Psoriasis

GLASGOW, SCOTLAND – The presence of specific autoantibodies may help to predict which patients with systemic sclerosis are likely to develop cancer within a few years of their diagnosis, according to the findings of a U.K.-based registry study.

Development of malignancy within 3 years of a diagnosis of scleroderma was positively correlated with the presence of antinuclear antibodies (ANA) directed against RNA polymerase (RNAP) III in more than half (55.3%) of the patients studied (n = 154).

Anticentromere antibodies (ACA) were found in almost a quarter (23.4%) of patients, and 13.6% had antitopoisomerase I (ATA) or anti-Scl70 (antibodies).

Furthermore, patients with anti-RNAP III antibodies had an almost threefold increased risk of cancer compared with patients with ACA (hazard ratio [HR] 2.907; 95% confidence interval [CI] 1.69-4.99, P less than .0001).

"We think that patients who develop scleroderma and cancer can be divided into two different groups," trainee dermatologist Dr. Pia Moinzadeh of the University of Cologne, Germany, said at the annual meeting of the British Society for Rheumatology.

"The first group are those who develop scleroderma and cancer in a very close temporal relationship, and we saw that these patients are most frequently anti-RNA polymerase positive. So scleroderma in these patients can be considered a paraneoplastic disease."

The other group includes patients who develop cancer after a delay of several years from the onset of systemic sclerosis.

Several epidemiological studies have shown an increased risk of malignancy in patients with systemic sclerosis compared with the general population (Br. J. Dermatol. 2010;163:800-6), Dr. Moinzadeh observed.

This includes increases in breast, lung, and hematologic malignancies (Ann. Rheum. Dis. 2003;62:728-31) in 3%-11% of scleroderma cases (South. Med. J. 2008;101:59-62).

"Late onset of scleroderma has been recognized as a significant risk factor for malignancies, and recent reports have also shown a close and, at times, concurrent onset of scleroderma and cancer," Dr. Moinzadeh added (Clin. Rheumatol. 2004;23:516-22; Curr. Opin. Rheumatol. 2011;23:530-5).

The aim of the current study (Rheumatology 2012;51:[suppl. 3]abstract O42) was to determine the risk of cancer and its association with autoantibodies in a large U.K. cohort. Dr. Moinzadeh performed the research while working at the Royal Free Hospital in London with Dr. Voon Ong and colleagues.

Of 2,177 patients with systemic sclerosis, 154 (7.1%) had a history of cancer. The majority (85.1%) of the patients who developed malignancy were female with a median age of 53 years. Almost two-thirds (63.3%) of the patients had limited disease, and 34.4% had diffuse systemic sclerosis. Anti-RNAP, ACA, and Scl70 were detected in 26.6%, 26%, and 18.2% of patients, respectively.

The most common type of cancer was breast cancer (42%), followed by hematologic malignancies (12%), gastrointestinal tumors (11%), gynecologic cancers (11%), and lung cancer (10.4%).

"We found no differences in gender, age, and disease subsets between patients with and without cancer," Dr. Moinzadeh said.

"When we looked closer at the autoantibody subgroups we saw that the overall frequency to develop cancer was significantly higher in the group of patients who were positive for anti-RNA polymerase antibodies compared with the ones which had anticentromere antibodies."

Differences were seen in the frequency of autoantibodies by tumor type. For example, a higher frequency of anti-RNAP antibodies than the other autoantibodies was seen in breast cancer patients, Scl70 was associated with lung cancer, and ACA with gastrointestinal tumors.

While further research is needed to confirm whether anti-RNAP antibodies could be a marker for early cancer in patients with scleroderma, Dr. Moinzadeh noted there were several "red flags" that could perhaps signal if patients were likely to have "paraneoplastic scleroderma."

These red flags included older age (older than 65 years) of scleroderma onset, male gender, contractural arthropathy or palmar fibrosis, lack of ANA antibodies, and no sign of Raynaud’s phenomenon.

"This is a retrospective study, so we are going to do a prospective study in collaboration with Johns Hopkins University School of Medicine," said coinvestigator Dr. Voon Ong, a consultant rheumatologist at the Royal Free Hospital. The collaboration is necessary given that scleroderma is rare, regardless of its association with cancer.

Dr. Moinzadeh and Dr. Ong reported that they had no financial disclosures.

GLASGOW, SCOTLAND – The presence of specific autoantibodies may help to predict which patients with systemic sclerosis are likely to develop cancer within a few years of their diagnosis, according to the findings of a U.K.-based registry study.

Development of malignancy within 3 years of a diagnosis of scleroderma was positively correlated with the presence of antinuclear antibodies (ANA) directed against RNA polymerase (RNAP) III in more than half (55.3%) of the patients studied (n = 154).

Anticentromere antibodies (ACA) were found in almost a quarter (23.4%) of patients, and 13.6% had antitopoisomerase I (ATA) or anti-Scl70 (antibodies).

Furthermore, patients with anti-RNAP III antibodies had an almost threefold increased risk of cancer compared with patients with ACA (hazard ratio [HR] 2.907; 95% confidence interval [CI] 1.69-4.99, P less than .0001).

"We think that patients who develop scleroderma and cancer can be divided into two different groups," trainee dermatologist Dr. Pia Moinzadeh of the University of Cologne, Germany, said at the annual meeting of the British Society for Rheumatology.

"The first group are those who develop scleroderma and cancer in a very close temporal relationship, and we saw that these patients are most frequently anti-RNA polymerase positive. So scleroderma in these patients can be considered a paraneoplastic disease."

The other group includes patients who develop cancer after a delay of several years from the onset of systemic sclerosis.

Several epidemiological studies have shown an increased risk of malignancy in patients with systemic sclerosis compared with the general population (Br. J. Dermatol. 2010;163:800-6), Dr. Moinzadeh observed.

This includes increases in breast, lung, and hematologic malignancies (Ann. Rheum. Dis. 2003;62:728-31) in 3%-11% of scleroderma cases (South. Med. J. 2008;101:59-62).

"Late onset of scleroderma has been recognized as a significant risk factor for malignancies, and recent reports have also shown a close and, at times, concurrent onset of scleroderma and cancer," Dr. Moinzadeh added (Clin. Rheumatol. 2004;23:516-22; Curr. Opin. Rheumatol. 2011;23:530-5).

The aim of the current study (Rheumatology 2012;51:[suppl. 3]abstract O42) was to determine the risk of cancer and its association with autoantibodies in a large U.K. cohort. Dr. Moinzadeh performed the research while working at the Royal Free Hospital in London with Dr. Voon Ong and colleagues.

Of 2,177 patients with systemic sclerosis, 154 (7.1%) had a history of cancer. The majority (85.1%) of the patients who developed malignancy were female with a median age of 53 years. Almost two-thirds (63.3%) of the patients had limited disease, and 34.4% had diffuse systemic sclerosis. Anti-RNAP, ACA, and Scl70 were detected in 26.6%, 26%, and 18.2% of patients, respectively.

The most common type of cancer was breast cancer (42%), followed by hematologic malignancies (12%), gastrointestinal tumors (11%), gynecologic cancers (11%), and lung cancer (10.4%).

"We found no differences in gender, age, and disease subsets between patients with and without cancer," Dr. Moinzadeh said.

"When we looked closer at the autoantibody subgroups we saw that the overall frequency to develop cancer was significantly higher in the group of patients who were positive for anti-RNA polymerase antibodies compared with the ones which had anticentromere antibodies."

Differences were seen in the frequency of autoantibodies by tumor type. For example, a higher frequency of anti-RNAP antibodies than the other autoantibodies was seen in breast cancer patients, Scl70 was associated with lung cancer, and ACA with gastrointestinal tumors.

While further research is needed to confirm whether anti-RNAP antibodies could be a marker for early cancer in patients with scleroderma, Dr. Moinzadeh noted there were several "red flags" that could perhaps signal if patients were likely to have "paraneoplastic scleroderma."

These red flags included older age (older than 65 years) of scleroderma onset, male gender, contractural arthropathy or palmar fibrosis, lack of ANA antibodies, and no sign of Raynaud’s phenomenon.

"This is a retrospective study, so we are going to do a prospective study in collaboration with Johns Hopkins University School of Medicine," said coinvestigator Dr. Voon Ong, a consultant rheumatologist at the Royal Free Hospital. The collaboration is necessary given that scleroderma is rare, regardless of its association with cancer.

Dr. Moinzadeh and Dr. Ong reported that they had no financial disclosures.

GLASGOW, SCOTLAND – The presence of specific autoantibodies may help to predict which patients with systemic sclerosis are likely to develop cancer within a few years of their diagnosis, according to the findings of a U.K.-based registry study.

Development of malignancy within 3 years of a diagnosis of scleroderma was positively correlated with the presence of antinuclear antibodies (ANA) directed against RNA polymerase (RNAP) III in more than half (55.3%) of the patients studied (n = 154).

Anticentromere antibodies (ACA) were found in almost a quarter (23.4%) of patients, and 13.6% had antitopoisomerase I (ATA) or anti-Scl70 (antibodies).

Furthermore, patients with anti-RNAP III antibodies had an almost threefold increased risk of cancer compared with patients with ACA (hazard ratio [HR] 2.907; 95% confidence interval [CI] 1.69-4.99, P less than .0001).

"We think that patients who develop scleroderma and cancer can be divided into two different groups," trainee dermatologist Dr. Pia Moinzadeh of the University of Cologne, Germany, said at the annual meeting of the British Society for Rheumatology.

"The first group are those who develop scleroderma and cancer in a very close temporal relationship, and we saw that these patients are most frequently anti-RNA polymerase positive. So scleroderma in these patients can be considered a paraneoplastic disease."

The other group includes patients who develop cancer after a delay of several years from the onset of systemic sclerosis.

Several epidemiological studies have shown an increased risk of malignancy in patients with systemic sclerosis compared with the general population (Br. J. Dermatol. 2010;163:800-6), Dr. Moinzadeh observed.

This includes increases in breast, lung, and hematologic malignancies (Ann. Rheum. Dis. 2003;62:728-31) in 3%-11% of scleroderma cases (South. Med. J. 2008;101:59-62).

"Late onset of scleroderma has been recognized as a significant risk factor for malignancies, and recent reports have also shown a close and, at times, concurrent onset of scleroderma and cancer," Dr. Moinzadeh added (Clin. Rheumatol. 2004;23:516-22; Curr. Opin. Rheumatol. 2011;23:530-5).

The aim of the current study (Rheumatology 2012;51:[suppl. 3]abstract O42) was to determine the risk of cancer and its association with autoantibodies in a large U.K. cohort. Dr. Moinzadeh performed the research while working at the Royal Free Hospital in London with Dr. Voon Ong and colleagues.

Of 2,177 patients with systemic sclerosis, 154 (7.1%) had a history of cancer. The majority (85.1%) of the patients who developed malignancy were female with a median age of 53 years. Almost two-thirds (63.3%) of the patients had limited disease, and 34.4% had diffuse systemic sclerosis. Anti-RNAP, ACA, and Scl70 were detected in 26.6%, 26%, and 18.2% of patients, respectively.

The most common type of cancer was breast cancer (42%), followed by hematologic malignancies (12%), gastrointestinal tumors (11%), gynecologic cancers (11%), and lung cancer (10.4%).

"We found no differences in gender, age, and disease subsets between patients with and without cancer," Dr. Moinzadeh said.

"When we looked closer at the autoantibody subgroups we saw that the overall frequency to develop cancer was significantly higher in the group of patients who were positive for anti-RNA polymerase antibodies compared with the ones which had anticentromere antibodies."

Differences were seen in the frequency of autoantibodies by tumor type. For example, a higher frequency of anti-RNAP antibodies than the other autoantibodies was seen in breast cancer patients, Scl70 was associated with lung cancer, and ACA with gastrointestinal tumors.

While further research is needed to confirm whether anti-RNAP antibodies could be a marker for early cancer in patients with scleroderma, Dr. Moinzadeh noted there were several "red flags" that could perhaps signal if patients were likely to have "paraneoplastic scleroderma."

These red flags included older age (older than 65 years) of scleroderma onset, male gender, contractural arthropathy or palmar fibrosis, lack of ANA antibodies, and no sign of Raynaud’s phenomenon.

"This is a retrospective study, so we are going to do a prospective study in collaboration with Johns Hopkins University School of Medicine," said coinvestigator Dr. Voon Ong, a consultant rheumatologist at the Royal Free Hospital. The collaboration is necessary given that scleroderma is rare, regardless of its association with cancer.

Dr. Moinzadeh and Dr. Ong reported that they had no financial disclosures.

DESTIN, FLA. – Management of lupus nephritis during pregnancy gets close attention in ACR’s new nephritis guidelines.

No treatment is necessary in pregnant women with prior lupus nephritis who have no current evidence of systemic or renal disease activity, while those with mild systemic activity may be treated with hydroxychloroquine, according to the guidelines, which are published in the June issue of Arthritis Care & Research.

"There are good data suggesting hydroxychloroquine controls lupus in women who are pregnant, resulting in fewer flares" Dr. Bevra H. Hahn said at the Congress of Clinical Rheumatology. Dr. Hahn, professor of medicine and chief of the division of rheumatology at the University of California, Los Angeles, led the ACR core working group that helped with development of the guidelines.

In patients with clinically active nephritis or with substantial extrarenal disease activity, glucocorticoids may be prescribed at doses necessary to control disease activity (Arthritis Care Res. 2012;64:797-08).

"I start at 0.5 mg/kg per day," Dr. Hahn said of glucocorticoids under these circumstances. She noted that only steroids that are metabolized by placental enzymes should be used so that the drug does not reach the fetus.

She and her coauthors cautioned, however, that high-dose glucocorticoid therapy is associated with a high risk of maternal complications – including hypertension and diabetes mellitus – in patients with systemic lupus erythematosus (SLE). They also stress that mycophenolate mofetil, cyclophosphamide, and methotrexate should be avoided in pregnancy, because they are established human teratogens.

Azathioprine, though listed as pregnancy category D indicating teratogenic risk, has been shown in cross-sectional studies to be associated with very low risk of fetal abnormalities and can be added if necessary, according to the task force panel charged with developing the guidelines.

The azathioprine dose, however, should not exceed 2 mg/kg per day in pregnant women, Dr. Hahn said.

The task force has recommended that pregnant patients with a persistently active nephritis and documented or suspected class III or IV disease with crescents may be candidates for delivery after 28 weeks if the fetus is viable. The recommendations with respect to pregnancy were based on level C evidence, indicating they were based on consensus, expert opinion, and case series.

For women with SLE and nephritis who are not pregnant, but who have concerns about fertility preservation, the task force panel recommended that mycophenolate mofetil was preferable to cyclophosphamide for induction therapy, because cyclophosphamide has been shown to cause permanent infertility in both women and men.

