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Predicting rituximab responses in lupus remains challenging
AMSTERDAM – Despite some “encouraging signs” seen in a cross-sectional study, it remains difficult to determine whether a patient with systemic lupus erythematosus (SLE) will respond to off-label rituximab therapy, according to David Isenberg, MD.
The presence of constitutional symptoms, which includes fatigue, at baseline were associated with a favorable response to rituximab at 6 months (odds ratio, 7.35; P = .01). Conversely, having more than one anti–extractable nuclear antigen (anti-ENA) antibody was associated with a worse response to rituximab at 12 months (OR, 0.33; P = .032).
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“It’s not a cure for lupus, that’s obvious, but used at the appropriate time in the right sort of patients, it can be very helpful,” Dr. Isenberg said in an interview at the European Congress of Rheumatology. That’s both in terms of improving disease activity and reducing the use of glucocorticosteroids and immunosuppressive drugs, he noted.
“The great mystery, as with all drugs, is: Are there any markers which might tell us that the disease is going to do better with rituximab than perhaps with another form of medication, or is it just saying to us, ‘Whatever you do, it doesn’t make much difference’?” Dr. Isenberg said. He discussed the results of a study involving the first 121 patients treated with rituximab at his institution, University College London Hospital (UCLH); he noted this is one of the largest single-center cohorts of individuals with SLE who have used rituximab.
The aim of the study, which was presented at the congress by Hiurma Sánchez Pérez, MD, was therefore to try to find demographic, clinical, and serological markers that might help in predicting the response to rituximab in SLE patients.
Response to treatment was determined using the British Isles Lupus Assessment Group (BILAG) Index. Patients who initially had markedly (BILAG A) or moderately (BILAG B) active disease but who no longer fell into these categories at 6 or 12 months were designated as responders. Those who remained were designated as nonresponders. In addition, any person moving into category A or B of the BILAG Index was said to have relapsed because of a flare in disease activity.
At 6 and 12 months, a respective 85% and 70% of patients exhibited a response to rituximab. Just under a quarter (24%) relapsed before 1 year, Dr. Sánchez Pérez reported.
Most of the patients in the cohort were white (n = 50) or Afro-Caribbean (n = 38), but ethnicity did not seem to play a role in predicting whether patients would respond to rituximab treatment.
Aside from constitutional symptoms and having more than one anti-ENA antibody, there were no other biological markers of response that remained significant after multivariate analysis.
The mean time to flare after rituximab was nearly 8 months, Dr. Sánchez Pérez said. Arthritis was the main manifestation seen during relapse (41% of patients), and mucocutaneous symptoms occurred in 21%. Biological markers of flare at 12 months after multivariate analysis were musculoskeletal symptoms at baseline (OR, 0.26; P = .039) and being anti-RNP antibody positive (OR, 10.56; P = .03).
“There were one or two encouraging signs,” said Dr. Isenberg, who was the senior author of the study. “Unfortunately, what I think the data show us, it remains pretty hard to know how any individual patient is going to respond to B-cell depletion using rituximab.”
Dr. Sánchez Pérez reported having no disclosures in relation to the study. Dr. Isenberg was one of the first people to use rituximab to treat patients with lupus but reported having no other competing interests.
SOURCE: Sánchez Pérez H and Isenberg D. Ann Rheum Dis. 2018;77(Suppl 2):177. EULAR 2018 Congress, Abstract OP0255.
AMSTERDAM – Despite some “encouraging signs” seen in a cross-sectional study, it remains difficult to determine whether a patient with systemic lupus erythematosus (SLE) will respond to off-label rituximab therapy, according to David Isenberg, MD.
The presence of constitutional symptoms, which includes fatigue, at baseline were associated with a favorable response to rituximab at 6 months (odds ratio, 7.35; P = .01). Conversely, having more than one anti–extractable nuclear antigen (anti-ENA) antibody was associated with a worse response to rituximab at 12 months (OR, 0.33; P = .032).
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“It’s not a cure for lupus, that’s obvious, but used at the appropriate time in the right sort of patients, it can be very helpful,” Dr. Isenberg said in an interview at the European Congress of Rheumatology. That’s both in terms of improving disease activity and reducing the use of glucocorticosteroids and immunosuppressive drugs, he noted.
“The great mystery, as with all drugs, is: Are there any markers which might tell us that the disease is going to do better with rituximab than perhaps with another form of medication, or is it just saying to us, ‘Whatever you do, it doesn’t make much difference’?” Dr. Isenberg said. He discussed the results of a study involving the first 121 patients treated with rituximab at his institution, University College London Hospital (UCLH); he noted this is one of the largest single-center cohorts of individuals with SLE who have used rituximab.
The aim of the study, which was presented at the congress by Hiurma Sánchez Pérez, MD, was therefore to try to find demographic, clinical, and serological markers that might help in predicting the response to rituximab in SLE patients.
Response to treatment was determined using the British Isles Lupus Assessment Group (BILAG) Index. Patients who initially had markedly (BILAG A) or moderately (BILAG B) active disease but who no longer fell into these categories at 6 or 12 months were designated as responders. Those who remained were designated as nonresponders. In addition, any person moving into category A or B of the BILAG Index was said to have relapsed because of a flare in disease activity.
At 6 and 12 months, a respective 85% and 70% of patients exhibited a response to rituximab. Just under a quarter (24%) relapsed before 1 year, Dr. Sánchez Pérez reported.
Most of the patients in the cohort were white (n = 50) or Afro-Caribbean (n = 38), but ethnicity did not seem to play a role in predicting whether patients would respond to rituximab treatment.
Aside from constitutional symptoms and having more than one anti-ENA antibody, there were no other biological markers of response that remained significant after multivariate analysis.
The mean time to flare after rituximab was nearly 8 months, Dr. Sánchez Pérez said. Arthritis was the main manifestation seen during relapse (41% of patients), and mucocutaneous symptoms occurred in 21%. Biological markers of flare at 12 months after multivariate analysis were musculoskeletal symptoms at baseline (OR, 0.26; P = .039) and being anti-RNP antibody positive (OR, 10.56; P = .03).
“There were one or two encouraging signs,” said Dr. Isenberg, who was the senior author of the study. “Unfortunately, what I think the data show us, it remains pretty hard to know how any individual patient is going to respond to B-cell depletion using rituximab.”
Dr. Sánchez Pérez reported having no disclosures in relation to the study. Dr. Isenberg was one of the first people to use rituximab to treat patients with lupus but reported having no other competing interests.
SOURCE: Sánchez Pérez H and Isenberg D. Ann Rheum Dis. 2018;77(Suppl 2):177. EULAR 2018 Congress, Abstract OP0255.
AMSTERDAM – Despite some “encouraging signs” seen in a cross-sectional study, it remains difficult to determine whether a patient with systemic lupus erythematosus (SLE) will respond to off-label rituximab therapy, according to David Isenberg, MD.
The presence of constitutional symptoms, which includes fatigue, at baseline were associated with a favorable response to rituximab at 6 months (odds ratio, 7.35; P = .01). Conversely, having more than one anti–extractable nuclear antigen (anti-ENA) antibody was associated with a worse response to rituximab at 12 months (OR, 0.33; P = .032).
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“It’s not a cure for lupus, that’s obvious, but used at the appropriate time in the right sort of patients, it can be very helpful,” Dr. Isenberg said in an interview at the European Congress of Rheumatology. That’s both in terms of improving disease activity and reducing the use of glucocorticosteroids and immunosuppressive drugs, he noted.
“The great mystery, as with all drugs, is: Are there any markers which might tell us that the disease is going to do better with rituximab than perhaps with another form of medication, or is it just saying to us, ‘Whatever you do, it doesn’t make much difference’?” Dr. Isenberg said. He discussed the results of a study involving the first 121 patients treated with rituximab at his institution, University College London Hospital (UCLH); he noted this is one of the largest single-center cohorts of individuals with SLE who have used rituximab.
The aim of the study, which was presented at the congress by Hiurma Sánchez Pérez, MD, was therefore to try to find demographic, clinical, and serological markers that might help in predicting the response to rituximab in SLE patients.
Response to treatment was determined using the British Isles Lupus Assessment Group (BILAG) Index. Patients who initially had markedly (BILAG A) or moderately (BILAG B) active disease but who no longer fell into these categories at 6 or 12 months were designated as responders. Those who remained were designated as nonresponders. In addition, any person moving into category A or B of the BILAG Index was said to have relapsed because of a flare in disease activity.
At 6 and 12 months, a respective 85% and 70% of patients exhibited a response to rituximab. Just under a quarter (24%) relapsed before 1 year, Dr. Sánchez Pérez reported.
Most of the patients in the cohort were white (n = 50) or Afro-Caribbean (n = 38), but ethnicity did not seem to play a role in predicting whether patients would respond to rituximab treatment.
Aside from constitutional symptoms and having more than one anti-ENA antibody, there were no other biological markers of response that remained significant after multivariate analysis.
The mean time to flare after rituximab was nearly 8 months, Dr. Sánchez Pérez said. Arthritis was the main manifestation seen during relapse (41% of patients), and mucocutaneous symptoms occurred in 21%. Biological markers of flare at 12 months after multivariate analysis were musculoskeletal symptoms at baseline (OR, 0.26; P = .039) and being anti-RNP antibody positive (OR, 10.56; P = .03).
“There were one or two encouraging signs,” said Dr. Isenberg, who was the senior author of the study. “Unfortunately, what I think the data show us, it remains pretty hard to know how any individual patient is going to respond to B-cell depletion using rituximab.”
Dr. Sánchez Pérez reported having no disclosures in relation to the study. Dr. Isenberg was one of the first people to use rituximab to treat patients with lupus but reported having no other competing interests.
SOURCE: Sánchez Pérez H and Isenberg D. Ann Rheum Dis. 2018;77(Suppl 2):177. EULAR 2018 Congress, Abstract OP0255.
REPORTING FROM THE EULAR 2018 CONGRESS
Key clinical point: Only the presence of constitutional symptoms at baseline and having more than one anti–extractable nuclear antigen (anti-ENA) antibody were related to rituximab response.
Major finding: Having more than one anti-ENA antibody was related to a worse response to rituximab at 12 months.
Study details: A cross-sectional study of 121 patients with systemic lupus erythematosus treated with rituximab during 2000-2016.
Disclosures: Dr. Isenberg has used rituximab to treat patients with lupus for almost 20 years but reported having no other competing interests. Dr. Sánchez Pérez reported having no disclosures in relation to the study.
Source: Sánchez Pérez H and Isenberg D. Ann Rheum Dis. 2018;77(Suppl 2):177. EULAR 2018 Congress, Abstract OP0255.
New SLE classification criteria reset disease definition
AMSTERDAM – The new systemic lupus erythematosus classification criteria of the American College of Rheumatology and the European League Against Rheumatism are based on a point system that will produce a “paradigm shift” in how the disease gets studied going forward, said Sindhu Johnson, MD, while presenting the latest version of the newly revised classification scheme at the European Congress of Rheumatology.
Until now, classification of systemic lupus erythematosus (SLE) was a yes-or-no decision, based on whether the patient had a minimum number of characteristic signs or symptoms. The new criteria, which are on track for formal endorsement before the end of 2018 by the two medical societies that sponsored the revision, instead use a point system that gives varying weight to each of the 22 criteria. A patient needs to score at least 10 points from these criteria, and all patients classified with SLE also must have an antinuclear antibody (ANA) titer of at least 1:80 on HEp-2 cells or an equivalent positive test. This means that the criteria also can define patients who just miss classification with SLE by meeting the ANA standard and by tallying 8 or 9 points, and the criteria also identify patients who far exceed the classification threshold by having the requisite ANA plus racking up as many as, perhaps, 20 or 30 points.
“This is a real research opportunity,” to follow patients who fall just short with 8 or 9 points to assess their longer-term prognosis, as well as to study whether “higher scores mean a higher risk for developing a bad outcome,” said Dr. Johnson, a rheumatologist at the University of Toronto and director of the Toronto Scleroderma Program. Other areas for future research with the new criteria include seeing how they work in various SLE subgroups, such as patients with renal-predominant disease or skin-predominant disease, and also seeing how they work in various ethnic populations.
“Diagnosis of lupus still falls within the realm of the treating physician,” but the classification criteria “inform our concept of the disease,” Dr. Johnson said in a video interview. “The new criteria allow for a shift in the way we think of the disease.”
