Rheumatoid Arthritis

PARIS — The combination of leflunomide and rituximab may offer an effective therapeutic option for patients with rheumatoid arthritis who can't tolerate methotrexate, a small study suggests.

The most effective therapy thus far for RA is a combination of a traditional disease-modifying antirheumatic drug (DMARD) and a biologic. While methotrexate is the most widely used DMARD, a significant number of patients are unable to tolerate this drug, said Dr. Edward M. Vital of the academic unit of musculoskeletal disease, University of Leeds (England).

Combination therapy substituting leflunomide for methotrexate has therefore been tried, first with infliximab as the biologic component. Initial experience, however, demonstrated that this combination was problematic, with a high incidence of vasculitis and 100% of patients who were on the regimen for an extended period developing antinuclear antibodies (ANA). Many also became positive for anti-double stranded (ds) DNA antibodies, Dr. Vital said at the annual European Congress of Rheumatology.

The probable reason for this induction of autoimmunity is that the removal of tumor necrosis factor (TNF) results in a shift in T cells from a predominant Th1 RA-type response to a Th2 lupus-type response, with the production of autoantibodies. “Therefore, using a strategy of B-cell depletion with rituximab seems logical and potentially synergistic in combination therapy,” he said.

Leflunomide in doses of 10–20 mg/day was administered to 15 patients with active RA in combination with rituximab, given as two infusions of 1,000 mg on days 1 and 15 following pretreatment with 100 mg methylprednisone. The primary end point was a EULAR moderate/good response at 6 months.

The mean age of the patients was 55 years and the mean disease duration was 10 years. The patients had received a mean of four previous DMARDs, and five had previously been treated with anti-TNF drugs.

All were inadequate responders to leflunomide alone.

Mean tender joint count was 18 and mean swollen joint count was 12. The mean disease activity score (DAS) was 6.8 and mean health assessment questionnaire disability index (HAQ-DI) was 2.3.

Thirteen of the patients were rheumatoid factor positive and the remaining two were positive for anticyclic citrullinated peptide (anti-CCP) antibody.

A total of 80% of patients achieved a EULAR moderate/good response with significant reductions in DAS28, said Dr. Vital, who had no financial disclosures.

ACR20, 50, and 70 responses were seen in 68%, 33%, and 20%, respectively, with significant improvements being seen in each component of the ACR core set.

Reductions were also seen in rheumatoid factor, IgM, and IgA.

At the time of Dr. Vital's presentation, eight patients had relapsed, at a mean time of 46 weeks post treatment. Four had not relapsed, with follow-up time of 62–85 weeks. Three partial responders were retreated with good results.

“Relapse-free survival has been somewhat better than expected, with one-third of responders still responding 20 months after treatment,” he said.

In contrast, mean time to retreatment among patients treated with rituximab and methotrexate is 45.5 weeks after an inadequate response to methotrexate (Arthritis Rheum. 2007;56:3896–908).

One serious adverse event, a case of gastroenteritis that required 24 hours of hospitalization, was seen. There were no infusion reactions and none of the patients developed ANA or anti-dsDNA antibodies.

“This is a potential treatment option—and a much needed one—for patients who are intolerant of methotrexate,” Dr. Vital said.

PARIS — The combination of leflunomide and rituximab may offer an effective therapeutic option for patients with rheumatoid arthritis who can't tolerate methotrexate, a small study suggests.

The most effective therapy thus far for RA is a combination of a traditional disease-modifying antirheumatic drug (DMARD) and a biologic. While methotrexate is the most widely used DMARD, a significant number of patients are unable to tolerate this drug, said Dr. Edward M. Vital of the academic unit of musculoskeletal disease, University of Leeds (England).

Combination therapy substituting leflunomide for methotrexate has therefore been tried, first with infliximab as the biologic component. Initial experience, however, demonstrated that this combination was problematic, with a high incidence of vasculitis and 100% of patients who were on the regimen for an extended period developing antinuclear antibodies (ANA). Many also became positive for anti-double stranded (ds) DNA antibodies, Dr. Vital said at the annual European Congress of Rheumatology.

The probable reason for this induction of autoimmunity is that the removal of tumor necrosis factor (TNF) results in a shift in T cells from a predominant Th1 RA-type response to a Th2 lupus-type response, with the production of autoantibodies. “Therefore, using a strategy of B-cell depletion with rituximab seems logical and potentially synergistic in combination therapy,” he said.

Leflunomide in doses of 10–20 mg/day was administered to 15 patients with active RA in combination with rituximab, given as two infusions of 1,000 mg on days 1 and 15 following pretreatment with 100 mg methylprednisone. The primary end point was a EULAR moderate/good response at 6 months.

The mean age of the patients was 55 years and the mean disease duration was 10 years. The patients had received a mean of four previous DMARDs, and five had previously been treated with anti-TNF drugs.

All were inadequate responders to leflunomide alone.

Mean tender joint count was 18 and mean swollen joint count was 12. The mean disease activity score (DAS) was 6.8 and mean health assessment questionnaire disability index (HAQ-DI) was 2.3.

Thirteen of the patients were rheumatoid factor positive and the remaining two were positive for anticyclic citrullinated peptide (anti-CCP) antibody.

A total of 80% of patients achieved a EULAR moderate/good response with significant reductions in DAS28, said Dr. Vital, who had no financial disclosures.

ACR20, 50, and 70 responses were seen in 68%, 33%, and 20%, respectively, with significant improvements being seen in each component of the ACR core set.

Reductions were also seen in rheumatoid factor, IgM, and IgA.

At the time of Dr. Vital's presentation, eight patients had relapsed, at a mean time of 46 weeks post treatment. Four had not relapsed, with follow-up time of 62–85 weeks. Three partial responders were retreated with good results.

“Relapse-free survival has been somewhat better than expected, with one-third of responders still responding 20 months after treatment,” he said.

In contrast, mean time to retreatment among patients treated with rituximab and methotrexate is 45.5 weeks after an inadequate response to methotrexate (Arthritis Rheum. 2007;56:3896–908).

One serious adverse event, a case of gastroenteritis that required 24 hours of hospitalization, was seen. There were no infusion reactions and none of the patients developed ANA or anti-dsDNA antibodies.

“This is a potential treatment option—and a much needed one—for patients who are intolerant of methotrexate,” Dr. Vital said.

PARIS — The combination of leflunomide and rituximab may offer an effective therapeutic option for patients with rheumatoid arthritis who can't tolerate methotrexate, a small study suggests.

The most effective therapy thus far for RA is a combination of a traditional disease-modifying antirheumatic drug (DMARD) and a biologic. While methotrexate is the most widely used DMARD, a significant number of patients are unable to tolerate this drug, said Dr. Edward M. Vital of the academic unit of musculoskeletal disease, University of Leeds (England).

Combination therapy substituting leflunomide for methotrexate has therefore been tried, first with infliximab as the biologic component. Initial experience, however, demonstrated that this combination was problematic, with a high incidence of vasculitis and 100% of patients who were on the regimen for an extended period developing antinuclear antibodies (ANA). Many also became positive for anti-double stranded (ds) DNA antibodies, Dr. Vital said at the annual European Congress of Rheumatology.

The probable reason for this induction of autoimmunity is that the removal of tumor necrosis factor (TNF) results in a shift in T cells from a predominant Th1 RA-type response to a Th2 lupus-type response, with the production of autoantibodies. “Therefore, using a strategy of B-cell depletion with rituximab seems logical and potentially synergistic in combination therapy,” he said.

Leflunomide in doses of 10–20 mg/day was administered to 15 patients with active RA in combination with rituximab, given as two infusions of 1,000 mg on days 1 and 15 following pretreatment with 100 mg methylprednisone. The primary end point was a EULAR moderate/good response at 6 months.

The mean age of the patients was 55 years and the mean disease duration was 10 years. The patients had received a mean of four previous DMARDs, and five had previously been treated with anti-TNF drugs.

All were inadequate responders to leflunomide alone.

Mean tender joint count was 18 and mean swollen joint count was 12. The mean disease activity score (DAS) was 6.8 and mean health assessment questionnaire disability index (HAQ-DI) was 2.3.

Thirteen of the patients were rheumatoid factor positive and the remaining two were positive for anticyclic citrullinated peptide (anti-CCP) antibody.

A total of 80% of patients achieved a EULAR moderate/good response with significant reductions in DAS28, said Dr. Vital, who had no financial disclosures.

ACR20, 50, and 70 responses were seen in 68%, 33%, and 20%, respectively, with significant improvements being seen in each component of the ACR core set.

Reductions were also seen in rheumatoid factor, IgM, and IgA.

At the time of Dr. Vital's presentation, eight patients had relapsed, at a mean time of 46 weeks post treatment. Four had not relapsed, with follow-up time of 62–85 weeks. Three partial responders were retreated with good results.

“Relapse-free survival has been somewhat better than expected, with one-third of responders still responding 20 months after treatment,” he said.

In contrast, mean time to retreatment among patients treated with rituximab and methotrexate is 45.5 weeks after an inadequate response to methotrexate (Arthritis Rheum. 2007;56:3896–908).