For example, one study showed that 6 months of high-dose intravenous cyclophosphamide with a cumulative dose of 4.4 g-10 g was associated with sustained amenorrhea in about 10% of young women, and the risk increased with age.

However, the physician should be certain the patient is not pregnant before prescribing mycophenolate mofetil or mycophenolic acid, and treatment should be stopped for at least 6 weeks before pregnancy is attempted.

The guidelines were sponsored by the American College of Rheumatology via a competitive grant mechanism. Dr. Hahn has received consultant fees, speaking fees, and/or honoraria from UCB and Abbott and has served on the data and safety monitoring board for Anthera. The complete list of disclosures for the guideline authors is available with the full text of the article.

DESTIN, FLA. – Management of lupus nephritis during pregnancy gets close attention in ACR’s new nephritis guidelines.

No treatment is necessary in pregnant women with prior lupus nephritis who have no current evidence of systemic or renal disease activity, while those with mild systemic activity may be treated with hydroxychloroquine, according to the guidelines, which are published in the June issue of Arthritis Care & Research.

"There are good data suggesting hydroxychloroquine controls lupus in women who are pregnant, resulting in fewer flares" Dr. Bevra H. Hahn said at the Congress of Clinical Rheumatology. Dr. Hahn, professor of medicine and chief of the division of rheumatology at the University of California, Los Angeles, led the ACR core working group that helped with development of the guidelines.

In patients with clinically active nephritis or with substantial extrarenal disease activity, glucocorticoids may be prescribed at doses necessary to control disease activity (Arthritis Care Res. 2012;64:797-08).

"I start at 0.5 mg/kg per day," Dr. Hahn said of glucocorticoids under these circumstances. She noted that only steroids that are metabolized by placental enzymes should be used so that the drug does not reach the fetus.

She and her coauthors cautioned, however, that high-dose glucocorticoid therapy is associated with a high risk of maternal complications – including hypertension and diabetes mellitus – in patients with systemic lupus erythematosus (SLE). They also stress that mycophenolate mofetil, cyclophosphamide, and methotrexate should be avoided in pregnancy, because they are established human teratogens.

Azathioprine, though listed as pregnancy category D indicating teratogenic risk, has been shown in cross-sectional studies to be associated with very low risk of fetal abnormalities and can be added if necessary, according to the task force panel charged with developing the guidelines.

The azathioprine dose, however, should not exceed 2 mg/kg per day in pregnant women, Dr. Hahn said.

The task force has recommended that pregnant patients with a persistently active nephritis and documented or suspected class III or IV disease with crescents may be candidates for delivery after 28 weeks if the fetus is viable. The recommendations with respect to pregnancy were based on level C evidence, indicating they were based on consensus, expert opinion, and case series.

For women with SLE and nephritis who are not pregnant, but who have concerns about fertility preservation, the task force panel recommended that mycophenolate mofetil was preferable to cyclophosphamide for induction therapy, because cyclophosphamide has been shown to cause permanent infertility in both women and men.

For example, one study showed that 6 months of high-dose intravenous cyclophosphamide with a cumulative dose of 4.4 g-10 g was associated with sustained amenorrhea in about 10% of young women, and the risk increased with age.

However, the physician should be certain the patient is not pregnant before prescribing mycophenolate mofetil or mycophenolic acid, and treatment should be stopped for at least 6 weeks before pregnancy is attempted.

The guidelines were sponsored by the American College of Rheumatology via a competitive grant mechanism. Dr. Hahn has received consultant fees, speaking fees, and/or honoraria from UCB and Abbott and has served on the data and safety monitoring board for Anthera. The complete list of disclosures for the guideline authors is available with the full text of the article.

DESTIN, FLA. – Management of lupus nephritis during pregnancy gets close attention in ACR’s new nephritis guidelines.

No treatment is necessary in pregnant women with prior lupus nephritis who have no current evidence of systemic or renal disease activity, while those with mild systemic activity may be treated with hydroxychloroquine, according to the guidelines, which are published in the June issue of Arthritis Care & Research.

"There are good data suggesting hydroxychloroquine controls lupus in women who are pregnant, resulting in fewer flares" Dr. Bevra H. Hahn said at the Congress of Clinical Rheumatology. Dr. Hahn, professor of medicine and chief of the division of rheumatology at the University of California, Los Angeles, led the ACR core working group that helped with development of the guidelines.

In patients with clinically active nephritis or with substantial extrarenal disease activity, glucocorticoids may be prescribed at doses necessary to control disease activity (Arthritis Care Res. 2012;64:797-08).

"I start at 0.5 mg/kg per day," Dr. Hahn said of glucocorticoids under these circumstances. She noted that only steroids that are metabolized by placental enzymes should be used so that the drug does not reach the fetus.

She and her coauthors cautioned, however, that high-dose glucocorticoid therapy is associated with a high risk of maternal complications – including hypertension and diabetes mellitus – in patients with systemic lupus erythematosus (SLE). They also stress that mycophenolate mofetil, cyclophosphamide, and methotrexate should be avoided in pregnancy, because they are established human teratogens.

Azathioprine, though listed as pregnancy category D indicating teratogenic risk, has been shown in cross-sectional studies to be associated with very low risk of fetal abnormalities and can be added if necessary, according to the task force panel charged with developing the guidelines.

The azathioprine dose, however, should not exceed 2 mg/kg per day in pregnant women, Dr. Hahn said.

The task force has recommended that pregnant patients with a persistently active nephritis and documented or suspected class III or IV disease with crescents may be candidates for delivery after 28 weeks if the fetus is viable. The recommendations with respect to pregnancy were based on level C evidence, indicating they were based on consensus, expert opinion, and case series.

For women with SLE and nephritis who are not pregnant, but who have concerns about fertility preservation, the task force panel recommended that mycophenolate mofetil was preferable to cyclophosphamide for induction therapy, because cyclophosphamide has been shown to cause permanent infertility in both women and men.

For example, one study showed that 6 months of high-dose intravenous cyclophosphamide with a cumulative dose of 4.4 g-10 g was associated with sustained amenorrhea in about 10% of young women, and the risk increased with age.

However, the physician should be certain the patient is not pregnant before prescribing mycophenolate mofetil or mycophenolic acid, and treatment should be stopped for at least 6 weeks before pregnancy is attempted.

The guidelines were sponsored by the American College of Rheumatology via a competitive grant mechanism. Dr. Hahn has received consultant fees, speaking fees, and/or honoraria from UCB and Abbott and has served on the data and safety monitoring board for Anthera. The complete list of disclosures for the guideline authors is available with the full text of the article.

DESTIN, Fla. – Renal biopsy, unless strongly contraindicated, should be performed in every patient with clinical evidence of active lupus nephritis that has not been previously treated so that glomerular disease can be classified by current International Society of Nephrology/Renal Pathology Society classification, according to updated lupus nephritis treatment guidelines from the American College of Rheumatology.

Biopsy also will allow evaluation of disease for activity and chronicity and for tubular and vascular changes, as well as for the identification of additional or alternative causes of renal disease, according to the guidelines, which are published in the June issue of Arthritis Care and Research (Arthritis Care Res. 2012;54:797-808).

In fact, the recommended therapeutic strategies in the updated guidelines require knowledge of the classification of nephritis based on renal biopsy, according to Dr. Bevra H. Hahn, speaking at a meeting that happened to coincide with the online release of the guidelines on May 4.

For example, histologic class I and class II disease generally do not require immunosuppressive treatment; class III and class IV disease – and class V disease when combined with class III and IV disease – require aggressive therapy with glucocorticoids and immunosuppressive agents; and patients with class V disease alone (pure membranous lupus nephritis) with nephritic range proteinuria should be started on prednisone at 0.5mg/kg per day plus mycophenolate mofetil at 2-3 g total daily. Class VI disease generally requires preparation for renal replacement therapy.

The guidelines update those published in 1999, which represented a more general approach to systemic lupus erythematosus (SLE). These new guidelines more directly address nephritis, including case identification, treatment, and monitoring, and they include data on newer therapeutic modalities, including mycophenolate mofetil, mycophenolic acid, and rituximab, which were not available at the time the previous guidelines were developed, said Dr. Hahn, who led the core working group that helped develop the new guidelines.

They also address special situations such as pregnancy.

The core working group, along with a core executive group and a task force panel of experts used the validated modified RAND/University of California at Los Angeles Appropriateness Method, which involves a systematic literature view and expert opinion (based on voting by the task force panel) to develop the new guidelines.

The biopsy recommendation and the related therapeutic recommendations are based on level C evidence, indicating they were derived by consensus, expert opinion, and case series. Indications for renal biopsy, according to the task force panel include increasing serum creatinine without compelling alternative causes, confirmed proteinuria of 1 g or more/24 hours, and combinations of proteinuria of 0.5 g or more/24 hours plus hematuria (defined as 5 or more red blood cells per high power field) and proteinuria of 0.5 g or more/24 hours plus cellular casts – as long at these findings are confirmed in at least two tests conducted within a short time period and in the absence of alternative causes.

The task force panel also addressed adjunctive treatments, specifically recommending that:

• All patients with SLE be treated with a background of hydroxychloroquine unless contraindicated. This level C recommendation is based on recent cross-sectional and prospective controlled trial data indicating it is of benefit for reducing flare rates, is associated with significantly lower damage accrual (including renal damage), and may be associated with reduced risk of clotting events.

• Careful attention be paid to control of hypertension, with a target of no more than 130/80 mm Hg. This recommendation is based on level A evidence for nondiabetic chronic renal disease, indicating it is derived from multiple randomized controlled trials or a meta-analysis.

• Women of child-bearing potential who have active or prior lupus nephritis be counseled about the pregnancy risks conferred by the disease and its treatments. This recommendation is based on level C evidence.

Other task force panel recommendations specifically address induction of improvement in patients with International Society of Nephrology class III/IV lupus glomerulonephritis, induction of improvement in those with class IV or IV/V disease with cellular crescents, maintaining improvement in those who respond to induction therapy, and changing therapies in those who do not. Additional recommendations address the identification of vascular disease in patients with SLE and renal abnormalities, treatment of lupus nephritis patients who are pregnant, and monitoring the activity of lupus nephritis, Dr. Hahn said.

The new recommendations are "heavily based on induction with mycophenolate mofetil or cyclophosphamide, and on maintenance with mycophenolate mofetil or azathioprine," she noted.

"Nephritis remains one of the most devastating complications of lupus," she and her coauthors wrote, noting that the incidence increased during the 1980s and 1990s, with no decline seen as of 2004, despite the availability of new therapeutic regimens.

Standardized incidence rates for end-stage renal disease in the United States have risen in a number of populations, including younger patients, African Americans, and those living in the South.

"We hope that institution of these recommendations might lead to reductions in these trends. Furthermore, they may allow us to evaluate whether those who receive the recommended therapies are less likely to develop end-stage renal disease," they continued, concluding that while much progress has been made since lupus nephritis was associated with a near-terminal prognosis, these recommendations represent an effort to further improve outcomes and decrease morbidity and mortality in SLE.

The guidelines were sponsored by the American College of Rheumatology via a competitive grant mechanism. Dr. Hahn has received consultant fees, speaking fees, and/or honoraria from UCB and Abbott and has served on the data and safety monitoring board for Anthera. The complete list of disclosures for the guideline authors is available with the full text of the article.

DESTIN, Fla. – Renal biopsy, unless strongly contraindicated, should be performed in every patient with clinical evidence of active lupus nephritis that has not been previously treated so that glomerular disease can be classified by current International Society of Nephrology/Renal Pathology Society classification, according to updated lupus nephritis treatment guidelines from the American College of Rheumatology.

Biopsy also will allow evaluation of disease for activity and chronicity and for tubular and vascular changes, as well as for the identification of additional or alternative causes of renal disease, according to the guidelines, which are published in the June issue of Arthritis Care and Research (Arthritis Care Res. 2012;54:797-808).

In fact, the recommended therapeutic strategies in the updated guidelines require knowledge of the classification of nephritis based on renal biopsy, according to Dr. Bevra H. Hahn, speaking at a meeting that happened to coincide with the online release of the guidelines on May 4.

For example, histologic class I and class II disease generally do not require immunosuppressive treatment; class III and class IV disease – and class V disease when combined with class III and IV disease – require aggressive therapy with glucocorticoids and immunosuppressive agents; and patients with class V disease alone (pure membranous lupus nephritis) with nephritic range proteinuria should be started on prednisone at 0.5mg/kg per day plus mycophenolate mofetil at 2-3 g total daily. Class VI disease generally requires preparation for renal replacement therapy.

The guidelines update those published in 1999, which represented a more general approach to systemic lupus erythematosus (SLE). These new guidelines more directly address nephritis, including case identification, treatment, and monitoring, and they include data on newer therapeutic modalities, including mycophenolate mofetil, mycophenolic acid, and rituximab, which were not available at the time the previous guidelines were developed, said Dr. Hahn, who led the core working group that helped develop the new guidelines.

They also address special situations such as pregnancy.

The core working group, along with a core executive group and a task force panel of experts used the validated modified RAND/University of California at Los Angeles Appropriateness Method, which involves a systematic literature view and expert opinion (based on voting by the task force panel) to develop the new guidelines.

The biopsy recommendation and the related therapeutic recommendations are based on level C evidence, indicating they were derived by consensus, expert opinion, and case series. Indications for renal biopsy, according to the task force panel include increasing serum creatinine without compelling alternative causes, confirmed proteinuria of 1 g or more/24 hours, and combinations of proteinuria of 0.5 g or more/24 hours plus hematuria (defined as 5 or more red blood cells per high power field) and proteinuria of 0.5 g or more/24 hours plus cellular casts – as long at these findings are confirmed in at least two tests conducted within a short time period and in the absence of alternative causes.

The task force panel also addressed adjunctive treatments, specifically recommending that:

• All patients with SLE be treated with a background of hydroxychloroquine unless contraindicated. This level C recommendation is based on recent cross-sectional and prospective controlled trial data indicating it is of benefit for reducing flare rates, is associated with significantly lower damage accrual (including renal damage), and may be associated with reduced risk of clotting events.

• Careful attention be paid to control of hypertension, with a target of no more than 130/80 mm Hg. This recommendation is based on level A evidence for nondiabetic chronic renal disease, indicating it is derived from multiple randomized controlled trials or a meta-analysis.

• Women of child-bearing potential who have active or prior lupus nephritis be counseled about the pregnancy risks conferred by the disease and its treatments. This recommendation is based on level C evidence.

Other task force panel recommendations specifically address induction of improvement in patients with International Society of Nephrology class III/IV lupus glomerulonephritis, induction of improvement in those with class IV or IV/V disease with cellular crescents, maintaining improvement in those who respond to induction therapy, and changing therapies in those who do not. Additional recommendations address the identification of vascular disease in patients with SLE and renal abnormalities, treatment of lupus nephritis patients who are pregnant, and monitoring the activity of lupus nephritis, Dr. Hahn said.

