr. Joel V. Weinstock.

Diseases such as inflammatory bowel disease (IBD) were rare before the 1920s, when public health efforts began making significant strides in cleaning up the water supply, modernizing sewage treatment, and improving farming practices. While these efforts clearly had major benefits in curtailing or eliminating exposure to many disease-causing pathogens, they also had the unintended consequence of removing exposure to beneficial or even necessary organisms.

“People today live very differently than they did throughout history. People used to live close to the soil, without indoor plumbing, often with direct exposure to animals,” said Dr. Weinstock, professor of medicine, Tufts Medical Center and Tufts University Sackler School of Graduate Biomedical Sciences, Boston.

The result was near universal colonization with helminths, which are complex wormlike animals that inhabit the gastrointestinal tract of mammals. Like the myriad bacteria also found in the gut performing important tasks such as producing vitamins and aiding in digestion, some helminths can cause disease in the host but many are relatively harmless and, in fact, are important regulators of our immune systems.

“We have known for many years that helminths exert a powerful effect on immunity in the host, primarily by inducing the regulatory arm of the immune system, which is important in reigning in the effector 'fight and kill' arm of the immune system,” he said. The regulatory arm hones and shapes the immune response to bacteria, viruses, and parasites, quelling the effects of the effector arm so as to prevent needless tissue damage.

At least one rheumatologist was skeptical. “This is an interesting theory—but just that. We need more documentation,” said Dr. Roy D. Altman, professor of medicine, rheumatology, and immunology at the University of California, Los Angeles, in an interview. “In addition, longevity increases with the elimination of parasites. It may be that people are living longer and this allows them to get immune diseases like rheumatoid arthritis.”

When other researchers were investigating possible environmental causes for the increase in these diseases, such as exposure to food dyes or from vaccinations, Dr. Weinstock took a different approach, looking for something in the environment that had been protective and had been lost. “It occurred to us that the deworming of the population—a major public health project early in the 20th century—took place at the same time as the incidence of immunologic diseases really took off,” he said.

Moreover, diseases such as asthma, IBD, rheumatoid arthritis, and multiple sclerosis remain uncommon in less-developed parts of the world where helminthic colonization is still widespread.

Because Dr. Weinstock is a gastroenterologist with a special interest in immunology, his subsequent investigations in animals and humans have focused on IBD.

In a pilot study of 29 adult patients with longstanding, refractory Crohn's disease, patients were given a drink containing 2,500 specially prepared ova of Trichuris suis, the pig whipworm, every 3 weeks for 24 weeks. Ingestion of this helminth, which is similar to the human whipworm, causes a short-term colonization in the human gastrointestinal tract.

By the 12th week, 22 patients (76%) had responded to the treatment, with a decrease in the Crohn's disease activity index (CDAI) of more than 100 points or below 150, and 19 patients (66%) were in remission, with a CDAI below 150. At the 24th week, 23 patients (79%) were responders and 21 (72%) were in remission (Gut 2005;54:87-90).

In a subsequent double-blind trial that enrolled 54 adult patients with ulcerative colitis, participants received 2,500 T. suis ova in a liquid drink or a placebo drink every 2 weeks for 12 weeks.

Favorable responses, with decreases in the ulcerative colitis disease activity index of 4 or more points on an index ranging from 0 to 12, were seen in 13 patients receiving the active treatment (43%) compared with 4 receiving placebo (17%).

Similar findings have been shown in several other autoimmune conditions. Prospective data have shown that children with helminths are less likely to develop allergies, and disease has been arrested in patients with multiple sclerosis following helminth colonization.

Dr. Weinstock believes that helminths and human hosts evolved to the benefit of both over millennia. Petrified human stool many thousands of years old has been found to contain helminth eggs, and autopsies of mummies have found traces of helminths. The frozen iceman Ötzi, found in the northern Italian Alps in 1991 where he had lain buried in a glacier since 3300 B.C., had T. trichiura in his gut.

“We are teeming with life, and we really are part of the environment. When we try to separate ourselves from the environment and exposures to these organisms, we leave ourselves predisposed to disease,” he said.

Dr. Weinstock is not advocating a return to 19th-century hygiene. Rather, he and other researchers are working to characterize more fully the interaction of helminths with the immune system and to identify factors responsible for the beneficial exposures so they can be reintroduced at an appropriate time early in life, when the immune system is developing. Clinical studies in IBD, asthma, rhinoconjunctivitis, and multiple sclerosis are underway and more are planned, and one helminth-derived medication, ASP1002, is under review by the Food and Drug Administration.

“There has been a revolution in our thinking,” Dr. Weinstock said. “We have learned that we are not insulated from the world around us.”

Helminth colonization appeared beneficial in Crohn's disease and other disorders. Courtesy Dr. Joel V. Weinstock

The epidemic of immune diseases that swept through the developed world during the 20th century may have resulted from a disruption in the delicate balance achieved throughout evolution between humans and certain parasitic fellow travelers, according to Dr. Joel V. Weinstock.

Diseases such as inflammatory bowel disease (IBD) were rare before the 1920s, when public health efforts began making significant strides in cleaning up the water supply, modernizing sewage treatment, and improving farming practices. While these efforts clearly had major benefits in curtailing or eliminating exposure to many disease-causing pathogens, they also had the unintended consequence of removing exposure to beneficial or even necessary organisms.

“People today live very differently than they did throughout history. People used to live close to the soil, without indoor plumbing, often with direct exposure to animals,” said Dr. Weinstock, professor of medicine, Tufts Medical Center and Tufts University Sackler School of Graduate Biomedical Sciences, Boston.

The result was near universal colonization with helminths, which are complex wormlike animals that inhabit the gastrointestinal tract of mammals. Like the myriad bacteria also found in the gut performing important tasks such as producing vitamins and aiding in digestion, some helminths can cause disease in the host but many are relatively harmless and, in fact, are important regulators of our immune systems.