One serious adverse event, a case of gastroenteritis that required 24 hours of hospitalization, was seen. There were no infusion reactions and none of the patients developed ANA or anti-dsDNA antibodies.

“This is a potential treatment option—and a much needed one—for patients who are intolerant of methotrexate,” Dr. Vital said.

Obese patients with osteoarthritis experience greater gains in physical function 7 years after undergoing total knee arthroplasty than do obese controls who did not have the surgery, according to an English study.

Based on data from 688 patients, there is no justification to withhold knee replacements from obese patients on the grounds that obesity is a risk factor for OA. At least one National Health Service trust has been reported to apply such a policy, the investigators wrote (Ann. Rheum. Dis. 2008 July 24 [doi:10.1136/ard.2008.093229]).

In a subgroup of 108 obese patients (body mass index greater than or equal to 30 kg/m

“Improvements in physical function following [TKA] for osteoarthritis are sustained,” wrote Janet Cushnaghan of the University of Southampton, England, and her associates. “These benefits extend to [obese patients] and, provided appropriate selection criteria are applied with regard to fitness for surgery, there seems no justification for withholding TKA.”

The researchers studied patients and controls aged 45 and older who had taken part in an earlier case-control study of knee OA. That study compared patients placed on a waiting list for TKA between 1995 and 1997 with controls in the community. Functional status and BMI were measured as part of data collection.

During 2001–2004, the authors wrote to the original study group with a questionnaire about their surgery and included the functional status sections of the SF-36 form. A total of 325 patients and 363 controls were included in this analysis.

Overall, at a mean follow-up of 7 years, median physical function scores in patients who underwent TKA improved from 20 to 26; scores in controls fell from 89 to 75.

Mental health scores on the SF-36 form improved equally in both groups. Vitality scores declined in both groups, but the decline was greater in patients than in controls (a loss of 10 points vs. a loss of 5 points).

Of 82 patients older than age 75, the median physical function score stayed steady at 17 points; scores declined from 83 to 43 points in 87 controls in that age group.

The researchers said their findings might have been biased by migration, although subjects were as likely to have moved, demonstrating greater function, as to have entered nursing care, demonstrating poorer function.

They also said OA might have been undetected in the controls at baseline, which would have biased their findings in favor of the intervention group.

Obese patients with osteoarthritis experience greater gains in physical function 7 years after undergoing total knee arthroplasty than do obese controls who did not have the surgery, according to an English study.

Based on data from 688 patients, there is no justification to withhold knee replacements from obese patients on the grounds that obesity is a risk factor for OA. At least one National Health Service trust has been reported to apply such a policy, the investigators wrote (Ann. Rheum. Dis. 2008 July 24 [doi:10.1136/ard.2008.093229]).

In a subgroup of 108 obese patients (body mass index greater than or equal to 30 kg/m

“Improvements in physical function following [TKA] for osteoarthritis are sustained,” wrote Janet Cushnaghan of the University of Southampton, England, and her associates. “These benefits extend to [obese patients] and, provided appropriate selection criteria are applied with regard to fitness for surgery, there seems no justification for withholding TKA.”

The researchers studied patients and controls aged 45 and older who had taken part in an earlier case-control study of knee OA. That study compared patients placed on a waiting list for TKA between 1995 and 1997 with controls in the community. Functional status and BMI were measured as part of data collection.

During 2001–2004, the authors wrote to the original study group with a questionnaire about their surgery and included the functional status sections of the SF-36 form. A total of 325 patients and 363 controls were included in this analysis.

Overall, at a mean follow-up of 7 years, median physical function scores in patients who underwent TKA improved from 20 to 26; scores in controls fell from 89 to 75.

Mental health scores on the SF-36 form improved equally in both groups. Vitality scores declined in both groups, but the decline was greater in patients than in controls (a loss of 10 points vs. a loss of 5 points).

Of 82 patients older than age 75, the median physical function score stayed steady at 17 points; scores declined from 83 to 43 points in 87 controls in that age group.

The researchers said their findings might have been biased by migration, although subjects were as likely to have moved, demonstrating greater function, as to have entered nursing care, demonstrating poorer function.

They also said OA might have been undetected in the controls at baseline, which would have biased their findings in favor of the intervention group.

Obese patients with osteoarthritis experience greater gains in physical function 7 years after undergoing total knee arthroplasty than do obese controls who did not have the surgery, according to an English study.

Based on data from 688 patients, there is no justification to withhold knee replacements from obese patients on the grounds that obesity is a risk factor for OA. At least one National Health Service trust has been reported to apply such a policy, the investigators wrote (Ann. Rheum. Dis. 2008 July 24 [doi:10.1136/ard.2008.093229]).

In a subgroup of 108 obese patients (body mass index greater than or equal to 30 kg/m

“Improvements in physical function following [TKA] for osteoarthritis are sustained,” wrote Janet Cushnaghan of the University of Southampton, England, and her associates. “These benefits extend to [obese patients] and, provided appropriate selection criteria are applied with regard to fitness for surgery, there seems no justification for withholding TKA.”

The researchers studied patients and controls aged 45 and older who had taken part in an earlier case-control study of knee OA. That study compared patients placed on a waiting list for TKA between 1995 and 1997 with controls in the community. Functional status and BMI were measured as part of data collection.

During 2001–2004, the authors wrote to the original study group with a questionnaire about their surgery and included the functional status sections of the SF-36 form. A total of 325 patients and 363 controls were included in this analysis.

Overall, at a mean follow-up of 7 years, median physical function scores in patients who underwent TKA improved from 20 to 26; scores in controls fell from 89 to 75.

Mental health scores on the SF-36 form improved equally in both groups. Vitality scores declined in both groups, but the decline was greater in patients than in controls (a loss of 10 points vs. a loss of 5 points).

Of 82 patients older than age 75, the median physical function score stayed steady at 17 points; scores declined from 83 to 43 points in 87 controls in that age group.

The researchers said their findings might have been biased by migration, although subjects were as likely to have moved, demonstrating greater function, as to have entered nursing care, demonstrating poorer function.

They also said OA might have been undetected in the controls at baseline, which would have biased their findings in favor of the intervention group.

PARIS — Rituximab may be a better choice than another tumor necrosis factor inhibitor for patients with rheumatoid arthritis whose disease remains active despite anti-TNF therapy, according to a study of more than 300 patients.

“We and others have shown that switching to a different class of biological agents may be more effective than going to a second or third anti-TNF agent,” Dr. Axel Finckh said at the annual European Congress of Rheumatology.

Patients interrupt anti-TNF therapy for various reasons, including lack of efficacy, adverse events, convenience, and preferences. To determine if the reason for discontinuation could influence the efficacy of subsequent therapy, a prospective longitudinal observational study was undertaken that included all rheumatoid arthritis (RA) patients in a Swiss national cohort who failed a course of TNF inhibitor therapy, said Dr. Finckh of Geneva University Hospital.

The primary outcome was the evolution in disease activity score 28 (DAS28) in the first year after switching, analyzed by multivariate regression models.

Among the 325 adult patients included in the study, 175 switched to another anti-TNF drug while 150 switched to the B-cell-depleting agent rituximab, according to Dr. Finckh.

Overall, the reason for discontinuation of the previous regimen was lack of efficacy in 65%. Of those, 28% were primary failures who experienced no response to therapy and 72% were secondary failures who initially responded but then lost the response.

The remaining 35% of patients switched because of adverse events, he said.

At the time of switching, there were no significant differences between the anti-TNF group and the rituximab group in terms of patient age, gender, disease duration, or concomitant steroid or conventional disease-modifying anti-rheumatic drug use.

Patients who switched to another anti-TNF drug had lower baseline DAS scores, however, at a mean of 4.0, compared with a mean of 4.97 in the rituximab group. After adjustment for this and other confounders, the evolution of DAS28 was overall more favorable for the rituximab group, he said.

When the motive for switching was lack of efficacy of the original TNF inhibitor, the evolution of DAS28 was significantly better for rituximab, with scores decreasing by 1.55 at 6 months, compared with a decrease of 1.03 for the anti-TNF group.

However, when the reason for switching was an adverse event, the evolution of DAS28 was similar in the two groups, with rituximab patients having a decrease in scores of 0.86 and the anti-TNF group decreasing by 0.77.

There was no effect modification by other variables, including primary versus secondary failure or concomitant DMARD use.

“This observational study suggests that patients who demonstrate therapeutic resistance to anti-TNF therapy may benefit from switching to rituximab,” Dr. Finckh concluded.

The study was partially supported by Roche.

PARIS — Rituximab may be a better choice than another tumor necrosis factor inhibitor for patients with rheumatoid arthritis whose disease remains active despite anti-TNF therapy, according to a study of more than 300 patients.

“We and others have shown that switching to a different class of biological agents may be more effective than going to a second or third anti-TNF agent,” Dr. Axel Finckh said at the annual European Congress of Rheumatology.

Patients interrupt anti-TNF therapy for various reasons, including lack of efficacy, adverse events, convenience, and preferences. To determine if the reason for discontinuation could influence the efficacy of subsequent therapy, a prospective longitudinal observational study was undertaken that included all rheumatoid arthritis (RA) patients in a Swiss national cohort who failed a course of TNF inhibitor therapy, said Dr. Finckh of Geneva University Hospital.