For example, for the first time, the new criteria includes fever as a classification criterion, which receives 2 points if an infectious or other non-SLE cause can be discounted. Fever has recently been identified as a marker of early-stage SLE in at least some patients, and its addition to the classification criteria “adds a new dimension to how we think about the disease and allows us to distinguish early disease from mimicking diseases,” she explained. At the other end of the classification spectrum, a finding of class III or IV lupus nephritis on renal biopsy receives 10 points, and hence, this one finding plus having a high enough level of ANA leads to SLE classification regardless of whether the patient has any other signs or symptoms of the disease.
That’s because “85% of our experts said that they would feel confident classifying a patient as having lupus based only on a renal biopsy” and ANA positivity, said Dr. Johnson, who served as the ACR-appointed cochair of the criteria-writing panel along with a cochair selected by EULAR, Martin Aringer, MD, PhD, of the Technical University of Dresden (Germany). She cautioned that other levels of lupus nephritis, class II or V, confer only 8 points to the classification and so by themselves are not enough to label a person as having lupus.
During her presentation, Dr. Johnson cited the high levels of sensitivity and specificity that the new classification criteria demonstrated in a validation cohort of more than 1,000 cases and controls. In the validation analysis, the new criteria had a sensitivity of 96.12% and specificity of 94.43% for classifying SLE, giving the new criteria a better result on both these measures than either the 1997 ACR criteria (Arthritis Rheum. 1997 Sept;40[9]:1725) or the 2012 Systemic Lupus International Collaborating Clinics criteria (Arthritis Rheum. 2012 Aug;64[8]:2677-86).
The 22 criteria cluster into seven separate clinical domains and three different immunologic domains. The point values assigned to each criterion range from 2 to 10 points.
Dr. Johnson had no disclosures.
AMSTERDAM – The new systemic lupus erythematosus classification criteria of the American College of Rheumatology and the European League Against Rheumatism are based on a point system that will produce a “paradigm shift” in how the disease gets studied going forward, said Sindhu Johnson, MD, while presenting the latest version of the newly revised classification scheme at the European Congress of Rheumatology.
Until now, classification of systemic lupus erythematosus (SLE) was a yes-or-no decision, based on whether the patient had a minimum number of characteristic signs or symptoms. The new criteria, which are on track for formal endorsement before the end of 2018 by the two medical societies that sponsored the revision, instead use a point system that gives varying weight to each of the 22 criteria. A patient needs to score at least 10 points from these criteria, and all patients classified with SLE also must have an antinuclear antibody (ANA) titer of at least 1:80 on HEp-2 cells or an equivalent positive test. This means that the criteria also can define patients who just miss classification with SLE by meeting the ANA standard and by tallying 8 or 9 points, and the criteria also identify patients who far exceed the classification threshold by having the requisite ANA plus racking up as many as, perhaps, 20 or 30 points.
“This is a real research opportunity,” to follow patients who fall just short with 8 or 9 points to assess their longer-term prognosis, as well as to study whether “higher scores mean a higher risk for developing a bad outcome,” said Dr. Johnson, a rheumatologist at the University of Toronto and director of the Toronto Scleroderma Program. Other areas for future research with the new criteria include seeing how they work in various SLE subgroups, such as patients with renal-predominant disease or skin-predominant disease, and also seeing how they work in various ethnic populations.
“Diagnosis of lupus still falls within the realm of the treating physician,” but the classification criteria “inform our concept of the disease,” Dr. Johnson said in a video interview. “The new criteria allow for a shift in the way we think of the disease.”
For example, for the first time, the new criteria includes fever as a classification criterion, which receives 2 points if an infectious or other non-SLE cause can be discounted. Fever has recently been identified as a marker of early-stage SLE in at least some patients, and its addition to the classification criteria “adds a new dimension to how we think about the disease and allows us to distinguish early disease from mimicking diseases,” she explained. At the other end of the classification spectrum, a finding of class III or IV lupus nephritis on renal biopsy receives 10 points, and hence, this one finding plus having a high enough level of ANA leads to SLE classification regardless of whether the patient has any other signs or symptoms of the disease.
That’s because “85% of our experts said that they would feel confident classifying a patient as having lupus based only on a renal biopsy” and ANA positivity, said Dr. Johnson, who served as the ACR-appointed cochair of the criteria-writing panel along with a cochair selected by EULAR, Martin Aringer, MD, PhD, of the Technical University of Dresden (Germany). She cautioned that other levels of lupus nephritis, class II or V, confer only 8 points to the classification and so by themselves are not enough to label a person as having lupus.
During her presentation, Dr. Johnson cited the high levels of sensitivity and specificity that the new classification criteria demonstrated in a validation cohort of more than 1,000 cases and controls. In the validation analysis, the new criteria had a sensitivity of 96.12% and specificity of 94.43% for classifying SLE, giving the new criteria a better result on both these measures than either the 1997 ACR criteria (Arthritis Rheum. 1997 Sept;40[9]:1725) or the 2012 Systemic Lupus International Collaborating Clinics criteria (Arthritis Rheum. 2012 Aug;64[8]:2677-86).
The 22 criteria cluster into seven separate clinical domains and three different immunologic domains. The point values assigned to each criterion range from 2 to 10 points.
Dr. Johnson had no disclosures.
AMSTERDAM – The new systemic lupus erythematosus classification criteria of the American College of Rheumatology and the European League Against Rheumatism are based on a point system that will produce a “paradigm shift” in how the disease gets studied going forward, said Sindhu Johnson, MD, while presenting the latest version of the newly revised classification scheme at the European Congress of Rheumatology.
Until now, classification of systemic lupus erythematosus (SLE) was a yes-or-no decision, based on whether the patient had a minimum number of characteristic signs or symptoms. The new criteria, which are on track for formal endorsement before the end of 2018 by the two medical societies that sponsored the revision, instead use a point system that gives varying weight to each of the 22 criteria. A patient needs to score at least 10 points from these criteria, and all patients classified with SLE also must have an antinuclear antibody (ANA) titer of at least 1:80 on HEp-2 cells or an equivalent positive test. This means that the criteria also can define patients who just miss classification with SLE by meeting the ANA standard and by tallying 8 or 9 points, and the criteria also identify patients who far exceed the classification threshold by having the requisite ANA plus racking up as many as, perhaps, 20 or 30 points.
“This is a real research opportunity,” to follow patients who fall just short with 8 or 9 points to assess their longer-term prognosis, as well as to study whether “higher scores mean a higher risk for developing a bad outcome,” said Dr. Johnson, a rheumatologist at the University of Toronto and director of the Toronto Scleroderma Program. Other areas for future research with the new criteria include seeing how they work in various SLE subgroups, such as patients with renal-predominant disease or skin-predominant disease, and also seeing how they work in various ethnic populations.
“Diagnosis of lupus still falls within the realm of the treating physician,” but the classification criteria “inform our concept of the disease,” Dr. Johnson said in a video interview. “The new criteria allow for a shift in the way we think of the disease.”
For example, for the first time, the new criteria includes fever as a classification criterion, which receives 2 points if an infectious or other non-SLE cause can be discounted. Fever has recently been identified as a marker of early-stage SLE in at least some patients, and its addition to the classification criteria “adds a new dimension to how we think about the disease and allows us to distinguish early disease from mimicking diseases,” she explained. At the other end of the classification spectrum, a finding of class III or IV lupus nephritis on renal biopsy receives 10 points, and hence, this one finding plus having a high enough level of ANA leads to SLE classification regardless of whether the patient has any other signs or symptoms of the disease.
That’s because “85% of our experts said that they would feel confident classifying a patient as having lupus based only on a renal biopsy” and ANA positivity, said Dr. Johnson, who served as the ACR-appointed cochair of the criteria-writing panel along with a cochair selected by EULAR, Martin Aringer, MD, PhD, of the Technical University of Dresden (Germany). She cautioned that other levels of lupus nephritis, class II or V, confer only 8 points to the classification and so by themselves are not enough to label a person as having lupus.
During her presentation, Dr. Johnson cited the high levels of sensitivity and specificity that the new classification criteria demonstrated in a validation cohort of more than 1,000 cases and controls. In the validation analysis, the new criteria had a sensitivity of 96.12% and specificity of 94.43% for classifying SLE, giving the new criteria a better result on both these measures than either the 1997 ACR criteria (Arthritis Rheum. 1997 Sept;40[9]:1725) or the 2012 Systemic Lupus International Collaborating Clinics criteria (Arthritis Rheum. 2012 Aug;64[8]:2677-86).
The 22 criteria cluster into seven separate clinical domains and three different immunologic domains. The point values assigned to each criterion range from 2 to 10 points.
Dr. Johnson had no disclosures.
REPORTING FROM THE EULAR 2018 CONGRESS
JAK inhibitor therapy promising for refractory dermatomyositis
ORLANDO – The according to Ruth Ann Vleugels, MD, director of the autoimmune skin diseases program at Brigham and Women’s Hospital, Boston.
“We will have patients who essentially fail all of our typical therapies and are still coming to us for help. This is a huge challenge,” said Dr. Vleugels, who, several years ago, started to use tofacitinib to treat these patients. “Similar to my colleagues who use tofacitinib to treat alopecia areata, we often have to push” beyond the dose used to treat rheumatoid arthritis, to 10 mg twice a day, she said at the International Conference on Cutaneous Lupus Erythematosus. Tofacitinib helps counter the overexpression of interferon in DM.
Getting insurance coverage for this off-label indication can be tough, however, but Dr. Vleugels said she’s had success when she tells insurers that tofacitinib will likely reduce the need for IVIg.
It’s safe to keep patients on methotrexate if there are concerns about muscle involvement while their skin is brought under control with tofacitinib. In terms of side effects, “we see increased shingles,” so recommending the shingles vaccine for these patients is a good idea, she added.
It’s also important to counsel DM patients that they are at particular risk for skin reactions with antimalarials, which can be serious, so that, “if there is a drug reaction that develops, it’s noticed right away” and the drug can be stopped, she said. “If you have a patient who has very severe disease, I might skip over an antimalarial altogether,” she commented.
Methotrexate is the next option, especially if there are work ups for cancer or the patients have cancer, but Dr. Femia, director of inpatient dermatology at NYU, said she leans towards mycophenolate if there’s concern about lung involvement.
The next step, if necessary, is IVIg, which she said is “particularly helpful” for recalcitrant skin disease and can help some patients discontinue other immunosuppressives. To counter headache, a common side effect, she will space dosing out over 3 days, instead of the usual 2, and have a bag of saline administered before and after the infusion to keep patients hydrated; this counters the headache-inducing viscosity of IVIg.
Patients often see a result after the first infusion, but if there’s no benefit by the third cycle, “it’s probably time to move on,” she said. “If you have a refractory muscle disease patient and skin isn’t the main issue, rituximab is reasonable to try,” she added, noting that the benefit of tumor necrosis factor blockers, “at best, is very mixed in the DM population. They are very low down in the treatment algorithm.”
Dr. Vleugels and Dr. Femia are both Pfizer investigators.
ORLANDO – The according to Ruth Ann Vleugels, MD, director of the autoimmune skin diseases program at Brigham and Women’s Hospital, Boston.
“We will have patients who essentially fail all of our typical therapies and are still coming to us for help. This is a huge challenge,” said Dr. Vleugels, who, several years ago, started to use tofacitinib to treat these patients. “Similar to my colleagues who use tofacitinib to treat alopecia areata, we often have to push” beyond the dose used to treat rheumatoid arthritis, to 10 mg twice a day, she said at the International Conference on Cutaneous Lupus Erythematosus. Tofacitinib helps counter the overexpression of interferon in DM.
Getting insurance coverage for this off-label indication can be tough, however, but Dr. Vleugels said she’s had success when she tells insurers that tofacitinib will likely reduce the need for IVIg.
It’s safe to keep patients on methotrexate if there are concerns about muscle involvement while their skin is brought under control with tofacitinib. In terms of side effects, “we see increased shingles,” so recommending the shingles vaccine for these patients is a good idea, she added.
It’s also important to counsel DM patients that they are at particular risk for skin reactions with antimalarials, which can be serious, so that, “if there is a drug reaction that develops, it’s noticed right away” and the drug can be stopped, she said. “If you have a patient who has very severe disease, I might skip over an antimalarial altogether,” she commented.
Methotrexate is the next option, especially if there are work ups for cancer or the patients have cancer, but Dr. Femia, director of inpatient dermatology at NYU, said she leans towards mycophenolate if there’s concern about lung involvement.