“We have known for many years that helminths exert a powerful effect on immunity in the host, primarily by inducing the regulatory arm of the immune system, which is important in reigning in the effector 'fight and kill' arm of the immune system,” he said. The regulatory arm hones and shapes the immune response to bacteria, viruses, and parasites, quelling the effects of the effector arm so as to prevent needless tissue damage.

At least one rheumatologist was skeptical. “This is an interesting theory—but just that. We need more documentation,” said Dr. Roy D. Altman, professor of medicine, rheumatology, and immunology at the University of California, Los Angeles, in an interview. “In addition, longevity increases with the elimination of parasites. It may be that people are living longer and this allows them to get immune diseases like rheumatoid arthritis.”

When other researchers were investigating possible environmental causes for the increase in these diseases, such as exposure to food dyes or from vaccinations, Dr. Weinstock took a different approach, looking for something in the environment that had been protective and had been lost. “It occurred to us that the deworming of the population—a major public health project early in the 20th century—took place at the same time as the incidence of immunologic diseases really took off,” he said.

Moreover, diseases such as asthma, IBD, rheumatoid arthritis, and multiple sclerosis remain uncommon in less-developed parts of the world where helminthic colonization is still widespread.

Because Dr. Weinstock is a gastroenterologist with a special interest in immunology, his subsequent investigations in animals and humans have focused on IBD.

In a pilot study of 29 adult patients with longstanding, refractory Crohn's disease, patients were given a drink containing 2,500 specially prepared ova of Trichuris suis, the pig whipworm, every 3 weeks for 24 weeks. Ingestion of this helminth, which is similar to the human whipworm, causes a short-term colonization in the human gastrointestinal tract.

By the 12th week, 22 patients (76%) had responded to the treatment, with a decrease in the Crohn's disease activity index (CDAI) of more than 100 points or below 150, and 19 patients (66%) were in remission, with a CDAI below 150. At the 24th week, 23 patients (79%) were responders and 21 (72%) were in remission (Gut 2005;54:87-90).

In a subsequent double-blind trial that enrolled 54 adult patients with ulcerative colitis, participants received 2,500 T. suis ova in a liquid drink or a placebo drink every 2 weeks for 12 weeks.

Favorable responses, with decreases in the ulcerative colitis disease activity index of 4 or more points on an index ranging from 0 to 12, were seen in 13 patients receiving the active treatment (43%) compared with 4 receiving placebo (17%).

Similar findings have been shown in several other autoimmune conditions. Prospective data have shown that children with helminths are less likely to develop allergies, and disease has been arrested in patients with multiple sclerosis following helminth colonization.

Dr. Weinstock believes that helminths and human hosts evolved to the benefit of both over millennia. Petrified human stool many thousands of years old has been found to contain helminth eggs, and autopsies of mummies have found traces of helminths. The frozen iceman Ötzi, found in the northern Italian Alps in 1991 where he had lain buried in a glacier since 3300 B.C., had T. trichiura in his gut.

“We are teeming with life, and we really are part of the environment. When we try to separate ourselves from the environment and exposures to these organisms, we leave ourselves predisposed to disease,” he said.

Dr. Weinstock is not advocating a return to 19th-century hygiene. Rather, he and other researchers are working to characterize more fully the interaction of helminths with the immune system and to identify factors responsible for the beneficial exposures so they can be reintroduced at an appropriate time early in life, when the immune system is developing. Clinical studies in IBD, asthma, rhinoconjunctivitis, and multiple sclerosis are underway and more are planned, and one helminth-derived medication, ASP1002, is under review by the Food and Drug Administration.

“There has been a revolution in our thinking,” Dr. Weinstock said. “We have learned that we are not insulated from the world around us.”

Helminth colonization appeared beneficial in Crohn's disease and other disorders. Courtesy Dr. Joel V. Weinstock

NEW YORK — More questions than answers remain regarding the use of methotrexate for giant cell arteritis and polymyalgia rheumatica, despite international efforts to identify a therapeutic approach that could avoid the adverse consequences of long-term corticosteroid use in the vulnerable population afflicted by these conditions.

Prednisone has long been the mainstay of treatment for patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR), disorders that are seen almost exclusively in patients older than 50 years, and it is clearly effective in reducing inflammation and controlling disease. The corticosteroid typically must be administered for at least 1–2 years, however, which places patients at risk for adverse effects such as osteoporosis, cataracts, hypertension, and hyperglycemia.

In one series of 124 PMR patients who were treated with an average daily dose of 9.6 mg prednisone for 1.6 years, 65% experienced at least one adverse event, said Dr. Marco A. Cimmino of the University of Genoa (Italy).

Methotrexate has been widely used in PMR, although early experience, which was largely uncontrolled, provided inconclusive results, Dr. Cimmino said at the Fourth International Conference on Giant Cell Arteritis and Polymyalgia Rheumatica.

In order to more clearly establish an evidence base for the use of methotrexate in PMR, a double-blind trial was done by the systemic vasculitis study group of the Italian Society for Rheumatology. The trial randomized 72 patients with newly diagnosed PMR to prednisone in initial dosages of 25 mg/day, plus either methotrexate (10 mg/week) or placebo for 48 weeks. Prednisone was tapered within 24 weeks and resumed if flare occurred.

The mean age was 72 years, two-thirds were women, and 62 patients completed the study (Ann. Intern. Med. 2004;141:493–500).

At 76 weeks, the proportion of patients who were steroid free was higher in the methotrexate group than in the placebo group, with 28 of 32 patients on methotrexate having discontinued prednisone, compared with 16 of 30 patients on placebo.

The effect of treatment also was positive: Patients receiving methotrexate also had fewer relapses, the duration of prednisone therapy was shorter, and the total dose of prednisone was significantly lower, Dr. Cimmino said.