The primary outcome was the evolution in disease activity score 28 (DAS28) in the first year after switching, analyzed by multivariate regression models.

Among the 325 adult patients included in the study, 175 switched to another anti-TNF drug while 150 switched to the B-cell-depleting agent rituximab, according to Dr. Finckh.

Overall, the reason for discontinuation of the previous regimen was lack of efficacy in 65%. Of those, 28% were primary failures who experienced no response to therapy and 72% were secondary failures who initially responded but then lost the response.

The remaining 35% of patients switched because of adverse events, he said.

At the time of switching, there were no significant differences between the anti-TNF group and the rituximab group in terms of patient age, gender, disease duration, or concomitant steroid or conventional disease-modifying anti-rheumatic drug use.

Patients who switched to another anti-TNF drug had lower baseline DAS scores, however, at a mean of 4.0, compared with a mean of 4.97 in the rituximab group. After adjustment for this and other confounders, the evolution of DAS28 was overall more favorable for the rituximab group, he said.

When the motive for switching was lack of efficacy of the original TNF inhibitor, the evolution of DAS28 was significantly better for rituximab, with scores decreasing by 1.55 at 6 months, compared with a decrease of 1.03 for the anti-TNF group.

However, when the reason for switching was an adverse event, the evolution of DAS28 was similar in the two groups, with rituximab patients having a decrease in scores of 0.86 and the anti-TNF group decreasing by 0.77.

There was no effect modification by other variables, including primary versus secondary failure or concomitant DMARD use.

“This observational study suggests that patients who demonstrate therapeutic resistance to anti-TNF therapy may benefit from switching to rituximab,” Dr. Finckh concluded.

The study was partially supported by Roche.

PARIS — Rituximab may be a better choice than another tumor necrosis factor inhibitor for patients with rheumatoid arthritis whose disease remains active despite anti-TNF therapy, according to a study of more than 300 patients.

“We and others have shown that switching to a different class of biological agents may be more effective than going to a second or third anti-TNF agent,” Dr. Axel Finckh said at the annual European Congress of Rheumatology.

Patients interrupt anti-TNF therapy for various reasons, including lack of efficacy, adverse events, convenience, and preferences. To determine if the reason for discontinuation could influence the efficacy of subsequent therapy, a prospective longitudinal observational study was undertaken that included all rheumatoid arthritis (RA) patients in a Swiss national cohort who failed a course of TNF inhibitor therapy, said Dr. Finckh of Geneva University Hospital.

The primary outcome was the evolution in disease activity score 28 (DAS28) in the first year after switching, analyzed by multivariate regression models.

Among the 325 adult patients included in the study, 175 switched to another anti-TNF drug while 150 switched to the B-cell-depleting agent rituximab, according to Dr. Finckh.

Overall, the reason for discontinuation of the previous regimen was lack of efficacy in 65%. Of those, 28% were primary failures who experienced no response to therapy and 72% were secondary failures who initially responded but then lost the response.

The remaining 35% of patients switched because of adverse events, he said.

At the time of switching, there were no significant differences between the anti-TNF group and the rituximab group in terms of patient age, gender, disease duration, or concomitant steroid or conventional disease-modifying anti-rheumatic drug use.

Patients who switched to another anti-TNF drug had lower baseline DAS scores, however, at a mean of 4.0, compared with a mean of 4.97 in the rituximab group. After adjustment for this and other confounders, the evolution of DAS28 was overall more favorable for the rituximab group, he said.

When the motive for switching was lack of efficacy of the original TNF inhibitor, the evolution of DAS28 was significantly better for rituximab, with scores decreasing by 1.55 at 6 months, compared with a decrease of 1.03 for the anti-TNF group.

However, when the reason for switching was an adverse event, the evolution of DAS28 was similar in the two groups, with rituximab patients having a decrease in scores of 0.86 and the anti-TNF group decreasing by 0.77.

There was no effect modification by other variables, including primary versus secondary failure or concomitant DMARD use.

“This observational study suggests that patients who demonstrate therapeutic resistance to anti-TNF therapy may benefit from switching to rituximab,” Dr. Finckh concluded.

The study was partially supported by 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 rates of remission and influence radiographic outcome.

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.

In conclusion, the intensive FIN-RICo combination strategy resulted in remission rates of 53% and sustained remission rates of 31%, but the addition of infliximab for 6 months further increased these rates and prevented radiographic damage, 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 rates of remission and influence radiographic outcome.

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.

In conclusion, the intensive FIN-RICo combination strategy resulted in remission rates of 53% and sustained remission rates of 31%, but the addition of infliximab for 6 months further increased these rates and prevented radiographic damage, 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 rates of remission and influence radiographic outcome.

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.

In conclusion, the intensive FIN-RICo combination strategy resulted in remission rates of 53% and sustained remission rates of 31%, but the addition of infliximab for 6 months further increased these rates and prevented radiographic damage, 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 — Repeated treatment with a new type of B-cell-depleting agent was well tolerated and reduced signs and symptoms of rheumatoid arthritis, according to an interim analysis of an ongoing open-label study.

Analysis of pooled clinical responses from two dosage groups found that approximately 50% of patients achieved a 20% improvement in American College of Rheumatology parameters (ACR20); 25% had ACR50 responses, and 10%–15% had ACR70 responses, Dr. Richard W. Martin said at the annual European Congress of Rheumatology.

TRU-015 is a small modular immunopharmaceutical (SMIP), a single-chain protein that is approximately one-half to one-third the size of a monoclonal antibody. It is directed against CD20 markers on the surfaces of B cells, Dr. Martin said.

TRU-015 differs from rituximab in that it is human rather than chimeric, and was designed using a custom drug assembly technology that reduces complement activation, which is thought to contribute to some rituximab-associated adverse events, such as infusion reactions, and may play a role in disease activity in RA.

In all, 36 patients have now had at least one retreatment (that is, a second infusion), and 29 have had more than one retreatment (at least three infusions).

At this point, more than 100 courses of the experimental agent have been administered, with some patients receiving up to six courses over 3 years, Dr. Martin said. Patients who had previously received an infusion of at least 5 mg/kg and who completed 24 weeks of follow-up with at least 70% of B-cell recovery were eligible for retreatment with either 5 mg/kg or 15 mg/kg of TRU-015.

The infusions have generally been well tolerated, and there have been no grade 3 or 4 adverse events. Four patients had grade 2 adverse events, including facial flushing, erythema, and pruritus, as well as worsening insomnia.

Whether these events were caused by the study agent or by pretreatment with corticosteroids is not known, said Dr. Martin, professor of medicine and rheumatology at Michigan State University, Grand Rapids.

Six patients withdrew from the study, primarily for administrative reasons. There were no withdrawals because of adverse events, and there have been no opportunistic infections or deaths.

Headache was reported by 28% of patients after their first infusion; this fell to 8% and 7% after the second and third infusions. Other adverse events, such as fatigue and edema, also decreased with repeated treatments.

Nine serious adverse events were seen in seven patients. One patient had two hospitalizations for exacerbations of chronic obstructive pulmonary disease, another patient experienced an episode of cholecystitis, and one reported shortness of breath of unknown cause.

The retreatment pharmacokinetics of TRU-015 following repeated infusions are indistinguishable from those seen with the initial treatment, suggesting that there is no significant early development of neutralizing antibodies. There also was no attenuation in B-cell depletion following retreatment.

Clinical responses have been maintained from the first treatment to the second and beyond, he added.

Dr. Martin did not say when the trial was expected to be complete.

The manufacturer of TRU-015, Trubion Pharmaceuticals Inc., is creating a pipeline of customized therapeutic products, including SMIPs, for the treatment of autoimmune and inflammatory diseases and cancer.

Additionally, Wyeth Pharmaceuticals and Trubion have a worldwide licensing and commercialization agreement for the development of TRU-015 and other CD20-targeted therapies.

Dr. Martin disclosed that he has had contracts for clinical trials with Trubion, but owns no stock in the company and is not a paid consultant.

PARIS — Repeated treatment with a new type of B-cell-depleting agent was well tolerated and reduced signs and symptoms of rheumatoid arthritis, according to an interim analysis of an ongoing open-label study.

Analysis of pooled clinical responses from two dosage groups found that approximately 50% of patients achieved a 20% improvement in American College of Rheumatology parameters (ACR20); 25% had ACR50 responses, and 10%–15% had ACR70 responses, Dr. Richard W. Martin said at the annual European Congress of Rheumatology.

TRU-015 is a small modular immunopharmaceutical (SMIP), a single-chain protein that is approximately one-half to one-third the size of a monoclonal antibody. It is directed against CD20 markers on the surfaces of B cells, Dr. Martin said.

TRU-015 differs from rituximab in that it is human rather than chimeric, and was designed using a custom drug assembly technology that reduces complement activation, which is thought to contribute to some rituximab-associated adverse events, such as infusion reactions, and may play a role in disease activity in RA.

