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Lack of lupus ‘gold standard’ definition hampers estimates of its incidence, prevalence
Two new studies representing the latest efforts to determine the incidence and prevalence of systemic lupus erythematosus in the United States have revealed the difficulty of ascertaining cases when definitions of the disease vary.
The two population-based registries on which the studies were based – the California Lupus Surveillance Project and the Manhattan Lupus Surveillance Program (MLSP) – confirmed that black women represent the highest risk group for systemic lupus erythematosus (SLE) and also reaffirmed the elevated risk observed in Hispanic and Asian women, compared with white women.
The MLSP researchers applied the updated 1997 American College of Rheumatology (ACR) classification criteria, the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria, or a treating rheumatologist’s diagnosis to records from hospitals, rheumatologists, and administrative databases, and looked at both the prevalence of the disease in 2007 and the incidence from the period of 2007-2009. Using the ACR’s definition of SLE, they found an age-standardized prevalence of 62.2 and an incidence rate of 4.6 per 100,000 person-years (Arthritis Rheumatol. 2017 Sep 11. doi: 10.1002/art.40192).
The prevalence was significantly higher in women than in men (107.4 vs. 12.5 per 100,000 persons), and was highest overall in non-Hispanic black women (210.9), followed by Hispanic women (138.3), non-Hispanic Asian women (91.2), and non-Hispanic white women (64.3).
However, use of the SLICC classification criteria increased the age-standardized prevalence by 17%-19%, to a prevalence of 73.8 per 100,000 person-years and resulted in a 35% increase in incidence, to 6.2 per 100,000 person-years, compared with the ACR rates.
“The small number of cases that met the ACR but not the SLICC case definition is reassuring as it suggests that few cases met ACR criteria for SLE without the presence of autoantibodies,” wrote Peter M. Izmirly, MD, of New York (N.Y.) University, and his coauthors.
“However, given the descriptive nature of the MLSP and the absence of a gold standard test that would unambiguously identify SLE, this project cannot assess which set of classification criteria is more sensitive or specific.”
Meanwhile, the California Lupus Surveillance Project, a registry of people with lupus living in San Francisco County between 2007 and 2009, used the ACR definition to record an age-standardized annual incidence rate of 4.6 per 100,000 person-years, and an average annual prevalence of 84.8 per 100,000 persons (Arthritis Rheumatol. 2017 Sep 11. doi: 10.1002/art.40191).
As with the MLSP, the prevalence was highest in black women (458.1), followed by Hispanic women (177.9), Asian women (149.7) and white women (109.8). The incidence was 30.5 per 100,000 person-years in black women, 8.9 in Hispanic women, 7.2 in Asian women, and 5.3 in white women.
Looking at the clinical manifestations of disease, researchers found hematologic was the most common, affecting 84% of patients, while neurologic disorder affected only 8% of the population. Immunologic manifestations were present in 80%, arthritis in 57%, renal disorders in 45%, pleuritis or pericarditis in 41%, and malar rash in 33%.
There were racial variations in manifestations, with renal manifestations being more common in black, Asian/Pacific Islander, and Hispanic patients, compared with whites. Discoid rash was most common among black patients, while it was not evident at all in Hispanic patients.
Maria Dall’Era, MD, of the Russell/Engleman Research Center at the University of California, San Francisco, and her coauthors said that given the changing demographic of the diverse San Francisco County, a reliable estimate of the burden of lupus in different racial and ethnic groups was essential for health care planning.
“Up until the recent completion of the Georgia and Michigan surveillance projects, most previous epidemiologic studies were limited by small geographic areas, homogeneous populations, varying case definitions, and incomplete case ascertainment that relied on administrative codes or patient self-reported diagnosis,” they wrote.
To overcome the previous lack of data in Asian and Hispanic populations, the authors worked with physicians serving these populations and performed extensive case-finding in hospitals and health care clinics.
“Our approach of partnering with the community and engaging culturally and linguistically concordant community members led to successful case ascertainment of these traditionally understudied populations,” they wrote. “Had we not taken these extra steps, we would have missed SLE cases in the Asian and Hispanic populations.”
Both studies noted that racial and ethnic data were determined from medical records, and may not have accurately reflected the patient’s race or ethnicity.
The Manhattan study was supported by the Centers for Disease Control and Prevention and the New York City Department of Health and Mental Hygiene. The San Francisco study was supported by the Centers for Disease Control and Prevention and the Russell/Engleman Rheumatology Research Center at UCSF. No conflict of interest disclosures were available.
Together, the five national lupus registries funded by the Centers for Disease Control and Prevention provide important information about lupus in populations totaling over 6.5 million from four states and three selected Indian Health Service regions, including mixed urban and rural areas. Studies of this magnitude hold great value because case definitions and case ascertainment methodologies have been standardized, and they incorporate capture-recapture analyses to estimate the completeness of case finding.
Susan Manzi, MD, is with the department of medicine at the Allegheny Health Network, Pittsburgh, and Joan Merrill, MD, is with the department of arthritis and clinical immunology at the Oklahoma Medical Research Foundation, Oklahoma City. These comments are taken from an accompanying editorial (Arthritis Rheumatol. 2017 Sep 11. doi: 10.1002/art.40190). No conflicts of interest were available.
Together, the five national lupus registries funded by the Centers for Disease Control and Prevention provide important information about lupus in populations totaling over 6.5 million from four states and three selected Indian Health Service regions, including mixed urban and rural areas. Studies of this magnitude hold great value because case definitions and case ascertainment methodologies have been standardized, and they incorporate capture-recapture analyses to estimate the completeness of case finding.
Susan Manzi, MD, is with the department of medicine at the Allegheny Health Network, Pittsburgh, and Joan Merrill, MD, is with the department of arthritis and clinical immunology at the Oklahoma Medical Research Foundation, Oklahoma City. These comments are taken from an accompanying editorial (Arthritis Rheumatol. 2017 Sep 11. doi: 10.1002/art.40190). No conflicts of interest were available.
Together, the five national lupus registries funded by the Centers for Disease Control and Prevention provide important information about lupus in populations totaling over 6.5 million from four states and three selected Indian Health Service regions, including mixed urban and rural areas. Studies of this magnitude hold great value because case definitions and case ascertainment methodologies have been standardized, and they incorporate capture-recapture analyses to estimate the completeness of case finding.
Susan Manzi, MD, is with the department of medicine at the Allegheny Health Network, Pittsburgh, and Joan Merrill, MD, is with the department of arthritis and clinical immunology at the Oklahoma Medical Research Foundation, Oklahoma City. These comments are taken from an accompanying editorial (Arthritis Rheumatol. 2017 Sep 11. doi: 10.1002/art.40190). No conflicts of interest were available.
Two new studies representing the latest efforts to determine the incidence and prevalence of systemic lupus erythematosus in the United States have revealed the difficulty of ascertaining cases when definitions of the disease vary.
The two population-based registries on which the studies were based – the California Lupus Surveillance Project and the Manhattan Lupus Surveillance Program (MLSP) – confirmed that black women represent the highest risk group for systemic lupus erythematosus (SLE) and also reaffirmed the elevated risk observed in Hispanic and Asian women, compared with white women.
The MLSP researchers applied the updated 1997 American College of Rheumatology (ACR) classification criteria, the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria, or a treating rheumatologist’s diagnosis to records from hospitals, rheumatologists, and administrative databases, and looked at both the prevalence of the disease in 2007 and the incidence from the period of 2007-2009. Using the ACR’s definition of SLE, they found an age-standardized prevalence of 62.2 and an incidence rate of 4.6 per 100,000 person-years (Arthritis Rheumatol. 2017 Sep 11. doi: 10.1002/art.40192).
The prevalence was significantly higher in women than in men (107.4 vs. 12.5 per 100,000 persons), and was highest overall in non-Hispanic black women (210.9), followed by Hispanic women (138.3), non-Hispanic Asian women (91.2), and non-Hispanic white women (64.3).
However, use of the SLICC classification criteria increased the age-standardized prevalence by 17%-19%, to a prevalence of 73.8 per 100,000 person-years and resulted in a 35% increase in incidence, to 6.2 per 100,000 person-years, compared with the ACR rates.