“However, when we looked at adverse events, there was no difference between treated patients and controls, and because steroid-sparing agents are used primarily to avoid steroid-related toxicity, in this sense the study was not successful,” he said.

Possible explanations for the negative result were the very narrow difference in cumulative prednisone dose between patients and controls, the overall low incidence of adverse events that were seen in the relatively healthy patients who were selected for inclusion in clinical trials, and the short duration of follow-up.

“For this last reason, we decided to review the charts of participating patients and revisit them 5 years after completion of the study,” Dr. Cimmino said.

In all, 29 methotrexate-treated patients and 28 placebo-treated patients were available for evaluation.

At the time of reevaluation, there were no differences in clinical and laboratory findings between the two groups, except for levels of C-reactive protein, which were higher in the placebo group (10.2 mg/dL), compared with those of the methotrexate group (2.7 mg/dL) (Clin. Exp. Rheum. 2008;26:395–400).

“This suggested that perhaps there was more residual disease activity and more inflammation in patients who did not receive methotrexate,” he said.

However, once again there were no differences in the incidence of steroid-related adverse events between treated patients and controls.

“Our conclusion was that we have many unanswered or incompletely answered questions,” he said. “What dosage of methotrexate to use? We used 10 mg, but many of you have suggested that 20 mg would be more appropriate,” Dr. Cimmino said.

Other questions include when to initiate methotrexate—at the same time as steroids are begun, or later, if response is inadequate?—and whether it may be more useful in certain subsets of PMR patients, such as those who also have vasculitis. Finally, more studies are needed if efficacy is to be demonstrated in real-life experience with sicker patients, he said at the meeting, which was sponsored by the Hospital for Special Surgery.

Clinical experience with methotrexate in GCA also was reviewed at the meeting by Dr. Alfred D. Mahr of Hópital Cochin, Paris.

As with PMR, studies of adjunctive methotrexate in GCA have yielded conflicting and inconclusive results. Numbers have been small, so a meta-analysis was undertaken to pool the data, according to Dr. Mahr.

Three randomized trials that included 161 patients were included in the meta-analysis, which found that methotrexate in dosages of 7.5–15 mg/week reduced first and second relapses by 35% and 51%, respectively.

Adjunctive methotrexate also cut cumulative steroid exposure and increased the probability of achieving a sustained 24-week discontinuation of steroids (Arthritis Rheum. 2007;56:2789–97).

The meta-analysis had limitations, Dr. Mahr said, including small numbers of patients and short follow-ups. As with the PMR trial, there were no differences in adverse events between the treatment and control groups.

“Methotrexate could be considered as a therapeutic option for patients with GCA, particularly for those who are at high risk for corticosteroid-related adverse events,” Dr. Mahr said.

This conclusion has recently been affirmed in a recommendation from the European League Against Rheumatism: “A meta-analysis of these three trials demonstrates a modest role for methotrexate (10–15 mg/week) in reducing relapse rate and lowering the cumulative dose of glucocorticoid therapy. … We recommend that an immunosuppressive agent should be considered for use in large vessel vasculitis as adjunctive therapy” (Ann. Rheum. Dis. 2008 April 15 [doi:10.1136/ard.2008.088351]).

Following the presentation, Dr. Gary Hoffman of the Cleveland Clinic stated that he did not agree with the conclusions of the study, noting that there was “enormous heterogeneity” in terms of study design, and significant differences in methotrexate doses and in the timing of the addition of methotrexate. “And ultimately, even if you buy into the validity of the meta-analysis, you are still left with patients with no differences in corticosteroid-related or methotrexate-related adverse events,” said Dr. Hoffman, who is Harold C. Schott Chair of Rheumatic and Immunological Diseases and professor of medicine at Case Western Reserve University, Cleveland.

He went on to say, “Given that we know methotrexate can cause problems such as pneumonitis, which can sometimes be a fatal disease, and that pneumonitis can occur in 1%–5% of patients who are treated with methotrexate, there may not have been enough patients in the individual studies to identify those one or two who might be affected. With just one such patient in the methotrexate group, our view of the outcome would be considerably different,” he said.

In a subsequent interview, session cochair Dr. Robert F. Spiera of Cornell University, New York, said that although there may be some justification for the use of methotrexate in these conditions, “it clearly is not the standard of care.”

“There has never been an unequivocally powerful signal for efficacy, and if you have to treat 11 or 12 patients to prevent one relapse, you are giving methotrexate to a lot of older patients who could have adverse events,” said Dr. Spiera, also director of the scleroderma and vasculitis program at the Hospital for Special Surgery, New York.

NEW YORK — More questions than answers remain regarding the use of methotrexate for giant cell arteritis and polymyalgia rheumatica, despite international efforts to identify a therapeutic approach that could avoid the adverse consequences of long-term corticosteroid use in the vulnerable population afflicted by these conditions.

Prednisone has long been the mainstay of treatment for patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR), disorders that are seen almost exclusively in patients older than 50 years, and it is clearly effective in reducing inflammation and controlling disease. The corticosteroid typically must be administered for at least 1–2 years, however, which places patients at risk for adverse effects such as osteoporosis, cataracts, hypertension, and hyperglycemia.

In one series of 124 PMR patients who were treated with an average daily dose of 9.6 mg prednisone for 1.6 years, 65% experienced at least one adverse event, said Dr. Marco A. Cimmino of the University of Genoa (Italy).

Methotrexate has been widely used in PMR, although early experience, which was largely uncontrolled, provided inconclusive results, Dr. Cimmino said at the Fourth International Conference on Giant Cell Arteritis and Polymyalgia Rheumatica.