In all, 36 patients have now had at least one retreatment (that is, a second infusion), and 29 have had more than one retreatment (at least three infusions).

At this point, more than 100 courses of the experimental agent have been administered, with some patients receiving up to six courses over 3 years, Dr. Martin said. Patients who had previously received an infusion of at least 5 mg/kg and who completed 24 weeks of follow-up with at least 70% of B-cell recovery were eligible for retreatment with either 5 mg/kg or 15 mg/kg of TRU-015.

The infusions have generally been well tolerated, and there have been no grade 3 or 4 adverse events. Four patients had grade 2 adverse events, including facial flushing, erythema, and pruritus, as well as worsening insomnia.

Whether these events were caused by the study agent or by pretreatment with corticosteroids is not known, said Dr. Martin, professor of medicine and rheumatology at Michigan State University, Grand Rapids.

Six patients withdrew from the study, primarily for administrative reasons. There were no withdrawals because of adverse events, and there have been no opportunistic infections or deaths.

Headache was reported by 28% of patients after their first infusion; this fell to 8% and 7% after the second and third infusions. Other adverse events, such as fatigue and edema, also decreased with repeated treatments.

Nine serious adverse events were seen in seven patients. One patient had two hospitalizations for exacerbations of chronic obstructive pulmonary disease, another patient experienced an episode of cholecystitis, and one reported shortness of breath of unknown cause.

The retreatment pharmacokinetics of TRU-015 following repeated infusions are indistinguishable from those seen with the initial treatment, suggesting that there is no significant early development of neutralizing antibodies. There also was no attenuation in B-cell depletion following retreatment.

Clinical responses have been maintained from the first treatment to the second and beyond, he added.

Dr. Martin did not say when the trial was expected to be complete.

The manufacturer of TRU-015, Trubion Pharmaceuticals Inc., is creating a pipeline of customized therapeutic products, including SMIPs, for the treatment of autoimmune and inflammatory diseases and cancer.

Additionally, Wyeth Pharmaceuticals and Trubion have a worldwide licensing and commercialization agreement for the development of TRU-015 and other CD20-targeted therapies.

Dr. Martin disclosed that he has had contracts for clinical trials with Trubion, but owns no stock in the company and is not a paid consultant.

PARIS — Repeated treatment with a new type of B-cell-depleting agent was well tolerated and reduced signs and symptoms of rheumatoid arthritis, according to an interim analysis of an ongoing open-label study.

Analysis of pooled clinical responses from two dosage groups found that approximately 50% of patients achieved a 20% improvement in American College of Rheumatology parameters (ACR20); 25% had ACR50 responses, and 10%–15% had ACR70 responses, Dr. Richard W. Martin said at the annual European Congress of Rheumatology.

TRU-015 is a small modular immunopharmaceutical (SMIP), a single-chain protein that is approximately one-half to one-third the size of a monoclonal antibody. It is directed against CD20 markers on the surfaces of B cells, Dr. Martin said.

TRU-015 differs from rituximab in that it is human rather than chimeric, and was designed using a custom drug assembly technology that reduces complement activation, which is thought to contribute to some rituximab-associated adverse events, such as infusion reactions, and may play a role in disease activity in RA.

In all, 36 patients have now had at least one retreatment (that is, a second infusion), and 29 have had more than one retreatment (at least three infusions).

At this point, more than 100 courses of the experimental agent have been administered, with some patients receiving up to six courses over 3 years, Dr. Martin said. Patients who had previously received an infusion of at least 5 mg/kg and who completed 24 weeks of follow-up with at least 70% of B-cell recovery were eligible for retreatment with either 5 mg/kg or 15 mg/kg of TRU-015.

The infusions have generally been well tolerated, and there have been no grade 3 or 4 adverse events. Four patients had grade 2 adverse events, including facial flushing, erythema, and pruritus, as well as worsening insomnia.

Whether these events were caused by the study agent or by pretreatment with corticosteroids is not known, said Dr. Martin, professor of medicine and rheumatology at Michigan State University, Grand Rapids.

Six patients withdrew from the study, primarily for administrative reasons. There were no withdrawals because of adverse events, and there have been no opportunistic infections or deaths.

Headache was reported by 28% of patients after their first infusion; this fell to 8% and 7% after the second and third infusions. Other adverse events, such as fatigue and edema, also decreased with repeated treatments.

Nine serious adverse events were seen in seven patients. One patient had two hospitalizations for exacerbations of chronic obstructive pulmonary disease, another patient experienced an episode of cholecystitis, and one reported shortness of breath of unknown cause.

The retreatment pharmacokinetics of TRU-015 following repeated infusions are indistinguishable from those seen with the initial treatment, suggesting that there is no significant early development of neutralizing antibodies. There also was no attenuation in B-cell depletion following retreatment.

Clinical responses have been maintained from the first treatment to the second and beyond, he added.

Dr. Martin did not say when the trial was expected to be complete.

The manufacturer of TRU-015, Trubion Pharmaceuticals Inc., is creating a pipeline of customized therapeutic products, including SMIPs, for the treatment of autoimmune and inflammatory diseases and cancer.

Additionally, Wyeth Pharmaceuticals and Trubion have a worldwide licensing and commercialization agreement for the development of TRU-015 and other CD20-targeted therapies.

Dr. Martin disclosed that he has had contracts for clinical trials with Trubion, but owns no stock in the company and is not a paid consultant.

Custom-made foot orthotics can reduce foot pain caused by rheumatoid arthritis, pes cavus, and hallus vagus, according to a Cochrane Collaboration meta-analysis.

The authors stressed, however, that there are very few high-quality studies evaluating the use of orthotics to treat such conditions, weakening the clinical relevance of their conclusions.

The researchers evaluated a total of 11 randomized controlled trials and controlled clinical trials, which together had 1,332 subjects. The strongest evidence supporting the use of customized orthotics was in the treatment of painful pes cavus (high arch).

They also found evidence supporting orthotic use to treat foot pain associated with juvenile idiopathic arthritis, rheumatoid arthritis, plantar fasciitis, and hallux valgus.

“Custom foot orthoses can be an effective treatment for a variety of conditions, but there are still many causes of foot pain for which the benefit of this treatment is unclear,” Fiona Hawke, the lead researcher, who works at the Central Coast campus of the University of Newcastle (Australia), said in a written statement.

“There is also a lack of data on the long-term effects of treating with orthoses.”

▸ Painful pes cavus. The researchers found a single study that showed custom orthotics were superior to sham orthotics at 3 months in treating 154 patients with this disorder.

Those wearing custom orthoses showed a statistically significant weighted mean difference of 10.9 points on the pain domain of the foot health status questionnaire and 11 points in the function domain (Cochrane Database Syst. Rev. 2008 July 15 [Epub doi: 10.1002/14651858.CD006801.pub2

▸ Juvenile idiopathic arthritis. A single study of 33 children showed that custom foot orthotics were linked to significant improvements at 3 months in pain, function, and disability, compared with a standardized intervention (supportive shoes).

Weighted mean improvements of 19.2 on the pain scale of the foot function index, 19.4 on the index's activity limitation scale, and 18.6 on the disability scale were reported.

▸ Rheumatoid arthritis. A single study with 101 subjects found foot orthotics were more effective than no intervention in reducing rear foot pain after 30 months.

▸ Plantar fasciitis. A study of 92 subjects assessed at 3 and 12 months demonstrated a statistically significant improvement in foot pain-related function for those who used custom orthotics to treat plantar fasciitis, compared with those using sham orthoses.

Treated subjects reported a weighted mean improvement of 10.4 at both time points on the foot health status questionnaire.

The investigators did not measure a statistically significant improvement over standard interventions, however, and found that customized orthotics were less effective than stretching and mobilization over 2 weeks.

▸ Painful bunions with hallux valgus. Foot orthotics were shown to be more effective than no intervention over 6 months in a study of 138 subjects, with a weighted mean improvement of 9 on the 100-mm visual analog scale.

That study did not find a statistically significant improvement over 12 months, however.

Researchers found data supporting the benefit of custom foot orthotics for some. Vivian E. Lee/Elsevier Global Medical News

Custom-made foot orthotics can reduce foot pain caused by rheumatoid arthritis, pes cavus, and hallus vagus, according to a Cochrane Collaboration meta-analysis.

The authors stressed, however, that there are very few high-quality studies evaluating the use of orthotics to treat such conditions, weakening the clinical relevance of their conclusions.

The researchers evaluated a total of 11 randomized controlled trials and controlled clinical trials, which together had 1,332 subjects. The strongest evidence supporting the use of customized orthotics was in the treatment of painful pes cavus (high arch).

They also found evidence supporting orthotic use to treat foot pain associated with juvenile idiopathic arthritis, rheumatoid arthritis, plantar fasciitis, and hallux valgus.

“Custom foot orthoses can be an effective treatment for a variety of conditions, but there are still many causes of foot pain for which the benefit of this treatment is unclear,” Fiona Hawke, the lead researcher, who works at the Central Coast campus of the University of Newcastle (Australia), said in a written statement.

“There is also a lack of data on the long-term effects of treating with orthoses.”