“The small number of cases that met the ACR but not the SLICC case definition is reassuring as it suggests that few cases met ACR criteria for SLE without the presence of autoantibodies,” wrote Peter M. Izmirly, MD, of New York (N.Y.) University, and his coauthors.
“However, given the descriptive nature of the MLSP and the absence of a gold standard test that would unambiguously identify SLE, this project cannot assess which set of classification criteria is more sensitive or specific.”
Meanwhile, the California Lupus Surveillance Project, a registry of people with lupus living in San Francisco County between 2007 and 2009, used the ACR definition to record an age-standardized annual incidence rate of 4.6 per 100,000 person-years, and an average annual prevalence of 84.8 per 100,000 persons (Arthritis Rheumatol. 2017 Sep 11. doi: 10.1002/art.40191).
As with the MLSP, the prevalence was highest in black women (458.1), followed by Hispanic women (177.9), Asian women (149.7) and white women (109.8). The incidence was 30.5 per 100,000 person-years in black women, 8.9 in Hispanic women, 7.2 in Asian women, and 5.3 in white women.
Looking at the clinical manifestations of disease, researchers found hematologic was the most common, affecting 84% of patients, while neurologic disorder affected only 8% of the population. Immunologic manifestations were present in 80%, arthritis in 57%, renal disorders in 45%, pleuritis or pericarditis in 41%, and malar rash in 33%.
There were racial variations in manifestations, with renal manifestations being more common in black, Asian/Pacific Islander, and Hispanic patients, compared with whites. Discoid rash was most common among black patients, while it was not evident at all in Hispanic patients.
Maria Dall’Era, MD, of the Russell/Engleman Research Center at the University of California, San Francisco, and her coauthors said that given the changing demographic of the diverse San Francisco County, a reliable estimate of the burden of lupus in different racial and ethnic groups was essential for health care planning.
“Up until the recent completion of the Georgia and Michigan surveillance projects, most previous epidemiologic studies were limited by small geographic areas, homogeneous populations, varying case definitions, and incomplete case ascertainment that relied on administrative codes or patient self-reported diagnosis,” they wrote.
To overcome the previous lack of data in Asian and Hispanic populations, the authors worked with physicians serving these populations and performed extensive case-finding in hospitals and health care clinics.
“Our approach of partnering with the community and engaging culturally and linguistically concordant community members led to successful case ascertainment of these traditionally understudied populations,” they wrote. “Had we not taken these extra steps, we would have missed SLE cases in the Asian and Hispanic populations.”
Both studies noted that racial and ethnic data were determined from medical records, and may not have accurately reflected the patient’s race or ethnicity.
The Manhattan study was supported by the Centers for Disease Control and Prevention and the New York City Department of Health and Mental Hygiene. The San Francisco study was supported by the Centers for Disease Control and Prevention and the Russell/Engleman Rheumatology Research Center at UCSF. No conflict of interest disclosures were available.
Two new studies representing the latest efforts to determine the incidence and prevalence of systemic lupus erythematosus in the United States have revealed the difficulty of ascertaining cases when definitions of the disease vary.
The two population-based registries on which the studies were based – the California Lupus Surveillance Project and the Manhattan Lupus Surveillance Program (MLSP) – confirmed that black women represent the highest risk group for systemic lupus erythematosus (SLE) and also reaffirmed the elevated risk observed in Hispanic and Asian women, compared with white women.
The MLSP researchers applied the updated 1997 American College of Rheumatology (ACR) classification criteria, the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria, or a treating rheumatologist’s diagnosis to records from hospitals, rheumatologists, and administrative databases, and looked at both the prevalence of the disease in 2007 and the incidence from the period of 2007-2009. Using the ACR’s definition of SLE, they found an age-standardized prevalence of 62.2 and an incidence rate of 4.6 per 100,000 person-years (Arthritis Rheumatol. 2017 Sep 11. doi: 10.1002/art.40192).
The prevalence was significantly higher in women than in men (107.4 vs. 12.5 per 100,000 persons), and was highest overall in non-Hispanic black women (210.9), followed by Hispanic women (138.3), non-Hispanic Asian women (91.2), and non-Hispanic white women (64.3).
However, use of the SLICC classification criteria increased the age-standardized prevalence by 17%-19%, to a prevalence of 73.8 per 100,000 person-years and resulted in a 35% increase in incidence, to 6.2 per 100,000 person-years, compared with the ACR rates.
“The small number of cases that met the ACR but not the SLICC case definition is reassuring as it suggests that few cases met ACR criteria for SLE without the presence of autoantibodies,” wrote Peter M. Izmirly, MD, of New York (N.Y.) University, and his coauthors.
“However, given the descriptive nature of the MLSP and the absence of a gold standard test that would unambiguously identify SLE, this project cannot assess which set of classification criteria is more sensitive or specific.”
Meanwhile, the California Lupus Surveillance Project, a registry of people with lupus living in San Francisco County between 2007 and 2009, used the ACR definition to record an age-standardized annual incidence rate of 4.6 per 100,000 person-years, and an average annual prevalence of 84.8 per 100,000 persons (Arthritis Rheumatol. 2017 Sep 11. doi: 10.1002/art.40191).
As with the MLSP, the prevalence was highest in black women (458.1), followed by Hispanic women (177.9), Asian women (149.7) and white women (109.8). The incidence was 30.5 per 100,000 person-years in black women, 8.9 in Hispanic women, 7.2 in Asian women, and 5.3 in white women.
Looking at the clinical manifestations of disease, researchers found hematologic was the most common, affecting 84% of patients, while neurologic disorder affected only 8% of the population. Immunologic manifestations were present in 80%, arthritis in 57%, renal disorders in 45%, pleuritis or pericarditis in 41%, and malar rash in 33%.
There were racial variations in manifestations, with renal manifestations being more common in black, Asian/Pacific Islander, and Hispanic patients, compared with whites. Discoid rash was most common among black patients, while it was not evident at all in Hispanic patients.
Maria Dall’Era, MD, of the Russell/Engleman Research Center at the University of California, San Francisco, and her coauthors said that given the changing demographic of the diverse San Francisco County, a reliable estimate of the burden of lupus in different racial and ethnic groups was essential for health care planning.
“Up until the recent completion of the Georgia and Michigan surveillance projects, most previous epidemiologic studies were limited by small geographic areas, homogeneous populations, varying case definitions, and incomplete case ascertainment that relied on administrative codes or patient self-reported diagnosis,” they wrote.
To overcome the previous lack of data in Asian and Hispanic populations, the authors worked with physicians serving these populations and performed extensive case-finding in hospitals and health care clinics.
“Our approach of partnering with the community and engaging culturally and linguistically concordant community members led to successful case ascertainment of these traditionally understudied populations,” they wrote. “Had we not taken these extra steps, we would have missed SLE cases in the Asian and Hispanic populations.”
Both studies noted that racial and ethnic data were determined from medical records, and may not have accurately reflected the patient’s race or ethnicity.
The Manhattan study was supported by the Centers for Disease Control and Prevention and the New York City Department of Health and Mental Hygiene. The San Francisco study was supported by the Centers for Disease Control and Prevention and the Russell/Engleman Rheumatology Research Center at UCSF. No conflict of interest disclosures were available.
FROM ARTHRITIS & RHEUMATOLOGY
Key clinical point: Black women have the highest prevalence and incidence of systemic lupus erythematosus.
Major finding: Use of the SLICC classification criteria increased the age-standardized prevalence by 17%-19% and resulted in a 35% increase in incidence, compared with the ACR criteria rates.
Data source: The Manhattan and California Lupus Surveillance Projects population-based registries.
Disclosures: The Manhattan study was supported by the Centers for Disease Control and Prevention and the New York City Department of Health and Mental Hygiene. The San Francisco study was supported by the Centers for Disease Control and Prevention and the Russell/Engleman Rheumatology Research Center at UCSF. No conflict of interest disclosures were available.
No obvious choice for treating pruritus in PBC patients
While multiple options exist for the treatment of pruritus in patients with primary biliary cholangitis (PBC), none have compelling evidence regarding their long-term efficacy and safety, according to a narrative review of literature by Hirsh D. Trivedi, MD, and associates.