In order to more clearly establish an evidence base for the use of methotrexate in PMR, a double-blind trial was done by the systemic vasculitis study group of the Italian Society for Rheumatology. The trial randomized 72 patients with newly diagnosed PMR to prednisone in initial dosages of 25 mg/day, plus either methotrexate (10 mg/week) or placebo for 48 weeks. Prednisone was tapered within 24 weeks and resumed if flare occurred.

The mean age was 72 years, two-thirds were women, and 62 patients completed the study (Ann. Intern. Med. 2004;141:493–500).

At 76 weeks, the proportion of patients who were steroid free was higher in the methotrexate group than in the placebo group, with 28 of 32 patients on methotrexate having discontinued prednisone, compared with 16 of 30 patients on placebo.

The effect of treatment also was positive: Patients receiving methotrexate also had fewer relapses, the duration of prednisone therapy was shorter, and the total dose of prednisone was significantly lower, Dr. Cimmino said.

“However, when we looked at adverse events, there was no difference between treated patients and controls, and because steroid-sparing agents are used primarily to avoid steroid-related toxicity, in this sense the study was not successful,” he said.

Possible explanations for the negative result were the very narrow difference in cumulative prednisone dose between patients and controls, the overall low incidence of adverse events that were seen in the relatively healthy patients who were selected for inclusion in clinical trials, and the short duration of follow-up.

“For this last reason, we decided to review the charts of participating patients and revisit them 5 years after completion of the study,” Dr. Cimmino said.

In all, 29 methotrexate-treated patients and 28 placebo-treated patients were available for evaluation.

At the time of reevaluation, there were no differences in clinical and laboratory findings between the two groups, except for levels of C-reactive protein, which were higher in the placebo group (10.2 mg/dL), compared with those of the methotrexate group (2.7 mg/dL) (Clin. Exp. Rheum. 2008;26:395–400).

“This suggested that perhaps there was more residual disease activity and more inflammation in patients who did not receive methotrexate,” he said.

However, once again there were no differences in the incidence of steroid-related adverse events between treated patients and controls.

“Our conclusion was that we have many unanswered or incompletely answered questions,” he said. “What dosage of methotrexate to use? We used 10 mg, but many of you have suggested that 20 mg would be more appropriate,” Dr. Cimmino said.

Other questions include when to initiate methotrexate—at the same time as steroids are begun, or later, if response is inadequate?—and whether it may be more useful in certain subsets of PMR patients, such as those who also have vasculitis. Finally, more studies are needed if efficacy is to be demonstrated in real-life experience with sicker patients, he said at the meeting, which was sponsored by the Hospital for Special Surgery.

Clinical experience with methotrexate in GCA also was reviewed at the meeting by Dr. Alfred D. Mahr of Hópital Cochin, Paris.

As with PMR, studies of adjunctive methotrexate in GCA have yielded conflicting and inconclusive results. Numbers have been small, so a meta-analysis was undertaken to pool the data, according to Dr. Mahr.

Three randomized trials that included 161 patients were included in the meta-analysis, which found that methotrexate in dosages of 7.5–15 mg/week reduced first and second relapses by 35% and 51%, respectively.

Adjunctive methotrexate also cut cumulative steroid exposure and increased the probability of achieving a sustained 24-week discontinuation of steroids (Arthritis Rheum. 2007;56:2789–97).

The meta-analysis had limitations, Dr. Mahr said, including small numbers of patients and short follow-ups. As with the PMR trial, there were no differences in adverse events between the treatment and control groups.

“Methotrexate could be considered as a therapeutic option for patients with GCA, particularly for those who are at high risk for corticosteroid-related adverse events,” Dr. Mahr said.

This conclusion has recently been affirmed in a recommendation from the European League Against Rheumatism: “A meta-analysis of these three trials demonstrates a modest role for methotrexate (10–15 mg/week) in reducing relapse rate and lowering the cumulative dose of glucocorticoid therapy. … We recommend that an immunosuppressive agent should be considered for use in large vessel vasculitis as adjunctive therapy” (Ann. Rheum. Dis. 2008 April 15 [doi:10.1136/ard.2008.088351]).

Following the presentation, Dr. Gary Hoffman of the Cleveland Clinic stated that he did not agree with the conclusions of the study, noting that there was “enormous heterogeneity” in terms of study design, and significant differences in methotrexate doses and in the timing of the addition of methotrexate. “And ultimately, even if you buy into the validity of the meta-analysis, you are still left with patients with no differences in corticosteroid-related or methotrexate-related adverse events,” said Dr. Hoffman, who is Harold C. Schott Chair of Rheumatic and Immunological Diseases and professor of medicine at Case Western Reserve University, Cleveland.

He went on to say, “Given that we know methotrexate can cause problems such as pneumonitis, which can sometimes be a fatal disease, and that pneumonitis can occur in 1%–5% of patients who are treated with methotrexate, there may not have been enough patients in the individual studies to identify those one or two who might be affected. With just one such patient in the methotrexate group, our view of the outcome would be considerably different,” he said.

In a subsequent interview, session cochair Dr. Robert F. Spiera of Cornell University, New York, said that although there may be some justification for the use of methotrexate in these conditions, “it clearly is not the standard of care.”

“There has never been an unequivocally powerful signal for efficacy, and if you have to treat 11 or 12 patients to prevent one relapse, you are giving methotrexate to a lot of older patients who could have adverse events,” said Dr. Spiera, also director of the scleroderma and vasculitis program at the Hospital for Special Surgery, New York.

NEW YORK — More questions than answers remain regarding the use of methotrexate for giant cell arteritis and polymyalgia rheumatica, despite international efforts to identify a therapeutic approach that could avoid the adverse consequences of long-term corticosteroid use in the vulnerable population afflicted by these conditions.