The new recommendations are "heavily based on induction with mycophenolate mofetil or cyclophosphamide, and on maintenance with mycophenolate mofetil or azathioprine," she noted.

"Nephritis remains one of the most devastating complications of lupus," she and her coauthors wrote, noting that the incidence increased during the 1980s and 1990s, with no decline seen as of 2004, despite the availability of new therapeutic regimens.

Standardized incidence rates for end-stage renal disease in the United States have risen in a number of populations, including younger patients, African Americans, and those living in the South.

"We hope that institution of these recommendations might lead to reductions in these trends. Furthermore, they may allow us to evaluate whether those who receive the recommended therapies are less likely to develop end-stage renal disease," they continued, concluding that while much progress has been made since lupus nephritis was associated with a near-terminal prognosis, these recommendations represent an effort to further improve outcomes and decrease morbidity and mortality in SLE.

The guidelines were sponsored by the American College of Rheumatology via a competitive grant mechanism. Dr. Hahn has received consultant fees, speaking fees, and/or honoraria from UCB and Abbott and has served on the data and safety monitoring board for Anthera. The complete list of disclosures for the guideline authors is available with the full text of the article.

DESTIN, Fla. – Renal biopsy, unless strongly contraindicated, should be performed in every patient with clinical evidence of active lupus nephritis that has not been previously treated so that glomerular disease can be classified by current International Society of Nephrology/Renal Pathology Society classification, according to updated lupus nephritis treatment guidelines from the American College of Rheumatology.

Biopsy also will allow evaluation of disease for activity and chronicity and for tubular and vascular changes, as well as for the identification of additional or alternative causes of renal disease, according to the guidelines, which are published in the June issue of Arthritis Care and Research (Arthritis Care Res. 2012;54:797-808).

In fact, the recommended therapeutic strategies in the updated guidelines require knowledge of the classification of nephritis based on renal biopsy, according to Dr. Bevra H. Hahn, speaking at a meeting that happened to coincide with the online release of the guidelines on May 4.

For example, histologic class I and class II disease generally do not require immunosuppressive treatment; class III and class IV disease – and class V disease when combined with class III and IV disease – require aggressive therapy with glucocorticoids and immunosuppressive agents; and patients with class V disease alone (pure membranous lupus nephritis) with nephritic range proteinuria should be started on prednisone at 0.5mg/kg per day plus mycophenolate mofetil at 2-3 g total daily. Class VI disease generally requires preparation for renal replacement therapy.

The guidelines update those published in 1999, which represented a more general approach to systemic lupus erythematosus (SLE). These new guidelines more directly address nephritis, including case identification, treatment, and monitoring, and they include data on newer therapeutic modalities, including mycophenolate mofetil, mycophenolic acid, and rituximab, which were not available at the time the previous guidelines were developed, said Dr. Hahn, who led the core working group that helped develop the new guidelines.

They also address special situations such as pregnancy.

The core working group, along with a core executive group and a task force panel of experts used the validated modified RAND/University of California at Los Angeles Appropriateness Method, which involves a systematic literature view and expert opinion (based on voting by the task force panel) to develop the new guidelines.

The biopsy recommendation and the related therapeutic recommendations are based on level C evidence, indicating they were derived by consensus, expert opinion, and case series. Indications for renal biopsy, according to the task force panel include increasing serum creatinine without compelling alternative causes, confirmed proteinuria of 1 g or more/24 hours, and combinations of proteinuria of 0.5 g or more/24 hours plus hematuria (defined as 5 or more red blood cells per high power field) and proteinuria of 0.5 g or more/24 hours plus cellular casts – as long at these findings are confirmed in at least two tests conducted within a short time period and in the absence of alternative causes.

The task force panel also addressed adjunctive treatments, specifically recommending that:

• All patients with SLE be treated with a background of hydroxychloroquine unless contraindicated. This level C recommendation is based on recent cross-sectional and prospective controlled trial data indicating it is of benefit for reducing flare rates, is associated with significantly lower damage accrual (including renal damage), and may be associated with reduced risk of clotting events.

• Careful attention be paid to control of hypertension, with a target of no more than 130/80 mm Hg. This recommendation is based on level A evidence for nondiabetic chronic renal disease, indicating it is derived from multiple randomized controlled trials or a meta-analysis.

• Women of child-bearing potential who have active or prior lupus nephritis be counseled about the pregnancy risks conferred by the disease and its treatments. This recommendation is based on level C evidence.

Other task force panel recommendations specifically address induction of improvement in patients with International Society of Nephrology class III/IV lupus glomerulonephritis, induction of improvement in those with class IV or IV/V disease with cellular crescents, maintaining improvement in those who respond to induction therapy, and changing therapies in those who do not. Additional recommendations address the identification of vascular disease in patients with SLE and renal abnormalities, treatment of lupus nephritis patients who are pregnant, and monitoring the activity of lupus nephritis, Dr. Hahn said.

The new recommendations are "heavily based on induction with mycophenolate mofetil or cyclophosphamide, and on maintenance with mycophenolate mofetil or azathioprine," she noted.

"Nephritis remains one of the most devastating complications of lupus," she and her coauthors wrote, noting that the incidence increased during the 1980s and 1990s, with no decline seen as of 2004, despite the availability of new therapeutic regimens.

Standardized incidence rates for end-stage renal disease in the United States have risen in a number of populations, including younger patients, African Americans, and those living in the South.

"We hope that institution of these recommendations might lead to reductions in these trends. Furthermore, they may allow us to evaluate whether those who receive the recommended therapies are less likely to develop end-stage renal disease," they continued, concluding that while much progress has been made since lupus nephritis was associated with a near-terminal prognosis, these recommendations represent an effort to further improve outcomes and decrease morbidity and mortality in SLE.

The guidelines were sponsored by the American College of Rheumatology via a competitive grant mechanism. Dr. Hahn has received consultant fees, speaking fees, and/or honoraria from UCB and Abbott and has served on the data and safety monitoring board for Anthera. The complete list of disclosures for the guideline authors is available with the full text of the article.

GLASGOW, SCOTLAND – Urine analysis might help to predict if patients with rheumatoid arthritis are likely to respond to biologic treatments, the results of a small metabolomics study suggest.

Pretreatment levels of histamine, glutamine, xanthurenic acid, and ethanolamine were consistently correlated to response to anti–tumor necrosis factor–alpha (anti-TNF-alpha) therapy at 12 weeks in the 36-patient evaluation.

Further research is needed, of course, before any practical application of the research can be confirmed, but the finding does raise the possibly that a simple urine-based dipstick test could one day be available in the physician’s office.

"TNF has huge effects on metabolism," said Dr. Sabrina Kapoor at the annual meeting of the British Society for Rheumatology. These include effects on rheumatoid cachexia, angiogenesis, the acute phase response, and the recruitment of leukocytes to sites of inflammation.

"Metabolomics assess many metabolites together in biological samples, such as urine or blood," explained Dr. Kapoor, an Arthritis U.K. clinical research fellow in the Rheumatology Research Group at the University of Birmingham (England). The questions were, could such metabolites be found in the urine of patients with arthritic disease, and if they were present, did the metabolites change in response to treatment?

Dr. Kapoor and her associates obtained frozen urine samples from 16 patients with RA and 20 with psoriatic arthritis (PsA).

The samples had been taken during a randomized, three-center clinical study investigating patient responses to treatment with infliximab or etanercept (Rheumatology 2012;51[suppl.3]:abstract O15).

Nuclear magnetic resonance (NMR) spectroscopy was used to analyze the metabolomic profiles of the urine samples that were taken before and 12 weeks after anti-TNF treatment.

All patients in the study received methotrexate and had a disease duration of more than 6 months. RA patients were rheumatoid factor (RF) positive, anti–cyclic citrullinated protein (CCP) antibody positive, or both, and had a DAS28 (Disease Activity Score based on a 28-joint count) greater than 4. PsA patients were negative for RF and anti-CCP antibodies, with three or more swollen or tender joints.

Only the samples from the patients with RA could be linked to treatment effect. All the patients with PsA had a good response to treatment according to EULAR criteria (defined as improvement in two or more of the following: tender joint score, swollen joint score, patient global score, and physician global score).

Changes in the DAS28 were used to identify patients with RA who did (n = 7) or did not (n = 9) respond to anti-TNF therapy at 12 weeks. Good responders were those who achieved a DAS28 lower than 3.2, or an improvement in score greater than 1.2.

The baseline clinical characteristics of "good responders" and "not good responders" were similar: The mean age was about 50 years, all patients were women, and all had a similar history of steroid or nonsteroidal anti-inflammatory drug use.

RA patients who responded well to anti-TNF therapy had a distinct metabolomic profile compared with those who did not exhibit a good response to treatment.

"There was a significant [P = .04] correlation between baseline metabolomic profiles in the urine samples and the extent of change in DAS28," Dr. Kapoor said.

Baseline metabolomic analysis of the urine in RA patients had 85.9% sensitivity and 85.7%, specificity to detect treatment response.

"Urine is actually a cleaner biofluid than other biofluids, such as serum," Dr. Kapoor noted in the discussion that followed her presentation, noting that there are fewer proteins involved that could interfere with the NMR.

The samples tested were randomly obtained, but there is no evidence that any special collection protocols (such as early-morning collection or dietary restrictions) would be needed, she said. There is also no suggestion that urine would need handling in a particular way, although perhaps antibacterial treatment might be needed to keep specimens fresh.

These data, of course, need to be confirmed in a much larger, independent cohort of patients before any subsequent investigation of specific collection or storage requirements.

Dr. Kapoor had no financial disclosures. Merck sponsored the original study, but the company did not sponsor the metabolomics analysis reported here.

GLASGOW, SCOTLAND – Urine analysis might help to predict if patients with rheumatoid arthritis are likely to respond to biologic treatments, the results of a small metabolomics study suggest.

Pretreatment levels of histamine, glutamine, xanthurenic acid, and ethanolamine were consistently correlated to response to anti–tumor necrosis factor–alpha (anti-TNF-alpha) therapy at 12 weeks in the 36-patient evaluation.

Further research is needed, of course, before any practical application of the research can be confirmed, but the finding does raise the possibly that a simple urine-based dipstick test could one day be available in the physician’s office.

"TNF has huge effects on metabolism," said Dr. Sabrina Kapoor at the annual meeting of the British Society for Rheumatology. These include effects on rheumatoid cachexia, angiogenesis, the acute phase response, and the recruitment of leukocytes to sites of inflammation.

"Metabolomics assess many metabolites together in biological samples, such as urine or blood," explained Dr. Kapoor, an Arthritis U.K. clinical research fellow in the Rheumatology Research Group at the University of Birmingham (England). The questions were, could such metabolites be found in the urine of patients with arthritic disease, and if they were present, did the metabolites change in response to treatment?

Dr. Kapoor and her associates obtained frozen urine samples from 16 patients with RA and 20 with psoriatic arthritis (PsA).

The samples had been taken during a randomized, three-center clinical study investigating patient responses to treatment with infliximab or etanercept (Rheumatology 2012;51[suppl.3]:abstract O15).

Nuclear magnetic resonance (NMR) spectroscopy was used to analyze the metabolomic profiles of the urine samples that were taken before and 12 weeks after anti-TNF treatment.

All patients in the study received methotrexate and had a disease duration of more than 6 months. RA patients were rheumatoid factor (RF) positive, anti–cyclic citrullinated protein (CCP) antibody positive, or both, and had a DAS28 (Disease Activity Score based on a 28-joint count) greater than 4. PsA patients were negative for RF and anti-CCP antibodies, with three or more swollen or tender joints.

Only the samples from the patients with RA could be linked to treatment effect. All the patients with PsA had a good response to treatment according to EULAR criteria (defined as improvement in two or more of the following: tender joint score, swollen joint score, patient global score, and physician global score).

Changes in the DAS28 were used to identify patients with RA who did (n = 7) or did not (n = 9) respond to anti-TNF therapy at 12 weeks. Good responders were those who achieved a DAS28 lower than 3.2, or an improvement in score greater than 1.2.

The baseline clinical characteristics of "good responders" and "not good responders" were similar: The mean age was about 50 years, all patients were women, and all had a similar history of steroid or nonsteroidal anti-inflammatory drug use.

RA patients who responded well to anti-TNF therapy had a distinct metabolomic profile compared with those who did not exhibit a good response to treatment.

"There was a significant [P = .04] correlation between baseline metabolomic profiles in the urine samples and the extent of change in DAS28," Dr. Kapoor said.

Baseline metabolomic analysis of the urine in RA patients had 85.9% sensitivity and 85.7%, specificity to detect treatment response.

"Urine is actually a cleaner biofluid than other biofluids, such as serum," Dr. Kapoor noted in the discussion that followed her presentation, noting that there are fewer proteins involved that could interfere with the NMR.

The samples tested were randomly obtained, but there is no evidence that any special collection protocols (such as early-morning collection or dietary restrictions) would be needed, she said. There is also no suggestion that urine would need handling in a particular way, although perhaps antibacterial treatment might be needed to keep specimens fresh.

These data, of course, need to be confirmed in a much larger, independent cohort of patients before any subsequent investigation of specific collection or storage requirements.

Dr. Kapoor had no financial disclosures. Merck sponsored the original study, but the company did not sponsor the metabolomics analysis reported here.

GLASGOW, SCOTLAND – Urine analysis might help to predict if patients with rheumatoid arthritis are likely to respond to biologic treatments, the results of a small metabolomics study suggest.

Pretreatment levels of histamine, glutamine, xanthurenic acid, and ethanolamine were consistently correlated to response to anti–tumor necrosis factor–alpha (anti-TNF-alpha) therapy at 12 weeks in the 36-patient evaluation.

Further research is needed, of course, before any practical application of the research can be confirmed, but the finding does raise the possibly that a simple urine-based dipstick test could one day be available in the physician’s office.

"TNF has huge effects on metabolism," said Dr. Sabrina Kapoor at the annual meeting of the British Society for Rheumatology. These include effects on rheumatoid cachexia, angiogenesis, the acute phase response, and the recruitment of leukocytes to sites of inflammation.

"Metabolomics assess many metabolites together in biological samples, such as urine or blood," explained Dr. Kapoor, an Arthritis U.K. clinical research fellow in the Rheumatology Research Group at the University of Birmingham (England). The questions were, could such metabolites be found in the urine of patients with arthritic disease, and if they were present, did the metabolites change in response to treatment?

Dr. Kapoor and her associates obtained frozen urine samples from 16 patients with RA and 20 with psoriatic arthritis (PsA).

The samples had been taken during a randomized, three-center clinical study investigating patient responses to treatment with infliximab or etanercept (Rheumatology 2012;51[suppl.3]:abstract O15).