▸ Painful pes cavus. The researchers found a single study that showed custom orthotics were superior to sham orthotics at 3 months in treating 154 patients with this disorder.

Those wearing custom orthoses showed a statistically significant weighted mean difference of 10.9 points on the pain domain of the foot health status questionnaire and 11 points in the function domain (Cochrane Database Syst. Rev. 2008 July 15 [Epub doi: 10.1002/14651858.CD006801.pub2

▸ Juvenile idiopathic arthritis. A single study of 33 children showed that custom foot orthotics were linked to significant improvements at 3 months in pain, function, and disability, compared with a standardized intervention (supportive shoes).

Weighted mean improvements of 19.2 on the pain scale of the foot function index, 19.4 on the index's activity limitation scale, and 18.6 on the disability scale were reported.

▸ Rheumatoid arthritis. A single study with 101 subjects found foot orthotics were more effective than no intervention in reducing rear foot pain after 30 months.

▸ Plantar fasciitis. A study of 92 subjects assessed at 3 and 12 months demonstrated a statistically significant improvement in foot pain-related function for those who used custom orthotics to treat plantar fasciitis, compared with those using sham orthoses.

Treated subjects reported a weighted mean improvement of 10.4 at both time points on the foot health status questionnaire.

The investigators did not measure a statistically significant improvement over standard interventions, however, and found that customized orthotics were less effective than stretching and mobilization over 2 weeks.

▸ Painful bunions with hallux valgus. Foot orthotics were shown to be more effective than no intervention over 6 months in a study of 138 subjects, with a weighted mean improvement of 9 on the 100-mm visual analog scale.

That study did not find a statistically significant improvement over 12 months, however.

Researchers found data supporting the benefit of custom foot orthotics for some. Vivian E. Lee/Elsevier Global Medical News

Custom-made foot orthotics can reduce foot pain caused by rheumatoid arthritis, pes cavus, and hallus vagus, according to a Cochrane Collaboration meta-analysis.

The authors stressed, however, that there are very few high-quality studies evaluating the use of orthotics to treat such conditions, weakening the clinical relevance of their conclusions.

The researchers evaluated a total of 11 randomized controlled trials and controlled clinical trials, which together had 1,332 subjects. The strongest evidence supporting the use of customized orthotics was in the treatment of painful pes cavus (high arch).

They also found evidence supporting orthotic use to treat foot pain associated with juvenile idiopathic arthritis, rheumatoid arthritis, plantar fasciitis, and hallux valgus.

“Custom foot orthoses can be an effective treatment for a variety of conditions, but there are still many causes of foot pain for which the benefit of this treatment is unclear,” Fiona Hawke, the lead researcher, who works at the Central Coast campus of the University of Newcastle (Australia), said in a written statement.

“There is also a lack of data on the long-term effects of treating with orthoses.”

▸ Painful pes cavus. The researchers found a single study that showed custom orthotics were superior to sham orthotics at 3 months in treating 154 patients with this disorder.

Those wearing custom orthoses showed a statistically significant weighted mean difference of 10.9 points on the pain domain of the foot health status questionnaire and 11 points in the function domain (Cochrane Database Syst. Rev. 2008 July 15 [Epub doi: 10.1002/14651858.CD006801.pub2

▸ Juvenile idiopathic arthritis. A single study of 33 children showed that custom foot orthotics were linked to significant improvements at 3 months in pain, function, and disability, compared with a standardized intervention (supportive shoes).

Weighted mean improvements of 19.2 on the pain scale of the foot function index, 19.4 on the index's activity limitation scale, and 18.6 on the disability scale were reported.

▸ Rheumatoid arthritis. A single study with 101 subjects found foot orthotics were more effective than no intervention in reducing rear foot pain after 30 months.

▸ Plantar fasciitis. A study of 92 subjects assessed at 3 and 12 months demonstrated a statistically significant improvement in foot pain-related function for those who used custom orthotics to treat plantar fasciitis, compared with those using sham orthoses.

Treated subjects reported a weighted mean improvement of 10.4 at both time points on the foot health status questionnaire.

The investigators did not measure a statistically significant improvement over standard interventions, however, and found that customized orthotics were less effective than stretching and mobilization over 2 weeks.

▸ Painful bunions with hallux valgus. Foot orthotics were shown to be more effective than no intervention over 6 months in a study of 138 subjects, with a weighted mean improvement of 9 on the 100-mm visual analog scale.

That study did not find a statistically significant improvement over 12 months, however.

Researchers found data supporting the benefit of custom foot orthotics for some. Vivian E. Lee/Elsevier Global Medical News

PARIS — Methotrexate is an effective therapy for psoriatic arthritis, albeit somewhat less so than for rheumatoid arthritis, according to findings from a large Norwegian registry.

The same data that confirm methotrexate's usefulness in RA offer promise that the agent may be of use in some patients with PsA, Dr. Elisabeth Lie said at the annual congress of the European League Against Rheumatism.

Although methotrexate is widely prescribed for psoriatic arthritis, the supporting evidence for this practice is quite sparse. So Dr. Lie and her coinvestigators examined how methotrexate performed over 6 months in the real-world, nonclinical trial setting of the NOR-DMARD (Norwegian Disease-Modifying Antirheumatic Drug) registry.

NOR-DMARD is a collaboration between five Norwegian rheumatology departments. It features longitudinal patient follow-up with periodic comprehensive collection of data on disease activity and patient outcome measures, explained Dr. Lie of Diakonhjemmet Hospital, Oslo.

The 430 participants with PsA and 1,218 with RA were methotrexate naive at the start. Two-thirds had a disease duration less than 3 years. After 6 months of methotrexate, the mean weekly dose was 13.7 mg in the PsA group and 13.9 mg in the RA patients.

Among the outcomes assessed were 6-month changes in C-reactive protein, erythrocyte sedimentation rate, number of involved joints, the bodily pain and physical functioning scales of the Short Form-36, and patient-assessed fatigue and joint pain. Both groups showed significant overall improvements after 6 months of methotrexate. In the unadjusted analysis, however, the RA patients showed significantly greater mean improvements over baseline than did the PsA patients on virtually all measures.

Yet the RA patients also tended to have worse baseline disease activity. After adjustment for this, as well as age, gender, and dose, the outcome differences between the PsA and RA groups shrank below the level of statistical significance with just two exceptions: The drug remained significantly more effective at improving fatigue and pain scores in the RA group than in patients with PsA.

At baseline, 3, and 6 months, patients in both groups were asked if they were satisfied with their level of function and pain. At baseline, 44% of RA patients and 34% of PsA patients answered affirmatively. At 3 months, the RA patients remained significantly more likely to answer “yes,” by a margin of 64% to 57%. By 6 months, the difference between the two groups was not significant.

Patients also were asked at 3 and 6 months if they'd experienced significant improvement since initiation of methotrexate. Both times, the RA patients were significantly more likely to reply affirmatively, Dr. Lie noted.

PARIS — Methotrexate is an effective therapy for psoriatic arthritis, albeit somewhat less so than for rheumatoid arthritis, according to findings from a large Norwegian registry.

The same data that confirm methotrexate's usefulness in RA offer promise that the agent may be of use in some patients with PsA, Dr. Elisabeth Lie said at the annual congress of the European League Against Rheumatism.

Although methotrexate is widely prescribed for psoriatic arthritis, the supporting evidence for this practice is quite sparse. So Dr. Lie and her coinvestigators examined how methotrexate performed over 6 months in the real-world, nonclinical trial setting of the NOR-DMARD (Norwegian Disease-Modifying Antirheumatic Drug) registry.

NOR-DMARD is a collaboration between five Norwegian rheumatology departments. It features longitudinal patient follow-up with periodic comprehensive collection of data on disease activity and patient outcome measures, explained Dr. Lie of Diakonhjemmet Hospital, Oslo.

The 430 participants with PsA and 1,218 with RA were methotrexate naive at the start. Two-thirds had a disease duration less than 3 years. After 6 months of methotrexate, the mean weekly dose was 13.7 mg in the PsA group and 13.9 mg in the RA patients.

Among the outcomes assessed were 6-month changes in C-reactive protein, erythrocyte sedimentation rate, number of involved joints, the bodily pain and physical functioning scales of the Short Form-36, and patient-assessed fatigue and joint pain. Both groups showed significant overall improvements after 6 months of methotrexate. In the unadjusted analysis, however, the RA patients showed significantly greater mean improvements over baseline than did the PsA patients on virtually all measures.

Yet the RA patients also tended to have worse baseline disease activity. After adjustment for this, as well as age, gender, and dose, the outcome differences between the PsA and RA groups shrank below the level of statistical significance with just two exceptions: The drug remained significantly more effective at improving fatigue and pain scores in the RA group than in patients with PsA.

At baseline, 3, and 6 months, patients in both groups were asked if they were satisfied with their level of function and pain. At baseline, 44% of RA patients and 34% of PsA patients answered affirmatively. At 3 months, the RA patients remained significantly more likely to answer “yes,” by a margin of 64% to 57%. By 6 months, the difference between the two groups was not significant.