Prednisone has long been the mainstay of treatment for patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR), disorders that are seen almost exclusively in patients older than 50 years, and it is clearly effective in reducing inflammation and controlling disease. The corticosteroid typically must be administered for at least 1–2 years, however, which places patients at risk for adverse effects such as osteoporosis, cataracts, hypertension, and hyperglycemia.

In one series of 124 PMR patients who were treated with an average daily dose of 9.6 mg prednisone for 1.6 years, 65% experienced at least one adverse event, said Dr. Marco A. Cimmino of the University of Genoa (Italy).

Methotrexate has been widely used in PMR, although early experience, which was largely uncontrolled, provided inconclusive results, Dr. Cimmino said at the Fourth International Conference on Giant Cell Arteritis and Polymyalgia Rheumatica.

In order to more clearly establish an evidence base for the use of methotrexate in PMR, a double-blind trial was done by the systemic vasculitis study group of the Italian Society for Rheumatology. The trial randomized 72 patients with newly diagnosed PMR to prednisone in initial dosages of 25 mg/day, plus either methotrexate (10 mg/week) or placebo for 48 weeks. Prednisone was tapered within 24 weeks and resumed if flare occurred.

The mean age was 72 years, two-thirds were women, and 62 patients completed the study (Ann. Intern. Med. 2004;141:493–500).

At 76 weeks, the proportion of patients who were steroid free was higher in the methotrexate group than in the placebo group, with 28 of 32 patients on methotrexate having discontinued prednisone, compared with 16 of 30 patients on placebo.

The effect of treatment also was positive: Patients receiving methotrexate also had fewer relapses, the duration of prednisone therapy was shorter, and the total dose of prednisone was significantly lower, Dr. Cimmino said.

“However, when we looked at adverse events, there was no difference between treated patients and controls, and because steroid-sparing agents are used primarily to avoid steroid-related toxicity, in this sense the study was not successful,” he said.

Possible explanations for the negative result were the very narrow difference in cumulative prednisone dose between patients and controls, the overall low incidence of adverse events that were seen in the relatively healthy patients who were selected for inclusion in clinical trials, and the short duration of follow-up.

“For this last reason, we decided to review the charts of participating patients and revisit them 5 years after completion of the study,” Dr. Cimmino said.

In all, 29 methotrexate-treated patients and 28 placebo-treated patients were available for evaluation.

At the time of reevaluation, there were no differences in clinical and laboratory findings between the two groups, except for levels of C-reactive protein, which were higher in the placebo group (10.2 mg/dL), compared with those of the methotrexate group (2.7 mg/dL) (Clin. Exp. Rheum. 2008;26:395–400).

“This suggested that perhaps there was more residual disease activity and more inflammation in patients who did not receive methotrexate,” he said.

However, once again there were no differences in the incidence of steroid-related adverse events between treated patients and controls.

“Our conclusion was that we have many unanswered or incompletely answered questions,” he said. “What dosage of methotrexate to use? We used 10 mg, but many of you have suggested that 20 mg would be more appropriate,” Dr. Cimmino said.

Other questions include when to initiate methotrexate—at the same time as steroids are begun, or later, if response is inadequate?—and whether it may be more useful in certain subsets of PMR patients, such as those who also have vasculitis. Finally, more studies are needed if efficacy is to be demonstrated in real-life experience with sicker patients, he said at the meeting, which was sponsored by the Hospital for Special Surgery.

Clinical experience with methotrexate in GCA also was reviewed at the meeting by Dr. Alfred D. Mahr of Hópital Cochin, Paris.

As with PMR, studies of adjunctive methotrexate in GCA have yielded conflicting and inconclusive results. Numbers have been small, so a meta-analysis was undertaken to pool the data, according to Dr. Mahr.

Three randomized trials that included 161 patients were included in the meta-analysis, which found that methotrexate in dosages of 7.5–15 mg/week reduced first and second relapses by 35% and 51%, respectively.

Adjunctive methotrexate also cut cumulative steroid exposure and increased the probability of achieving a sustained 24-week discontinuation of steroids (Arthritis Rheum. 2007;56:2789–97).

The meta-analysis had limitations, Dr. Mahr said, including small numbers of patients and short follow-ups. As with the PMR trial, there were no differences in adverse events between the treatment and control groups.

“Methotrexate could be considered as a therapeutic option for patients with GCA, particularly for those who are at high risk for corticosteroid-related adverse events,” Dr. Mahr said.

This conclusion has recently been affirmed in a recommendation from the European League Against Rheumatism: “A meta-analysis of these three trials demonstrates a modest role for methotrexate (10–15 mg/week) in reducing relapse rate and lowering the cumulative dose of glucocorticoid therapy. … We recommend that an immunosuppressive agent should be considered for use in large vessel vasculitis as adjunctive therapy” (Ann. Rheum. Dis. 2008 April 15 [doi:10.1136/ard.2008.088351]).

Following the presentation, Dr. Gary Hoffman of the Cleveland Clinic stated that he did not agree with the conclusions of the study, noting that there was “enormous heterogeneity” in terms of study design, and significant differences in methotrexate doses and in the timing of the addition of methotrexate. “And ultimately, even if you buy into the validity of the meta-analysis, you are still left with patients with no differences in corticosteroid-related or methotrexate-related adverse events,” said Dr. Hoffman, who is Harold C. Schott Chair of Rheumatic and Immunological Diseases and professor of medicine at Case Western Reserve University, Cleveland.

He went on to say, “Given that we know methotrexate can cause problems such as pneumonitis, which can sometimes be a fatal disease, and that pneumonitis can occur in 1%–5% of patients who are treated with methotrexate, there may not have been enough patients in the individual studies to identify those one or two who might be affected. With just one such patient in the methotrexate group, our view of the outcome would be considerably different,” he said.

In a subsequent interview, session cochair Dr. Robert F. Spiera of Cornell University, New York, said that although there may be some justification for the use of methotrexate in these conditions, “it clearly is not the standard of care.”