The next step, if necessary, is IVIg, which she said is “particularly helpful” for recalcitrant skin disease and can help some patients discontinue other immunosuppressives. To counter headache, a common side effect, she will space dosing out over 3 days, instead of the usual 2, and have a bag of saline administered before and after the infusion to keep patients hydrated; this counters the headache-inducing viscosity of IVIg.
Patients often see a result after the first infusion, but if there’s no benefit by the third cycle, “it’s probably time to move on,” she said. “If you have a refractory muscle disease patient and skin isn’t the main issue, rituximab is reasonable to try,” she added, noting that the benefit of tumor necrosis factor blockers, “at best, is very mixed in the DM population. They are very low down in the treatment algorithm.”
Dr. Vleugels and Dr. Femia are both Pfizer investigators.
ORLANDO – The according to Ruth Ann Vleugels, MD, director of the autoimmune skin diseases program at Brigham and Women’s Hospital, Boston.
“We will have patients who essentially fail all of our typical therapies and are still coming to us for help. This is a huge challenge,” said Dr. Vleugels, who, several years ago, started to use tofacitinib to treat these patients. “Similar to my colleagues who use tofacitinib to treat alopecia areata, we often have to push” beyond the dose used to treat rheumatoid arthritis, to 10 mg twice a day, she said at the International Conference on Cutaneous Lupus Erythematosus. Tofacitinib helps counter the overexpression of interferon in DM.
Getting insurance coverage for this off-label indication can be tough, however, but Dr. Vleugels said she’s had success when she tells insurers that tofacitinib will likely reduce the need for IVIg.
It’s safe to keep patients on methotrexate if there are concerns about muscle involvement while their skin is brought under control with tofacitinib. In terms of side effects, “we see increased shingles,” so recommending the shingles vaccine for these patients is a good idea, she added.
It’s also important to counsel DM patients that they are at particular risk for skin reactions with antimalarials, which can be serious, so that, “if there is a drug reaction that develops, it’s noticed right away” and the drug can be stopped, she said. “If you have a patient who has very severe disease, I might skip over an antimalarial altogether,” she commented.
Methotrexate is the next option, especially if there are work ups for cancer or the patients have cancer, but Dr. Femia, director of inpatient dermatology at NYU, said she leans towards mycophenolate if there’s concern about lung involvement.
The next step, if necessary, is IVIg, which she said is “particularly helpful” for recalcitrant skin disease and can help some patients discontinue other immunosuppressives. To counter headache, a common side effect, she will space dosing out over 3 days, instead of the usual 2, and have a bag of saline administered before and after the infusion to keep patients hydrated; this counters the headache-inducing viscosity of IVIg.
Patients often see a result after the first infusion, but if there’s no benefit by the third cycle, “it’s probably time to move on,” she said. “If you have a refractory muscle disease patient and skin isn’t the main issue, rituximab is reasonable to try,” she added, noting that the benefit of tumor necrosis factor blockers, “at best, is very mixed in the DM population. They are very low down in the treatment algorithm.”
Dr. Vleugels and Dr. Femia are both Pfizer investigators.
EXPERT ANALYSIS FROM ICCLE 2018
SLE classification criteria perform well in validation study
AMSTERDAM – The first European League Against Rheumatism and American College of Rheumatology joint criteria for classifying systemic lupus erythematosus have a sensitivity and a specificity of more than 90%.
This is important because they improve upon the existing ACR and Systemic Lupus International Collaborating Clinics (SLICC) criteria, said Martin Aringer, MD, PhD, who cochaired the Steering Committee that produced the new classification criteria.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Most clinicians working with lupus are familiar with the 1997 ACR criteria for the classification of systemic lupus erythematosus (SLE), which “had a relatively simple structure,” Dr. Aringer said during the opening plenary abstract session at the European Congress of Rheumatology. These considered items such as the presence of malar or discoid rash, photosensitivity, oral ulcers and arthritis, among others. These had a high specificity but a lower sensitivity. The development of the SLICC criteria in 2012 improved upon the sensitivity of the ACR criteria (92%-99% vs. 77%-91%), but at a loss in specificity (74%–88% vs. 91%-96%).
The SLICC criteria introduced two novel ideas, said Dr. Aringer, professor of medicine and chief of the division of rheumatology at the Technical University of Dresden (Germany). The first was that there had to be at least one immunologic criterion met, and the second was that biopsy-proven lupus nephritis had to be present with antinuclear antibodies (ANA) and anti-DNA antibodies detected.
One of the goals in developing the joint EULAR/ACR criteria therefore was to try to maintain the respective sensitivity and specificity achieved with the SLICC and ACR criteria. One of the key things that the new criteria looked at was to see if ANA could be used as an entry criterion. Investigations involving more than 13,000 patients with SLE showed that it could, with a antibody titer threshold of 1:80, exhibit a sensitivity of 98% (Arthritis Care Res. 2018;70[3]:428-38). Another goal was to see if histology-proven nephritis was a stronger predictor of SLE than clinical factors, such as oral ulcers, and to identify items that would only be included if there was no other more likely explanation (Lupus. 2016;25[8]:805-11).
Draft SLE classification criteria were developed based on an expert Delphi process and included ANA as an entry criterion and weighted items according to the likelihood of being associated with lupus. Items considered included the presence and severity of lupus nephritis, serology and other antibody tests, skin and central nervous system involvement, and hematologic and immunologic criteria such as the presence of thrombocytopenia and low complement (C3 and/or C4).
The final, simplified draft SLE classification criteria include 22 items in addition to the presence of ANA. A cut-off score of 10 or more is required for a classification of SLE. For example, a patient with an ANA of 1:80 or higher plus class III/IV nephritis (scoring 10) would be classified as having SLE. A patient with class II/V nephritis (scoring 8) would need another factor to be classified as having lupus, such as the presence of arthritis (scoring 6).
“Performance characteristics find sensitivity similar to the SLICC criteria while maintaining the specificity of the ACR 1997 criteria,” Dr. Aringer said, adding that these criteria will now be formally submitted to and reviewed by EULAR and ACR.
The sensitivity and specificity of the new criteria were 98% and 96% in the derivation cohort and 96% and 93% in the validation cohort.
“I was really very pleased and very happy to see that the revised or the new ACR/EULAR classification criteria had sensitivity and specificity of above 90%,” Thomas Dörner, MD, PhD, said in an interview at the congress. Dr. Dörner was a codeveloper of these criteria.
Over the past 10-15 years there have been several therapies that have failed to live up to their early promise as a potential treatment for lupus, said Dr. Dörner, professor of medicine at Charité–Universitätsmedizin Berlin. He noted that the failed treatment trials had led investigators to try to determine ways in which lupus might be best treated, such as by a “treat-to-target” approach to attain remission and low-disease activity. It also led to the reevaluation of how lupus is classified to see if that might be affecting the population of patients recruited into clinical trials.
“We had the feeling, and this is now confirmed by the new classification criteria, that a number of patients studied in earlier trials may have not fulfilled what we think is the classical lupus profile, so-called lupus or SLE mimickers,” Dr. Dörner said. This could have affected the chances of a treatment approach being successful versus placebo.
The new classification criteria are similar to those in other rheumatic diseases in that they give different weight to the effects on different organ systems, Dr. Dörner said. The stipulation that there must be a positive ANA test is also an important step, “really to make sure that we are looking at an autoimmune disease and nothing else,” he observed.
For patients who do not have a positive ANA test, they can of course still be treated, Dr. Dörner reassured, but for the classification criteria and entering patients into clinical trials, it’s really important to have strict classification criteria so that the results may be compared.
Dr. Aringer and Dr. Dörner had no relevant disclosures besides their involvement in developing the new classification criteria.
SOURCE: Aringer M et al. Ann Rheum Dis. 2018;77(Suppl 2):60. Abstract OP0020.
AMSTERDAM – The first European League Against Rheumatism and American College of Rheumatology joint criteria for classifying systemic lupus erythematosus have a sensitivity and a specificity of more than 90%.
This is important because they improve upon the existing ACR and Systemic Lupus International Collaborating Clinics (SLICC) criteria, said Martin Aringer, MD, PhD, who cochaired the Steering Committee that produced the new classification criteria.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Most clinicians working with lupus are familiar with the 1997 ACR criteria for the classification of systemic lupus erythematosus (SLE), which “had a relatively simple structure,” Dr. Aringer said during the opening plenary abstract session at the European Congress of Rheumatology. These considered items such as the presence of malar or discoid rash, photosensitivity, oral ulcers and arthritis, among others. These had a high specificity but a lower sensitivity. The development of the SLICC criteria in 2012 improved upon the sensitivity of the ACR criteria (92%-99% vs. 77%-91%), but at a loss in specificity (74%–88% vs. 91%-96%).
The SLICC criteria introduced two novel ideas, said Dr. Aringer, professor of medicine and chief of the division of rheumatology at the Technical University of Dresden (Germany). The first was that there had to be at least one immunologic criterion met, and the second was that biopsy-proven lupus nephritis had to be present with antinuclear antibodies (ANA) and anti-DNA antibodies detected.
One of the goals in developing the joint EULAR/ACR criteria therefore was to try to maintain the respective sensitivity and specificity achieved with the SLICC and ACR criteria. One of the key things that the new criteria looked at was to see if ANA could be used as an entry criterion. Investigations involving more than 13,000 patients with SLE showed that it could, with a antibody titer threshold of 1:80, exhibit a sensitivity of 98% (Arthritis Care Res. 2018;70[3]:428-38). Another goal was to see if histology-proven nephritis was a stronger predictor of SLE than clinical factors, such as oral ulcers, and to identify items that would only be included if there was no other more likely explanation (Lupus. 2016;25[8]:805-11).
Draft SLE classification criteria were developed based on an expert Delphi process and included ANA as an entry criterion and weighted items according to the likelihood of being associated with lupus. Items considered included the presence and severity of lupus nephritis, serology and other antibody tests, skin and central nervous system involvement, and hematologic and immunologic criteria such as the presence of thrombocytopenia and low complement (C3 and/or C4).
The final, simplified draft SLE classification criteria include 22 items in addition to the presence of ANA. A cut-off score of 10 or more is required for a classification of SLE. For example, a patient with an ANA of 1:80 or higher plus class III/IV nephritis (scoring 10) would be classified as having SLE. A patient with class II/V nephritis (scoring 8) would need another factor to be classified as having lupus, such as the presence of arthritis (scoring 6).
“Performance characteristics find sensitivity similar to the SLICC criteria while maintaining the specificity of the ACR 1997 criteria,” Dr. Aringer said, adding that these criteria will now be formally submitted to and reviewed by EULAR and ACR.
The sensitivity and specificity of the new criteria were 98% and 96% in the derivation cohort and 96% and 93% in the validation cohort.
“I was really very pleased and very happy to see that the revised or the new ACR/EULAR classification criteria had sensitivity and specificity of above 90%,” Thomas Dörner, MD, PhD, said in an interview at the congress. Dr. Dörner was a codeveloper of these criteria.
Over the past 10-15 years there have been several therapies that have failed to live up to their early promise as a potential treatment for lupus, said Dr. Dörner, professor of medicine at Charité–Universitätsmedizin Berlin. He noted that the failed treatment trials had led investigators to try to determine ways in which lupus might be best treated, such as by a “treat-to-target” approach to attain remission and low-disease activity. It also led to the reevaluation of how lupus is classified to see if that might be affecting the population of patients recruited into clinical trials.
“We had the feeling, and this is now confirmed by the new classification criteria, that a number of patients studied in earlier trials may have not fulfilled what we think is the classical lupus profile, so-called lupus or SLE mimickers,” Dr. Dörner said. This could have affected the chances of a treatment approach being successful versus placebo.
The new classification criteria are similar to those in other rheumatic diseases in that they give different weight to the effects on different organ systems, Dr. Dörner said. The stipulation that there must be a positive ANA test is also an important step, “really to make sure that we are looking at an autoimmune disease and nothing else,” he observed.
For patients who do not have a positive ANA test, they can of course still be treated, Dr. Dörner reassured, but for the classification criteria and entering patients into clinical trials, it’s really important to have strict classification criteria so that the results may be compared.
Dr. Aringer and Dr. Dörner had no relevant disclosures besides their involvement in developing the new classification criteria.
SOURCE: Aringer M et al. Ann Rheum Dis. 2018;77(Suppl 2):60. Abstract OP0020.
AMSTERDAM – The first European League Against Rheumatism and American College of Rheumatology joint criteria for classifying systemic lupus erythematosus have a sensitivity and a specificity of more than 90%.