Patients also were asked at 3 and 6 months if they'd experienced significant improvement since initiation of methotrexate. Both times, the RA patients were significantly more likely to reply affirmatively, Dr. Lie noted.

PARIS — Methotrexate is an effective therapy for psoriatic arthritis, albeit somewhat less so than for rheumatoid arthritis, according to findings from a large Norwegian registry.

The same data that confirm methotrexate's usefulness in RA offer promise that the agent may be of use in some patients with PsA, Dr. Elisabeth Lie said at the annual congress of the European League Against Rheumatism.

Although methotrexate is widely prescribed for psoriatic arthritis, the supporting evidence for this practice is quite sparse. So Dr. Lie and her coinvestigators examined how methotrexate performed over 6 months in the real-world, nonclinical trial setting of the NOR-DMARD (Norwegian Disease-Modifying Antirheumatic Drug) registry.

NOR-DMARD is a collaboration between five Norwegian rheumatology departments. It features longitudinal patient follow-up with periodic comprehensive collection of data on disease activity and patient outcome measures, explained Dr. Lie of Diakonhjemmet Hospital, Oslo.

The 430 participants with PsA and 1,218 with RA were methotrexate naive at the start. Two-thirds had a disease duration less than 3 years. After 6 months of methotrexate, the mean weekly dose was 13.7 mg in the PsA group and 13.9 mg in the RA patients.

Among the outcomes assessed were 6-month changes in C-reactive protein, erythrocyte sedimentation rate, number of involved joints, the bodily pain and physical functioning scales of the Short Form-36, and patient-assessed fatigue and joint pain. Both groups showed significant overall improvements after 6 months of methotrexate. In the unadjusted analysis, however, the RA patients showed significantly greater mean improvements over baseline than did the PsA patients on virtually all measures.

Yet the RA patients also tended to have worse baseline disease activity. After adjustment for this, as well as age, gender, and dose, the outcome differences between the PsA and RA groups shrank below the level of statistical significance with just two exceptions: The drug remained significantly more effective at improving fatigue and pain scores in the RA group than in patients with PsA.

At baseline, 3, and 6 months, patients in both groups were asked if they were satisfied with their level of function and pain. At baseline, 44% of RA patients and 34% of PsA patients answered affirmatively. At 3 months, the RA patients remained significantly more likely to answer “yes,” by a margin of 64% to 57%. By 6 months, the difference between the two groups was not significant.

Patients also were asked at 3 and 6 months if they'd experienced significant improvement since initiation of methotrexate. Both times, the RA patients were significantly more likely to reply affirmatively, Dr. Lie noted.

PARIS — Serum urate levels are often normal during acute gouty arthritis attacks, according to Dr. Naomi Schlesinger.

In the study of 339 patients with acute gouty arthritis whose serum urate levels were measured, 29% of individuals on chronicallopurinol had a true-normal serum urate level, defined as 6 mg/dL or less. Among patients not on the hypouricemic agent, 11% had a true-normal serum urate level during their acute episode of gout.

“This may be attributed to the persistence of tophi and a resultant increased body uric acid pool,” commented Dr. Schlesinger, chief of rheumatology at Robert Wood Johnson Medical School, Camden, N.J.

With a less stringent definition of normal serum urate—a value of 8 mg/dL or less—49% of allopurinol users were classified as having a normal level during their acute attack, as were 29% not on allopurinol, according to data she presented at the annual congress of the European League Against Rheumatism.

The 339 patients included in Dr. Schlesinger's analysis were participants in one of two earlier randomized clinical trials assessing the efficacy of 1 week of etoricoxib or indomethacin therapy in acute gout. Although Dr. Schlesinger wasn't involved in the original studies, she obtained the complete data for both and combined the two study populations because efficacy was similar for both drugs. Prior investigations included just 41 patients (J. Rheumatol. 2002;29:1950-3), and her own earlier study of 59 patients (J. Rheumatol. 1997;24:2265-6).

Laboratory measurements in 339 patients—including serum urate as assessed by the uricase enzyme method—were obtained at baseline and on days 2, 5, and 8. The mean serum urate at baseline was 7.6 mg/dL in patients on long-term allopurinol and 8.5 mg/dL in those who weren't. Similarly, on day 8, following a week of non-steroidal anti-inflammatory drug therapy, the mean serum urate was 7.4 mg/dL in those on allopurinol and 8.7 mg/dL in those who were not. Patients with a history of more than four gouty attacks per year or with polyarticular attacks had higher serum urate during the episode studied than those without those characteristics.

In response to audience questions, Dr. Schlesinger said it has previously been shown that an acute gouty arthritis attack can be initiated by any significant change in serum urate, whether an increase or decrease. In some cases, however, serum urate falls secondary to the acute attack as a result of cytokines released during the episode.

Dr. Schlesinger disclosed that Merck & Co. provided her with access to the complete data from the two company-sponsored clinical trials as well as support in data analysis.

PARIS — Serum urate levels are often normal during acute gouty arthritis attacks, according to Dr. Naomi Schlesinger.

In the study of 339 patients with acute gouty arthritis whose serum urate levels were measured, 29% of individuals on chronicallopurinol had a true-normal serum urate level, defined as 6 mg/dL or less. Among patients not on the hypouricemic agent, 11% had a true-normal serum urate level during their acute episode of gout.

“This may be attributed to the persistence of tophi and a resultant increased body uric acid pool,” commented Dr. Schlesinger, chief of rheumatology at Robert Wood Johnson Medical School, Camden, N.J.

With a less stringent definition of normal serum urate—a value of 8 mg/dL or less—49% of allopurinol users were classified as having a normal level during their acute attack, as were 29% not on allopurinol, according to data she presented at the annual congress of the European League Against Rheumatism.

The 339 patients included in Dr. Schlesinger's analysis were participants in one of two earlier randomized clinical trials assessing the efficacy of 1 week of etoricoxib or indomethacin therapy in acute gout. Although Dr. Schlesinger wasn't involved in the original studies, she obtained the complete data for both and combined the two study populations because efficacy was similar for both drugs. Prior investigations included just 41 patients (J. Rheumatol. 2002;29:1950-3), and her own earlier study of 59 patients (J. Rheumatol. 1997;24:2265-6).

Laboratory measurements in 339 patients—including serum urate as assessed by the uricase enzyme method—were obtained at baseline and on days 2, 5, and 8. The mean serum urate at baseline was 7.6 mg/dL in patients on long-term allopurinol and 8.5 mg/dL in those who weren't. Similarly, on day 8, following a week of non-steroidal anti-inflammatory drug therapy, the mean serum urate was 7.4 mg/dL in those on allopurinol and 8.7 mg/dL in those who were not. Patients with a history of more than four gouty attacks per year or with polyarticular attacks had higher serum urate during the episode studied than those without those characteristics.

In response to audience questions, Dr. Schlesinger said it has previously been shown that an acute gouty arthritis attack can be initiated by any significant change in serum urate, whether an increase or decrease. In some cases, however, serum urate falls secondary to the acute attack as a result of cytokines released during the episode.

Dr. Schlesinger disclosed that Merck & Co. provided her with access to the complete data from the two company-sponsored clinical trials as well as support in data analysis.

PARIS — Serum urate levels are often normal during acute gouty arthritis attacks, according to Dr. Naomi Schlesinger.

In the study of 339 patients with acute gouty arthritis whose serum urate levels were measured, 29% of individuals on chronicallopurinol had a true-normal serum urate level, defined as 6 mg/dL or less. Among patients not on the hypouricemic agent, 11% had a true-normal serum urate level during their acute episode of gout.

“This may be attributed to the persistence of tophi and a resultant increased body uric acid pool,” commented Dr. Schlesinger, chief of rheumatology at Robert Wood Johnson Medical School, Camden, N.J.

With a less stringent definition of normal serum urate—a value of 8 mg/dL or less—49% of allopurinol users were classified as having a normal level during their acute attack, as were 29% not on allopurinol, according to data she presented at the annual congress of the European League Against Rheumatism.

The 339 patients included in Dr. Schlesinger's analysis were participants in one of two earlier randomized clinical trials assessing the efficacy of 1 week of etoricoxib or indomethacin therapy in acute gout. Although Dr. Schlesinger wasn't involved in the original studies, she obtained the complete data for both and combined the two study populations because efficacy was similar for both drugs. Prior investigations included just 41 patients (J. Rheumatol. 2002;29:1950-3), and her own earlier study of 59 patients (J. Rheumatol. 1997;24:2265-6).

Laboratory measurements in 339 patients—including serum urate as assessed by the uricase enzyme method—were obtained at baseline and on days 2, 5, and 8. The mean serum urate at baseline was 7.6 mg/dL in patients on long-term allopurinol and 8.5 mg/dL in those who weren't. Similarly, on day 8, following a week of non-steroidal anti-inflammatory drug therapy, the mean serum urate was 7.4 mg/dL in those on allopurinol and 8.7 mg/dL in those who were not. Patients with a history of more than four gouty attacks per year or with polyarticular attacks had higher serum urate during the episode studied than those without those characteristics.