There are four treatments commonly used for treating pruritus in PBC patients: bile acid–binding resins, rifampicin, opioid antagonists, and sertraline. In the cases of bile acid–binding resins, rifampicin, and opioid antagonists, significant side effects and a lack of proof of long-term efficacy prevent the treatments from standing out. Sertraline seems to have no significant side effects, but research is lacking, and further investigation is required.
Several experimental treatments for refractory pruritus also exist: These include phototherapy, plasmapheresis, albumin dialysis, nasobiliary drainage, ileal bile acid transporter–inhibitors, methotrexate and colchicine, and fibrates. In extreme cases, liver transplant can also be utilized to reduce pruritus symptoms.
“Our ongoing learning [about] this multifaceted symptom will hopefully lead to the development of more effective therapies and improve the quality of life for patients with primary biliary cholangitis,” the investigators concluded.
Find the full narrative review in the American Journal of Medicine (doi: 10.1016/j.amjmed.2017.01.037).
While multiple options exist for the treatment of pruritus in patients with primary biliary cholangitis (PBC), none have compelling evidence regarding their long-term efficacy and safety, according to a narrative review of literature by Hirsh D. Trivedi, MD, and associates.
There are four treatments commonly used for treating pruritus in PBC patients: bile acid–binding resins, rifampicin, opioid antagonists, and sertraline. In the cases of bile acid–binding resins, rifampicin, and opioid antagonists, significant side effects and a lack of proof of long-term efficacy prevent the treatments from standing out. Sertraline seems to have no significant side effects, but research is lacking, and further investigation is required.
Several experimental treatments for refractory pruritus also exist: These include phototherapy, plasmapheresis, albumin dialysis, nasobiliary drainage, ileal bile acid transporter–inhibitors, methotrexate and colchicine, and fibrates. In extreme cases, liver transplant can also be utilized to reduce pruritus symptoms.
“Our ongoing learning [about] this multifaceted symptom will hopefully lead to the development of more effective therapies and improve the quality of life for patients with primary biliary cholangitis,” the investigators concluded.
Find the full narrative review in the American Journal of Medicine (doi: 10.1016/j.amjmed.2017.01.037).
While multiple options exist for the treatment of pruritus in patients with primary biliary cholangitis (PBC), none have compelling evidence regarding their long-term efficacy and safety, according to a narrative review of literature by Hirsh D. Trivedi, MD, and associates.
There are four treatments commonly used for treating pruritus in PBC patients: bile acid–binding resins, rifampicin, opioid antagonists, and sertraline. In the cases of bile acid–binding resins, rifampicin, and opioid antagonists, significant side effects and a lack of proof of long-term efficacy prevent the treatments from standing out. Sertraline seems to have no significant side effects, but research is lacking, and further investigation is required.
Several experimental treatments for refractory pruritus also exist: These include phototherapy, plasmapheresis, albumin dialysis, nasobiliary drainage, ileal bile acid transporter–inhibitors, methotrexate and colchicine, and fibrates. In extreme cases, liver transplant can also be utilized to reduce pruritus symptoms.
“Our ongoing learning [about] this multifaceted symptom will hopefully lead to the development of more effective therapies and improve the quality of life for patients with primary biliary cholangitis,” the investigators concluded.
Find the full narrative review in the American Journal of Medicine (doi: 10.1016/j.amjmed.2017.01.037).
FROM THE AMERICAN JOURNAL OF MEDICINE
POLL: Draft classification criteria for SLE stir controversy
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Lupus classification criteria effort is going in the wrong direction
Editor’s note: This commentary relates to the story, “New classification system for systemic lupus erythematosus moves forward.”
While work to develop a new set of lupus classification criteria more suitable for clinical research is important, the Lupus Foundation of America believes the current work is going in the wrong direction.
Increasingly, key opinion leaders understand lupus to be a spectrum of disease, and there is ample justification of this from scientific evidence (Nat Rev Rheumatol. 2015;11[7]:385-6) The criteria being worked on by ACR and EULAR draws upon an archaic concept with the musty name of “systemic lupus erythematosus,” which relies on a 19th century approach to categorizing disease by counting the signs and symptoms instead of by modern concepts of pathophysiology and prognostic severity. This imposes a homogeneity on the population that simply does not exist. Attempts to re-order obsolescent arrays of organs and autoantibodies to classify lupus will be futile, especially if the aim is to improve the rationale for clinical trial recruitment. Recent clinical trials and modern immunologic methods have already demonstrated, beyond a doubt, that subsets of patients, definable by gene expression patterns or state-of-the-art pharmacodynamic responses, do or do not respond to individual targeted treatments. We now know that patients who require different treatments may well share many of their symptoms in many of the same organs, and this fact defies the outmoded, abacus-based approach to disease classification.
We are concerned that redefining SLE by weighting all disease in one organ as more or less impactful than all disease in another organ flies in the face of current scientific knowledge. If this is the direction in which the effort is going, there is the potential for a negative impact on drug development, clinical care, and access to treatment. The term itself, “SLE,” interferes with selecting appropriate lupus patients for participation in trials. Many people have moderate and even severe lupus syndromes who do not meet enough criteria to be labeled “SLE” (for example, immune thrombocytopenia, hemolytic anemia, discoid lupus, or subacute cutaneous lupus, which can cause severe rashes covering wide areas of the body). In this iteration, assigning less weight to cutaneous lupus as currently proposed is not just problematic; it will set the field back.
By not viewing cutaneous lupus as part of the lupus spectrum, we develop a false sense that this subset of people with lupus will not progress to “SLE,” yet many of them do. Even those who do not later develop features in other organs besides the skin may have more severe disease than other patients who do. Minimizing the “score” for cutaneous lupus will lead to individuals who carry a significant burden of disease being barred from trials, and from access to the treatments they need, once approved.
Conversely, people who do meet criteria for “SLE” under any algorithm, past or present, may have a range of severity, from very severe to very mild. The very mild patients (who may have, in their lifetime, met the multiorgan criteria) are entering trials in large numbers and contributing to the high placebo responses which have stopped many promising investigational treatments from further development. Additionally, the common misuse of the current classification criteria as diagnostic criteria has become an unacceptable norm in the lupus community. This leads us to believe that new criteria will continue to be misused, further disenfranchising a huge segment of the population who have lupus from access to state-of-the-art research and care.
Advancing the development of new classification criteria deserves a wider discussion among the field’s stakeholders, particularly those with expertise in clinical trial outcomes and the clinical care of the full spectrum of lupus patients.
Sandra C. Raymond is CEO and President, Leslie M. Hanrahan is VP of Education and Research, and Joan Merrill, MD, is the Chief Adviser for Clinical Development at the Lupus Foundation of America. Dr. Merrill is also the Oklahoma Medical Research Foundation Professor of Medicine at the University of Oklahoma, Oklahoma City.
Editor’s note: This commentary relates to the story, “New classification system for systemic lupus erythematosus moves forward.”
While work to develop a new set of lupus classification criteria more suitable for clinical research is important, the Lupus Foundation of America believes the current work is going in the wrong direction.
Increasingly, key opinion leaders understand lupus to be a spectrum of disease, and there is ample justification of this from scientific evidence (Nat Rev Rheumatol. 2015;11[7]:385-6) The criteria being worked on by ACR and EULAR draws upon an archaic concept with the musty name of “systemic lupus erythematosus,” which relies on a 19th century approach to categorizing disease by counting the signs and symptoms instead of by modern concepts of pathophysiology and prognostic severity. This imposes a homogeneity on the population that simply does not exist. Attempts to re-order obsolescent arrays of organs and autoantibodies to classify lupus will be futile, especially if the aim is to improve the rationale for clinical trial recruitment. Recent clinical trials and modern immunologic methods have already demonstrated, beyond a doubt, that subsets of patients, definable by gene expression patterns or state-of-the-art pharmacodynamic responses, do or do not respond to individual targeted treatments. We now know that patients who require different treatments may well share many of their symptoms in many of the same organs, and this fact defies the outmoded, abacus-based approach to disease classification.