“There has never been an unequivocally powerful signal for efficacy, and if you have to treat 11 or 12 patients to prevent one relapse, you are giving methotrexate to a lot of older patients who could have adverse events,” said Dr. Spiera, also director of the scleroderma and vasculitis program at the Hospital for Special Surgery, New York.

PARIS — The anti-CD22 monoclonal antibody epratuzumab showed promise as a targeted therapy for systemic lupus erythematosus in two small studies, providing improvements in disease activity and health-related quality of life.

B cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE), and a new potential therapeutic target is CD22, which is a glycoprotein present on the surface of B cells.

Unlike rituximab, which acts by depleting B cells, epratuzumab acts through regulating the activation of B cells and their interactions with T cells, Dr. Vibeke B. Strand reported at the annual European Congress of Rheumatology.

In all, 90 patients with severe SLE were randomized to receive placebo or epratuzumab in infusions of 360 mg/m

All patients had antinuclear antibody (ANA)-positive disease and had experienced a severe (grade A) or moderate (grade B) British Isles Lupus Assessment Group (BILAG) flare. Stable doses of corticosteroids, immunosuppressants, and antimalarial drugs were permitted.

The two studies were initiated in 2005 but recruitment and dosing were discontinued prematurely in September 2006 because of an interruption in the drug supply. Patients continued to be followed, however, and the available data have now been analyzed.

At the time of study discontinuation, 29% of the intent-to-treat population had received all infusions over the entire 48-week period, and 91% had received at least four infusions.

Health-related quality of life was assessed using the Medical Outcomes Study short form-36 (SF-36), which evaluates physical functioning, pain, general health, vitality, social functioning, and mental health.

The treatment groups were comparable at baseline: Mean age was 37 years, mean body weight was 69 kg, 94% were female, and 67% were white.

Overall, patients had high disease activity, with 43% having one or more BILAG grade A flare; the mean total BILAG score was 13.2, according to Dr. Strand of Stanford (Calif.) University.

Burden of disease was also high, as shown by baseline scores on the physical and mental components of the SF-36 that were 1.5–2.0 and 0.6–1.2 standard deviations lower, respectively, than age and sex-matched controls and patients in previously reported SLE trials, she noted.

In all, 63% were receiving immunosuppressive drugs, 71% were receiving antimalarials, and 43% were being treated with doses of prednisone exceeding 25 mg/day at baseline.

By week 48, total BILAG scores in the epratuzumab groups were reduced to 6.3 from 13.2 at baseline, compared with reductions to 8.6 from 13.2 in the placebo group, Dr. Strand wrote.

“Although most patients did not receive full treatment courses and sample sizes were small, epratuzumab treatment resulted in clinically meaningful improvements in health-related quality of life,” she concluded.

In a separate poster that also analyzed data from the two preliminary studies, Dr. Daniel Wallace of the University of California, Los Angeles, reported that cumulative corticosteroid use over 24 weeks—adjusted for race, baseline medications, and baseline differences—was lower in the epratuzumab groups.

At week 24, 24 (75%) patients receiving the 360-mg dose and 6 (100%) of those receiving the 720-mg dose were able to taper their corticosteroids, compared with 13 (57%) of those receiving placebo, according to Dr. Wallace.

Cumulative exposure to steroids was lower in the active treatment groups, with a least squares mean difference from placebo at 24 weeks of −1,051 mg and −1,973 mg for the 360-mg and 720-mg groups, respectively.

The incidence of treatment-emergent adverse events was similar in the active and placebo groups, with serious adverse events occurring in 30%, 25%, and 36% of patients in the placebo, 360-mg, and 720-mg groups, respectively, reported Dr. Wallace.

Serious infections occurred in 18% of the epratuzumab groups and in 22% of the placebo group.

Adverse events leading to discontinuation occurred in three patients in the placebo group and in three patients in the 720-mg group.

The manufacturer of epratuzumab, UCB Inc., has now initiated another pair of phase IIB trials, with the primary objective of determining the dose response and frequency.

Dr. Strand has disclosed receiving consulting fees from UCB.

ELSEVIER GLOBAL MEDICAL NEWS

PARIS — The anti-CD22 monoclonal antibody epratuzumab showed promise as a targeted therapy for systemic lupus erythematosus in two small studies, providing improvements in disease activity and health-related quality of life.

B cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE), and a new potential therapeutic target is CD22, which is a glycoprotein present on the surface of B cells.

Unlike rituximab, which acts by depleting B cells, epratuzumab acts through regulating the activation of B cells and their interactions with T cells, Dr. Vibeke B. Strand reported at the annual European Congress of Rheumatology.

In all, 90 patients with severe SLE were randomized to receive placebo or epratuzumab in infusions of 360 mg/m

All patients had antinuclear antibody (ANA)-positive disease and had experienced a severe (grade A) or moderate (grade B) British Isles Lupus Assessment Group (BILAG) flare. Stable doses of corticosteroids, immunosuppressants, and antimalarial drugs were permitted.

The two studies were initiated in 2005 but recruitment and dosing were discontinued prematurely in September 2006 because of an interruption in the drug supply. Patients continued to be followed, however, and the available data have now been analyzed.

At the time of study discontinuation, 29% of the intent-to-treat population had received all infusions over the entire 48-week period, and 91% had received at least four infusions.

Health-related quality of life was assessed using the Medical Outcomes Study short form-36 (SF-36), which evaluates physical functioning, pain, general health, vitality, social functioning, and mental health.

The treatment groups were comparable at baseline: Mean age was 37 years, mean body weight was 69 kg, 94% were female, and 67% were white.

Overall, patients had high disease activity, with 43% having one or more BILAG grade A flare; the mean total BILAG score was 13.2, according to Dr. Strand of Stanford (Calif.) University.