This is important because they improve upon the existing ACR and Systemic Lupus International Collaborating Clinics (SLICC) criteria, said Martin Aringer, MD, PhD, who cochaired the Steering Committee that produced the new classification criteria.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Most clinicians working with lupus are familiar with the 1997 ACR criteria for the classification of systemic lupus erythematosus (SLE), which “had a relatively simple structure,” Dr. Aringer said during the opening plenary abstract session at the European Congress of Rheumatology. These considered items such as the presence of malar or discoid rash, photosensitivity, oral ulcers and arthritis, among others. These had a high specificity but a lower sensitivity. The development of the SLICC criteria in 2012 improved upon the sensitivity of the ACR criteria (92%-99% vs. 77%-91%), but at a loss in specificity (74%–88% vs. 91%-96%).
The SLICC criteria introduced two novel ideas, said Dr. Aringer, professor of medicine and chief of the division of rheumatology at the Technical University of Dresden (Germany). The first was that there had to be at least one immunologic criterion met, and the second was that biopsy-proven lupus nephritis had to be present with antinuclear antibodies (ANA) and anti-DNA antibodies detected.
One of the goals in developing the joint EULAR/ACR criteria therefore was to try to maintain the respective sensitivity and specificity achieved with the SLICC and ACR criteria. One of the key things that the new criteria looked at was to see if ANA could be used as an entry criterion. Investigations involving more than 13,000 patients with SLE showed that it could, with a antibody titer threshold of 1:80, exhibit a sensitivity of 98% (Arthritis Care Res. 2018;70[3]:428-38). Another goal was to see if histology-proven nephritis was a stronger predictor of SLE than clinical factors, such as oral ulcers, and to identify items that would only be included if there was no other more likely explanation (Lupus. 2016;25[8]:805-11).
Draft SLE classification criteria were developed based on an expert Delphi process and included ANA as an entry criterion and weighted items according to the likelihood of being associated with lupus. Items considered included the presence and severity of lupus nephritis, serology and other antibody tests, skin and central nervous system involvement, and hematologic and immunologic criteria such as the presence of thrombocytopenia and low complement (C3 and/or C4).
The final, simplified draft SLE classification criteria include 22 items in addition to the presence of ANA. A cut-off score of 10 or more is required for a classification of SLE. For example, a patient with an ANA of 1:80 or higher plus class III/IV nephritis (scoring 10) would be classified as having SLE. A patient with class II/V nephritis (scoring 8) would need another factor to be classified as having lupus, such as the presence of arthritis (scoring 6).
“Performance characteristics find sensitivity similar to the SLICC criteria while maintaining the specificity of the ACR 1997 criteria,” Dr. Aringer said, adding that these criteria will now be formally submitted to and reviewed by EULAR and ACR.
The sensitivity and specificity of the new criteria were 98% and 96% in the derivation cohort and 96% and 93% in the validation cohort.
“I was really very pleased and very happy to see that the revised or the new ACR/EULAR classification criteria had sensitivity and specificity of above 90%,” Thomas Dörner, MD, PhD, said in an interview at the congress. Dr. Dörner was a codeveloper of these criteria.
Over the past 10-15 years there have been several therapies that have failed to live up to their early promise as a potential treatment for lupus, said Dr. Dörner, professor of medicine at Charité–Universitätsmedizin Berlin. He noted that the failed treatment trials had led investigators to try to determine ways in which lupus might be best treated, such as by a “treat-to-target” approach to attain remission and low-disease activity. It also led to the reevaluation of how lupus is classified to see if that might be affecting the population of patients recruited into clinical trials.
“We had the feeling, and this is now confirmed by the new classification criteria, that a number of patients studied in earlier trials may have not fulfilled what we think is the classical lupus profile, so-called lupus or SLE mimickers,” Dr. Dörner said. This could have affected the chances of a treatment approach being successful versus placebo.
The new classification criteria are similar to those in other rheumatic diseases in that they give different weight to the effects on different organ systems, Dr. Dörner said. The stipulation that there must be a positive ANA test is also an important step, “really to make sure that we are looking at an autoimmune disease and nothing else,” he observed.
For patients who do not have a positive ANA test, they can of course still be treated, Dr. Dörner reassured, but for the classification criteria and entering patients into clinical trials, it’s really important to have strict classification criteria so that the results may be compared.
Dr. Aringer and Dr. Dörner had no relevant disclosures besides their involvement in developing the new classification criteria.
SOURCE: Aringer M et al. Ann Rheum Dis. 2018;77(Suppl 2):60. Abstract OP0020.
REPORTING FROM THE EULAR 2018 CONGRESS
Key clinical point: New classification criteria for systemic lupus erythematosus (SLE) achieve both high sensitivity and specificity.
Major finding: The sensitivity and specificity of the new criteria were 98% and 96% in the derivation cohort and 96% and 93% in the validation cohort.
Study details: An international cohort of 1,160 SLE patients and 1,058 non-SLE patients in whom the new criteria were tested and validated.
Disclosures: Dr. Aringer and Dr. Dörner had no relevant disclosures besides their involvement in developing the new classification criteria.
Source: Aringer M et al. Ann Rheum Dis. 2018;77(Suppl 2):60. Abstract OP0020.
LLDAS shows potential as routine lupus treatment target
AMSTERDAM – The Lupus Low Disease Activity State measure of treatment response offers clinicians an attainable target for patients with systemic lupus erythematosus that correlates with a substantially reduced rate of organ damage, based on a retrospective assessment of data collected from more than 2,000 lupus patients at a single U.S. center.
The analysis showed that when patients with systemic lupus erythematosus (SLE) met the Lupus Low Disease Activity State (LLDAS) criteria at least half the time while on treatment, their overall rate of organ damage was reduced by 52%, compared with patients who never achieved LLDAS, Michelle A. Petri, MD, said at the European Congress of Rheumatology.
“LLDAS is something that anyone can use in practice,” and has the advantage of including a low steroid dose – no more than 7.5 mg prednisolone/day or an equivalent steroid – as one of its criteria, “a major bad actor” for SLE patients, Dr. Petri said in an interview. LLDAS “is absolutely ready for routine use,” although until now few clinicians have used it to monitor SLE patients, she noted.
“The LLDAS can be a useful target,” commented Ian N. Bruce, MD, professor of rheumatology at the University of Manchester (England), adding that the steroid dosage an SLE patient receives “is an important parameter to measure when assessing an SLE patient.
“It’s not far from being ready for routine use, but I’d like to see more evidence” that it’s a meaningful measure of an SLE patient’s disease status, he said in an interview.
To examine the clinical relevance of the LLDAS criteria, a five-point assessment for SLE first introduced in a 2016 report (Ann Rheum Dis. 2016 Sept;75[9]:1615-21), Dr. Petri and her associates applied it retrospectively to their records for 2,026 SLE patients in a Johns Hopkins registry. Clinicians at Johns Hopkins routinely assessed their SLE patients every 3 months and followed the patients for a median of about 10 years, and so had data from more than 81,000 patient encounters. The researchers used the longitudinal follow-up records to calculate an area under the curve for each patient that tracked their LLDAS state over time. This showed a clear dose-response relationship: The more time an SLE patient spent in LLDAS, the less organ damage they had. Patients who remained in LLDAS at least 75% of the time had a 60% reduction in cumulative organ damage, compared with patients who never achieved LLDAS, Dr. Petri said. The analysis also showed that LLDAS was substantially easier for patients to achieve than the Definitions of Remission in SLE (Ann Rheum Dis. 2017 March;76[3]:554-61). The Johns Hopkins cohort met the LLDAS definition about three times more often than they met the Definitions of Remission in SLE criteria, Dr. Petri said.
The new analysis also showed that LLDAS was especially effective in correlating with statistically significant reductions in future strokes, MI, and end-stage renal disease, though it did not significantly correlate with subsequent reductions in the incidence of cognitive impairment, deep vein thrombosis, malignancy, pulmonary fibrosis, pulmonary hypertension, or cataract development. But the strong correlation of time in LLDAS and the future rate of stroke, MI, or end-stage renal disease was very meaningful because those are the most important types of damage associated with SLE, Dr. Petri said. “LLDAS is a good treatment target as a surrogate” for future risk of SLE complications.
The study had no commercial funding, and Dr. Petri had no disclosures to report. Dr. Bruce has been a consultant to and speaker for GlaxoSmithKline, MedImmune, Pfizer, Roche, and UCB, and he has received research support from Genzyme, GlaxoSmithKline, Human Genome Sciences, Roche, and UCB.
SOURCE: Petri MA et al. Ann Rheum Dis. 2018;77(Suppl 2):111. Abstract OP0122.
AMSTERDAM – The Lupus Low Disease Activity State measure of treatment response offers clinicians an attainable target for patients with systemic lupus erythematosus that correlates with a substantially reduced rate of organ damage, based on a retrospective assessment of data collected from more than 2,000 lupus patients at a single U.S. center.
The analysis showed that when patients with systemic lupus erythematosus (SLE) met the Lupus Low Disease Activity State (LLDAS) criteria at least half the time while on treatment, their overall rate of organ damage was reduced by 52%, compared with patients who never achieved LLDAS, Michelle A. Petri, MD, said at the European Congress of Rheumatology.
“LLDAS is something that anyone can use in practice,” and has the advantage of including a low steroid dose – no more than 7.5 mg prednisolone/day or an equivalent steroid – as one of its criteria, “a major bad actor” for SLE patients, Dr. Petri said in an interview. LLDAS “is absolutely ready for routine use,” although until now few clinicians have used it to monitor SLE patients, she noted.
“The LLDAS can be a useful target,” commented Ian N. Bruce, MD, professor of rheumatology at the University of Manchester (England), adding that the steroid dosage an SLE patient receives “is an important parameter to measure when assessing an SLE patient.
“It’s not far from being ready for routine use, but I’d like to see more evidence” that it’s a meaningful measure of an SLE patient’s disease status, he said in an interview.
To examine the clinical relevance of the LLDAS criteria, a five-point assessment for SLE first introduced in a 2016 report (Ann Rheum Dis. 2016 Sept;75[9]:1615-21), Dr. Petri and her associates applied it retrospectively to their records for 2,026 SLE patients in a Johns Hopkins registry. Clinicians at Johns Hopkins routinely assessed their SLE patients every 3 months and followed the patients for a median of about 10 years, and so had data from more than 81,000 patient encounters. The researchers used the longitudinal follow-up records to calculate an area under the curve for each patient that tracked their LLDAS state over time. This showed a clear dose-response relationship: The more time an SLE patient spent in LLDAS, the less organ damage they had. Patients who remained in LLDAS at least 75% of the time had a 60% reduction in cumulative organ damage, compared with patients who never achieved LLDAS, Dr. Petri said. The analysis also showed that LLDAS was substantially easier for patients to achieve than the Definitions of Remission in SLE (Ann Rheum Dis. 2017 March;76[3]:554-61). The Johns Hopkins cohort met the LLDAS definition about three times more often than they met the Definitions of Remission in SLE criteria, Dr. Petri said.
The new analysis also showed that LLDAS was especially effective in correlating with statistically significant reductions in future strokes, MI, and end-stage renal disease, though it did not significantly correlate with subsequent reductions in the incidence of cognitive impairment, deep vein thrombosis, malignancy, pulmonary fibrosis, pulmonary hypertension, or cataract development. But the strong correlation of time in LLDAS and the future rate of stroke, MI, or end-stage renal disease was very meaningful because those are the most important types of damage associated with SLE, Dr. Petri said. “LLDAS is a good treatment target as a surrogate” for future risk of SLE complications.
The study had no commercial funding, and Dr. Petri had no disclosures to report. Dr. Bruce has been a consultant to and speaker for GlaxoSmithKline, MedImmune, Pfizer, Roche, and UCB, and he has received research support from Genzyme, GlaxoSmithKline, Human Genome Sciences, Roche, and UCB.
SOURCE: Petri MA et al. Ann Rheum Dis. 2018;77(Suppl 2):111. Abstract OP0122.
AMSTERDAM – The Lupus Low Disease Activity State measure of treatment response offers clinicians an attainable target for patients with systemic lupus erythematosus that correlates with a substantially reduced rate of organ damage, based on a retrospective assessment of data collected from more than 2,000 lupus patients at a single U.S. center.
The analysis showed that when patients with systemic lupus erythematosus (SLE) met the Lupus Low Disease Activity State (LLDAS) criteria at least half the time while on treatment, their overall rate of organ damage was reduced by 52%, compared with patients who never achieved LLDAS, Michelle A. Petri, MD, said at the European Congress of Rheumatology.