In response to audience questions, Dr. Schlesinger said it has previously been shown that an acute gouty arthritis attack can be initiated by any significant change in serum urate, whether an increase or decrease. In some cases, however, serum urate falls secondary to the acute attack as a result of cytokines released during the episode.

Dr. Schlesinger disclosed that Merck & Co. provided her with access to the complete data from the two company-sponsored clinical trials as well as support in data analysis.

Afully sustained, disease-modifying-antirheumatic-drug-free remission occurred in 15% of patients using conventional, nonbiologic therapy, according to results from a large 10-year study.

“We were surprised by the high number of patients who achieved remission,” Dr. Diane van der Woude of Leiden University Medical Centre (Netherlands), and the study's lead author, said in an interview. The data was reported at the annual European Congress of Rheumatology. “The patients we studied were enrolled between 1993 and 2003, a time when there were no biological agents available and disease activity was not strictly monitored. That 15% of patients treated with conventional therapy achieved remission is a useful number to keep in mind as a reference when reading reports of remission percentages after treatment with novel agents.”

She looked at 454 RA patients. Patients were treated with a delayed or early treatment strategy with chloroquine, sulfasalazine, or methotrexate. They defined DMARD-free remission as absence of synovitis without concomitant use of disease-modifying antirheumatic drugs (DMARDs) for more than 1 year. Average follow-up was 8 years. Of the 454 RA patients, 69 (15%) achieved DMARD-free remission.

Univariate analysis revealed that the following were significantly associated with achieving DMARD-free remission: negative family history (hazard ratio of 1.8), short duration of complaints before presentation (HR 1.08 per month), nonsmoking (HR 1.8), low C-reactive protein at baseline (HR 1.01 per mg/L), absence of IgM rheumatoid factor and anti-CCP antibodies (HR 5.9 and 11.6, respectively), and absence of HLA shared epitope alleles (HR 2.1).

Multivariate analysis revealed that low C-reactive protein at baseline and absence of anti-CCP antibodies were significant independent predictors for DMARD-free remission.

“We are currently working on replication of these data in another large [non-Dutch] early arthritis cohort, also consisting of patients treated with conventional antirheumatic therapy,” Dr. van der Woude said in an interview. “It will be interesting to see if we and our collaborators will find a similar prevalence of DMARD-free remission and similar predictive characteristics,” she added.

Afully sustained, disease-modifying-antirheumatic-drug-free remission occurred in 15% of patients using conventional, nonbiologic therapy, according to results from a large 10-year study.

“We were surprised by the high number of patients who achieved remission,” Dr. Diane van der Woude of Leiden University Medical Centre (Netherlands), and the study's lead author, said in an interview. The data was reported at the annual European Congress of Rheumatology. “The patients we studied were enrolled between 1993 and 2003, a time when there were no biological agents available and disease activity was not strictly monitored. That 15% of patients treated with conventional therapy achieved remission is a useful number to keep in mind as a reference when reading reports of remission percentages after treatment with novel agents.”

She looked at 454 RA patients. Patients were treated with a delayed or early treatment strategy with chloroquine, sulfasalazine, or methotrexate. They defined DMARD-free remission as absence of synovitis without concomitant use of disease-modifying antirheumatic drugs (DMARDs) for more than 1 year. Average follow-up was 8 years. Of the 454 RA patients, 69 (15%) achieved DMARD-free remission.

Univariate analysis revealed that the following were significantly associated with achieving DMARD-free remission: negative family history (hazard ratio of 1.8), short duration of complaints before presentation (HR 1.08 per month), nonsmoking (HR 1.8), low C-reactive protein at baseline (HR 1.01 per mg/L), absence of IgM rheumatoid factor and anti-CCP antibodies (HR 5.9 and 11.6, respectively), and absence of HLA shared epitope alleles (HR 2.1).

Multivariate analysis revealed that low C-reactive protein at baseline and absence of anti-CCP antibodies were significant independent predictors for DMARD-free remission.

“We are currently working on replication of these data in another large [non-Dutch] early arthritis cohort, also consisting of patients treated with conventional antirheumatic therapy,” Dr. van der Woude said in an interview. “It will be interesting to see if we and our collaborators will find a similar prevalence of DMARD-free remission and similar predictive characteristics,” she added.

Afully sustained, disease-modifying-antirheumatic-drug-free remission occurred in 15% of patients using conventional, nonbiologic therapy, according to results from a large 10-year study.

“We were surprised by the high number of patients who achieved remission,” Dr. Diane van der Woude of Leiden University Medical Centre (Netherlands), and the study's lead author, said in an interview. The data was reported at the annual European Congress of Rheumatology. “The patients we studied were enrolled between 1993 and 2003, a time when there were no biological agents available and disease activity was not strictly monitored. That 15% of patients treated with conventional therapy achieved remission is a useful number to keep in mind as a reference when reading reports of remission percentages after treatment with novel agents.”

She looked at 454 RA patients. Patients were treated with a delayed or early treatment strategy with chloroquine, sulfasalazine, or methotrexate. They defined DMARD-free remission as absence of synovitis without concomitant use of disease-modifying antirheumatic drugs (DMARDs) for more than 1 year. Average follow-up was 8 years. Of the 454 RA patients, 69 (15%) achieved DMARD-free remission.

Univariate analysis revealed that the following were significantly associated with achieving DMARD-free remission: negative family history (hazard ratio of 1.8), short duration of complaints before presentation (HR 1.08 per month), nonsmoking (HR 1.8), low C-reactive protein at baseline (HR 1.01 per mg/L), absence of IgM rheumatoid factor and anti-CCP antibodies (HR 5.9 and 11.6, respectively), and absence of HLA shared epitope alleles (HR 2.1).

Multivariate analysis revealed that low C-reactive protein at baseline and absence of anti-CCP antibodies were significant independent predictors for DMARD-free remission.

“We are currently working on replication of these data in another large [non-Dutch] early arthritis cohort, also consisting of patients treated with conventional antirheumatic therapy,” Dr. van der Woude said in an interview. “It will be interesting to see if we and our collaborators will find a similar prevalence of DMARD-free remission and similar predictive characteristics,” she added.

PARIS — Earlier diagnosis of ankylosing spondylitis has emerged as a high priority, and MRI is vital in accomplishing it, according to Dr. Martin Rudwaleit.

The average interval between onset of symptoms of ankylosing spondylitis (AS)—chiefly inflammatory low back pain—and the time of diagnosis is 6-10 years.

Moreover, AS, a disease with an estimated prevalence of about 0.5%, has its onset predominantly in young adulthood. Symptoms occur by age 30 in 80% of cases and by age 45 in 95%. So the lengthy delays in diagnosis, which often involve extensive work absenteeism, take place during what would ordinarily be among the most productive years of life.

A major reason for the long delay in diagnosis is that the standard diagnostic criteria for AS used for nearly the past quarter century—the 1984 modified New York criteria—require unequivocal radiographic evidence of sacroiliitis. Because x-ray changes are a late disease manifestation, they typically don't appear until years after symptom onset.

Long before the classic radiographic findings are evident, however, active inflammatory lesions are present on MRI, stressed Dr. Rudwaleit, a rheumatologist at the University Hospital Charité, Berlin.

Bone marrow edema located periarticularly, adjacent to the sacroiliac joint space, indicates active inflammatory osteitis. This is the most important MRI finding in establishing the diagnosis of AS, he added.

Another big reason for the long delay in diagnosis is that the core clinical features required under the modified New York criteria—namely, restricted spinal mobility and restricted chest expansion—are, like the radiographic changes, late disease manifestations. Similarly, the distinctive postural changes often considered pathognomonic for AS aren't apparent until the disease is well along.

Dr. Rudwaleit and coworkers have proposed a new diagnostic algorithm for AS. It focuses on identifying disease in the preradiographic stages and relies upon MRI and HLA-B27 testing (Ann. Rheum. Dis. 2004;63:535-43). The criteria are now undergoing minor alterations in a multicenter validation study, in which 650 patients with chronic low back pain have been enrolled to date.

“We think diagnosis of axial spondyloarthritis without radiographic changes is feasible in daily clinical practice,” he said at the annual European Congress of Rheumatology.

As part of the effort to develop improved diagnostic criteria, he and his coworkers have devised a simpler method for differentiating inflammatory from mechanical low back pain. The distinction is critical because inflammatory low back pain is the earliest and most important symptom of AS. The diagnostic challenge arises from the fact that AS accounts for only 5% of chronic low back pain.

By analyzing the clinical histories of 101 patients with confirmed AS and 112 others with mechanical low back pain, Dr. Rudwaleit identified four parameters that best discriminated between the two: morning stiffness of more than 30 minutes' duration, improvement of back pain with exercise but not with rest, nighttime awakening due to back pain during only the second half of the night, and alternating buttock pain. When any two of these four criteria were met, the sensitivity and specificity for inflammatory back pain were 70% and 81%, respectively (Arthritis Rheum. 2006;54:569-78).

But the presence of inflammatory back pain doesn't suffice to make the diagnosis of AS; that requires additional criteria, ideally including a positive MRI, which has the greatest sensitivity and specificity of the various diagnostic criteria, according to Dr. Rudwaleit.