We are concerned that redefining SLE by weighting all disease in one organ as more or less impactful than all disease in another organ flies in the face of current scientific knowledge. If this is the direction in which the effort is going, there is the potential for a negative impact on drug development, clinical care, and access to treatment. The term itself, “SLE,” interferes with selecting appropriate lupus patients for participation in trials. Many people have moderate and even severe lupus syndromes who do not meet enough criteria to be labeled “SLE” (for example, immune thrombocytopenia, hemolytic anemia, discoid lupus, or subacute cutaneous lupus, which can cause severe rashes covering wide areas of the body). In this iteration, assigning less weight to cutaneous lupus as currently proposed is not just problematic; it will set the field back.
By not viewing cutaneous lupus as part of the lupus spectrum, we develop a false sense that this subset of people with lupus will not progress to “SLE,” yet many of them do. Even those who do not later develop features in other organs besides the skin may have more severe disease than other patients who do. Minimizing the “score” for cutaneous lupus will lead to individuals who carry a significant burden of disease being barred from trials, and from access to the treatments they need, once approved.
Conversely, people who do meet criteria for “SLE” under any algorithm, past or present, may have a range of severity, from very severe to very mild. The very mild patients (who may have, in their lifetime, met the multiorgan criteria) are entering trials in large numbers and contributing to the high placebo responses which have stopped many promising investigational treatments from further development. Additionally, the common misuse of the current classification criteria as diagnostic criteria has become an unacceptable norm in the lupus community. This leads us to believe that new criteria will continue to be misused, further disenfranchising a huge segment of the population who have lupus from access to state-of-the-art research and care.
Advancing the development of new classification criteria deserves a wider discussion among the field’s stakeholders, particularly those with expertise in clinical trial outcomes and the clinical care of the full spectrum of lupus patients.
Sandra C. Raymond is CEO and President, Leslie M. Hanrahan is VP of Education and Research, and Joan Merrill, MD, is the Chief Adviser for Clinical Development at the Lupus Foundation of America. Dr. Merrill is also the Oklahoma Medical Research Foundation Professor of Medicine at the University of Oklahoma, Oklahoma City.
Editor’s note: This commentary relates to the story, “New classification system for systemic lupus erythematosus moves forward.”
While work to develop a new set of lupus classification criteria more suitable for clinical research is important, the Lupus Foundation of America believes the current work is going in the wrong direction.
Increasingly, key opinion leaders understand lupus to be a spectrum of disease, and there is ample justification of this from scientific evidence (Nat Rev Rheumatol. 2015;11[7]:385-6) The criteria being worked on by ACR and EULAR draws upon an archaic concept with the musty name of “systemic lupus erythematosus,” which relies on a 19th century approach to categorizing disease by counting the signs and symptoms instead of by modern concepts of pathophysiology and prognostic severity. This imposes a homogeneity on the population that simply does not exist. Attempts to re-order obsolescent arrays of organs and autoantibodies to classify lupus will be futile, especially if the aim is to improve the rationale for clinical trial recruitment. Recent clinical trials and modern immunologic methods have already demonstrated, beyond a doubt, that subsets of patients, definable by gene expression patterns or state-of-the-art pharmacodynamic responses, do or do not respond to individual targeted treatments. We now know that patients who require different treatments may well share many of their symptoms in many of the same organs, and this fact defies the outmoded, abacus-based approach to disease classification.
We are concerned that redefining SLE by weighting all disease in one organ as more or less impactful than all disease in another organ flies in the face of current scientific knowledge. If this is the direction in which the effort is going, there is the potential for a negative impact on drug development, clinical care, and access to treatment. The term itself, “SLE,” interferes with selecting appropriate lupus patients for participation in trials. Many people have moderate and even severe lupus syndromes who do not meet enough criteria to be labeled “SLE” (for example, immune thrombocytopenia, hemolytic anemia, discoid lupus, or subacute cutaneous lupus, which can cause severe rashes covering wide areas of the body). In this iteration, assigning less weight to cutaneous lupus as currently proposed is not just problematic; it will set the field back.
By not viewing cutaneous lupus as part of the lupus spectrum, we develop a false sense that this subset of people with lupus will not progress to “SLE,” yet many of them do. Even those who do not later develop features in other organs besides the skin may have more severe disease than other patients who do. Minimizing the “score” for cutaneous lupus will lead to individuals who carry a significant burden of disease being barred from trials, and from access to the treatments they need, once approved.
Conversely, people who do meet criteria for “SLE” under any algorithm, past or present, may have a range of severity, from very severe to very mild. The very mild patients (who may have, in their lifetime, met the multiorgan criteria) are entering trials in large numbers and contributing to the high placebo responses which have stopped many promising investigational treatments from further development. Additionally, the common misuse of the current classification criteria as diagnostic criteria has become an unacceptable norm in the lupus community. This leads us to believe that new criteria will continue to be misused, further disenfranchising a huge segment of the population who have lupus from access to state-of-the-art research and care.
Advancing the development of new classification criteria deserves a wider discussion among the field’s stakeholders, particularly those with expertise in clinical trial outcomes and the clinical care of the full spectrum of lupus patients.
Sandra C. Raymond is CEO and President, Leslie M. Hanrahan is VP of Education and Research, and Joan Merrill, MD, is the Chief Adviser for Clinical Development at the Lupus Foundation of America. Dr. Merrill is also the Oklahoma Medical Research Foundation Professor of Medicine at the University of Oklahoma, Oklahoma City.
Lupus classification criteria need input from dermatologists
Editor’s note: This commentary relates to the story, “ New classification system for systemic lupus erythematosus moves forward .”
The ACR/EULAR committee that is developing new classification criteria for systemic lupus erythematosus (SLE) has done the field a service by releasing its draft version in a presentation at the recent EULAR meeting. Releasing the draft version facilitates comments before the new classification criteria become finalized.
Many in the derm-rheum field, ourselves included, classify patients with skin-predominant lupus as lupus, but the new draft classification would place a significant percentage of these patients outside of lupus.
The presentation by Dr. Johnson at EULAR stated, “... a patient can’t be classified on skin findings alone. There is concern that skin findings by themselves may not be lupus, but something else, and some people even consider that cutaneous and systemic lupus are two different things.”
Abundant data indicate instead that lupus is a spectrum that includes skin-predominant lupus. For example, the histology is identical between discoid lupus erythematosus whether or not there is SLE. Moreover, we and others have published significant rates of progression of cutaneous lupus erythematosus (CLE) to SLE. By not viewing CLE in the lupus spectrum, we have a false sense that the patients won’t progress to SLE, yet many of them do.
Importantly, patients respond similarly to therapies when they have either CLE or SLE, so removing this subset of lupus hurts their inclusion in trials and access to new treatments.
When criteria are devised by one group without input from experts who see a specific subset of the disease, that is also a problem. We went down that path in dermatomyositis and missed a lot of patients with the disease when criteria were devised that said the patient had to have muscle involvement. Those criteria have now finally been revised as the ACR/EULAR myositis criteria.
We and others from the derm-rheum community would be happy to speak with the ACR/EULAR committee about these concerns.
Victoria P. Werth, MD, is professor of medicine and dermatology at the University of Pennsylvania, Philadelphia. Joseph F. Merola, MD, is codirector of the Center for Skin and Related Musculoskeletal Diseases at Brigham and Women’s Hospital, Boston. Andrew G. Franks, MD, is a clinical professor in the departments of medicine and dermatology at New York University. Benjamin F. Chong, MD, is an assistant professor of dermatology at the University of Texas, Dallas.
Editor’s note: This commentary relates to the story, “ New classification system for systemic lupus erythematosus moves forward .”
The ACR/EULAR committee that is developing new classification criteria for systemic lupus erythematosus (SLE) has done the field a service by releasing its draft version in a presentation at the recent EULAR meeting. Releasing the draft version facilitates comments before the new classification criteria become finalized.
Many in the derm-rheum field, ourselves included, classify patients with skin-predominant lupus as lupus, but the new draft classification would place a significant percentage of these patients outside of lupus.
The presentation by Dr. Johnson at EULAR stated, “... a patient can’t be classified on skin findings alone. There is concern that skin findings by themselves may not be lupus, but something else, and some people even consider that cutaneous and systemic lupus are two different things.”