“LLDAS is something that anyone can use in practice,” and has the advantage of including a low steroid dose – no more than 7.5 mg prednisolone/day or an equivalent steroid – as one of its criteria, “a major bad actor” for SLE patients, Dr. Petri said in an interview. LLDAS “is absolutely ready for routine use,” although until now few clinicians have used it to monitor SLE patients, she noted.
“The LLDAS can be a useful target,” commented Ian N. Bruce, MD, professor of rheumatology at the University of Manchester (England), adding that the steroid dosage an SLE patient receives “is an important parameter to measure when assessing an SLE patient.
“It’s not far from being ready for routine use, but I’d like to see more evidence” that it’s a meaningful measure of an SLE patient’s disease status, he said in an interview.
To examine the clinical relevance of the LLDAS criteria, a five-point assessment for SLE first introduced in a 2016 report (Ann Rheum Dis. 2016 Sept;75[9]:1615-21), Dr. Petri and her associates applied it retrospectively to their records for 2,026 SLE patients in a Johns Hopkins registry. Clinicians at Johns Hopkins routinely assessed their SLE patients every 3 months and followed the patients for a median of about 10 years, and so had data from more than 81,000 patient encounters. The researchers used the longitudinal follow-up records to calculate an area under the curve for each patient that tracked their LLDAS state over time. This showed a clear dose-response relationship: The more time an SLE patient spent in LLDAS, the less organ damage they had. Patients who remained in LLDAS at least 75% of the time had a 60% reduction in cumulative organ damage, compared with patients who never achieved LLDAS, Dr. Petri said. The analysis also showed that LLDAS was substantially easier for patients to achieve than the Definitions of Remission in SLE (Ann Rheum Dis. 2017 March;76[3]:554-61). The Johns Hopkins cohort met the LLDAS definition about three times more often than they met the Definitions of Remission in SLE criteria, Dr. Petri said.
The new analysis also showed that LLDAS was especially effective in correlating with statistically significant reductions in future strokes, MI, and end-stage renal disease, though it did not significantly correlate with subsequent reductions in the incidence of cognitive impairment, deep vein thrombosis, malignancy, pulmonary fibrosis, pulmonary hypertension, or cataract development. But the strong correlation of time in LLDAS and the future rate of stroke, MI, or end-stage renal disease was very meaningful because those are the most important types of damage associated with SLE, Dr. Petri said. “LLDAS is a good treatment target as a surrogate” for future risk of SLE complications.
The study had no commercial funding, and Dr. Petri had no disclosures to report. Dr. Bruce has been a consultant to and speaker for GlaxoSmithKline, MedImmune, Pfizer, Roche, and UCB, and he has received research support from Genzyme, GlaxoSmithKline, Human Genome Sciences, Roche, and UCB.
SOURCE: Petri MA et al. Ann Rheum Dis. 2018;77(Suppl 2):111. Abstract OP0122.
REPORTING FROM THE EULAR 2018 CONGRESS
Key clinical point: The Lupus Low Disease Activity State is a good treatment target for systemic lupus erythematosus patients.
Major finding: Patients who achieved LLDAS at least half the time had 52% less organ damage than patients who never achieved LLDAS.
Study details: A review of case records from 2,026 SLE patients followed regularly at one U.S. center.
Disclosures: The study had no commercial funding, and Dr. Petri had no disclosures to report. Dr. Bruce has been a consultant to and speaker for GlaxoSmithKline, MedImmune, Pfizer, Roche, and UCB, and he has received research support from Genzyme, GlaxoSmithKline, Human Genome Sciences, Roche, and UCB.
Source: Petri MA et al. Ann Rheum Dis. 2018;77(Suppl 2):111. Abstract OP0122.
Baricitinib shows potential as lupus treatment
AMSTERDAM – A significantly higher proportion of patients with lupus experienced improvements in joint and skin symptoms if they were treated with baricitinib (Olumiant) than if they received placebo in a phase 2 trial.
The primary endpoint of arthritis or rash resolution as measured by the Systemic Lupus Erythematosus (SLE) Disease Activity Index 2000 (SLEDAI-2K) was met by approximately 67% of patients who were treated with 4 mg baricitinib once daily and by around 53% of patients given a matching placebo (P less than .05).
With no new safety concerns, these findings suggest that baricitinib could be of benefit in patients with SLE and further study is warranted in a phase 3 trial, said the presenting study investigator Daniel J. Wallace, MD, at the European Congress of Rheumatology. Dr. Wallace is the associate director of the Rheumatology Fellowship Program at Cedars-Sinai Medical Center, Los Angeles.
Baricitinib is already approved for use as a treatment for RA in more than 40 countries. On June 1, Eli Lilly announced that the Food and Drug Administration had given the green light for its use in RA in the United States, but only at a dose of 2 mg once daily, whereas a 2-mg and 4-mg once-daily dose is approved in most other countries.
Data from the phase 2 trial presented by Dr. Wallace did include a 2-mg dose arm, but the difference in treatment response rates versus placebo was not statistically significant.
“I think the placebo response is mainly inflated by the use of corticosteroids,” said Dr. Dörner, professor of medicine at Charité–Universitätsmedizin Berlin. “If one would have applied a steroid tapering regimen, I would have expected a larger effect size, and possibly also the 2-mg [dose] be more effective as compared to placebo.” This is something to consider when moving into a phase 3 trial, he suggested.
For inclusion in the phase 2 trial, patients had to meet the following criteria: Be positive for antinuclear antibodies and/or a positive anti-dsDNA test, have a SLEDAI-2K clinical score of 4 or more, and have active SLEDAI arthritis and/or rash. Patients with severe active lupus nephritis or CNS involvement were excluded.
The mean age of patients was around 44 years, and as might be expected, the study population was predominantly female (99%). Around two-thirds of patients were white, 19% were of Asian descent, and the rest were designated as “other”. The average time to SLE onset was 9.7 years in the placebo group and just over 11 years in the baricitinib arms, with similar SLEDAI-2K scores of about 8-9, about 7-8 tender joints, and about five swollen joints at baseline.
A number of other secondary endpoints were also met by the 4 mg baricitinib group, Dr. Wallace reported. This included the relatively new Lupus Low Disease Activity State, he said, which was met by 38% (n = 27) of patients treated with 4 mg baricitinib, 33% (n = 35) treated with 2 mg baricitinib, and 26% (n = 27) of those given placebo (P less than .05 for the 4-mg dose vs. placebo). There were also numerically fewer SLE flares, including fewer severe flares.
“Some of the other outcomes demonstrated statistical significance: Physician Global Assessment, tender joint count, worst joint pain, and worst pain on a numeric rating scale,” Dr. Wallace said. A trend towards improvement was seen in the swollen joint count, with modest improvement in fatigue.
Treatment-emergent adverse events were seen in around 71%-73% of patients given baricitinib and 65% of patients given placebo. Most were mild or moderate in nature, but serious adverse events did occur in approximately 10% of patients who received baricitinib and in 4% of those who received placebo.
What’s noteworthy, Dr. Dörner said during a press briefing, is the very low rate of venous thromboembolism seen in the trial. “We’d have expected to see more deep vein thrombosis,” he said. Only one case occurred, in a patent taking the 4-mg dose, but this patient had preexisting antiphospholipid antibodies.
Additionally, although the percentage of patients with serious infections was slightly higher in the 2 and 4 mg baricitinib arms than for placebo (1.9% and 5.8% vs. 1%, respectively) “this is what we expect for lupus patients,” Dr. Dörner said. Furthermore, herpes zoster infection, which is very often reactivated in lupus because of the disease or its treatment, was only reported in one patient in the placebo group and in one patient in the 4 mg group.
“I think there is a very promising outlook, at least for the 4-mg dose of baricitinib,” Dr. Dörner said. “There have been no new safety or tolerability issues when compared to the RA population, and we’re looking forward to seeing subsequent studies in this [SLE] patient population where we have a need for more efficacious therapies.”
The study was funded by Eli Lilly. Dr. Dörner was part of the trial’s steering committee and has acted as a consultant for Eli Lilly. He has also received grant or research support from Roche/Chugai, Janssen, and Sanofi-Aventis; consulted for AbbVie, Celgene, Roche, UCB, Merck Sharp & Dohme, Pfizer/Hospira, and Novartis; and he is part of the speakers bureaus for Amgen, Celgene, and Biogen. Dr. Wallace has acted as a consultant for Eli Lilly, as well as EMD Serono, Pfizer, and GlaxoSmithKline.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SOURCE: Wallace DJ et al. Ann Rheum Dis. 2018;77(Suppl 2):59. Abstract OP0019.
AMSTERDAM – A significantly higher proportion of patients with lupus experienced improvements in joint and skin symptoms if they were treated with baricitinib (Olumiant) than if they received placebo in a phase 2 trial.
The primary endpoint of arthritis or rash resolution as measured by the Systemic Lupus Erythematosus (SLE) Disease Activity Index 2000 (SLEDAI-2K) was met by approximately 67% of patients who were treated with 4 mg baricitinib once daily and by around 53% of patients given a matching placebo (P less than .05).
With no new safety concerns, these findings suggest that baricitinib could be of benefit in patients with SLE and further study is warranted in a phase 3 trial, said the presenting study investigator Daniel J. Wallace, MD, at the European Congress of Rheumatology. Dr. Wallace is the associate director of the Rheumatology Fellowship Program at Cedars-Sinai Medical Center, Los Angeles.
Baricitinib is already approved for use as a treatment for RA in more than 40 countries. On June 1, Eli Lilly announced that the Food and Drug Administration had given the green light for its use in RA in the United States, but only at a dose of 2 mg once daily, whereas a 2-mg and 4-mg once-daily dose is approved in most other countries.
Data from the phase 2 trial presented by Dr. Wallace did include a 2-mg dose arm, but the difference in treatment response rates versus placebo was not statistically significant.
“I think the placebo response is mainly inflated by the use of corticosteroids,” said Dr. Dörner, professor of medicine at Charité–Universitätsmedizin Berlin. “If one would have applied a steroid tapering regimen, I would have expected a larger effect size, and possibly also the 2-mg [dose] be more effective as compared to placebo.” This is something to consider when moving into a phase 3 trial, he suggested.
For inclusion in the phase 2 trial, patients had to meet the following criteria: Be positive for antinuclear antibodies and/or a positive anti-dsDNA test, have a SLEDAI-2K clinical score of 4 or more, and have active SLEDAI arthritis and/or rash. Patients with severe active lupus nephritis or CNS involvement were excluded.
The mean age of patients was around 44 years, and as might be expected, the study population was predominantly female (99%). Around two-thirds of patients were white, 19% were of Asian descent, and the rest were designated as “other”. The average time to SLE onset was 9.7 years in the placebo group and just over 11 years in the baricitinib arms, with similar SLEDAI-2K scores of about 8-9, about 7-8 tender joints, and about five swollen joints at baseline.
A number of other secondary endpoints were also met by the 4 mg baricitinib group, Dr. Wallace reported. This included the relatively new Lupus Low Disease Activity State, he said, which was met by 38% (n = 27) of patients treated with 4 mg baricitinib, 33% (n = 35) treated with 2 mg baricitinib, and 26% (n = 27) of those given placebo (P less than .05 for the 4-mg dose vs. placebo). There were also numerically fewer SLE flares, including fewer severe flares.
“Some of the other outcomes demonstrated statistical significance: Physician Global Assessment, tender joint count, worst joint pain, and worst pain on a numeric rating scale,” Dr. Wallace said. A trend towards improvement was seen in the swollen joint count, with modest improvement in fatigue.
Treatment-emergent adverse events were seen in around 71%-73% of patients given baricitinib and 65% of patients given placebo. Most were mild or moderate in nature, but serious adverse events did occur in approximately 10% of patients who received baricitinib and in 4% of those who received placebo.
What’s noteworthy, Dr. Dörner said during a press briefing, is the very low rate of venous thromboembolism seen in the trial. “We’d have expected to see more deep vein thrombosis,” he said. Only one case occurred, in a patent taking the 4-mg dose, but this patient had preexisting antiphospholipid antibodies.
Additionally, although the percentage of patients with serious infections was slightly higher in the 2 and 4 mg baricitinib arms than for placebo (1.9% and 5.8% vs. 1%, respectively) “this is what we expect for lupus patients,” Dr. Dörner said. Furthermore, herpes zoster infection, which is very often reactivated in lupus because of the disease or its treatment, was only reported in one patient in the placebo group and in one patient in the 4 mg group.