Nuclear magnetic resonance (NMR) spectroscopy was used to analyze the metabolomic profiles of the urine samples that were taken before and 12 weeks after anti-TNF treatment.

All patients in the study received methotrexate and had a disease duration of more than 6 months. RA patients were rheumatoid factor (RF) positive, anti–cyclic citrullinated protein (CCP) antibody positive, or both, and had a DAS28 (Disease Activity Score based on a 28-joint count) greater than 4. PsA patients were negative for RF and anti-CCP antibodies, with three or more swollen or tender joints.

Only the samples from the patients with RA could be linked to treatment effect. All the patients with PsA had a good response to treatment according to EULAR criteria (defined as improvement in two or more of the following: tender joint score, swollen joint score, patient global score, and physician global score).

Changes in the DAS28 were used to identify patients with RA who did (n = 7) or did not (n = 9) respond to anti-TNF therapy at 12 weeks. Good responders were those who achieved a DAS28 lower than 3.2, or an improvement in score greater than 1.2.

The baseline clinical characteristics of "good responders" and "not good responders" were similar: The mean age was about 50 years, all patients were women, and all had a similar history of steroid or nonsteroidal anti-inflammatory drug use.

RA patients who responded well to anti-TNF therapy had a distinct metabolomic profile compared with those who did not exhibit a good response to treatment.

"There was a significant [P = .04] correlation between baseline metabolomic profiles in the urine samples and the extent of change in DAS28," Dr. Kapoor said.

Baseline metabolomic analysis of the urine in RA patients had 85.9% sensitivity and 85.7%, specificity to detect treatment response.

"Urine is actually a cleaner biofluid than other biofluids, such as serum," Dr. Kapoor noted in the discussion that followed her presentation, noting that there are fewer proteins involved that could interfere with the NMR.

The samples tested were randomly obtained, but there is no evidence that any special collection protocols (such as early-morning collection or dietary restrictions) would be needed, she said. There is also no suggestion that urine would need handling in a particular way, although perhaps antibacterial treatment might be needed to keep specimens fresh.

These data, of course, need to be confirmed in a much larger, independent cohort of patients before any subsequent investigation of specific collection or storage requirements.

Dr. Kapoor had no financial disclosures. Merck sponsored the original study, but the company did not sponsor the metabolomics analysis reported here.

GLASGOW, SCOTLAND – Patients who smoke are substantially less likely to respond to biologic treatment for rheumatoid arthritis than are those who have never smoked.

The percentage of current smokers who responded to treatment with anti–tumor necrosis factor-alpha (anti-TNF-alpha) drugs at 6 months was just 27%, compared with 90% of never smokers and 63% of ex-smokers in a retrospective study of 359 patients.

Similarly poor response to rituximab was seen in patients who were current smokers, with respective response rates for current, ex-, and never smokers of 20%, 68%, and 98%.

©Sveta Kashkina/iStockphoto.com

A response was defined as a mean change in 28-joint disease activity score (DAS28) of 1.2 or greater, according to the U.K. National Clinical for Health and Clinical of Excellence (NICE) definition.

This begs the controversial question of whether current smokers should be given treatment with biologic agents unless they quit smoking, said Dr. Abdul Khan, a rheumatology specialist trainee at St. George’s Hospital in London, speaking at the annual meeting of the British Society for Rheumatology.

Working with Dr. David L. Scott, Dr. Khan assessed whether two simple pretreatment biomarkers – rheumatoid factor (RF) and smoking status – could help predict the response to biologic therapy for RA (Rheumatology 2012;51:iii41-2, abstract O40). They studied 209 patients treated with anti-TNFs and 150 treated with rituximab. The mean age of patients was 56 years for the anti-TNF treated patients and 61 years for the rituximab group. The mean disease duration was 8 years and 13 years, respectively, and 61% and 53% were RF positive.

Primary outcome assessments included the 6-month change in DAS28 and calculation of NICE responders (DAS28 change greater than or equal to 1.2). Smoking status was assessed as being current, previous, or never. Dr. Khan observed that a more detailed evaluation of smoking history might be warranted in future investigations, such as the calculation of pack years. RF status was determined, and anticitrullinated protein autoantibody (ACPA) positivity was determined for patients receiving rituximab therapy.

The mean change in DAS28 scores after 6 months’ anti-TNF therapy for never smokers was 2.6. For current smokers, the mean change was just 0.9 and for ex-smokers, it was 1.39. Corresponding figures for rituximab were 2.92, 0.63, and 1.49.

RF status predicted responses to rituximab but not to anti-TNFs, with a mean change of 2.14 for RF-positive patients and 0.98 for RF-negative patients treated with rituximab after 6 months.

Combining RF and ACPA status showed significant effects with regards to response to rituximab – 80% of never but only 22% of current smokers responded to treatment at 6 month if they were positive for both RF and ACPA

"Smoking and rheumatoid factor/ACPA status had an additive effect on DAS28 responses," Dr. Khan reported. Of 55 never smokers, 46 were RF/ACPA positive and nine were negative and almost all (98%) were NICE responders, with the mean fall in DAS28 score of 2.77.

Strikingly different results were seen for current smokers, however, with 50% of RF-positive patients responding, compared with 3% of RF-negative patients. Previous smokers showed intermediate response rates between those of current and never smokers.

Aside from the other well-documented health risks of smoking – including an increased risk of cardiovascular and pulmonary complications such as chronic obstructive pulmonary disease and lung cancer – these data suggest that patients with RA would do well to give up smoking if they currently smoke.

Indeed, in a press statement, Dr. Scott, professor of rheumatology at King’s College in London, suggested that "these findings show what a dramatic effect modifying your lifestyle, such as giving up smoking, can have on treatment outcomes."

Dr. Khan noted that they also raise an ethical dilemma for clinicians. "The balance of evidence suggests that biologics are unlikely to be cost effective in RA patients who continue to smoke.

"This observation creates a complex ethical dilemma which needs to be addressed."

Dr. Khan and Dr. Scott had no financial disclosures.

GLASGOW, SCOTLAND – Patients who smoke are substantially less likely to respond to biologic treatment for rheumatoid arthritis than are those who have never smoked.

The percentage of current smokers who responded to treatment with anti–tumor necrosis factor-alpha (anti-TNF-alpha) drugs at 6 months was just 27%, compared with 90% of never smokers and 63% of ex-smokers in a retrospective study of 359 patients.

Similarly poor response to rituximab was seen in patients who were current smokers, with respective response rates for current, ex-, and never smokers of 20%, 68%, and 98%.

©Sveta Kashkina/iStockphoto.com

A response was defined as a mean change in 28-joint disease activity score (DAS28) of 1.2 or greater, according to the U.K. National Clinical for Health and Clinical of Excellence (NICE) definition.

This begs the controversial question of whether current smokers should be given treatment with biologic agents unless they quit smoking, said Dr. Abdul Khan, a rheumatology specialist trainee at St. George’s Hospital in London, speaking at the annual meeting of the British Society for Rheumatology.

Working with Dr. David L. Scott, Dr. Khan assessed whether two simple pretreatment biomarkers – rheumatoid factor (RF) and smoking status – could help predict the response to biologic therapy for RA (Rheumatology 2012;51:iii41-2, abstract O40). They studied 209 patients treated with anti-TNFs and 150 treated with rituximab. The mean age of patients was 56 years for the anti-TNF treated patients and 61 years for the rituximab group. The mean disease duration was 8 years and 13 years, respectively, and 61% and 53% were RF positive.

Primary outcome assessments included the 6-month change in DAS28 and calculation of NICE responders (DAS28 change greater than or equal to 1.2). Smoking status was assessed as being current, previous, or never. Dr. Khan observed that a more detailed evaluation of smoking history might be warranted in future investigations, such as the calculation of pack years. RF status was determined, and anticitrullinated protein autoantibody (ACPA) positivity was determined for patients receiving rituximab therapy.

The mean change in DAS28 scores after 6 months’ anti-TNF therapy for never smokers was 2.6. For current smokers, the mean change was just 0.9 and for ex-smokers, it was 1.39. Corresponding figures for rituximab were 2.92, 0.63, and 1.49.

RF status predicted responses to rituximab but not to anti-TNFs, with a mean change of 2.14 for RF-positive patients and 0.98 for RF-negative patients treated with rituximab after 6 months.

Combining RF and ACPA status showed significant effects with regards to response to rituximab – 80% of never but only 22% of current smokers responded to treatment at 6 month if they were positive for both RF and ACPA

"Smoking and rheumatoid factor/ACPA status had an additive effect on DAS28 responses," Dr. Khan reported. Of 55 never smokers, 46 were RF/ACPA positive and nine were negative and almost all (98%) were NICE responders, with the mean fall in DAS28 score of 2.77.

Strikingly different results were seen for current smokers, however, with 50% of RF-positive patients responding, compared with 3% of RF-negative patients. Previous smokers showed intermediate response rates between those of current and never smokers.

Aside from the other well-documented health risks of smoking – including an increased risk of cardiovascular and pulmonary complications such as chronic obstructive pulmonary disease and lung cancer – these data suggest that patients with RA would do well to give up smoking if they currently smoke.

Indeed, in a press statement, Dr. Scott, professor of rheumatology at King’s College in London, suggested that "these findings show what a dramatic effect modifying your lifestyle, such as giving up smoking, can have on treatment outcomes."

Dr. Khan noted that they also raise an ethical dilemma for clinicians. "The balance of evidence suggests that biologics are unlikely to be cost effective in RA patients who continue to smoke.

"This observation creates a complex ethical dilemma which needs to be addressed."

Dr. Khan and Dr. Scott had no financial disclosures.

GLASGOW, SCOTLAND – Patients who smoke are substantially less likely to respond to biologic treatment for rheumatoid arthritis than are those who have never smoked.

The percentage of current smokers who responded to treatment with anti–tumor necrosis factor-alpha (anti-TNF-alpha) drugs at 6 months was just 27%, compared with 90% of never smokers and 63% of ex-smokers in a retrospective study of 359 patients.

Similarly poor response to rituximab was seen in patients who were current smokers, with respective response rates for current, ex-, and never smokers of 20%, 68%, and 98%.

©Sveta Kashkina/iStockphoto.com

A response was defined as a mean change in 28-joint disease activity score (DAS28) of 1.2 or greater, according to the U.K. National Clinical for Health and Clinical of Excellence (NICE) definition.

This begs the controversial question of whether current smokers should be given treatment with biologic agents unless they quit smoking, said Dr. Abdul Khan, a rheumatology specialist trainee at St. George’s Hospital in London, speaking at the annual meeting of the British Society for Rheumatology.

Working with Dr. David L. Scott, Dr. Khan assessed whether two simple pretreatment biomarkers – rheumatoid factor (RF) and smoking status – could help predict the response to biologic therapy for RA (Rheumatology 2012;51:iii41-2, abstract O40). They studied 209 patients treated with anti-TNFs and 150 treated with rituximab. The mean age of patients was 56 years for the anti-TNF treated patients and 61 years for the rituximab group. The mean disease duration was 8 years and 13 years, respectively, and 61% and 53% were RF positive.

Primary outcome assessments included the 6-month change in DAS28 and calculation of NICE responders (DAS28 change greater than or equal to 1.2). Smoking status was assessed as being current, previous, or never. Dr. Khan observed that a more detailed evaluation of smoking history might be warranted in future investigations, such as the calculation of pack years. RF status was determined, and anticitrullinated protein autoantibody (ACPA) positivity was determined for patients receiving rituximab therapy.

The mean change in DAS28 scores after 6 months’ anti-TNF therapy for never smokers was 2.6. For current smokers, the mean change was just 0.9 and for ex-smokers, it was 1.39. Corresponding figures for rituximab were 2.92, 0.63, and 1.49.

RF status predicted responses to rituximab but not to anti-TNFs, with a mean change of 2.14 for RF-positive patients and 0.98 for RF-negative patients treated with rituximab after 6 months.

Combining RF and ACPA status showed significant effects with regards to response to rituximab – 80% of never but only 22% of current smokers responded to treatment at 6 month if they were positive for both RF and ACPA

"Smoking and rheumatoid factor/ACPA status had an additive effect on DAS28 responses," Dr. Khan reported. Of 55 never smokers, 46 were RF/ACPA positive and nine were negative and almost all (98%) were NICE responders, with the mean fall in DAS28 score of 2.77.

Strikingly different results were seen for current smokers, however, with 50% of RF-positive patients responding, compared with 3% of RF-negative patients. Previous smokers showed intermediate response rates between those of current and never smokers.

Aside from the other well-documented health risks of smoking – including an increased risk of cardiovascular and pulmonary complications such as chronic obstructive pulmonary disease and lung cancer – these data suggest that patients with RA would do well to give up smoking if they currently smoke.

Indeed, in a press statement, Dr. Scott, professor of rheumatology at King’s College in London, suggested that "these findings show what a dramatic effect modifying your lifestyle, such as giving up smoking, can have on treatment outcomes."

Dr. Khan noted that they also raise an ethical dilemma for clinicians. "The balance of evidence suggests that biologics are unlikely to be cost effective in RA patients who continue to smoke.

"This observation creates a complex ethical dilemma which needs to be addressed."

Dr. Khan and Dr. Scott had no financial disclosures.

NEW YORK – Handy mnemonic devices can help predict vaccine response in patients taking biologics for rheumatoid arthritis, according to Dr. Daniel E. Furst.

Vaccinating patients taking biologic agents for rheumatoid arthritis is tricky. The effects of both the vaccine and biologic can be T-cell dependent or independent, or sometimes both, and when the mechanisms match, the vaccine’s response will likely be attenuated, he said at a rheumatology meeting sponsored by New York University.

Think ‘PITH’ – (Human) Papillomavirus, Influenza A/B, Tetanus, and Hepatitis B – to remember which vaccines have protein-based antigens and are T-cell dependent, said Dr. Furst, a rheumatology professor at the University of California in Los Angeles.

For vaccines that have carbohydrate-based antigens, which are largely T-cell independent (B-cell dependent), remember ‘PHIM’: Pneumococcus, H. influenzae B, Influenza A/B, and Meningococcus.

Biologic agents that affect T-cells include methotrexate, the TNF inhibitors, abatacept, and tocilizumab. As a general rule, biologics that affect T-cells decrease one’s response to T-cell dependent vaccines. For example, etanercept has been shown to decrease by as much as half, as well as delay the response to, the hepatitis B vaccine in both normal controls and patients with RA.

In normal volunteers abatacept blunted the response to tetanus vaccine given 2 weeks later by about 50% and given 8 weeks later by about 20%, compared to normal controls (Arthritis Res. Ther. 2007;9:R38).