Burden of disease was also high, as shown by baseline scores on the physical and mental components of the SF-36 that were 1.5–2.0 and 0.6–1.2 standard deviations lower, respectively, than age and sex-matched controls and patients in previously reported SLE trials, she noted.

In all, 63% were receiving immunosuppressive drugs, 71% were receiving antimalarials, and 43% were being treated with doses of prednisone exceeding 25 mg/day at baseline.

By week 48, total BILAG scores in the epratuzumab groups were reduced to 6.3 from 13.2 at baseline, compared with reductions to 8.6 from 13.2 in the placebo group, Dr. Strand wrote.

“Although most patients did not receive full treatment courses and sample sizes were small, epratuzumab treatment resulted in clinically meaningful improvements in health-related quality of life,” she concluded.

In a separate poster that also analyzed data from the two preliminary studies, Dr. Daniel Wallace of the University of California, Los Angeles, reported that cumulative corticosteroid use over 24 weeks—adjusted for race, baseline medications, and baseline differences—was lower in the epratuzumab groups.

At week 24, 24 (75%) patients receiving the 360-mg dose and 6 (100%) of those receiving the 720-mg dose were able to taper their corticosteroids, compared with 13 (57%) of those receiving placebo, according to Dr. Wallace.

Cumulative exposure to steroids was lower in the active treatment groups, with a least squares mean difference from placebo at 24 weeks of −1,051 mg and −1,973 mg for the 360-mg and 720-mg groups, respectively.

The incidence of treatment-emergent adverse events was similar in the active and placebo groups, with serious adverse events occurring in 30%, 25%, and 36% of patients in the placebo, 360-mg, and 720-mg groups, respectively, reported Dr. Wallace.

Serious infections occurred in 18% of the epratuzumab groups and in 22% of the placebo group.

Adverse events leading to discontinuation occurred in three patients in the placebo group and in three patients in the 720-mg group.

The manufacturer of epratuzumab, UCB Inc., has now initiated another pair of phase IIB trials, with the primary objective of determining the dose response and frequency.

Dr. Strand has disclosed receiving consulting fees from UCB.

ELSEVIER GLOBAL MEDICAL NEWS

PARIS — The anti-CD22 monoclonal antibody epratuzumab showed promise as a targeted therapy for systemic lupus erythematosus in two small studies, providing improvements in disease activity and health-related quality of life.

B cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE), and a new potential therapeutic target is CD22, which is a glycoprotein present on the surface of B cells.

Unlike rituximab, which acts by depleting B cells, epratuzumab acts through regulating the activation of B cells and their interactions with T cells, Dr. Vibeke B. Strand reported at the annual European Congress of Rheumatology.

In all, 90 patients with severe SLE were randomized to receive placebo or epratuzumab in infusions of 360 mg/m

All patients had antinuclear antibody (ANA)-positive disease and had experienced a severe (grade A) or moderate (grade B) British Isles Lupus Assessment Group (BILAG) flare. Stable doses of corticosteroids, immunosuppressants, and antimalarial drugs were permitted.

The two studies were initiated in 2005 but recruitment and dosing were discontinued prematurely in September 2006 because of an interruption in the drug supply. Patients continued to be followed, however, and the available data have now been analyzed.

At the time of study discontinuation, 29% of the intent-to-treat population had received all infusions over the entire 48-week period, and 91% had received at least four infusions.

Health-related quality of life was assessed using the Medical Outcomes Study short form-36 (SF-36), which evaluates physical functioning, pain, general health, vitality, social functioning, and mental health.

The treatment groups were comparable at baseline: Mean age was 37 years, mean body weight was 69 kg, 94% were female, and 67% were white.

Overall, patients had high disease activity, with 43% having one or more BILAG grade A flare; the mean total BILAG score was 13.2, according to Dr. Strand of Stanford (Calif.) University.

Burden of disease was also high, as shown by baseline scores on the physical and mental components of the SF-36 that were 1.5–2.0 and 0.6–1.2 standard deviations lower, respectively, than age and sex-matched controls and patients in previously reported SLE trials, she noted.

In all, 63% were receiving immunosuppressive drugs, 71% were receiving antimalarials, and 43% were being treated with doses of prednisone exceeding 25 mg/day at baseline.

By week 48, total BILAG scores in the epratuzumab groups were reduced to 6.3 from 13.2 at baseline, compared with reductions to 8.6 from 13.2 in the placebo group, Dr. Strand wrote.

“Although most patients did not receive full treatment courses and sample sizes were small, epratuzumab treatment resulted in clinically meaningful improvements in health-related quality of life,” she concluded.

In a separate poster that also analyzed data from the two preliminary studies, Dr. Daniel Wallace of the University of California, Los Angeles, reported that cumulative corticosteroid use over 24 weeks—adjusted for race, baseline medications, and baseline differences—was lower in the epratuzumab groups.

At week 24, 24 (75%) patients receiving the 360-mg dose and 6 (100%) of those receiving the 720-mg dose were able to taper their corticosteroids, compared with 13 (57%) of those receiving placebo, according to Dr. Wallace.

Cumulative exposure to steroids was lower in the active treatment groups, with a least squares mean difference from placebo at 24 weeks of −1,051 mg and −1,973 mg for the 360-mg and 720-mg groups, respectively.

The incidence of treatment-emergent adverse events was similar in the active and placebo groups, with serious adverse events occurring in 30%, 25%, and 36% of patients in the placebo, 360-mg, and 720-mg groups, respectively, reported Dr. Wallace.

Serious infections occurred in 18% of the epratuzumab groups and in 22% of the placebo group.

Adverse events leading to discontinuation occurred in three patients in the placebo group and in three patients in the 720-mg group.

The manufacturer of epratuzumab, UCB Inc., has now initiated another pair of phase IIB trials, with the primary objective of determining the dose response and frequency.