“I think there is a very promising outlook, at least for the 4-mg dose of baricitinib,” Dr. Dörner said. “There have been no new safety or tolerability issues when compared to the RA population, and we’re looking forward to seeing subsequent studies in this [SLE] patient population where we have a need for more efficacious therapies.”
The study was funded by Eli Lilly. Dr. Dörner was part of the trial’s steering committee and has acted as a consultant for Eli Lilly. He has also received grant or research support from Roche/Chugai, Janssen, and Sanofi-Aventis; consulted for AbbVie, Celgene, Roche, UCB, Merck Sharp & Dohme, Pfizer/Hospira, and Novartis; and he is part of the speakers bureaus for Amgen, Celgene, and Biogen. Dr. Wallace has acted as a consultant for Eli Lilly, as well as EMD Serono, Pfizer, and GlaxoSmithKline.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SOURCE: Wallace DJ et al. Ann Rheum Dis. 2018;77(Suppl 2):59. Abstract OP0019.
AMSTERDAM – A significantly higher proportion of patients with lupus experienced improvements in joint and skin symptoms if they were treated with baricitinib (Olumiant) than if they received placebo in a phase 2 trial.
The primary endpoint of arthritis or rash resolution as measured by the Systemic Lupus Erythematosus (SLE) Disease Activity Index 2000 (SLEDAI-2K) was met by approximately 67% of patients who were treated with 4 mg baricitinib once daily and by around 53% of patients given a matching placebo (P less than .05).
With no new safety concerns, these findings suggest that baricitinib could be of benefit in patients with SLE and further study is warranted in a phase 3 trial, said the presenting study investigator Daniel J. Wallace, MD, at the European Congress of Rheumatology. Dr. Wallace is the associate director of the Rheumatology Fellowship Program at Cedars-Sinai Medical Center, Los Angeles.
Baricitinib is already approved for use as a treatment for RA in more than 40 countries. On June 1, Eli Lilly announced that the Food and Drug Administration had given the green light for its use in RA in the United States, but only at a dose of 2 mg once daily, whereas a 2-mg and 4-mg once-daily dose is approved in most other countries.
Data from the phase 2 trial presented by Dr. Wallace did include a 2-mg dose arm, but the difference in treatment response rates versus placebo was not statistically significant.
“I think the placebo response is mainly inflated by the use of corticosteroids,” said Dr. Dörner, professor of medicine at Charité–Universitätsmedizin Berlin. “If one would have applied a steroid tapering regimen, I would have expected a larger effect size, and possibly also the 2-mg [dose] be more effective as compared to placebo.” This is something to consider when moving into a phase 3 trial, he suggested.
For inclusion in the phase 2 trial, patients had to meet the following criteria: Be positive for antinuclear antibodies and/or a positive anti-dsDNA test, have a SLEDAI-2K clinical score of 4 or more, and have active SLEDAI arthritis and/or rash. Patients with severe active lupus nephritis or CNS involvement were excluded.
The mean age of patients was around 44 years, and as might be expected, the study population was predominantly female (99%). Around two-thirds of patients were white, 19% were of Asian descent, and the rest were designated as “other”. The average time to SLE onset was 9.7 years in the placebo group and just over 11 years in the baricitinib arms, with similar SLEDAI-2K scores of about 8-9, about 7-8 tender joints, and about five swollen joints at baseline.
A number of other secondary endpoints were also met by the 4 mg baricitinib group, Dr. Wallace reported. This included the relatively new Lupus Low Disease Activity State, he said, which was met by 38% (n = 27) of patients treated with 4 mg baricitinib, 33% (n = 35) treated with 2 mg baricitinib, and 26% (n = 27) of those given placebo (P less than .05 for the 4-mg dose vs. placebo). There were also numerically fewer SLE flares, including fewer severe flares.
“Some of the other outcomes demonstrated statistical significance: Physician Global Assessment, tender joint count, worst joint pain, and worst pain on a numeric rating scale,” Dr. Wallace said. A trend towards improvement was seen in the swollen joint count, with modest improvement in fatigue.
Treatment-emergent adverse events were seen in around 71%-73% of patients given baricitinib and 65% of patients given placebo. Most were mild or moderate in nature, but serious adverse events did occur in approximately 10% of patients who received baricitinib and in 4% of those who received placebo.
What’s noteworthy, Dr. Dörner said during a press briefing, is the very low rate of venous thromboembolism seen in the trial. “We’d have expected to see more deep vein thrombosis,” he said. Only one case occurred, in a patent taking the 4-mg dose, but this patient had preexisting antiphospholipid antibodies.
Additionally, although the percentage of patients with serious infections was slightly higher in the 2 and 4 mg baricitinib arms than for placebo (1.9% and 5.8% vs. 1%, respectively) “this is what we expect for lupus patients,” Dr. Dörner said. Furthermore, herpes zoster infection, which is very often reactivated in lupus because of the disease or its treatment, was only reported in one patient in the placebo group and in one patient in the 4 mg group.
“I think there is a very promising outlook, at least for the 4-mg dose of baricitinib,” Dr. Dörner said. “There have been no new safety or tolerability issues when compared to the RA population, and we’re looking forward to seeing subsequent studies in this [SLE] patient population where we have a need for more efficacious therapies.”
The study was funded by Eli Lilly. Dr. Dörner was part of the trial’s steering committee and has acted as a consultant for Eli Lilly. He has also received grant or research support from Roche/Chugai, Janssen, and Sanofi-Aventis; consulted for AbbVie, Celgene, Roche, UCB, Merck Sharp & Dohme, Pfizer/Hospira, and Novartis; and he is part of the speakers bureaus for Amgen, Celgene, and Biogen. Dr. Wallace has acted as a consultant for Eli Lilly, as well as EMD Serono, Pfizer, and GlaxoSmithKline.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SOURCE: Wallace DJ et al. Ann Rheum Dis. 2018;77(Suppl 2):59. Abstract OP0019.
REPORTING FROM THE EULAR 2018 CONGRESS
Key clinical point: Baricitinib at 4 mg was associated with significant clinical improvements versus placebo and had an acceptable safety and tolerability profile.
Major finding: A higher percentage of patients receiving 4 mg of baricitinib than those receiving placebo achieved the primary endpoint of arthritis and/or rash remission as defined by the Systemic Lupus Erythematosus Disease Activity Index 2000 at week 24 (P less than .05).
Study details: A phase 2, multinational, double-blind, placebo-controlled, parallel group study of once-daily, oral baricitinib (2 mg and 4 mg) in 314 patients with SLE receiving standard therapy.
Disclosures: The study was funded by Eli Lilly. Dr. Dörner was part of the trial’s steering committee and has acted as a consultant for Eli Lilly. He has also received grant or research support from Roche/Chugai, Janssen, and Sanofi-Aventis; consulted for AbbVie, Celgene, Roche, UCB, Merck Sharp & Dohme, Pfizer/Hospira, and Novartis; and he is part of the speakers bureaus for Amgen, Celgene, and Biogen. Dr. Wallace has acted as a consultant for Eli Lilly, as well as EMD Serono, Pfizer, and GlaxoSmithKline.
Source: Wallace DJ et al. Ann Rheum Dis. 2018;77(Suppl 2):59. Abstract OP0019.
FDA approves rituximab for treating pemphigus vulgaris
Rituximab (Rituxan) has been approved for the treatment of adults with moderate to severe pemphigus vulgaris, the manufacturer announced on June 7.
Rituximab is the first biologic approved for treating pemphigus vulgaris, Genentech, a member of the Roche group, stated in a press release announcing the approval.
The prospective, multicenter, open-label, randomized trial, conducted in France, compared the rituximab product approved in the European Union, plus short-term corticosteroid therapy (1,000 mg rituximab administered intravenously at baseline and day 14, then 500 mg at 12 and 18 months, plus 0.5 mg/kg or 1.0 mg/kg per day of prednisone tapered over 3 or 6 months) to corticosteroid therapy alone (oral prednisone 1.0 or 1.5 mg/kg per day tapered over 12 or 18 months), in 90 patients newly diagnosed with moderate to severe pemphigus.
At 24 months, 89% of those in the rituximab group met the primary endpoint, complete remission off therapy at 24 months, compared with 34% of those on corticosteroids (P less than .0001), the investigators reported (Lancet. 2017 May 20;389[10083]:2031-40). Severe adverse events were more commonly reported in the prednisone-only group.
First approved in 1997, rituximab, an anti-CD20 monoclonal antibody, is approved for non-Hodgkin lymphoma, rheumatoid arthritis, chronic lymphocytic leukemia, and granulomatosis with polyangiitis. The prescribing information includes a boxed warning about the risks of fatal infusion reactions, severe mucocutaneous reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy.
The study published in the Lancet was funded by Roche, the French Ministry of Health, and the French Society of Dermatology.
Rituximab (Rituxan) has been approved for the treatment of adults with moderate to severe pemphigus vulgaris, the manufacturer announced on June 7.
Rituximab is the first biologic approved for treating pemphigus vulgaris, Genentech, a member of the Roche group, stated in a press release announcing the approval.
The prospective, multicenter, open-label, randomized trial, conducted in France, compared the rituximab product approved in the European Union, plus short-term corticosteroid therapy (1,000 mg rituximab administered intravenously at baseline and day 14, then 500 mg at 12 and 18 months, plus 0.5 mg/kg or 1.0 mg/kg per day of prednisone tapered over 3 or 6 months) to corticosteroid therapy alone (oral prednisone 1.0 or 1.5 mg/kg per day tapered over 12 or 18 months), in 90 patients newly diagnosed with moderate to severe pemphigus.
At 24 months, 89% of those in the rituximab group met the primary endpoint, complete remission off therapy at 24 months, compared with 34% of those on corticosteroids (P less than .0001), the investigators reported (Lancet. 2017 May 20;389[10083]:2031-40). Severe adverse events were more commonly reported in the prednisone-only group.
First approved in 1997, rituximab, an anti-CD20 monoclonal antibody, is approved for non-Hodgkin lymphoma, rheumatoid arthritis, chronic lymphocytic leukemia, and granulomatosis with polyangiitis. The prescribing information includes a boxed warning about the risks of fatal infusion reactions, severe mucocutaneous reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy.
The study published in the Lancet was funded by Roche, the French Ministry of Health, and the French Society of Dermatology.
Rituximab (Rituxan) has been approved for the treatment of adults with moderate to severe pemphigus vulgaris, the manufacturer announced on June 7.
Rituximab is the first biologic approved for treating pemphigus vulgaris, Genentech, a member of the Roche group, stated in a press release announcing the approval.
The prospective, multicenter, open-label, randomized trial, conducted in France, compared the rituximab product approved in the European Union, plus short-term corticosteroid therapy (1,000 mg rituximab administered intravenously at baseline and day 14, then 500 mg at 12 and 18 months, plus 0.5 mg/kg or 1.0 mg/kg per day of prednisone tapered over 3 or 6 months) to corticosteroid therapy alone (oral prednisone 1.0 or 1.5 mg/kg per day tapered over 12 or 18 months), in 90 patients newly diagnosed with moderate to severe pemphigus.
At 24 months, 89% of those in the rituximab group met the primary endpoint, complete remission off therapy at 24 months, compared with 34% of those on corticosteroids (P less than .0001), the investigators reported (Lancet. 2017 May 20;389[10083]:2031-40). Severe adverse events were more commonly reported in the prednisone-only group.
First approved in 1997, rituximab, an anti-CD20 monoclonal antibody, is approved for non-Hodgkin lymphoma, rheumatoid arthritis, chronic lymphocytic leukemia, and granulomatosis with polyangiitis. The prescribing information includes a boxed warning about the risks of fatal infusion reactions, severe mucocutaneous reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy.
The study published in the Lancet was funded by Roche, the French Ministry of Health, and the French Society of Dermatology.
Long-term follow-up most important for hydroxychloroquine retinal screening
LIVERPOOL, ENGLAND – , but long-term follow-up is much more important, according to data presented at the British Society for Rheumatology annual conference.
In just one specialist rheumatology center in England, which treats more than 8,000 patients annually, the cost of the first year’s optical coherence tomography (OCT) assessment would be more than $60,000. Additional costs would be incurred to screen those who had been on the drug for more than 5 years ,who were known to be at greater risk of hydroxychloroquine-induced retinopathy. This is within the National Health Service in England where the cost of a single OCT scan is around $70; in the private health sector, the cost of one test can be as high as $400.