Likewise, tocilizumab has been shown to reduce the response to the influenza vaccine by about 15%, according to a study presented at EULAR 2007 in Barcelona.

B-cell dependent vaccine responses are diminished by B-cell directed therapy. For example, the SIERRA study of pneumococcal vaccination in rituximab-treated patients showed that, compared to methotrexate alone, a combination of rituximab plus methotrexate decreased the response to the vaccination at 4 weeks by 30% to 60% (Arthritis Rheum. 2010;62:64-74). "That’s just what we would expect," Dr. Furst noted.

It is important to note that biologics that affect T-cell independent mechanisms (B-cell directed therapy), such as rituximab, will not usually affect T-cell mediated vaccine responses. For example, rituximab does not change the response to tetanus toxoid, said Dr. Furst. Similarly, T-cell dependent biologics will not affect T-cell independent vaccinations, citing as an example the lack of effect of adalimumab on the response to the pneumococcal vaccine, according to a paper presented at EULAR in 2006.

The influenza A/B vaccine is an exception to the rule, because it first requires an early B-cell response followed by a T-cell response.

Dr. Furst recommends avoiding live attenuated virus vaccines in patients on biologics or immunosuppressive agents. Vaccines that are likely to be affected include those for varicella/zoster, intranasal influenza/H1N1, measles/mumps/rubella (MMR), yellow fever, oral polio, typhoid (Ty21a oral), vaccinia (smallpox), the BCG vaccine for tuberculosis, and rotavirus. Live viruses can result in disseminated disease in such patients, he said. Ideally patients should be immunized with these vaccines as needed before starting a biologic or any other immunosuppressive therapy.

Dr. Furst is the recipient of research funding/consultant/advisory board member of Abbott Laboratories, Actelion Pharmaceuticals, Amgen, Biogen Idec, Bristol-Myers Squibb, Centocor Ortho Biotech, CORRONA, Gilead Sciences, GlaxoSmithKline, Novartis Pharmaceuticals, Pfizer, Roche Pharmaceuticals/Genentech, and UCB.

NEW YORK – Handy mnemonic devices can help predict vaccine response in patients taking biologics for rheumatoid arthritis, according to Dr. Daniel E. Furst.

Vaccinating patients taking biologic agents for rheumatoid arthritis is tricky. The effects of both the vaccine and biologic can be T-cell dependent or independent, or sometimes both, and when the mechanisms match, the vaccine’s response will likely be attenuated, he said at a rheumatology meeting sponsored by New York University.

Think ‘PITH’ – (Human) Papillomavirus, Influenza A/B, Tetanus, and Hepatitis B – to remember which vaccines have protein-based antigens and are T-cell dependent, said Dr. Furst, a rheumatology professor at the University of California in Los Angeles.

For vaccines that have carbohydrate-based antigens, which are largely T-cell independent (B-cell dependent), remember ‘PHIM’: Pneumococcus, H. influenzae B, Influenza A/B, and Meningococcus.

Biologic agents that affect T-cells include methotrexate, the TNF inhibitors, abatacept, and tocilizumab. As a general rule, biologics that affect T-cells decrease one’s response to T-cell dependent vaccines. For example, etanercept has been shown to decrease by as much as half, as well as delay the response to, the hepatitis B vaccine in both normal controls and patients with RA.

In normal volunteers abatacept blunted the response to tetanus vaccine given 2 weeks later by about 50% and given 8 weeks later by about 20%, compared to normal controls (Arthritis Res. Ther. 2007;9:R38).

Likewise, tocilizumab has been shown to reduce the response to the influenza vaccine by about 15%, according to a study presented at EULAR 2007 in Barcelona.

B-cell dependent vaccine responses are diminished by B-cell directed therapy. For example, the SIERRA study of pneumococcal vaccination in rituximab-treated patients showed that, compared to methotrexate alone, a combination of rituximab plus methotrexate decreased the response to the vaccination at 4 weeks by 30% to 60% (Arthritis Rheum. 2010;62:64-74). "That’s just what we would expect," Dr. Furst noted.

It is important to note that biologics that affect T-cell independent mechanisms (B-cell directed therapy), such as rituximab, will not usually affect T-cell mediated vaccine responses. For example, rituximab does not change the response to tetanus toxoid, said Dr. Furst. Similarly, T-cell dependent biologics will not affect T-cell independent vaccinations, citing as an example the lack of effect of adalimumab on the response to the pneumococcal vaccine, according to a paper presented at EULAR in 2006.

The influenza A/B vaccine is an exception to the rule, because it first requires an early B-cell response followed by a T-cell response.

Dr. Furst recommends avoiding live attenuated virus vaccines in patients on biologics or immunosuppressive agents. Vaccines that are likely to be affected include those for varicella/zoster, intranasal influenza/H1N1, measles/mumps/rubella (MMR), yellow fever, oral polio, typhoid (Ty21a oral), vaccinia (smallpox), the BCG vaccine for tuberculosis, and rotavirus. Live viruses can result in disseminated disease in such patients, he said. Ideally patients should be immunized with these vaccines as needed before starting a biologic or any other immunosuppressive therapy.

Dr. Furst is the recipient of research funding/consultant/advisory board member of Abbott Laboratories, Actelion Pharmaceuticals, Amgen, Biogen Idec, Bristol-Myers Squibb, Centocor Ortho Biotech, CORRONA, Gilead Sciences, GlaxoSmithKline, Novartis Pharmaceuticals, Pfizer, Roche Pharmaceuticals/Genentech, and UCB.

NEW YORK – Handy mnemonic devices can help predict vaccine response in patients taking biologics for rheumatoid arthritis, according to Dr. Daniel E. Furst.

Vaccinating patients taking biologic agents for rheumatoid arthritis is tricky. The effects of both the vaccine and biologic can be T-cell dependent or independent, or sometimes both, and when the mechanisms match, the vaccine’s response will likely be attenuated, he said at a rheumatology meeting sponsored by New York University.

Think ‘PITH’ – (Human) Papillomavirus, Influenza A/B, Tetanus, and Hepatitis B – to remember which vaccines have protein-based antigens and are T-cell dependent, said Dr. Furst, a rheumatology professor at the University of California in Los Angeles.

For vaccines that have carbohydrate-based antigens, which are largely T-cell independent (B-cell dependent), remember ‘PHIM’: Pneumococcus, H. influenzae B, Influenza A/B, and Meningococcus.

Biologic agents that affect T-cells include methotrexate, the TNF inhibitors, abatacept, and tocilizumab. As a general rule, biologics that affect T-cells decrease one’s response to T-cell dependent vaccines. For example, etanercept has been shown to decrease by as much as half, as well as delay the response to, the hepatitis B vaccine in both normal controls and patients with RA.

In normal volunteers abatacept blunted the response to tetanus vaccine given 2 weeks later by about 50% and given 8 weeks later by about 20%, compared to normal controls (Arthritis Res. Ther. 2007;9:R38).

Likewise, tocilizumab has been shown to reduce the response to the influenza vaccine by about 15%, according to a study presented at EULAR 2007 in Barcelona.

B-cell dependent vaccine responses are diminished by B-cell directed therapy. For example, the SIERRA study of pneumococcal vaccination in rituximab-treated patients showed that, compared to methotrexate alone, a combination of rituximab plus methotrexate decreased the response to the vaccination at 4 weeks by 30% to 60% (Arthritis Rheum. 2010;62:64-74). "That’s just what we would expect," Dr. Furst noted.

It is important to note that biologics that affect T-cell independent mechanisms (B-cell directed therapy), such as rituximab, will not usually affect T-cell mediated vaccine responses. For example, rituximab does not change the response to tetanus toxoid, said Dr. Furst. Similarly, T-cell dependent biologics will not affect T-cell independent vaccinations, citing as an example the lack of effect of adalimumab on the response to the pneumococcal vaccine, according to a paper presented at EULAR in 2006.

The influenza A/B vaccine is an exception to the rule, because it first requires an early B-cell response followed by a T-cell response.

Dr. Furst recommends avoiding live attenuated virus vaccines in patients on biologics or immunosuppressive agents. Vaccines that are likely to be affected include those for varicella/zoster, intranasal influenza/H1N1, measles/mumps/rubella (MMR), yellow fever, oral polio, typhoid (Ty21a oral), vaccinia (smallpox), the BCG vaccine for tuberculosis, and rotavirus. Live viruses can result in disseminated disease in such patients, he said. Ideally patients should be immunized with these vaccines as needed before starting a biologic or any other immunosuppressive therapy.

Dr. Furst is the recipient of research funding/consultant/advisory board member of Abbott Laboratories, Actelion Pharmaceuticals, Amgen, Biogen Idec, Bristol-Myers Squibb, Centocor Ortho Biotech, CORRONA, Gilead Sciences, GlaxoSmithKline, Novartis Pharmaceuticals, Pfizer, Roche Pharmaceuticals/Genentech, and UCB.

GLASGOW, SCOTLAND – Two subtypes of the anti-Ro autoantibody that are commonly associated with primary Sjögren’s syndrome could possibly help to predict disease severity and clinical outcomes.

Interim data on the first 314 patients included in the UK Primary Sjögren’s Syndrome Registry (UKPSSR) showed that anti-Ro52 was associated with a reduced risk of articular manifestations, while anti-Ro60 was associated with cutaneous manifestations of the disease.

Patients who were positive for either antibody were at increased risk for increased disease activity in the biological domains. Neither subtype was associated with myositis nor liver involvement, however, which is in contrast to the findings of other studies.

"There has been quite a lot of controversy regarding whether there are associations [between anti-Ro] and particular clinical manifestations in primary Sjögren’s syndrome, or indeed in other autoimmune diseases," said Dr. Wan-Fai Ng, the chief investigator for the UKPSSR and clinical senior lecturer at Newcastle (England) University.

Dr. Ng presented the research on behalf of lead author Dr. Josephine Vila of Newcastle upon Tyne Hospitals NHS Foundation Trust, May 3, at the British Society for Rheumatology Annual Conference (Rheumatology. 2012;51:iii35, abstract O30).

The UKPSSR is a U.K.-based cohort and biobank of more than 600 people diagnosed with primary Sjögren’s syndrome (Rheumatology. 2011;50:32-9). Patients have been recruited from 32 centers and have been assessed prospectively using standardized criteria and validated tools such as the Sjögren’s syndrome clinical activity index (SCAI) and Sjögren’s syndrome damage index (SSDI).

Previous research has suggested anti-Ro 52 may be associated with an increase in muscle and liver problems, whereas anti-Ro60 may be associated with a lower likelihood of liver involvement. Anti-Ro52 has also been associated with Sjögren’s syndrome while anti-Ro60 has been associated with systemic lupus erythematosus.

Conflicting data, however, led Dr. Vila and her team to explore the associations between the anti-Ro autoantibody subtypes and clinical manifestations in primary Sjögren’s syndrome using data from the UKPSSR.

Anti-Ro52 and anti-Ro60 autoantibodies were measured prospectively in the serum of patients using a high-sensitivity assay. The EULAR Sjögren’s system disease activity index (ESSDAI) was then used to stratify patients according to 12 organ-specific domains, which mostly relate to clinical data (Ann. Rheum. Dis. 2010;69:1103-9).

A high percentage of patients were positive for the anti-Ro52 (81%) and anti-Ro60 (82%) autoantibodies. Very few patients were positive for only one of these autoantibodies, with just eight (2.5%) patients positive only for anti-Ro52 and 10 (3.1%) positive only for anti-Ro60. Forty-nine (15.6%) were negative for both.

The relative risk for articular manifestations with anti-Ro52 was 0.7 (95% confidence interval, 0.5-0.9; P = .039). There was an increased risk of biological manifestations (RR 4.6; 95% confidence interval, 2.3-9.2; P less than .0001). Patients with anti-Ro52 autoantibodies were also more likely than those without to have decreased tear expression with an abnormal Schirmer’s test (RR 1.6; 95% CI, 1.3-2.1; P less than .0001) and abnormal salivary flow (RR 1.13; 95% CI, 1.0-1.3; P = .042).

Cutaneous manifestations were increased in patients positive for anti-Ro60 (RR 6.9; 95% CI, 1.0-49.3; P = .037). This autoantibody was also associated with a higher risk of biological manifestations (RR 6.2; 95% CI, 2.7-14.5; P less than .0001) and an abnormal Schirmer’s test (RR 1.4; 95% CI, 1.1-1.7; P less than .0001).

In addition, anti-Ro52 was significantly associated with disease duration and fatigue (P = .034) and anti-Ro60 with ESSDAI.

"We have planned to look at the other autoantibodies and disease association as well, but we’d rather do it in the entire cohort," Dr. Ng commented.

Dr. Ng reported no financial disclosures or relevant conflicts of interest. The UKPSSR is funded by the UK Medical Research Council.

GLASGOW, SCOTLAND – Two subtypes of the anti-Ro autoantibody that are commonly associated with primary Sjögren’s syndrome could possibly help to predict disease severity and clinical outcomes.

Interim data on the first 314 patients included in the UK Primary Sjögren’s Syndrome Registry (UKPSSR) showed that anti-Ro52 was associated with a reduced risk of articular manifestations, while anti-Ro60 was associated with cutaneous manifestations of the disease.

Patients who were positive for either antibody were at increased risk for increased disease activity in the biological domains. Neither subtype was associated with myositis nor liver involvement, however, which is in contrast to the findings of other studies.

"There has been quite a lot of controversy regarding whether there are associations [between anti-Ro] and particular clinical manifestations in primary Sjögren’s syndrome, or indeed in other autoimmune diseases," said Dr. Wan-Fai Ng, the chief investigator for the UKPSSR and clinical senior lecturer at Newcastle (England) University.

Dr. Ng presented the research on behalf of lead author Dr. Josephine Vila of Newcastle upon Tyne Hospitals NHS Foundation Trust, May 3, at the British Society for Rheumatology Annual Conference (Rheumatology. 2012;51:iii35, abstract O30).

The UKPSSR is a U.K.-based cohort and biobank of more than 600 people diagnosed with primary Sjögren’s syndrome (Rheumatology. 2011;50:32-9). Patients have been recruited from 32 centers and have been assessed prospectively using standardized criteria and validated tools such as the Sjögren’s syndrome clinical activity index (SCAI) and Sjögren’s syndrome damage index (SSDI).

Previous research has suggested anti-Ro 52 may be associated with an increase in muscle and liver problems, whereas anti-Ro60 may be associated with a lower likelihood of liver involvement. Anti-Ro52 has also been associated with Sjögren’s syndrome while anti-Ro60 has been associated with systemic lupus erythematosus.

Conflicting data, however, led Dr. Vila and her team to explore the associations between the anti-Ro autoantibody subtypes and clinical manifestations in primary Sjögren’s syndrome using data from the UKPSSR.