Abundant data indicate instead that lupus is a spectrum that includes skin-predominant lupus. For example, the histology is identical between discoid lupus erythematosus whether or not there is SLE. Moreover, we and others have published significant rates of progression of cutaneous lupus erythematosus (CLE) to SLE. By not viewing CLE in the lupus spectrum, we have a false sense that the patients won’t progress to SLE, yet many of them do.
Importantly, patients respond similarly to therapies when they have either CLE or SLE, so removing this subset of lupus hurts their inclusion in trials and access to new treatments.
When criteria are devised by one group without input from experts who see a specific subset of the disease, that is also a problem. We went down that path in dermatomyositis and missed a lot of patients with the disease when criteria were devised that said the patient had to have muscle involvement. Those criteria have now finally been revised as the ACR/EULAR myositis criteria.
We and others from the derm-rheum community would be happy to speak with the ACR/EULAR committee about these concerns.
Victoria P. Werth, MD, is professor of medicine and dermatology at the University of Pennsylvania, Philadelphia. Joseph F. Merola, MD, is codirector of the Center for Skin and Related Musculoskeletal Diseases at Brigham and Women’s Hospital, Boston. Andrew G. Franks, MD, is a clinical professor in the departments of medicine and dermatology at New York University. Benjamin F. Chong, MD, is an assistant professor of dermatology at the University of Texas, Dallas.
Editor’s note: This commentary relates to the story, “ New classification system for systemic lupus erythematosus moves forward .”
The ACR/EULAR committee that is developing new classification criteria for systemic lupus erythematosus (SLE) has done the field a service by releasing its draft version in a presentation at the recent EULAR meeting. Releasing the draft version facilitates comments before the new classification criteria become finalized.
Many in the derm-rheum field, ourselves included, classify patients with skin-predominant lupus as lupus, but the new draft classification would place a significant percentage of these patients outside of lupus.
The presentation by Dr. Johnson at EULAR stated, “... a patient can’t be classified on skin findings alone. There is concern that skin findings by themselves may not be lupus, but something else, and some people even consider that cutaneous and systemic lupus are two different things.”
Abundant data indicate instead that lupus is a spectrum that includes skin-predominant lupus. For example, the histology is identical between discoid lupus erythematosus whether or not there is SLE. Moreover, we and others have published significant rates of progression of cutaneous lupus erythematosus (CLE) to SLE. By not viewing CLE in the lupus spectrum, we have a false sense that the patients won’t progress to SLE, yet many of them do.
Importantly, patients respond similarly to therapies when they have either CLE or SLE, so removing this subset of lupus hurts their inclusion in trials and access to new treatments.
When criteria are devised by one group without input from experts who see a specific subset of the disease, that is also a problem. We went down that path in dermatomyositis and missed a lot of patients with the disease when criteria were devised that said the patient had to have muscle involvement. Those criteria have now finally been revised as the ACR/EULAR myositis criteria.
We and others from the derm-rheum community would be happy to speak with the ACR/EULAR committee about these concerns.
Victoria P. Werth, MD, is professor of medicine and dermatology at the University of Pennsylvania, Philadelphia. Joseph F. Merola, MD, is codirector of the Center for Skin and Related Musculoskeletal Diseases at Brigham and Women’s Hospital, Boston. Andrew G. Franks, MD, is a clinical professor in the departments of medicine and dermatology at New York University. Benjamin F. Chong, MD, is an assistant professor of dermatology at the University of Texas, Dallas.
Self-injectable belimumab receives FDA approval for systemic lupus erythematosus
GlaxoSmithKline announced on July 21 that it had received approval from the U.S. Food and Drug Administration for a new, self-injectable form of belimumab (Benlysta) for adult patients with systemic lupus erythematosus (SLE). Belimumab has previously been approved for SLE, in 2011, in an intravenous formulation.
The new formulation is the first self-injectable subcutaneous treatment available for patients with SLE. The previous treatment required 1 hour of intravenous infusion every 4 weeks, while the new treatment is 1 weekly injection.
Two of the 280 patients receiving placebo (0.7%) died during the study, as did 3 of the 556 patients receiving belimumab (0.5%). Serious infections occurred in 4.1% and 5.4% of patients receiving belimumab and placebo, respectively.
“The safety profile observed for Benlysta administered subcutaneously was consistent with the known safety profile of Benlysta administered intravenously, with the exception of local injection site reactions,” noted GlaxoSmithKline in its announcement. Each form of the drug has a risk of a reaction, whether an infusion reaction for IV administration or a hypersensitivity reaction for self-injection. A patient who reacted to the intravenous formulation with anaphylaxis is contraindicated for the self-injectable version.
It is not known what effect belimumab has on the risk of birth defects or miscarriage, so birth control is recommended for patients on the drug. Likewise, the effects of the drug on breast milk are not known. As belimumab may interfere with immunizations, a patient should not be vaccinated 30 days before or after taking the drug.
GlaxoSmithKline announced on July 21 that it had received approval from the U.S. Food and Drug Administration for a new, self-injectable form of belimumab (Benlysta) for adult patients with systemic lupus erythematosus (SLE). Belimumab has previously been approved for SLE, in 2011, in an intravenous formulation.
The new formulation is the first self-injectable subcutaneous treatment available for patients with SLE. The previous treatment required 1 hour of intravenous infusion every 4 weeks, while the new treatment is 1 weekly injection.
Two of the 280 patients receiving placebo (0.7%) died during the study, as did 3 of the 556 patients receiving belimumab (0.5%). Serious infections occurred in 4.1% and 5.4% of patients receiving belimumab and placebo, respectively.
“The safety profile observed for Benlysta administered subcutaneously was consistent with the known safety profile of Benlysta administered intravenously, with the exception of local injection site reactions,” noted GlaxoSmithKline in its announcement. Each form of the drug has a risk of a reaction, whether an infusion reaction for IV administration or a hypersensitivity reaction for self-injection. A patient who reacted to the intravenous formulation with anaphylaxis is contraindicated for the self-injectable version.
It is not known what effect belimumab has on the risk of birth defects or miscarriage, so birth control is recommended for patients on the drug. Likewise, the effects of the drug on breast milk are not known. As belimumab may interfere with immunizations, a patient should not be vaccinated 30 days before or after taking the drug.
GlaxoSmithKline announced on July 21 that it had received approval from the U.S. Food and Drug Administration for a new, self-injectable form of belimumab (Benlysta) for adult patients with systemic lupus erythematosus (SLE). Belimumab has previously been approved for SLE, in 2011, in an intravenous formulation.
The new formulation is the first self-injectable subcutaneous treatment available for patients with SLE. The previous treatment required 1 hour of intravenous infusion every 4 weeks, while the new treatment is 1 weekly injection.
Two of the 280 patients receiving placebo (0.7%) died during the study, as did 3 of the 556 patients receiving belimumab (0.5%). Serious infections occurred in 4.1% and 5.4% of patients receiving belimumab and placebo, respectively.
“The safety profile observed for Benlysta administered subcutaneously was consistent with the known safety profile of Benlysta administered intravenously, with the exception of local injection site reactions,” noted GlaxoSmithKline in its announcement. Each form of the drug has a risk of a reaction, whether an infusion reaction for IV administration or a hypersensitivity reaction for self-injection. A patient who reacted to the intravenous formulation with anaphylaxis is contraindicated for the self-injectable version.
It is not known what effect belimumab has on the risk of birth defects or miscarriage, so birth control is recommended for patients on the drug. Likewise, the effects of the drug on breast milk are not known. As belimumab may interfere with immunizations, a patient should not be vaccinated 30 days before or after taking the drug.
New classification system for systemic lupus erythematosus moves forward
MADRID – A proposed classification scheme for systemic lupus erythematosus (SLE) relies on a combination of antinuclear antibody titer and the weighted scoring of signs and symptoms in seven clinical and three immunologic domains.
Anyone with an ANA titer of at least 1:80 on immunofluorescence and 84 points accumulated from the domains can be classified as having the disease, according to the proposed system. An international collaboration between the American College of Rheumatology and the European League Against Rheumatism, the system is the first classification scheme update since 2012, said Sindhu Johnson, MD, PhD, who discussed it during the European Congress of Rheumatology.