Indeed, of 887 hydroxychloroquine users identified, 44% had at least one risk factor for hydroxychloroquine-induced retinopathy. These included being older than 60 years of age (30% of all users), having renal (10%) or hepatic (2%) impairment, retinal disease at baseline (8%), or using high (more than 6.5 mg/kg) doses of the drug based on their actual (9%) or ideal (4%) body weight.
“The retinal toxicity of hydroxychloroquine is a bit of a hot topic at the moment,” Dr. Yates said at the conference. While the drug has been around for years and used successfully to treat many patients with rheumatoid arthritis and systemic lupus erythematosus (SLE), a known side effect is retinal toxicity.
Traditionally, retinopathy has been quoted as being a relatively rare side effect, affecting around 0.5%-2% of the treated population. Recent data (JAMA Ophthalmol. 2014;132[12]:1453-60) suggest, however, that is probably a vast underestimate, with 7.5% of patients taking hydroxychloroquine for more than 5 years likely to be affected, as are up to 20% of those taking the drug for up to 20 years of treatment.
Dr. Yates and associates wanted to assess the burden of hydroxychloroquine use at their center and look at the risk factors and impact of the recent screening guidelines issued by the British Society for Rheumatology (Rheumatology [Oxford]. 2017;56[6]:865-8) in 2017 and by the Royal College of Ophthalmologists in 2018. These state that patients should have a formal baseline ophthalmic examination, ideally including OCT, within 6-12 months of starting therapy and an annual eye assessment with repeat OCT thereafter for the following 5 years; the ophthalmology guidelines recommending annual screening for the duration of therapy.
One criticism of increased screening for retinal toxicity in routine practice is consultants saying that they see only a handful of cases during their career, Dr. Yates observed. However, if you consider that in an average rheumatology department there are five consultants and 900 patients on hydroxychloroquine, 500 patients take the drug for 5 years or longer, 2% are picked up with non-OCT screening, that amounts to around two cases per year over a 5- to 10-year period. “So that fits with the narrative of only having seen a handful of cases pre-OCT,” Dr. Yates reasoned.
“I believe that this is a real problem, but I’m afraid this is the tip of the iceberg,” commented Caroline Gordon, MD, after her presentation. “We’ve been screening our patients in Birmingham now for about 5 years and we are definitely finding a significant number of patients with hydroxychloroquine toxicity who can be picked up with OCT and visual fields screening.”
Dr. Gordon, professor of rheumatology at the University of Birmingham (England) and a consultant rheumatologist for the University Hospitals NHS Foundation Trust and the Sandwell & West Birmingham Hospitals NHS Trust, helps look after one of the largest cohorts of patients with SLE in the United Kingdom.
A baseline eye examination has always been recommended, Dr. Gordon said, but she suggested that this could remain in the realm of the opticians with further assessment and referral as needed.
“I’m not convinced, from the work we’ve done, that there is any value in the baseline OCT,” Dr. Gordon said, “because we never find anything on the baseline OCT that we didn’t already expect from the opticians’ assessment.”
It is the long-term (longer than10 years) follow-up that needs to be the focus, rather than the initial period, she stressed, as the highest risk appears to be in patients who have been taking the drug for 15 years or longer. Prior to this, different types of retinopathy can occur that are actually attributable to the underlying disease and are not related hydroxychloroquine. Of course, patients on higher doses of hydroxychloroquine may need closer monitoring early on, “as they are at risk,” she acknowledged.
Dr. Gordon suggested that the guidelines as they currently stand may not be that useful for real-life practice. Following them could result in a large amount of money being spent on early tests that are perhaps not necessary.
“What we do need to do is focus on the patients who’ve been on treatment long term,” she said.
SOURCE: Yates M et al. Rheumatology. 2018;57(Suppl. 3):key075.188.
LIVERPOOL, ENGLAND – , but long-term follow-up is much more important, according to data presented at the British Society for Rheumatology annual conference.
In just one specialist rheumatology center in England, which treats more than 8,000 patients annually, the cost of the first year’s optical coherence tomography (OCT) assessment would be more than $60,000. Additional costs would be incurred to screen those who had been on the drug for more than 5 years ,who were known to be at greater risk of hydroxychloroquine-induced retinopathy. This is within the National Health Service in England where the cost of a single OCT scan is around $70; in the private health sector, the cost of one test can be as high as $400.
Indeed, of 887 hydroxychloroquine users identified, 44% had at least one risk factor for hydroxychloroquine-induced retinopathy. These included being older than 60 years of age (30% of all users), having renal (10%) or hepatic (2%) impairment, retinal disease at baseline (8%), or using high (more than 6.5 mg/kg) doses of the drug based on their actual (9%) or ideal (4%) body weight.
“The retinal toxicity of hydroxychloroquine is a bit of a hot topic at the moment,” Dr. Yates said at the conference. While the drug has been around for years and used successfully to treat many patients with rheumatoid arthritis and systemic lupus erythematosus (SLE), a known side effect is retinal toxicity.
Traditionally, retinopathy has been quoted as being a relatively rare side effect, affecting around 0.5%-2% of the treated population. Recent data (JAMA Ophthalmol. 2014;132[12]:1453-60) suggest, however, that is probably a vast underestimate, with 7.5% of patients taking hydroxychloroquine for more than 5 years likely to be affected, as are up to 20% of those taking the drug for up to 20 years of treatment.
Dr. Yates and associates wanted to assess the burden of hydroxychloroquine use at their center and look at the risk factors and impact of the recent screening guidelines issued by the British Society for Rheumatology (Rheumatology [Oxford]. 2017;56[6]:865-8) in 2017 and by the Royal College of Ophthalmologists in 2018. These state that patients should have a formal baseline ophthalmic examination, ideally including OCT, within 6-12 months of starting therapy and an annual eye assessment with repeat OCT thereafter for the following 5 years; the ophthalmology guidelines recommending annual screening for the duration of therapy.
One criticism of increased screening for retinal toxicity in routine practice is consultants saying that they see only a handful of cases during their career, Dr. Yates observed. However, if you consider that in an average rheumatology department there are five consultants and 900 patients on hydroxychloroquine, 500 patients take the drug for 5 years or longer, 2% are picked up with non-OCT screening, that amounts to around two cases per year over a 5- to 10-year period. “So that fits with the narrative of only having seen a handful of cases pre-OCT,” Dr. Yates reasoned.
“I believe that this is a real problem, but I’m afraid this is the tip of the iceberg,” commented Caroline Gordon, MD, after her presentation. “We’ve been screening our patients in Birmingham now for about 5 years and we are definitely finding a significant number of patients with hydroxychloroquine toxicity who can be picked up with OCT and visual fields screening.”
Dr. Gordon, professor of rheumatology at the University of Birmingham (England) and a consultant rheumatologist for the University Hospitals NHS Foundation Trust and the Sandwell & West Birmingham Hospitals NHS Trust, helps look after one of the largest cohorts of patients with SLE in the United Kingdom.
A baseline eye examination has always been recommended, Dr. Gordon said, but she suggested that this could remain in the realm of the opticians with further assessment and referral as needed.
“I’m not convinced, from the work we’ve done, that there is any value in the baseline OCT,” Dr. Gordon said, “because we never find anything on the baseline OCT that we didn’t already expect from the opticians’ assessment.”
It is the long-term (longer than10 years) follow-up that needs to be the focus, rather than the initial period, she stressed, as the highest risk appears to be in patients who have been taking the drug for 15 years or longer. Prior to this, different types of retinopathy can occur that are actually attributable to the underlying disease and are not related hydroxychloroquine. Of course, patients on higher doses of hydroxychloroquine may need closer monitoring early on, “as they are at risk,” she acknowledged.
Dr. Gordon suggested that the guidelines as they currently stand may not be that useful for real-life practice. Following them could result in a large amount of money being spent on early tests that are perhaps not necessary.
“What we do need to do is focus on the patients who’ve been on treatment long term,” she said.
SOURCE: Yates M et al. Rheumatology. 2018;57(Suppl. 3):key075.188.
LIVERPOOL, ENGLAND – , but long-term follow-up is much more important, according to data presented at the British Society for Rheumatology annual conference.
In just one specialist rheumatology center in England, which treats more than 8,000 patients annually, the cost of the first year’s optical coherence tomography (OCT) assessment would be more than $60,000. Additional costs would be incurred to screen those who had been on the drug for more than 5 years ,who were known to be at greater risk of hydroxychloroquine-induced retinopathy. This is within the National Health Service in England where the cost of a single OCT scan is around $70; in the private health sector, the cost of one test can be as high as $400.
Indeed, of 887 hydroxychloroquine users identified, 44% had at least one risk factor for hydroxychloroquine-induced retinopathy. These included being older than 60 years of age (30% of all users), having renal (10%) or hepatic (2%) impairment, retinal disease at baseline (8%), or using high (more than 6.5 mg/kg) doses of the drug based on their actual (9%) or ideal (4%) body weight.
“The retinal toxicity of hydroxychloroquine is a bit of a hot topic at the moment,” Dr. Yates said at the conference. While the drug has been around for years and used successfully to treat many patients with rheumatoid arthritis and systemic lupus erythematosus (SLE), a known side effect is retinal toxicity.
Traditionally, retinopathy has been quoted as being a relatively rare side effect, affecting around 0.5%-2% of the treated population. Recent data (JAMA Ophthalmol. 2014;132[12]:1453-60) suggest, however, that is probably a vast underestimate, with 7.5% of patients taking hydroxychloroquine for more than 5 years likely to be affected, as are up to 20% of those taking the drug for up to 20 years of treatment.
Dr. Yates and associates wanted to assess the burden of hydroxychloroquine use at their center and look at the risk factors and impact of the recent screening guidelines issued by the British Society for Rheumatology (Rheumatology [Oxford]. 2017;56[6]:865-8) in 2017 and by the Royal College of Ophthalmologists in 2018. These state that patients should have a formal baseline ophthalmic examination, ideally including OCT, within 6-12 months of starting therapy and an annual eye assessment with repeat OCT thereafter for the following 5 years; the ophthalmology guidelines recommending annual screening for the duration of therapy.
One criticism of increased screening for retinal toxicity in routine practice is consultants saying that they see only a handful of cases during their career, Dr. Yates observed. However, if you consider that in an average rheumatology department there are five consultants and 900 patients on hydroxychloroquine, 500 patients take the drug for 5 years or longer, 2% are picked up with non-OCT screening, that amounts to around two cases per year over a 5- to 10-year period. “So that fits with the narrative of only having seen a handful of cases pre-OCT,” Dr. Yates reasoned.
“I believe that this is a real problem, but I’m afraid this is the tip of the iceberg,” commented Caroline Gordon, MD, after her presentation. “We’ve been screening our patients in Birmingham now for about 5 years and we are definitely finding a significant number of patients with hydroxychloroquine toxicity who can be picked up with OCT and visual fields screening.”
Dr. Gordon, professor of rheumatology at the University of Birmingham (England) and a consultant rheumatologist for the University Hospitals NHS Foundation Trust and the Sandwell & West Birmingham Hospitals NHS Trust, helps look after one of the largest cohorts of patients with SLE in the United Kingdom.
A baseline eye examination has always been recommended, Dr. Gordon said, but she suggested that this could remain in the realm of the opticians with further assessment and referral as needed.
“I’m not convinced, from the work we’ve done, that there is any value in the baseline OCT,” Dr. Gordon said, “because we never find anything on the baseline OCT that we didn’t already expect from the opticians’ assessment.”
It is the long-term (longer than10 years) follow-up that needs to be the focus, rather than the initial period, she stressed, as the highest risk appears to be in patients who have been taking the drug for 15 years or longer. Prior to this, different types of retinopathy can occur that are actually attributable to the underlying disease and are not related hydroxychloroquine. Of course, patients on higher doses of hydroxychloroquine may need closer monitoring early on, “as they are at risk,” she acknowledged.
Dr. Gordon suggested that the guidelines as they currently stand may not be that useful for real-life practice. Following them could result in a large amount of money being spent on early tests that are perhaps not necessary.
“What we do need to do is focus on the patients who’ve been on treatment long term,” she said.
SOURCE: Yates M et al. Rheumatology. 2018;57(Suppl. 3):key075.188.
REPORTING FROM BSR 2018
Key clinical point: Long-term follow up is important for assessing hydroxychloroquine toxicity.
Major finding: 44% of patients had at least one risk factor for hydroxychloroquine-induced retinopathy after more than 5 years of treatment.