Anti-Ro52 and anti-Ro60 autoantibodies were measured prospectively in the serum of patients using a high-sensitivity assay. The EULAR Sjögren’s system disease activity index (ESSDAI) was then used to stratify patients according to 12 organ-specific domains, which mostly relate to clinical data (Ann. Rheum. Dis. 2010;69:1103-9).

A high percentage of patients were positive for the anti-Ro52 (81%) and anti-Ro60 (82%) autoantibodies. Very few patients were positive for only one of these autoantibodies, with just eight (2.5%) patients positive only for anti-Ro52 and 10 (3.1%) positive only for anti-Ro60. Forty-nine (15.6%) were negative for both.

The relative risk for articular manifestations with anti-Ro52 was 0.7 (95% confidence interval, 0.5-0.9; P = .039). There was an increased risk of biological manifestations (RR 4.6; 95% confidence interval, 2.3-9.2; P less than .0001). Patients with anti-Ro52 autoantibodies were also more likely than those without to have decreased tear expression with an abnormal Schirmer’s test (RR 1.6; 95% CI, 1.3-2.1; P less than .0001) and abnormal salivary flow (RR 1.13; 95% CI, 1.0-1.3; P = .042).

Cutaneous manifestations were increased in patients positive for anti-Ro60 (RR 6.9; 95% CI, 1.0-49.3; P = .037). This autoantibody was also associated with a higher risk of biological manifestations (RR 6.2; 95% CI, 2.7-14.5; P less than .0001) and an abnormal Schirmer’s test (RR 1.4; 95% CI, 1.1-1.7; P less than .0001).

In addition, anti-Ro52 was significantly associated with disease duration and fatigue (P = .034) and anti-Ro60 with ESSDAI.

"We have planned to look at the other autoantibodies and disease association as well, but we’d rather do it in the entire cohort," Dr. Ng commented.

Dr. Ng reported no financial disclosures or relevant conflicts of interest. The UKPSSR is funded by the UK Medical Research Council.

GLASGOW, SCOTLAND – Two subtypes of the anti-Ro autoantibody that are commonly associated with primary Sjögren’s syndrome could possibly help to predict disease severity and clinical outcomes.

Interim data on the first 314 patients included in the UK Primary Sjögren’s Syndrome Registry (UKPSSR) showed that anti-Ro52 was associated with a reduced risk of articular manifestations, while anti-Ro60 was associated with cutaneous manifestations of the disease.

Patients who were positive for either antibody were at increased risk for increased disease activity in the biological domains. Neither subtype was associated with myositis nor liver involvement, however, which is in contrast to the findings of other studies.

"There has been quite a lot of controversy regarding whether there are associations [between anti-Ro] and particular clinical manifestations in primary Sjögren’s syndrome, or indeed in other autoimmune diseases," said Dr. Wan-Fai Ng, the chief investigator for the UKPSSR and clinical senior lecturer at Newcastle (England) University.

Dr. Ng presented the research on behalf of lead author Dr. Josephine Vila of Newcastle upon Tyne Hospitals NHS Foundation Trust, May 3, at the British Society for Rheumatology Annual Conference (Rheumatology. 2012;51:iii35, abstract O30).

The UKPSSR is a U.K.-based cohort and biobank of more than 600 people diagnosed with primary Sjögren’s syndrome (Rheumatology. 2011;50:32-9). Patients have been recruited from 32 centers and have been assessed prospectively using standardized criteria and validated tools such as the Sjögren’s syndrome clinical activity index (SCAI) and Sjögren’s syndrome damage index (SSDI).

Previous research has suggested anti-Ro 52 may be associated with an increase in muscle and liver problems, whereas anti-Ro60 may be associated with a lower likelihood of liver involvement. Anti-Ro52 has also been associated with Sjögren’s syndrome while anti-Ro60 has been associated with systemic lupus erythematosus.

Conflicting data, however, led Dr. Vila and her team to explore the associations between the anti-Ro autoantibody subtypes and clinical manifestations in primary Sjögren’s syndrome using data from the UKPSSR.

Anti-Ro52 and anti-Ro60 autoantibodies were measured prospectively in the serum of patients using a high-sensitivity assay. The EULAR Sjögren’s system disease activity index (ESSDAI) was then used to stratify patients according to 12 organ-specific domains, which mostly relate to clinical data (Ann. Rheum. Dis. 2010;69:1103-9).

A high percentage of patients were positive for the anti-Ro52 (81%) and anti-Ro60 (82%) autoantibodies. Very few patients were positive for only one of these autoantibodies, with just eight (2.5%) patients positive only for anti-Ro52 and 10 (3.1%) positive only for anti-Ro60. Forty-nine (15.6%) were negative for both.

The relative risk for articular manifestations with anti-Ro52 was 0.7 (95% confidence interval, 0.5-0.9; P = .039). There was an increased risk of biological manifestations (RR 4.6; 95% confidence interval, 2.3-9.2; P less than .0001). Patients with anti-Ro52 autoantibodies were also more likely than those without to have decreased tear expression with an abnormal Schirmer’s test (RR 1.6; 95% CI, 1.3-2.1; P less than .0001) and abnormal salivary flow (RR 1.13; 95% CI, 1.0-1.3; P = .042).

Cutaneous manifestations were increased in patients positive for anti-Ro60 (RR 6.9; 95% CI, 1.0-49.3; P = .037). This autoantibody was also associated with a higher risk of biological manifestations (RR 6.2; 95% CI, 2.7-14.5; P less than .0001) and an abnormal Schirmer’s test (RR 1.4; 95% CI, 1.1-1.7; P less than .0001).

In addition, anti-Ro52 was significantly associated with disease duration and fatigue (P = .034) and anti-Ro60 with ESSDAI.

"We have planned to look at the other autoantibodies and disease association as well, but we’d rather do it in the entire cohort," Dr. Ng commented.

Dr. Ng reported no financial disclosures or relevant conflicts of interest. The UKPSSR is funded by the UK Medical Research Council.

GLASGOW – Biologic treatment for rheumatoid arthritis does not increase the overall risk of solid cancers beyond that of more traditional, nonbiologic drugs, according to long-awaited data from the British Society for Rheumatology Biologics Register.

At a median follow-up of almost 5 years, the adjusted hazard ratio for all solid cancers was 0.88 (95% confidence interval, 0.65-1.17) in a comparison between anti–tumor necrosis factor (anti-TNF)-alpha therapy and nonbiologic disease-modifying antirheumatic drugs (nbDMARDs, n = 3,543) in patients without a prior history of cancer.

There was no significant difference in cancer risk between the anti-TNF drugs included in the analysis, namely etanercept (adjusted hazard ratio, 0.94; 95% CI, 0.68-1.29), infliximab (aHR, 0.87; 95% CI, 0.61-1.25), and adalimumab (aHR, 0.81; 95% CI, 0.57-1.14) versus nbDMARDs. Neither duration of follow-up nor the overall site where tumors occurred had any effect on the occurrence of solid cancers.

These data lend further support to the general safety of TNF inhibitors, and add to findings reported from the British Society for Rheumatology Biologics Register (BSRBR) and other European registries, such as the Danish Biologics Registry (DANBIO), with regard to malignancy (Rheumatology News, June 2011, p. 22).

"We do still need further follow-up to address site-specific [cancer] risk and to allow for longer latency," said Dr. Louise Mercer, May 3, at the British Society for Rheumatology annual conference (Rheumatology 2012;51:iii40, abstract O37).

Dr. Mercer, a clinical research fellow at the Arthritis Research UK Epidemiology Unit, University of Manchester (England), noted that that cancer risk is already higher in patients with RA than in the general population (Rheumatology News, April 2011, p. 31). However, these latest findings from the BSRBR highlight that the use of biologic therapy doesn’t appear to add to this risk over that seen with nbDMARDs.

Data on 11,719 patients without a history of cancer who were enrolled in the BSRBR between 2001 and 2009 were used for the current analysis. Data after 2009 were not considered in order to allow for the lag time in cancer reporting from the U.K.’s National Cancer Registry into the Biologics Register. A group of 3,543 patients treated with nbDMARDs was used as the reference population.

Data adjustment took account of patients’ age at baseline, gender, duration of disease, use of nonsteroidal anti-inflammatory drugs, comorbidities, and age at time of enrollment in the U.K.-based register.

A total of 295 cancers were reported in patients treated with anti-TNF agents during a mean follow up of 4.6 years, giving a crude cancer rate of 63 per 10,000 patient-years. A total of 91 cancers were reported in patients treated with nbDMARDs over a median follow-up of 3.4 years, representing a crude cancer rate of 84 per 10,000 patient years.

With regard to the site of cancer, anti-TNFs appeared to be associated with a lower risk of lung cancer (aHR, 0.89; 95% CI, 0.46-1.74) and breast cancer (aHR, 0.99; 95% CI, 0.51-1.92) than were nbDMARDs. There was an increase in the risk of colorectal cancer (HR, 1.21; 95% CI, 0.54-2.70), but "the confidence intervals have become wider," Dr. Mercer observed.

Data on patients with a prior history of cancer have already been published by the team (Arthritis Care Res. 2010;62:755-63), but new data on patients with cervical carcinoma in situ (CIS) were reported during a poster presentation at the meeting (Rheumatology 2012;51:iii77, abstract 70).

Considering data collated through March 2011, 238 women had a prior history of cervical CIS – 48 of 2,654 (1.8%) women treated with nbDMARDs and 190 of 9,084 (2.1%) treated with anti-TNFs. Two women subsequently developed genitourinary cancer – both were treated with nbDMARDs. The rate of incident cancer was 13 per 1,000 person-years (95% CI, 2-45).

Dr. Mercer and her associates noted that there was a low level of reporting cervical CIS, which could reflect rheumatologists not being aware of abnormal cervical changes or choosing not to report in situ cancers or these prior cancers at baseline.

They concluded that "there were no new or recurrent female genital cancers among women with preexisting cervical CIS selected for treatment with anti-TNF," which should prove reassuring to women who may have a history of cervical abnormalities and who are considering anti-TNF therapy.

The BSRBR is funded by a grant from the British Society for Rheumatology. The BSR receives funding from Abbott Laboratories, Swedish Orphan Biovitrum (SOBI), Merck, Pfizer, Roche Products, and UCB Pharma. This income finances a separate contract between the BSR and the University of Manchester, which provides and runs the BSRBR. All decisions concerning data analysis, interpretation, and publications are made autonomously of any industrial contribution. Dr. Mercer reported having no personal conflicts of interest.

GLASGOW – Biologic treatment for rheumatoid arthritis does not increase the overall risk of solid cancers beyond that of more traditional, nonbiologic drugs, according to long-awaited data from the British Society for Rheumatology Biologics Register.

At a median follow-up of almost 5 years, the adjusted hazard ratio for all solid cancers was 0.88 (95% confidence interval, 0.65-1.17) in a comparison between anti–tumor necrosis factor (anti-TNF)-alpha therapy and nonbiologic disease-modifying antirheumatic drugs (nbDMARDs, n = 3,543) in patients without a prior history of cancer.

There was no significant difference in cancer risk between the anti-TNF drugs included in the analysis, namely etanercept (adjusted hazard ratio, 0.94; 95% CI, 0.68-1.29), infliximab (aHR, 0.87; 95% CI, 0.61-1.25), and adalimumab (aHR, 0.81; 95% CI, 0.57-1.14) versus nbDMARDs. Neither duration of follow-up nor the overall site where tumors occurred had any effect on the occurrence of solid cancers.

These data lend further support to the general safety of TNF inhibitors, and add to findings reported from the British Society for Rheumatology Biologics Register (BSRBR) and other European registries, such as the Danish Biologics Registry (DANBIO), with regard to malignancy (Rheumatology News, June 2011, p. 22).

"We do still need further follow-up to address site-specific [cancer] risk and to allow for longer latency," said Dr. Louise Mercer, May 3, at the British Society for Rheumatology annual conference (Rheumatology 2012;51:iii40, abstract O37).

Dr. Mercer, a clinical research fellow at the Arthritis Research UK Epidemiology Unit, University of Manchester (England), noted that that cancer risk is already higher in patients with RA than in the general population (Rheumatology News, April 2011, p. 31). However, these latest findings from the BSRBR highlight that the use of biologic therapy doesn’t appear to add to this risk over that seen with nbDMARDs.

Data on 11,719 patients without a history of cancer who were enrolled in the BSRBR between 2001 and 2009 were used for the current analysis. Data after 2009 were not considered in order to allow for the lag time in cancer reporting from the U.K.’s National Cancer Registry into the Biologics Register. A group of 3,543 patients treated with nbDMARDs was used as the reference population.

Data adjustment took account of patients’ age at baseline, gender, duration of disease, use of nonsteroidal anti-inflammatory drugs, comorbidities, and age at time of enrollment in the U.K.-based register.

A total of 295 cancers were reported in patients treated with anti-TNF agents during a mean follow up of 4.6 years, giving a crude cancer rate of 63 per 10,000 patient-years. A total of 91 cancers were reported in patients treated with nbDMARDs over a median follow-up of 3.4 years, representing a crude cancer rate of 84 per 10,000 patient years.

With regard to the site of cancer, anti-TNFs appeared to be associated with a lower risk of lung cancer (aHR, 0.89; 95% CI, 0.46-1.74) and breast cancer (aHR, 0.99; 95% CI, 0.51-1.92) than were nbDMARDs. There was an increase in the risk of colorectal cancer (HR, 1.21; 95% CI, 0.54-2.70), but "the confidence intervals have become wider," Dr. Mercer observed.

Data on patients with a prior history of cancer have already been published by the team (Arthritis Care Res. 2010;62:755-63), but new data on patients with cervical carcinoma in situ (CIS) were reported during a poster presentation at the meeting (Rheumatology 2012;51:iii77, abstract 70).

Considering data collated through March 2011, 238 women had a prior history of cervical CIS – 48 of 2,654 (1.8%) women treated with nbDMARDs and 190 of 9,084 (2.1%) treated with anti-TNFs. Two women subsequently developed genitourinary cancer – both were treated with nbDMARDs. The rate of incident cancer was 13 per 1,000 person-years (95% CI, 2-45).

Dr. Mercer and her associates noted that there was a low level of reporting cervical CIS, which could reflect rheumatologists not being aware of abnormal cervical changes or choosing not to report in situ cancers or these prior cancers at baseline.

They concluded that "there were no new or recurrent female genital cancers among women with preexisting cervical CIS selected for treatment with anti-TNF," which should prove reassuring to women who may have a history of cervical abnormalities and who are considering anti-TNF therapy.

The BSRBR is funded by a grant from the British Society for Rheumatology. The BSR receives funding from Abbott Laboratories, Swedish Orphan Biovitrum (SOBI), Merck, Pfizer, Roche Products, and UCB Pharma. This income finances a separate contract between the BSR and the University of Manchester, which provides and runs the BSRBR. All decisions concerning data analysis, interpretation, and publications are made autonomously of any industrial contribution. Dr. Mercer reported having no personal conflicts of interest.