[polldaddy:9802068]
The proposed system is not intended to be a diagnostic tool, Dr. Johnson said in an interview. Rather, it’s meant to better stratify patients into research studies. “The prior criteria were missing patients. And, since classification criteria are used to decide whether patients can get into a clinical trial, we all felt that we were doing patients an injustice if the criteria were excluding some and denying them an opportunity to receive a novel therapy.”
There are currently two classification criteria in use: the 1982 American College of Rheumatology criteria and the Systemic Lupus International Collaborating Clinics Criteria (SLICC 2012). New understandings of SLE pathogenesis have rendered the 1982 ACR criteria outdated, according to a recently published paper (Arthritis Care Res. 2017 July 10. doi: 10.1002/acr.23317). While the SLICC 2012 criteria incorporated some of the new concepts and have increased sensitivity, compared with the 1982 ACR criteria, their specificity actually declined, partially because the document assigned equal weight to each of the clinical and immunologic criteria. The ACR/EULAR project takes a different tack. Criteria are weighted to reflect the clinical impact of different signs and symptoms, Dr. Johnson said.
“In clinical practice, if someone has class III/IV lupus nephritis, that’s a very different patient than someone who has leukopenia. As clinicians, we weight things differently, and so do these criteria, putting more weight on serious or internal organ manifestations of SLE.”
The ACR/EULAR criteria begin with a confirmed ANA titer of at least 1:80. “This has never been a requirement before, but the consensus now is that you need to have a positive ANA to be classified.”
Once that baseline is established, patients can be assessed in seven clinical domains and three immunologic domains. Each contains a subgroup of weighted signs and symptoms. These are ordered from those with least impact to those with most impact. Within each domain, only the highest-scoring criterion is counted toward the total score. When assessing, clinicians should not score any symptom if a cause other than SLE is more likely. The symptoms are not time-bound either, Dr. Johnson said. A symptom may have occurred only one time in the past, and that’s sufficient to earn a score. At least one clinical criterion must be present to be classified as SLE-positive.
The clinical domains
Constitutional: Fever (13 points). The only symptom in this domain, it’s never before been assessed in SLE criteria, Dr. Johnson said. “Our inclusion of fever is new, but our work in phase 1 of this project found that fever is a feature that can distinguish early lupus from mimickers. We want to identify patients as early in the disease course as possible so we can intervene, and fever appears to improve the ability to detect those patients.”
Cutaneous: Nonscarring alopecia (13), oral ulcers (14), subacute cutaneous or discoid lupus (29), and acute cutaneous lupus (38).
“Skin has long been recognized as an important part of lupus, but it got a lot of weight that some people felt was inappropriate. These criteria still include skin, but a patient can’t be classified on skin findings alone. There is concern that skin findings by themselves may not be lupus but something else, and some people even consider that cutaneous and systemic lupus are two different things.”
Arthritis: Synovitis in at least two joints (34).
Neurologic: Delirium (12), psychosis (20), and seizure (34).
Serositis: Pleural or pericardial effusion (34) and acute pericarditis (38).
Hematologic: Leukopenia (12), thrombocytopenia (26), and autoimmune hemolysis (28).
Renal: Proteinuria more than 0.5 g/24 hours (27), renal biopsy with class II or V lupus nephritis (55), and renal biopsy with class III or IV lupus nephritis (74).
The immunologic domains
Antiphospholipid antibodies: Anticardiolipin immunoglobulin G more than 40 GPL units, anti-beta2GP1 IgG more than 40 units, or lupus anticoagulant positive (13).
Complement proteins: Low C3 or low C4 (19) and low C3 and low C4 (27).
Highly specific antibodies: Anti-dsDNA antibody (38) and anti-Smith antibody (40).
Moving forward
Screening 10 domains with their attendant components may seem a bit clunky now, Dr. Johnson noted, but the final iteration should be more streamlined. Plus, she said, the system will be presented on a computer application that makes calculation much easier. “We’re aiming for feasibility and simplicity, but, at the same time, when you have a complex disease, you don’t want oversimplification. You may lose sensitivity and specificity.”
After further streamlining, Dr. Johnson said, the next step will be validating in a large retrospective patient cohort. “Right now, we are still collecting data for the validation cohort, which will be drawn from 36 centers. We’ll analyze sensitivity and specificity, comparing this system with the other two. We hope to present all these data at the ACR meeting in the fall.”
While research classification is the system’s raison d’être, it will undoubtedly influence diagnosis and clinical assessment as well, Dr. Johnson said. “ACR and EULAR are very clear that they only support the validation of classification criteria. The diagnosis of SLE is still within the hands of the physician. But, we know that classification criteria do inform our concept of the disease, so it’s likely these will shift the way we think about diagnosing lupus as well. We do hope to identify patients with earlier disease, so they have the opportunity to be involved in research” that may modify their disease course and, ultimately, prevent permanent damage and improve quality of life.
Dr. Johnson had no disclosures related to the development of the classification criteria.
[email protected]
On Twitter @alz_gal
This joint ACR/EULAR effort is very large, involving over 40 international SLE experts and centers, including many Systemic Lupus International Collaborating Clinics Criteria members. The goals are to develop new criteria that will be both sensitive and specific for SLE, which is a very heterogeneous and often elusive disease, using newer rigorous expert opinion–based and data-driven methodologies (as has been accomplished recently for rheumatoid arthritis, scleroderma, and gout).
This is a tall order! While genetic and cytokine-based biomarkers are being developed for the identification of SLE, unfortunately, we were not able incorporate them as they are not available for routine use at this time. The SLE classification criteria are used worldwide for inclusion in clinical trials and studies.
The work has been preceding in phases: phase 1, item generation; phase 2, item reduction and definition of criteria; phase 3, multicriteria decision analysis and threshold identification; and phase 4, validation. Phases 1-3 involved many iterative, group discussions, data collection and review, and novel “forced choice” methodologies for arriving at group consensus. In phase 4 (validation), the goal is to compare classification using these criteria with the existing ACR and SLICC criteria, as well as SLE expert physician diagnosis. We will see how they do after all this effort!
Karen H. Costenbader, MD, is the lupus program director at Brigham and Women’s Hospital, Boston. She is a member of the classification criteria steering committee and is the senior author on a paper describing the process to develop the draft classification criteria (Arthritis Care Res. 2017 July 10. doi: 10.1002/acr.23317).
This joint ACR/EULAR effort is very large, involving over 40 international SLE experts and centers, including many Systemic Lupus International Collaborating Clinics Criteria members. The goals are to develop new criteria that will be both sensitive and specific for SLE, which is a very heterogeneous and often elusive disease, using newer rigorous expert opinion–based and data-driven methodologies (as has been accomplished recently for rheumatoid arthritis, scleroderma, and gout).
This is a tall order! While genetic and cytokine-based biomarkers are being developed for the identification of SLE, unfortunately, we were not able incorporate them as they are not available for routine use at this time. The SLE classification criteria are used worldwide for inclusion in clinical trials and studies.
The work has been preceding in phases: phase 1, item generation; phase 2, item reduction and definition of criteria; phase 3, multicriteria decision analysis and threshold identification; and phase 4, validation. Phases 1-3 involved many iterative, group discussions, data collection and review, and novel “forced choice” methodologies for arriving at group consensus. In phase 4 (validation), the goal is to compare classification using these criteria with the existing ACR and SLICC criteria, as well as SLE expert physician diagnosis. We will see how they do after all this effort!
Karen H. Costenbader, MD, is the lupus program director at Brigham and Women’s Hospital, Boston. She is a member of the classification criteria steering committee and is the senior author on a paper describing the process to develop the draft classification criteria (Arthritis Care Res. 2017 July 10. doi: 10.1002/acr.23317).
This joint ACR/EULAR effort is very large, involving over 40 international SLE experts and centers, including many Systemic Lupus International Collaborating Clinics Criteria members. The goals are to develop new criteria that will be both sensitive and specific for SLE, which is a very heterogeneous and often elusive disease, using newer rigorous expert opinion–based and data-driven methodologies (as has been accomplished recently for rheumatoid arthritis, scleroderma, and gout).
This is a tall order! While genetic and cytokine-based biomarkers are being developed for the identification of SLE, unfortunately, we were not able incorporate them as they are not available for routine use at this time. The SLE classification criteria are used worldwide for inclusion in clinical trials and studies.