Study details: Electronic record review of 887 patients treated with hydroxychloroquine for about 5 years in a large tertiary rheumatology service.
Disclosures: Dr. Yates had nothing to disclose.
Source: Yates M et al. Rheumatology. 2018;57(Suppl. 3):key075.312.
Hydroxychloroquine throws off Quantiferon-TB Gold results, study finds
ORLANDO – according to investigators from the University of Pennsylvania, Philadelphia.
Among 46 patients with lupus, dermatomyositis, or blistering diseases who had been on hydroxychloroquine within a year of testing, QuantiFERON-TB Gold (QFT-G) – the go-to TB test in many places – yielded indeterminate results in 37%. Meanwhile, just 9.6% of tests were indeterminate among 73 patients with those diseases who had not been on hydroxychloroquine (P less than .001). The findings could not be explained by concomitant use of prednisone and other immunosuppressives; there were no statistically significant differences between the groups. “This was shocking to us. We need to come up with a better screening test in this patient population,” said lead investigator Rebecca Gaffney, a research fellow at the University of Pennsylvania, and a medical student at Robert Wood Johnson Medical School, New Brunswick, NJ.*
It’s widely known that immunosuppressives interfere with QFT-G results, but antimalarials are considered immunomodulators, not immunosuppressives. The new study is probably the first to investigate the issue. The team is now pitting QFT-G against another TB blood test, the T-SPOT, in 100 patients to see if it’s a better option, in a trial that they expect to complete in 2018.
The investigators have a hunch that the T-SPOT might be better because, while QFT-G measures interferon-gamma concentrations in response to TB antigens, the T-SPOT “counts cells first to make sure you have a standard amount of cells, then looks at how many cells are releasing interferon-gamma,” Ms. Gaffney said, adding that “it seems like a more sensitive test,” especially for lymphocytopenic autoimmune patients. “We are really excited to see if there’s a better test for our patients, given all the clinical trials we do. We want to see what’s best, so there’s no barrier to receiving therapy.”
Subjects were around 50 years old on average, and the majority were women. Most were white, and about 20% were black.
There was no industry funding for the work, and Ms. Gaffney reported no disclosures.
*This article was updated on June 13. 2018.
ORLANDO – according to investigators from the University of Pennsylvania, Philadelphia.
Among 46 patients with lupus, dermatomyositis, or blistering diseases who had been on hydroxychloroquine within a year of testing, QuantiFERON-TB Gold (QFT-G) – the go-to TB test in many places – yielded indeterminate results in 37%. Meanwhile, just 9.6% of tests were indeterminate among 73 patients with those diseases who had not been on hydroxychloroquine (P less than .001). The findings could not be explained by concomitant use of prednisone and other immunosuppressives; there were no statistically significant differences between the groups. “This was shocking to us. We need to come up with a better screening test in this patient population,” said lead investigator Rebecca Gaffney, a research fellow at the University of Pennsylvania, and a medical student at Robert Wood Johnson Medical School, New Brunswick, NJ.*
It’s widely known that immunosuppressives interfere with QFT-G results, but antimalarials are considered immunomodulators, not immunosuppressives. The new study is probably the first to investigate the issue. The team is now pitting QFT-G against another TB blood test, the T-SPOT, in 100 patients to see if it’s a better option, in a trial that they expect to complete in 2018.
The investigators have a hunch that the T-SPOT might be better because, while QFT-G measures interferon-gamma concentrations in response to TB antigens, the T-SPOT “counts cells first to make sure you have a standard amount of cells, then looks at how many cells are releasing interferon-gamma,” Ms. Gaffney said, adding that “it seems like a more sensitive test,” especially for lymphocytopenic autoimmune patients. “We are really excited to see if there’s a better test for our patients, given all the clinical trials we do. We want to see what’s best, so there’s no barrier to receiving therapy.”
Subjects were around 50 years old on average, and the majority were women. Most were white, and about 20% were black.
There was no industry funding for the work, and Ms. Gaffney reported no disclosures.
*This article was updated on June 13. 2018.
ORLANDO – according to investigators from the University of Pennsylvania, Philadelphia.
Among 46 patients with lupus, dermatomyositis, or blistering diseases who had been on hydroxychloroquine within a year of testing, QuantiFERON-TB Gold (QFT-G) – the go-to TB test in many places – yielded indeterminate results in 37%. Meanwhile, just 9.6% of tests were indeterminate among 73 patients with those diseases who had not been on hydroxychloroquine (P less than .001). The findings could not be explained by concomitant use of prednisone and other immunosuppressives; there were no statistically significant differences between the groups. “This was shocking to us. We need to come up with a better screening test in this patient population,” said lead investigator Rebecca Gaffney, a research fellow at the University of Pennsylvania, and a medical student at Robert Wood Johnson Medical School, New Brunswick, NJ.*
It’s widely known that immunosuppressives interfere with QFT-G results, but antimalarials are considered immunomodulators, not immunosuppressives. The new study is probably the first to investigate the issue. The team is now pitting QFT-G against another TB blood test, the T-SPOT, in 100 patients to see if it’s a better option, in a trial that they expect to complete in 2018.
The investigators have a hunch that the T-SPOT might be better because, while QFT-G measures interferon-gamma concentrations in response to TB antigens, the T-SPOT “counts cells first to make sure you have a standard amount of cells, then looks at how many cells are releasing interferon-gamma,” Ms. Gaffney said, adding that “it seems like a more sensitive test,” especially for lymphocytopenic autoimmune patients. “We are really excited to see if there’s a better test for our patients, given all the clinical trials we do. We want to see what’s best, so there’s no barrier to receiving therapy.”
Subjects were around 50 years old on average, and the majority were women. Most were white, and about 20% were black.
There was no industry funding for the work, and Ms. Gaffney reported no disclosures.
*This article was updated on June 13. 2018.
REPORTING FROM ICCLE 2018
Median time to progression from discoid to systemic lupus may be less than a year
ORLANDO – Progression from cutaneous to systemic lupus happens far more quickly than is commonly reported in the literature, according to an investigation from Brigham and Women’s Hospital, Boston.
Most studies have emphasized mean time to progression, which is generally said to be about 8 years. The problem is that the range is broad, anywhere from a few months to 30 or more years, so “the outliers influence the mean, and therefore, may not provide a fully accurate representation of the interval in which [most] patients progress” from discoid lupus erythematosus (DLE) to systemic lupus erythematosus (SLE), lead investigator Scott Elman, MD, said at the International Conference on Cutaneous Lupus Erythematosus.
He and his team thought it would be more useful to instead look at median time to progression, the point at which half of patients develop systemic disease. They found that , with the first quartile progressing by 303 days. The mean time to progression, meanwhile, was over 4 years, because of outliers who progressed at anywhere from 27 days to 30 years.
“The median progression of DLE to SLE occurs much sooner than previously reported” with mean progression times, said Dr. Elman, an internal medicine and dermatology resident at Brigham and Women’s. “We believe the use of median [time] is [more] clinically useful for both providers and patients in their understanding of what a diagnosis of DLE means for the risk of developing systemic disease.
“As clinicians seeing DLE patients, the primary question we are asking ourselves is how frequently we should be monitoring for signs and symptoms of systemic lupus,” he said. Relying on mean time instead of median time might give a false sense of security – and even delay checking for arthritis, nephritis, and other manifestations. There’s no current standard of practice about when monitoring should occur, but “I certainly think that closer monitoring of new patients with a diagnosis of DLE, especially in their first couple of years,” is a good idea, he noted, adding that for most patients, “it seems that if it’s going to happen, it’s going to happen sooner” rather than later. At Brigham and Women’s, newly diagnosed patients are generally brought back every 3-6 months for lab tests and a thorough review of symptoms, Dr. Elman said.
The next step is to identify risk factors for early progression. The study did not find any significant differences in lab values, medication exposures, or disease manifestations between early and late progressors, perhaps because of the small sample size. The work continues.
There was no external funding for the work. Dr. Elman had no disclosures.
ORLANDO – Progression from cutaneous to systemic lupus happens far more quickly than is commonly reported in the literature, according to an investigation from Brigham and Women’s Hospital, Boston.
Most studies have emphasized mean time to progression, which is generally said to be about 8 years. The problem is that the range is broad, anywhere from a few months to 30 or more years, so “the outliers influence the mean, and therefore, may not provide a fully accurate representation of the interval in which [most] patients progress” from discoid lupus erythematosus (DLE) to systemic lupus erythematosus (SLE), lead investigator Scott Elman, MD, said at the International Conference on Cutaneous Lupus Erythematosus.
He and his team thought it would be more useful to instead look at median time to progression, the point at which half of patients develop systemic disease. They found that , with the first quartile progressing by 303 days. The mean time to progression, meanwhile, was over 4 years, because of outliers who progressed at anywhere from 27 days to 30 years.
“The median progression of DLE to SLE occurs much sooner than previously reported” with mean progression times, said Dr. Elman, an internal medicine and dermatology resident at Brigham and Women’s. “We believe the use of median [time] is [more] clinically useful for both providers and patients in their understanding of what a diagnosis of DLE means for the risk of developing systemic disease.
“As clinicians seeing DLE patients, the primary question we are asking ourselves is how frequently we should be monitoring for signs and symptoms of systemic lupus,” he said. Relying on mean time instead of median time might give a false sense of security – and even delay checking for arthritis, nephritis, and other manifestations. There’s no current standard of practice about when monitoring should occur, but “I certainly think that closer monitoring of new patients with a diagnosis of DLE, especially in their first couple of years,” is a good idea, he noted, adding that for most patients, “it seems that if it’s going to happen, it’s going to happen sooner” rather than later. At Brigham and Women’s, newly diagnosed patients are generally brought back every 3-6 months for lab tests and a thorough review of symptoms, Dr. Elman said.
The next step is to identify risk factors for early progression. The study did not find any significant differences in lab values, medication exposures, or disease manifestations between early and late progressors, perhaps because of the small sample size. The work continues.
There was no external funding for the work. Dr. Elman had no disclosures.
ORLANDO – Progression from cutaneous to systemic lupus happens far more quickly than is commonly reported in the literature, according to an investigation from Brigham and Women’s Hospital, Boston.
Most studies have emphasized mean time to progression, which is generally said to be about 8 years. The problem is that the range is broad, anywhere from a few months to 30 or more years, so “the outliers influence the mean, and therefore, may not provide a fully accurate representation of the interval in which [most] patients progress” from discoid lupus erythematosus (DLE) to systemic lupus erythematosus (SLE), lead investigator Scott Elman, MD, said at the International Conference on Cutaneous Lupus Erythematosus.
He and his team thought it would be more useful to instead look at median time to progression, the point at which half of patients develop systemic disease. They found that , with the first quartile progressing by 303 days. The mean time to progression, meanwhile, was over 4 years, because of outliers who progressed at anywhere from 27 days to 30 years.
“The median progression of DLE to SLE occurs much sooner than previously reported” with mean progression times, said Dr. Elman, an internal medicine and dermatology resident at Brigham and Women’s. “We believe the use of median [time] is [more] clinically useful for both providers and patients in their understanding of what a diagnosis of DLE means for the risk of developing systemic disease.
“As clinicians seeing DLE patients, the primary question we are asking ourselves is how frequently we should be monitoring for signs and symptoms of systemic lupus,” he said. Relying on mean time instead of median time might give a false sense of security – and even delay checking for arthritis, nephritis, and other manifestations. There’s no current standard of practice about when monitoring should occur, but “I certainly think that closer monitoring of new patients with a diagnosis of DLE, especially in their first couple of years,” is a good idea, he noted, adding that for most patients, “it seems that if it’s going to happen, it’s going to happen sooner” rather than later. At Brigham and Women’s, newly diagnosed patients are generally brought back every 3-6 months for lab tests and a thorough review of symptoms, Dr. Elman said.
The next step is to identify risk factors for early progression. The study did not find any significant differences in lab values, medication exposures, or disease manifestations between early and late progressors, perhaps because of the small sample size. The work continues.
There was no external funding for the work. Dr. Elman had no disclosures.
REPORTING FROM ICCLE 2018
Key clinical point: Progression from cutaneous to systemic lupus happens far more quickly than is commonly reported in the literature.
Major finding: The median time to progression was 398 days, among a group of patients diagnosed with discoid lupus erythematosus.
Study details: A review of 32 patients who converted to systemic disease.
Disclosures: There was no external funding for the work, and the lead investigator had no disclosures.