GLASGOW – Biologic treatment for rheumatoid arthritis does not increase the overall risk of solid cancers beyond that of more traditional, nonbiologic drugs, according to long-awaited data from the British Society for Rheumatology Biologics Register.

At a median follow-up of almost 5 years, the adjusted hazard ratio for all solid cancers was 0.88 (95% confidence interval, 0.65-1.17) in a comparison between anti–tumor necrosis factor (anti-TNF)-alpha therapy and nonbiologic disease-modifying antirheumatic drugs (nbDMARDs, n = 3,543) in patients without a prior history of cancer.

There was no significant difference in cancer risk between the anti-TNF drugs included in the analysis, namely etanercept (adjusted hazard ratio, 0.94; 95% CI, 0.68-1.29), infliximab (aHR, 0.87; 95% CI, 0.61-1.25), and adalimumab (aHR, 0.81; 95% CI, 0.57-1.14) versus nbDMARDs. Neither duration of follow-up nor the overall site where tumors occurred had any effect on the occurrence of solid cancers.

These data lend further support to the general safety of TNF inhibitors, and add to findings reported from the British Society for Rheumatology Biologics Register (BSRBR) and other European registries, such as the Danish Biologics Registry (DANBIO), with regard to malignancy (Rheumatology News, June 2011, p. 22).

"We do still need further follow-up to address site-specific [cancer] risk and to allow for longer latency," said Dr. Louise Mercer, May 3, at the British Society for Rheumatology annual conference (Rheumatology 2012;51:iii40, abstract O37).

Dr. Mercer, a clinical research fellow at the Arthritis Research UK Epidemiology Unit, University of Manchester (England), noted that that cancer risk is already higher in patients with RA than in the general population (Rheumatology News, April 2011, p. 31). However, these latest findings from the BSRBR highlight that the use of biologic therapy doesn’t appear to add to this risk over that seen with nbDMARDs.

Data on 11,719 patients without a history of cancer who were enrolled in the BSRBR between 2001 and 2009 were used for the current analysis. Data after 2009 were not considered in order to allow for the lag time in cancer reporting from the U.K.’s National Cancer Registry into the Biologics Register. A group of 3,543 patients treated with nbDMARDs was used as the reference population.

Data adjustment took account of patients’ age at baseline, gender, duration of disease, use of nonsteroidal anti-inflammatory drugs, comorbidities, and age at time of enrollment in the U.K.-based register.

A total of 295 cancers were reported in patients treated with anti-TNF agents during a mean follow up of 4.6 years, giving a crude cancer rate of 63 per 10,000 patient-years. A total of 91 cancers were reported in patients treated with nbDMARDs over a median follow-up of 3.4 years, representing a crude cancer rate of 84 per 10,000 patient years.

With regard to the site of cancer, anti-TNFs appeared to be associated with a lower risk of lung cancer (aHR, 0.89; 95% CI, 0.46-1.74) and breast cancer (aHR, 0.99; 95% CI, 0.51-1.92) than were nbDMARDs. There was an increase in the risk of colorectal cancer (HR, 1.21; 95% CI, 0.54-2.70), but "the confidence intervals have become wider," Dr. Mercer observed.

Data on patients with a prior history of cancer have already been published by the team (Arthritis Care Res. 2010;62:755-63), but new data on patients with cervical carcinoma in situ (CIS) were reported during a poster presentation at the meeting (Rheumatology 2012;51:iii77, abstract 70).

Considering data collated through March 2011, 238 women had a prior history of cervical CIS – 48 of 2,654 (1.8%) women treated with nbDMARDs and 190 of 9,084 (2.1%) treated with anti-TNFs. Two women subsequently developed genitourinary cancer – both were treated with nbDMARDs. The rate of incident cancer was 13 per 1,000 person-years (95% CI, 2-45).

Dr. Mercer and her associates noted that there was a low level of reporting cervical CIS, which could reflect rheumatologists not being aware of abnormal cervical changes or choosing not to report in situ cancers or these prior cancers at baseline.

They concluded that "there were no new or recurrent female genital cancers among women with preexisting cervical CIS selected for treatment with anti-TNF," which should prove reassuring to women who may have a history of cervical abnormalities and who are considering anti-TNF therapy.

The BSRBR is funded by a grant from the British Society for Rheumatology. The BSR receives funding from Abbott Laboratories, Swedish Orphan Biovitrum (SOBI), Merck, Pfizer, Roche Products, and UCB Pharma. This income finances a separate contract between the BSR and the University of Manchester, which provides and runs the BSRBR. All decisions concerning data analysis, interpretation, and publications are made autonomously of any industrial contribution. Dr. Mercer reported having no personal conflicts of interest.

SILVER SPRING, MD. – There soon may be a new oral disease-modifying antirheumatic drug in town, the first in more than 10 years to be approved for the treatment of rheumatoid arthritis.

The drug is tofacitinib, and it is the first in a new class of agents for RA patients.

On May 9 the Food and Drug Administration’s Arthritis Advisory Committee voted 8 to 2 in favor of approving tofacitinib for RA patients who have had inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

A small-molecule inhibitor of the Janus kinase (JAK) pathways, Pfizer’s tofacitinib blocks inflammatory cytokines that play a role in the pathogenesis of RA. If approved, tofacitinib would be the first JAK inhibitor for RA. Another JAK inhibitor, ruxolitinib (Incyte’s Jakafi) was approved to treat myelofibrosis in November.

Pfizer’s application was based on five randomized controlled phase III efficacy trials involving a total 3,315 patients. The application also included safety data for a total of 4,816 patients from the phase II and III studies, of whom 4,053 were treated for at least 6 months and 567 for more than 3 years, up to 42 months. Among the trials was one that compared tofacitinib with placebo in patients with moderate to severe RA who had incomplete responses to tumor necrosis factor (TNF) inhibitors, and four studies of patients who had inadequate responses to other DMARDs. One study included an arm with adalimumab as an active comparator, and one evaluated radiographic response. In three studies, the participants were taking background methotrexate, and in one study, tofacitinib was used as monotherapy. The studies were conducted in a total of 44 countries.

All five of the phase III studies were designed to show the superiority of 5-mg and 10-mg twice-daily doses of tofacitinib to placebo for the primary end points: a 20% or better increase in the American College of Rheumatology’s definition of improvement in the signs and symptoms of RA (ACR20), improvement in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, and a Disease Activity Score-28 (DAS28) of less than 2.6. In most of the assessments conducted at 6 and 12 months, both doses exhibited statistical superiority over placebo, with the 10-mg dose showing greater improvement than the 5-mg dose.

However, the fact that only one study evaluated radiographic evidence, which the FDA reviewers deemed inconclusive, was cause for concern for the FDA reviewers and committee members. According to the FDA’s Dr. Yongman Kim, 18% of the 278 patients on 5 mg of tofacitinib, 16% of the 290 with 10 mg of tofacitinib, and 14% of the 140 placebo patients showed an "improved" modified total sharp score (mTSS) of less than 0, suggesting it inhibited joint damage.

The FDA was also concerned about dose- and time-dependent elevations in malignancies, and particularly lymphomas, with a standardized incidence ratio of 2.35 at a median 9 months duration of exposure. Of the seven total patients who developed lymphoma, three were on 5 mg of tofacitinib, three were on 10 mg, and one was in a still-blinded arm of the trial. Overall malignancy rates increased with time, from 0.79 per 100 patient-years at 0-6 months to 1.06 at 12-18 months to 1.43 beyond 24 months.

Several of the committee members who voted in favor of tofacitinib said that they did so because they wanted a new oral option for RA patients and that they don’t anticipate any better data from clinical trials. They strongly urged postmarketing studies of both radiologic efficacy and safety. Pfizer has proposed a Risk Evaluation and Mitigation Strategy that will include, alongside labeling provisions, a Medication Guide, a "Dear Health Care Professional" letter, and routine pharmacovigilance. Additional clinical studies that are ongoing or planned include long-term extension studies to assess cardiovascular safety, serious and opportunistic infections, malignancies, and gastrointestinal perforations; studies to monitor any unidentified risks; a cholesterol kinetic study; and studies to evaluate the effect of tofacitinib on the immune response to pneumococcal and influenza vaccines as well as to further delineate the effects of tofacitinib on lymphocyte subsets.

The panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver but not at this meeting.

Martin Bermin-Gorvine of "The Pink Sheet" contributed to this story. This news service and "The Pink Sheet" are both owned by Elsevier.

SILVER SPRING, MD. – There soon may be a new oral disease-modifying antirheumatic drug in town, the first in more than 10 years to be approved for the treatment of rheumatoid arthritis.

The drug is tofacitinib, and it is the first in a new class of agents for RA patients.

On May 9 the Food and Drug Administration’s Arthritis Advisory Committee voted 8 to 2 in favor of approving tofacitinib for RA patients who have had inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

A small-molecule inhibitor of the Janus kinase (JAK) pathways, Pfizer’s tofacitinib blocks inflammatory cytokines that play a role in the pathogenesis of RA. If approved, tofacitinib would be the first JAK inhibitor for RA. Another JAK inhibitor, ruxolitinib (Incyte’s Jakafi) was approved to treat myelofibrosis in November.

Pfizer’s application was based on five randomized controlled phase III efficacy trials involving a total 3,315 patients. The application also included safety data for a total of 4,816 patients from the phase II and III studies, of whom 4,053 were treated for at least 6 months and 567 for more than 3 years, up to 42 months. Among the trials was one that compared tofacitinib with placebo in patients with moderate to severe RA who had incomplete responses to tumor necrosis factor (TNF) inhibitors, and four studies of patients who had inadequate responses to other DMARDs. One study included an arm with adalimumab as an active comparator, and one evaluated radiographic response. In three studies, the participants were taking background methotrexate, and in one study, tofacitinib was used as monotherapy. The studies were conducted in a total of 44 countries.

All five of the phase III studies were designed to show the superiority of 5-mg and 10-mg twice-daily doses of tofacitinib to placebo for the primary end points: a 20% or better increase in the American College of Rheumatology’s definition of improvement in the signs and symptoms of RA (ACR20), improvement in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, and a Disease Activity Score-28 (DAS28) of less than 2.6. In most of the assessments conducted at 6 and 12 months, both doses exhibited statistical superiority over placebo, with the 10-mg dose showing greater improvement than the 5-mg dose.

However, the fact that only one study evaluated radiographic evidence, which the FDA reviewers deemed inconclusive, was cause for concern for the FDA reviewers and committee members. According to the FDA’s Dr. Yongman Kim, 18% of the 278 patients on 5 mg of tofacitinib, 16% of the 290 with 10 mg of tofacitinib, and 14% of the 140 placebo patients showed an "improved" modified total sharp score (mTSS) of less than 0, suggesting it inhibited joint damage.

The FDA was also concerned about dose- and time-dependent elevations in malignancies, and particularly lymphomas, with a standardized incidence ratio of 2.35 at a median 9 months duration of exposure. Of the seven total patients who developed lymphoma, three were on 5 mg of tofacitinib, three were on 10 mg, and one was in a still-blinded arm of the trial. Overall malignancy rates increased with time, from 0.79 per 100 patient-years at 0-6 months to 1.06 at 12-18 months to 1.43 beyond 24 months.

Several of the committee members who voted in favor of tofacitinib said that they did so because they wanted a new oral option for RA patients and that they don’t anticipate any better data from clinical trials. They strongly urged postmarketing studies of both radiologic efficacy and safety. Pfizer has proposed a Risk Evaluation and Mitigation Strategy that will include, alongside labeling provisions, a Medication Guide, a "Dear Health Care Professional" letter, and routine pharmacovigilance. Additional clinical studies that are ongoing or planned include long-term extension studies to assess cardiovascular safety, serious and opportunistic infections, malignancies, and gastrointestinal perforations; studies to monitor any unidentified risks; a cholesterol kinetic study; and studies to evaluate the effect of tofacitinib on the immune response to pneumococcal and influenza vaccines as well as to further delineate the effects of tofacitinib on lymphocyte subsets.

The panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver but not at this meeting.

Martin Bermin-Gorvine of "The Pink Sheet" contributed to this story. This news service and "The Pink Sheet" are both owned by Elsevier.

SILVER SPRING, MD. – There soon may be a new oral disease-modifying antirheumatic drug in town, the first in more than 10 years to be approved for the treatment of rheumatoid arthritis.

The drug is tofacitinib, and it is the first in a new class of agents for RA patients.

On May 9 the Food and Drug Administration’s Arthritis Advisory Committee voted 8 to 2 in favor of approving tofacitinib for RA patients who have had inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

A small-molecule inhibitor of the Janus kinase (JAK) pathways, Pfizer’s tofacitinib blocks inflammatory cytokines that play a role in the pathogenesis of RA. If approved, tofacitinib would be the first JAK inhibitor for RA. Another JAK inhibitor, ruxolitinib (Incyte’s Jakafi) was approved to treat myelofibrosis in November.

Pfizer’s application was based on five randomized controlled phase III efficacy trials involving a total 3,315 patients. The application also included safety data for a total of 4,816 patients from the phase II and III studies, of whom 4,053 were treated for at least 6 months and 567 for more than 3 years, up to 42 months. Among the trials was one that compared tofacitinib with placebo in patients with moderate to severe RA who had incomplete responses to tumor necrosis factor (TNF) inhibitors, and four studies of patients who had inadequate responses to other DMARDs. One study included an arm with adalimumab as an active comparator, and one evaluated radiographic response. In three studies, the participants were taking background methotrexate, and in one study, tofacitinib was used as monotherapy. The studies were conducted in a total of 44 countries.

All five of the phase III studies were designed to show the superiority of 5-mg and 10-mg twice-daily doses of tofacitinib to placebo for the primary end points: a 20% or better increase in the American College of Rheumatology’s definition of improvement in the signs and symptoms of RA (ACR20), improvement in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, and a Disease Activity Score-28 (DAS28) of less than 2.6. In most of the assessments conducted at 6 and 12 months, both doses exhibited statistical superiority over placebo, with the 10-mg dose showing greater improvement than the 5-mg dose.

However, the fact that only one study evaluated radiographic evidence, which the FDA reviewers deemed inconclusive, was cause for concern for the FDA reviewers and committee members. According to the FDA’s Dr. Yongman Kim, 18% of the 278 patients on 5 mg of tofacitinib, 16% of the 290 with 10 mg of tofacitinib, and 14% of the 140 placebo patients showed an "improved" modified total sharp score (mTSS) of less than 0, suggesting it inhibited joint damage.