The work has been preceding in phases: phase 1, item generation; phase 2, item reduction and definition of criteria; phase 3, multicriteria decision analysis and threshold identification; and phase 4, validation. Phases 1-3 involved many iterative, group discussions, data collection and review, and novel “forced choice” methodologies for arriving at group consensus. In phase 4 (validation), the goal is to compare classification using these criteria with the existing ACR and SLICC criteria, as well as SLE expert physician diagnosis. We will see how they do after all this effort!
Karen H. Costenbader, MD, is the lupus program director at Brigham and Women’s Hospital, Boston. She is a member of the classification criteria steering committee and is the senior author on a paper describing the process to develop the draft classification criteria (Arthritis Care Res. 2017 July 10. doi: 10.1002/acr.23317).
MADRID – A proposed classification scheme for systemic lupus erythematosus (SLE) relies on a combination of antinuclear antibody titer and the weighted scoring of signs and symptoms in seven clinical and three immunologic domains.
Anyone with an ANA titer of at least 1:80 on immunofluorescence and 84 points accumulated from the domains can be classified as having the disease, according to the proposed system. An international collaboration between the American College of Rheumatology and the European League Against Rheumatism, the system is the first classification scheme update since 2012, said Sindhu Johnson, MD, PhD, who discussed it during the European Congress of Rheumatology.
[polldaddy:9802068]
The proposed system is not intended to be a diagnostic tool, Dr. Johnson said in an interview. Rather, it’s meant to better stratify patients into research studies. “The prior criteria were missing patients. And, since classification criteria are used to decide whether patients can get into a clinical trial, we all felt that we were doing patients an injustice if the criteria were excluding some and denying them an opportunity to receive a novel therapy.”
There are currently two classification criteria in use: the 1982 American College of Rheumatology criteria and the Systemic Lupus International Collaborating Clinics Criteria (SLICC 2012). New understandings of SLE pathogenesis have rendered the 1982 ACR criteria outdated, according to a recently published paper (Arthritis Care Res. 2017 July 10. doi: 10.1002/acr.23317). While the SLICC 2012 criteria incorporated some of the new concepts and have increased sensitivity, compared with the 1982 ACR criteria, their specificity actually declined, partially because the document assigned equal weight to each of the clinical and immunologic criteria. The ACR/EULAR project takes a different tack. Criteria are weighted to reflect the clinical impact of different signs and symptoms, Dr. Johnson said.
“In clinical practice, if someone has class III/IV lupus nephritis, that’s a very different patient than someone who has leukopenia. As clinicians, we weight things differently, and so do these criteria, putting more weight on serious or internal organ manifestations of SLE.”
The ACR/EULAR criteria begin with a confirmed ANA titer of at least 1:80. “This has never been a requirement before, but the consensus now is that you need to have a positive ANA to be classified.”
Once that baseline is established, patients can be assessed in seven clinical domains and three immunologic domains. Each contains a subgroup of weighted signs and symptoms. These are ordered from those with least impact to those with most impact. Within each domain, only the highest-scoring criterion is counted toward the total score. When assessing, clinicians should not score any symptom if a cause other than SLE is more likely. The symptoms are not time-bound either, Dr. Johnson said. A symptom may have occurred only one time in the past, and that’s sufficient to earn a score. At least one clinical criterion must be present to be classified as SLE-positive.
The clinical domains
Constitutional: Fever (13 points). The only symptom in this domain, it’s never before been assessed in SLE criteria, Dr. Johnson said. “Our inclusion of fever is new, but our work in phase 1 of this project found that fever is a feature that can distinguish early lupus from mimickers. We want to identify patients as early in the disease course as possible so we can intervene, and fever appears to improve the ability to detect those patients.”
Cutaneous: Nonscarring alopecia (13), oral ulcers (14), subacute cutaneous or discoid lupus (29), and acute cutaneous lupus (38).
“Skin has long been recognized as an important part of lupus, but it got a lot of weight that some people felt was inappropriate. These criteria still include skin, but a patient can’t be classified on skin findings alone. There is concern that skin findings by themselves may not be lupus but something else, and some people even consider that cutaneous and systemic lupus are two different things.”
Arthritis: Synovitis in at least two joints (34).
Neurologic: Delirium (12), psychosis (20), and seizure (34).
Serositis: Pleural or pericardial effusion (34) and acute pericarditis (38).
Hematologic: Leukopenia (12), thrombocytopenia (26), and autoimmune hemolysis (28).
Renal: Proteinuria more than 0.5 g/24 hours (27), renal biopsy with class II or V lupus nephritis (55), and renal biopsy with class III or IV lupus nephritis (74).
The immunologic domains
Antiphospholipid antibodies: Anticardiolipin immunoglobulin G more than 40 GPL units, anti-beta2GP1 IgG more than 40 units, or lupus anticoagulant positive (13).
Complement proteins: Low C3 or low C4 (19) and low C3 and low C4 (27).
Highly specific antibodies: Anti-dsDNA antibody (38) and anti-Smith antibody (40).
Moving forward
Screening 10 domains with their attendant components may seem a bit clunky now, Dr. Johnson noted, but the final iteration should be more streamlined. Plus, she said, the system will be presented on a computer application that makes calculation much easier. “We’re aiming for feasibility and simplicity, but, at the same time, when you have a complex disease, you don’t want oversimplification. You may lose sensitivity and specificity.”
After further streamlining, Dr. Johnson said, the next step will be validating in a large retrospective patient cohort. “Right now, we are still collecting data for the validation cohort, which will be drawn from 36 centers. We’ll analyze sensitivity and specificity, comparing this system with the other two. We hope to present all these data at the ACR meeting in the fall.”
While research classification is the system’s raison d’être, it will undoubtedly influence diagnosis and clinical assessment as well, Dr. Johnson said. “ACR and EULAR are very clear that they only support the validation of classification criteria. The diagnosis of SLE is still within the hands of the physician. But, we know that classification criteria do inform our concept of the disease, so it’s likely these will shift the way we think about diagnosing lupus as well. We do hope to identify patients with earlier disease, so they have the opportunity to be involved in research” that may modify their disease course and, ultimately, prevent permanent damage and improve quality of life.
Dr. Johnson had no disclosures related to the development of the classification criteria.
[email protected]
On Twitter @alz_gal
MADRID – A proposed classification scheme for systemic lupus erythematosus (SLE) relies on a combination of antinuclear antibody titer and the weighted scoring of signs and symptoms in seven clinical and three immunologic domains.
Anyone with an ANA titer of at least 1:80 on immunofluorescence and 84 points accumulated from the domains can be classified as having the disease, according to the proposed system. An international collaboration between the American College of Rheumatology and the European League Against Rheumatism, the system is the first classification scheme update since 2012, said Sindhu Johnson, MD, PhD, who discussed it during the European Congress of Rheumatology.
[polldaddy:9802068]
The proposed system is not intended to be a diagnostic tool, Dr. Johnson said in an interview. Rather, it’s meant to better stratify patients into research studies. “The prior criteria were missing patients. And, since classification criteria are used to decide whether patients can get into a clinical trial, we all felt that we were doing patients an injustice if the criteria were excluding some and denying them an opportunity to receive a novel therapy.”
There are currently two classification criteria in use: the 1982 American College of Rheumatology criteria and the Systemic Lupus International Collaborating Clinics Criteria (SLICC 2012). New understandings of SLE pathogenesis have rendered the 1982 ACR criteria outdated, according to a recently published paper (Arthritis Care Res. 2017 July 10. doi: 10.1002/acr.23317). While the SLICC 2012 criteria incorporated some of the new concepts and have increased sensitivity, compared with the 1982 ACR criteria, their specificity actually declined, partially because the document assigned equal weight to each of the clinical and immunologic criteria. The ACR/EULAR project takes a different tack. Criteria are weighted to reflect the clinical impact of different signs and symptoms, Dr. Johnson said.
“In clinical practice, if someone has class III/IV lupus nephritis, that’s a very different patient than someone who has leukopenia. As clinicians, we weight things differently, and so do these criteria, putting more weight on serious or internal organ manifestations of SLE.”