He and his coworkers have developed a method of calculating AS probability derived by multiplying the likelihood ratios (LRs) of the individual AS parameters. For example, a positive MRI carries an LR of 9.0 based upon its high sensitivity and specificity. If a patient has a positive MRI plus inflammatory back pain, which has an LR of 3.1, plus heel pain, with an LR of 3.4, and elevated acute phase reactants, with an LR of 2.5, the resultant LR product is 237, indicating a greater than 90% probability of AS.

Dr. Rudwaleit considers a clearly positive MRI to be a prerequisite for anti-tumor necrosis factor therapy. Anti-TNF agents have proved highly effective in AS. There is hope that their early use can prevent or at least retard disease evolution.

The definitive evidence for this isn't in yet, but it's an exciting possibility that has added further impetus to efforts to diagnose AS earlier.

STIR MRIs (right top and bottom) show inflammation adjacent to the sacroiliac joints (white areas) not seen on x-ray (left). Images courtesy Dr. Martin Rudwaleit

PARIS — Earlier diagnosis of ankylosing spondylitis has emerged as a high priority, and MRI is vital in accomplishing it, according to Dr. Martin Rudwaleit.

The average interval between onset of symptoms of ankylosing spondylitis (AS)—chiefly inflammatory low back pain—and the time of diagnosis is 6-10 years.

Moreover, AS, a disease with an estimated prevalence of about 0.5%, has its onset predominantly in young adulthood. Symptoms occur by age 30 in 80% of cases and by age 45 in 95%. So the lengthy delays in diagnosis, which often involve extensive work absenteeism, take place during what would ordinarily be among the most productive years of life.

A major reason for the long delay in diagnosis is that the standard diagnostic criteria for AS used for nearly the past quarter century—the 1984 modified New York criteria—require unequivocal radiographic evidence of sacroiliitis. Because x-ray changes are a late disease manifestation, they typically don't appear until years after symptom onset.

Long before the classic radiographic findings are evident, however, active inflammatory lesions are present on MRI, stressed Dr. Rudwaleit, a rheumatologist at the University Hospital Charité, Berlin.

Bone marrow edema located periarticularly, adjacent to the sacroiliac joint space, indicates active inflammatory osteitis. This is the most important MRI finding in establishing the diagnosis of AS, he added.

Another big reason for the long delay in diagnosis is that the core clinical features required under the modified New York criteria—namely, restricted spinal mobility and restricted chest expansion—are, like the radiographic changes, late disease manifestations. Similarly, the distinctive postural changes often considered pathognomonic for AS aren't apparent until the disease is well along.

Dr. Rudwaleit and coworkers have proposed a new diagnostic algorithm for AS. It focuses on identifying disease in the preradiographic stages and relies upon MRI and HLA-B27 testing (Ann. Rheum. Dis. 2004;63:535-43). The criteria are now undergoing minor alterations in a multicenter validation study, in which 650 patients with chronic low back pain have been enrolled to date.

“We think diagnosis of axial spondyloarthritis without radiographic changes is feasible in daily clinical practice,” he said at the annual European Congress of Rheumatology.

As part of the effort to develop improved diagnostic criteria, he and his coworkers have devised a simpler method for differentiating inflammatory from mechanical low back pain. The distinction is critical because inflammatory low back pain is the earliest and most important symptom of AS. The diagnostic challenge arises from the fact that AS accounts for only 5% of chronic low back pain.

By analyzing the clinical histories of 101 patients with confirmed AS and 112 others with mechanical low back pain, Dr. Rudwaleit identified four parameters that best discriminated between the two: morning stiffness of more than 30 minutes' duration, improvement of back pain with exercise but not with rest, nighttime awakening due to back pain during only the second half of the night, and alternating buttock pain. When any two of these four criteria were met, the sensitivity and specificity for inflammatory back pain were 70% and 81%, respectively (Arthritis Rheum. 2006;54:569-78).

But the presence of inflammatory back pain doesn't suffice to make the diagnosis of AS; that requires additional criteria, ideally including a positive MRI, which has the greatest sensitivity and specificity of the various diagnostic criteria, according to Dr. Rudwaleit.

He and his coworkers have developed a method of calculating AS probability derived by multiplying the likelihood ratios (LRs) of the individual AS parameters. For example, a positive MRI carries an LR of 9.0 based upon its high sensitivity and specificity. If a patient has a positive MRI plus inflammatory back pain, which has an LR of 3.1, plus heel pain, with an LR of 3.4, and elevated acute phase reactants, with an LR of 2.5, the resultant LR product is 237, indicating a greater than 90% probability of AS.

Dr. Rudwaleit considers a clearly positive MRI to be a prerequisite for anti-tumor necrosis factor therapy. Anti-TNF agents have proved highly effective in AS. There is hope that their early use can prevent or at least retard disease evolution.

The definitive evidence for this isn't in yet, but it's an exciting possibility that has added further impetus to efforts to diagnose AS earlier.

STIR MRIs (right top and bottom) show inflammation adjacent to the sacroiliac joints (white areas) not seen on x-ray (left). Images courtesy Dr. Martin Rudwaleit

PARIS — Earlier diagnosis of ankylosing spondylitis has emerged as a high priority, and MRI is vital in accomplishing it, according to Dr. Martin Rudwaleit.

The average interval between onset of symptoms of ankylosing spondylitis (AS)—chiefly inflammatory low back pain—and the time of diagnosis is 6-10 years.

Moreover, AS, a disease with an estimated prevalence of about 0.5%, has its onset predominantly in young adulthood. Symptoms occur by age 30 in 80% of cases and by age 45 in 95%. So the lengthy delays in diagnosis, which often involve extensive work absenteeism, take place during what would ordinarily be among the most productive years of life.

A major reason for the long delay in diagnosis is that the standard diagnostic criteria for AS used for nearly the past quarter century—the 1984 modified New York criteria—require unequivocal radiographic evidence of sacroiliitis. Because x-ray changes are a late disease manifestation, they typically don't appear until years after symptom onset.

Long before the classic radiographic findings are evident, however, active inflammatory lesions are present on MRI, stressed Dr. Rudwaleit, a rheumatologist at the University Hospital Charité, Berlin.

Bone marrow edema located periarticularly, adjacent to the sacroiliac joint space, indicates active inflammatory osteitis. This is the most important MRI finding in establishing the diagnosis of AS, he added.

Another big reason for the long delay in diagnosis is that the core clinical features required under the modified New York criteria—namely, restricted spinal mobility and restricted chest expansion—are, like the radiographic changes, late disease manifestations. Similarly, the distinctive postural changes often considered pathognomonic for AS aren't apparent until the disease is well along.

Dr. Rudwaleit and coworkers have proposed a new diagnostic algorithm for AS. It focuses on identifying disease in the preradiographic stages and relies upon MRI and HLA-B27 testing (Ann. Rheum. Dis. 2004;63:535-43). The criteria are now undergoing minor alterations in a multicenter validation study, in which 650 patients with chronic low back pain have been enrolled to date.

“We think diagnosis of axial spondyloarthritis without radiographic changes is feasible in daily clinical practice,” he said at the annual European Congress of Rheumatology.

As part of the effort to develop improved diagnostic criteria, he and his coworkers have devised a simpler method for differentiating inflammatory from mechanical low back pain. The distinction is critical because inflammatory low back pain is the earliest and most important symptom of AS. The diagnostic challenge arises from the fact that AS accounts for only 5% of chronic low back pain.

By analyzing the clinical histories of 101 patients with confirmed AS and 112 others with mechanical low back pain, Dr. Rudwaleit identified four parameters that best discriminated between the two: morning stiffness of more than 30 minutes' duration, improvement of back pain with exercise but not with rest, nighttime awakening due to back pain during only the second half of the night, and alternating buttock pain. When any two of these four criteria were met, the sensitivity and specificity for inflammatory back pain were 70% and 81%, respectively (Arthritis Rheum. 2006;54:569-78).

But the presence of inflammatory back pain doesn't suffice to make the diagnosis of AS; that requires additional criteria, ideally including a positive MRI, which has the greatest sensitivity and specificity of the various diagnostic criteria, according to Dr. Rudwaleit.

He and his coworkers have developed a method of calculating AS probability derived by multiplying the likelihood ratios (LRs) of the individual AS parameters. For example, a positive MRI carries an LR of 9.0 based upon its high sensitivity and specificity. If a patient has a positive MRI plus inflammatory back pain, which has an LR of 3.1, plus heel pain, with an LR of 3.4, and elevated acute phase reactants, with an LR of 2.5, the resultant LR product is 237, indicating a greater than 90% probability of AS.

Dr. Rudwaleit considers a clearly positive MRI to be a prerequisite for anti-tumor necrosis factor therapy. Anti-TNF agents have proved highly effective in AS. There is hope that their early use can prevent or at least retard disease evolution.

The definitive evidence for this isn't in yet, but it's an exciting possibility that has added further impetus to efforts to diagnose AS earlier.

STIR MRIs (right top and bottom) show inflammation adjacent to the sacroiliac joints (white areas) not seen on x-ray (left). Images courtesy Dr. Martin Rudwaleit