Dr. Strand has disclosed receiving consulting fees from UCB.

ELSEVIER GLOBAL MEDICAL NEWS

PARIS — Factors that predict which rheumatoid arthritis patients will achieve and maintain remission after disease-modifying drugs include low body mass index, low erythrocyte sedimentation rate levels, and absence of anti-cyclic citrullinated peptide antibody at baseline.

“Remission is increasingly becoming an attainable goal in rheumatoid arthritis treatment, and it would be useful to be able to predict which patients are likely to achieve remission in the long run, and so to be able to avoid overly aggressive treatment,” Dr. Diane van der Woude said at the annual European Congress of Rheumatology.

Although factors have been identified that predict the achievement of very low disease activity with biologics, little is known about the predictive factors of patients treated with DMARDs, said Dr. van der Woude of the department of rheumatology at Leiden (the Netherlands) University Medical Center.

She analyzed clinical, laboratory, and genetic data from patients enrolled in an inception cohort at the Leiden Early Arthritis Clinic between 1993 and 2003.

Among more than 1,900 patients referred to the clinic, 454 were diagnosed with RA and treated with chloroquine, sulfasalazine, or methotrexate, she said.

Sustained remission, or the absence of synovitis for longer than 1 year without DMARDs, was achieved by 69 patients (15%) with an average follow-up of 8 years. Six patients discharged because of remission had a recurrence of synovitis and were excluded from the remission group.

Univariate analysis revealed the following were significantly associated with less likelihood of achieving DMARD-free remission: positive family history (hazard ratio 0.56); high body mass index (HR 0.90); long duration of symptoms at presentation (HR 0.93); smoking (HR 0.55); and the presence of IgM rheumatoid factor (HR 0.17), anti-cyclic citrullinated peptide (CCP) antibodies (HR 0.09), and shared epitope alleles (HR 0.47).

Multivariate analysis identified older age, low BMI, low ESR, short duration of symptoms, nonsmoking status, and the absence of anti-CCP antibodies as independent predictors for DMARD-free remission.

PARIS — Factors that predict which rheumatoid arthritis patients will achieve and maintain remission after disease-modifying drugs include low body mass index, low erythrocyte sedimentation rate levels, and absence of anti-cyclic citrullinated peptide antibody at baseline.

“Remission is increasingly becoming an attainable goal in rheumatoid arthritis treatment, and it would be useful to be able to predict which patients are likely to achieve remission in the long run, and so to be able to avoid overly aggressive treatment,” Dr. Diane van der Woude said at the annual European Congress of Rheumatology.

Although factors have been identified that predict the achievement of very low disease activity with biologics, little is known about the predictive factors of patients treated with DMARDs, said Dr. van der Woude of the department of rheumatology at Leiden (the Netherlands) University Medical Center.

She analyzed clinical, laboratory, and genetic data from patients enrolled in an inception cohort at the Leiden Early Arthritis Clinic between 1993 and 2003.

Among more than 1,900 patients referred to the clinic, 454 were diagnosed with RA and treated with chloroquine, sulfasalazine, or methotrexate, she said.

Sustained remission, or the absence of synovitis for longer than 1 year without DMARDs, was achieved by 69 patients (15%) with an average follow-up of 8 years. Six patients discharged because of remission had a recurrence of synovitis and were excluded from the remission group.

Univariate analysis revealed the following were significantly associated with less likelihood of achieving DMARD-free remission: positive family history (hazard ratio 0.56); high body mass index (HR 0.90); long duration of symptoms at presentation (HR 0.93); smoking (HR 0.55); and the presence of IgM rheumatoid factor (HR 0.17), anti-cyclic citrullinated peptide (CCP) antibodies (HR 0.09), and shared epitope alleles (HR 0.47).

Multivariate analysis identified older age, low BMI, low ESR, short duration of symptoms, nonsmoking status, and the absence of anti-CCP antibodies as independent predictors for DMARD-free remission.

PARIS — Factors that predict which rheumatoid arthritis patients will achieve and maintain remission after disease-modifying drugs include low body mass index, low erythrocyte sedimentation rate levels, and absence of anti-cyclic citrullinated peptide antibody at baseline.

“Remission is increasingly becoming an attainable goal in rheumatoid arthritis treatment, and it would be useful to be able to predict which patients are likely to achieve remission in the long run, and so to be able to avoid overly aggressive treatment,” Dr. Diane van der Woude said at the annual European Congress of Rheumatology.

Although factors have been identified that predict the achievement of very low disease activity with biologics, little is known about the predictive factors of patients treated with DMARDs, said Dr. van der Woude of the department of rheumatology at Leiden (the Netherlands) University Medical Center.

She analyzed clinical, laboratory, and genetic data from patients enrolled in an inception cohort at the Leiden Early Arthritis Clinic between 1993 and 2003.

Among more than 1,900 patients referred to the clinic, 454 were diagnosed with RA and treated with chloroquine, sulfasalazine, or methotrexate, she said.

Sustained remission, or the absence of synovitis for longer than 1 year without DMARDs, was achieved by 69 patients (15%) with an average follow-up of 8 years. Six patients discharged because of remission had a recurrence of synovitis and were excluded from the remission group.

Univariate analysis revealed the following were significantly associated with less likelihood of achieving DMARD-free remission: positive family history (hazard ratio 0.56); high body mass index (HR 0.90); long duration of symptoms at presentation (HR 0.93); smoking (HR 0.55); and the presence of IgM rheumatoid factor (HR 0.17), anti-cyclic citrullinated peptide (CCP) antibodies (HR 0.09), and shared epitope alleles (HR 0.47).

Multivariate analysis identified older age, low BMI, low ESR, short duration of symptoms, nonsmoking status, and the absence of anti-CCP antibodies as independent predictors for DMARD-free remission.