The FDA was also concerned about dose- and time-dependent elevations in malignancies, and particularly lymphomas, with a standardized incidence ratio of 2.35 at a median 9 months duration of exposure. Of the seven total patients who developed lymphoma, three were on 5 mg of tofacitinib, three were on 10 mg, and one was in a still-blinded arm of the trial. Overall malignancy rates increased with time, from 0.79 per 100 patient-years at 0-6 months to 1.06 at 12-18 months to 1.43 beyond 24 months.

Several of the committee members who voted in favor of tofacitinib said that they did so because they wanted a new oral option for RA patients and that they don’t anticipate any better data from clinical trials. They strongly urged postmarketing studies of both radiologic efficacy and safety. Pfizer has proposed a Risk Evaluation and Mitigation Strategy that will include, alongside labeling provisions, a Medication Guide, a "Dear Health Care Professional" letter, and routine pharmacovigilance. Additional clinical studies that are ongoing or planned include long-term extension studies to assess cardiovascular safety, serious and opportunistic infections, malignancies, and gastrointestinal perforations; studies to monitor any unidentified risks; a cholesterol kinetic study; and studies to evaluate the effect of tofacitinib on the immune response to pneumococcal and influenza vaccines as well as to further delineate the effects of tofacitinib on lymphocyte subsets.

The panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver but not at this meeting.

Martin Bermin-Gorvine of "The Pink Sheet" contributed to this story. This news service and "The Pink Sheet" are both owned by Elsevier.

CHICAGO – Rheumatic conditions associated with HIV infection have declined since the introduction of highly active antiretroviral therapy, but they remain common in patients with HIV infection.

Rheumatic conditions have been described in HIV infection since the 1980s, with a recent review suggesting an overall prevalence today of about 9% (Curr. Opin. Rheumatol. 2009;21:404-10).

In the era before widespread use of highly active antiretroviral therapy (HAART), the presentation of many individuals with HIV involved arthralgias, psoriatic arthritis, reactive arthritis, and diffuse infiltrative lymphocytosis syndrome (DILS). The prevalence of these syndromes decreased dramatically after the introduction of HAART in 1997. Findings from a recent chart review showed that 34% of 306 new HIV referrals to a Houston rheumatology clinic between 1994 and 1997 had DILS, compared with only 7.5% of 346 new referrals between 1998 and 2003 (odds ratio, 4.8; P less than .000001) (Arthritis Rheum. 2006;55:466-72).

In the HAART era, however, there has been an increase in osteoporosis and osteonecrosis in patients with HIV infection, which is actually thought to be secondary to some of the medications they take, said Dr. Michael P. Angarone, a clinical instructor in medicine–infectious diseases at Northwestern University in Chicago.

"Antiretroviral therapy has had a substantial impact on the development of rheumatologic conditions," he said at a symposium sponsored by the American College of Rheumatology.

The use of immunomodulating therapy can be challenging in patients with compromised immunity due to chronic HIV infection. Immunomodulatory therapy may decrease further their already lowered CD4 T-cell count, thereby increasing their risk for infection and the consequences of immunodeficiency. In addition, the therapy may actually promote viral replication.

There is a paucity of data in the rheumatology setting, but successful immunomodulatory therapy has been reported among HIV-infected patients in the transplant literature. CD4 counts and HIV viral loads remained stable, and there was no evidence of worsening HIV in 150 patients on a stable antiretroviral regimen who underwent kidney transplantation and received antithymocyte antibodies, calcineurin inhibitors, or high-dose corticosteroids (N. Engl. J. Med. 2010;363:2004-14). The one caveat to the prospective data is that those receiving antithymocyte antibodies initially experienced a decrease in CD4 T cells, but over time antibody levels slowly increased, said Dr. Angarone, who pointed out that this pattern is also seen in HIV-negative individuals who undergo antithymocyte antibody therapy.

"So the lesson we’ve learned from the transplant population is that we can indeed immunosuppress our HIV-infected individuals," he added.

Although anti–tumor necrosis factor (anti-TNF) therapies are being used to treat rheumatologic conditions, there have been no prospective trials of anti-TNF agents in HIV-infected patients and little in the way of adverse event reporting in patients with chronic viral infections. Initial thinking was that HIV utilizes TNF to replicate, and subsequently causes a decrease in CD-4 T cells, Dr. Angarone explained. A study involving an early TNF-alpha inhibitor, however, demonstrated no changes in CD4 cell counts or plasma HIV RNA levels, as feared, among six HIV-infected patients (J. Infect. Dis. 1996;174:63-8).

In addition, a recent case series reported excellent clinical responses in five of eight HIV-positive patients who received etanercept, infliximab, or adalimumab for a variety of rheumatologic diseases, including rheumatoid, psoriatic, and reactive arthritis; ankylosing spondylitis; and undifferentiated spondyloarthritis that was refractory to standard therapy (Ann. Rheum. Dis. 2008;67:710-2). CD4 counts reached a low of 240-923 cells/mm³ during treatment versus 268-974 cells/mm³ at baseline, while HIV viral loads remained undetectable in 50% versus 63% at baseline. No significant clinical adverse effects were reported. One patient had a substantial increase in HIV viral load, but this patient was not on antivirals, and the viral load decreased with anti-TNF discontinuation, Dr. Angarone pointed out.

"Immunomodulatory therapy appears to be safe in individuals with HIV infection. However, I think careful selection of patients needs to be undertaken, and you have to monitor these patients very closely," he said. "Ideally, you want an individual with a CD4 count greater than 200 [cells/mm³] and an HIV viral load that is undetectable [greater than 50 copies/mL] and you want that individual on antiretroviral therapy."

Given the variety of rheumatologic presentations of HIV, Dr. Angarone suggested that screening for HIV infection should be considered for all patients. Routine testing for HIV has been shown to be as cost effective as breast and colon cancer screening, and is recommended by the Centers for Disease Control and Prevention as part of routine screening in all health care settings for those ages 13 to 64, regardless of risk, he noted.

Dr. Angarone reported no relevant financial relationships.

CHICAGO – Rheumatic conditions associated with HIV infection have declined since the introduction of highly active antiretroviral therapy, but they remain common in patients with HIV infection.

Rheumatic conditions have been described in HIV infection since the 1980s, with a recent review suggesting an overall prevalence today of about 9% (Curr. Opin. Rheumatol. 2009;21:404-10).

In the era before widespread use of highly active antiretroviral therapy (HAART), the presentation of many individuals with HIV involved arthralgias, psoriatic arthritis, reactive arthritis, and diffuse infiltrative lymphocytosis syndrome (DILS). The prevalence of these syndromes decreased dramatically after the introduction of HAART in 1997. Findings from a recent chart review showed that 34% of 306 new HIV referrals to a Houston rheumatology clinic between 1994 and 1997 had DILS, compared with only 7.5% of 346 new referrals between 1998 and 2003 (odds ratio, 4.8; P less than .000001) (Arthritis Rheum. 2006;55:466-72).

In the HAART era, however, there has been an increase in osteoporosis and osteonecrosis in patients with HIV infection, which is actually thought to be secondary to some of the medications they take, said Dr. Michael P. Angarone, a clinical instructor in medicine–infectious diseases at Northwestern University in Chicago.

"Antiretroviral therapy has had a substantial impact on the development of rheumatologic conditions," he said at a symposium sponsored by the American College of Rheumatology.

The use of immunomodulating therapy can be challenging in patients with compromised immunity due to chronic HIV infection. Immunomodulatory therapy may decrease further their already lowered CD4 T-cell count, thereby increasing their risk for infection and the consequences of immunodeficiency. In addition, the therapy may actually promote viral replication.

There is a paucity of data in the rheumatology setting, but successful immunomodulatory therapy has been reported among HIV-infected patients in the transplant literature. CD4 counts and HIV viral loads remained stable, and there was no evidence of worsening HIV in 150 patients on a stable antiretroviral regimen who underwent kidney transplantation and received antithymocyte antibodies, calcineurin inhibitors, or high-dose corticosteroids (N. Engl. J. Med. 2010;363:2004-14). The one caveat to the prospective data is that those receiving antithymocyte antibodies initially experienced a decrease in CD4 T cells, but over time antibody levels slowly increased, said Dr. Angarone, who pointed out that this pattern is also seen in HIV-negative individuals who undergo antithymocyte antibody therapy.

"So the lesson we’ve learned from the transplant population is that we can indeed immunosuppress our HIV-infected individuals," he added.

Although anti–tumor necrosis factor (anti-TNF) therapies are being used to treat rheumatologic conditions, there have been no prospective trials of anti-TNF agents in HIV-infected patients and little in the way of adverse event reporting in patients with chronic viral infections. Initial thinking was that HIV utilizes TNF to replicate, and subsequently causes a decrease in CD-4 T cells, Dr. Angarone explained. A study involving an early TNF-alpha inhibitor, however, demonstrated no changes in CD4 cell counts or plasma HIV RNA levels, as feared, among six HIV-infected patients (J. Infect. Dis. 1996;174:63-8).

In addition, a recent case series reported excellent clinical responses in five of eight HIV-positive patients who received etanercept, infliximab, or adalimumab for a variety of rheumatologic diseases, including rheumatoid, psoriatic, and reactive arthritis; ankylosing spondylitis; and undifferentiated spondyloarthritis that was refractory to standard therapy (Ann. Rheum. Dis. 2008;67:710-2). CD4 counts reached a low of 240-923 cells/mm³ during treatment versus 268-974 cells/mm³ at baseline, while HIV viral loads remained undetectable in 50% versus 63% at baseline. No significant clinical adverse effects were reported. One patient had a substantial increase in HIV viral load, but this patient was not on antivirals, and the viral load decreased with anti-TNF discontinuation, Dr. Angarone pointed out.

"Immunomodulatory therapy appears to be safe in individuals with HIV infection. However, I think careful selection of patients needs to be undertaken, and you have to monitor these patients very closely," he said. "Ideally, you want an individual with a CD4 count greater than 200 [cells/mm³] and an HIV viral load that is undetectable [greater than 50 copies/mL] and you want that individual on antiretroviral therapy."

Given the variety of rheumatologic presentations of HIV, Dr. Angarone suggested that screening for HIV infection should be considered for all patients. Routine testing for HIV has been shown to be as cost effective as breast and colon cancer screening, and is recommended by the Centers for Disease Control and Prevention as part of routine screening in all health care settings for those ages 13 to 64, regardless of risk, he noted.

Dr. Angarone reported no relevant financial relationships.

CHICAGO – Rheumatic conditions associated with HIV infection have declined since the introduction of highly active antiretroviral therapy, but they remain common in patients with HIV infection.

Rheumatic conditions have been described in HIV infection since the 1980s, with a recent review suggesting an overall prevalence today of about 9% (Curr. Opin. Rheumatol. 2009;21:404-10).

In the era before widespread use of highly active antiretroviral therapy (HAART), the presentation of many individuals with HIV involved arthralgias, psoriatic arthritis, reactive arthritis, and diffuse infiltrative lymphocytosis syndrome (DILS). The prevalence of these syndromes decreased dramatically after the introduction of HAART in 1997. Findings from a recent chart review showed that 34% of 306 new HIV referrals to a Houston rheumatology clinic between 1994 and 1997 had DILS, compared with only 7.5% of 346 new referrals between 1998 and 2003 (odds ratio, 4.8; P less than .000001) (Arthritis Rheum. 2006;55:466-72).

In the HAART era, however, there has been an increase in osteoporosis and osteonecrosis in patients with HIV infection, which is actually thought to be secondary to some of the medications they take, said Dr. Michael P. Angarone, a clinical instructor in medicine–infectious diseases at Northwestern University in Chicago.

"Antiretroviral therapy has had a substantial impact on the development of rheumatologic conditions," he said at a symposium sponsored by the American College of Rheumatology.

The use of immunomodulating therapy can be challenging in patients with compromised immunity due to chronic HIV infection. Immunomodulatory therapy may decrease further their already lowered CD4 T-cell count, thereby increasing their risk for infection and the consequences of immunodeficiency. In addition, the therapy may actually promote viral replication.

There is a paucity of data in the rheumatology setting, but successful immunomodulatory therapy has been reported among HIV-infected patients in the transplant literature. CD4 counts and HIV viral loads remained stable, and there was no evidence of worsening HIV in 150 patients on a stable antiretroviral regimen who underwent kidney transplantation and received antithymocyte antibodies, calcineurin inhibitors, or high-dose corticosteroids (N. Engl. J. Med. 2010;363:2004-14). The one caveat to the prospective data is that those receiving antithymocyte antibodies initially experienced a decrease in CD4 T cells, but over time antibody levels slowly increased, said Dr. Angarone, who pointed out that this pattern is also seen in HIV-negative individuals who undergo antithymocyte antibody therapy.

"So the lesson we’ve learned from the transplant population is that we can indeed immunosuppress our HIV-infected individuals," he added.

Although anti–tumor necrosis factor (anti-TNF) therapies are being used to treat rheumatologic conditions, there have been no prospective trials of anti-TNF agents in HIV-infected patients and little in the way of adverse event reporting in patients with chronic viral infections. Initial thinking was that HIV utilizes TNF to replicate, and subsequently causes a decrease in CD-4 T cells, Dr. Angarone explained. A study involving an early TNF-alpha inhibitor, however, demonstrated no changes in CD4 cell counts or plasma HIV RNA levels, as feared, among six HIV-infected patients (J. Infect. Dis. 1996;174:63-8).

In addition, a recent case series reported excellent clinical responses in five of eight HIV-positive patients who received etanercept, infliximab, or adalimumab for a variety of rheumatologic diseases, including rheumatoid, psoriatic, and reactive arthritis; ankylosing spondylitis; and undifferentiated spondyloarthritis that was refractory to standard therapy (Ann. Rheum. Dis. 2008;67:710-2). CD4 counts reached a low of 240-923 cells/mm³ during treatment versus 268-974 cells/mm³ at baseline, while HIV viral loads remained undetectable in 50% versus 63% at baseline. No significant clinical adverse effects were reported. One patient had a substantial increase in HIV viral load, but this patient was not on antivirals, and the viral load decreased with anti-TNF discontinuation, Dr. Angarone pointed out.

"Immunomodulatory therapy appears to be safe in individuals with HIV infection. However, I think careful selection of patients needs to be undertaken, and you have to monitor these patients very closely," he said. "Ideally, you want an individual with a CD4 count greater than 200 [cells/mm³] and an HIV viral load that is undetectable [greater than 50 copies/mL] and you want that individual on antiretroviral therapy."

Given the variety of rheumatologic presentations of HIV, Dr. Angarone suggested that screening for HIV infection should be considered for all patients. Routine testing for HIV has been shown to be as cost effective as breast and colon cancer screening, and is recommended by the Centers for Disease Control and Prevention as part of routine screening in all health care settings for those ages 13 to 64, regardless of risk, he noted.

Dr. Angarone reported no relevant financial relationships.