The ACR/EULAR criteria begin with a confirmed ANA titer of at least 1:80. “This has never been a requirement before, but the consensus now is that you need to have a positive ANA to be classified.”
Once that baseline is established, patients can be assessed in seven clinical domains and three immunologic domains. Each contains a subgroup of weighted signs and symptoms. These are ordered from those with least impact to those with most impact. Within each domain, only the highest-scoring criterion is counted toward the total score. When assessing, clinicians should not score any symptom if a cause other than SLE is more likely. The symptoms are not time-bound either, Dr. Johnson said. A symptom may have occurred only one time in the past, and that’s sufficient to earn a score. At least one clinical criterion must be present to be classified as SLE-positive.
The clinical domains
Constitutional: Fever (13 points). The only symptom in this domain, it’s never before been assessed in SLE criteria, Dr. Johnson said. “Our inclusion of fever is new, but our work in phase 1 of this project found that fever is a feature that can distinguish early lupus from mimickers. We want to identify patients as early in the disease course as possible so we can intervene, and fever appears to improve the ability to detect those patients.”
Cutaneous: Nonscarring alopecia (13), oral ulcers (14), subacute cutaneous or discoid lupus (29), and acute cutaneous lupus (38).
“Skin has long been recognized as an important part of lupus, but it got a lot of weight that some people felt was inappropriate. These criteria still include skin, but a patient can’t be classified on skin findings alone. There is concern that skin findings by themselves may not be lupus but something else, and some people even consider that cutaneous and systemic lupus are two different things.”
Arthritis: Synovitis in at least two joints (34).
Neurologic: Delirium (12), psychosis (20), and seizure (34).
Serositis: Pleural or pericardial effusion (34) and acute pericarditis (38).
Hematologic: Leukopenia (12), thrombocytopenia (26), and autoimmune hemolysis (28).
Renal: Proteinuria more than 0.5 g/24 hours (27), renal biopsy with class II or V lupus nephritis (55), and renal biopsy with class III or IV lupus nephritis (74).
The immunologic domains
Antiphospholipid antibodies: Anticardiolipin immunoglobulin G more than 40 GPL units, anti-beta2GP1 IgG more than 40 units, or lupus anticoagulant positive (13).
Complement proteins: Low C3 or low C4 (19) and low C3 and low C4 (27).
Highly specific antibodies: Anti-dsDNA antibody (38) and anti-Smith antibody (40).
Moving forward
Screening 10 domains with their attendant components may seem a bit clunky now, Dr. Johnson noted, but the final iteration should be more streamlined. Plus, she said, the system will be presented on a computer application that makes calculation much easier. “We’re aiming for feasibility and simplicity, but, at the same time, when you have a complex disease, you don’t want oversimplification. You may lose sensitivity and specificity.”
After further streamlining, Dr. Johnson said, the next step will be validating in a large retrospective patient cohort. “Right now, we are still collecting data for the validation cohort, which will be drawn from 36 centers. We’ll analyze sensitivity and specificity, comparing this system with the other two. We hope to present all these data at the ACR meeting in the fall.”
While research classification is the system’s raison d’être, it will undoubtedly influence diagnosis and clinical assessment as well, Dr. Johnson said. “ACR and EULAR are very clear that they only support the validation of classification criteria. The diagnosis of SLE is still within the hands of the physician. But, we know that classification criteria do inform our concept of the disease, so it’s likely these will shift the way we think about diagnosing lupus as well. We do hope to identify patients with earlier disease, so they have the opportunity to be involved in research” that may modify their disease course and, ultimately, prevent permanent damage and improve quality of life.
Dr. Johnson had no disclosures related to the development of the classification criteria.
[email protected]
On Twitter @alz_gal
AT THE EULAR 2017 CONGRESS
TWEAKing inflammation: Studies reflect potential treatment target for psoriasis, atopic dermatitis
An immunomodulatory pathway that has been linked to cancer, kidney disease, and other disease processes is becoming a focus of dermatologic research.
New evidence suggests that TNF-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis family (TNF) superfamily, may be involved in both atopic dermatitis (AD) and psoriasis (Nat Commun. 2017 May 22;8:15395. doi: 10.1038/ncomms15395). The research showed that mice engineered to have low TWEAK levels had less severe disease when both AD and psoriasis were induced.
The TWEAK receptor, Fn14, was upregulated in keratinocytes and dermal fibroblasts in mouse disease models of AD and psoriasis, and TWEAK induced production of a range of cytokines associated with both AD and psoriasis. Subcutaneous injection of recombinant TWEAK led to cutaneous inflammation, as well as histological and molecular signals of the two diseases.
The pathophysiology of both AD and psoriasis is nebulously complex, sharing a similar theme of immune dysregulation, but historically polar opposites based on the different branches of the immune response implicated.
The study is not the only recent work tying TWEAK/Fn14 to dermatologic diseases. Other recent papers have shown evidence of their involvement in chronic cutaneous lupus (J Invest Dermatol. 2015;135[8]:1986-95), UVB irradiation-induced cutaneous lupus (Exp Dermatol. 2016 Dec;25[12]:969-76), and bullous pemphigoid (J Invest Dermatol. 2017 Jul;137[7]:1512-22).
The spate of findings hint that TWEAK/Fn14 could be a novel therapeutic pathway to attack inflammatory disease. Many therapies for autoimmune disease focus on immunosuppressive agents, which are associated with an increased risk of infection. But mice engineered to lack either TWEAK or Fn14 appear normal, and a phase I trial of an anti-TWEAK antibody in patients with rheumatoid arthritis did not reveal any worrisome safety concerns. “It doesn’t seem to have the broad immunosuppressive effects which characterize the therapies we currently use,” said Chaim Putterman, MD, chief of the division of rheumatology and professor of medicine and microbiology & immunology at the Albert Einstein College of Medicine, New York.
Instead, TWEAK seems to be regulating inflammation in target organs. It almost certainly plays a role in healthy functions like wound healing and cell survival, but Dr. Putterman believes there are redundant mechanisms that can pick up the slack, as the healthy knockout mice attest. The evidence suggests that the TWEAK pathway may become overactive in some diseases and, if so, a therapeutic antibody might be able to reset it to a more normal balance. “The utopian vision is that you would block this cytokine and bring its downstream effects back to normal levels, rather than totally abrogating its homeostatic functions,” Dr. Putterman noted.
Because blocking TWEAK has no apparent immunosuppressive effects, it might be a candidate for combination therapy with existing cytotoxic drugs. “If you have a disease like psoriasis where some standard of care medications are immunosuppressive, such as methotrexate, you might not get more risk by adding an antibody targeting TWEAK, as opposed to using immunosuppressives in combination. That, I think, has potential,” he said.
Work remains, however. A proof-of-concept study in lupus nephritis, sponsored by Biogen, failed to show a benefit when an anti-TWEAK antibody was combined with the standard of care.
But the potential impact of this approach holds much promise, and the fact that TWEAK has been linked to multiple diseases should make it a more attractive drug target for drug companies. “Now we have a target, that if you knock it out, or its receptor, you can potentially affect both diseases. This may the start of a whole new direction for biologics to treat inflammatory disease, and cancer as well,” Dr. Friedman said.
Dr. Putterman and Dr. Friedman were among the authors of the 2015 JID study on TWEAK/Fn14 signaling in spontaneous lupus and the Experimental Dermatology study. Dr. Putterman has research funding from Biogen Idec. Dr. Friedman had no related disclosures. The authors of the Nature Communications study were from the La Jolla Institute for Allergy and Immunology, and Biogen.
An immunomodulatory pathway that has been linked to cancer, kidney disease, and other disease processes is becoming a focus of dermatologic research.
New evidence suggests that TNF-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis family (TNF) superfamily, may be involved in both atopic dermatitis (AD) and psoriasis (Nat Commun. 2017 May 22;8:15395. doi: 10.1038/ncomms15395). The research showed that mice engineered to have low TWEAK levels had less severe disease when both AD and psoriasis were induced.
The TWEAK receptor, Fn14, was upregulated in keratinocytes and dermal fibroblasts in mouse disease models of AD and psoriasis, and TWEAK induced production of a range of cytokines associated with both AD and psoriasis. Subcutaneous injection of recombinant TWEAK led to cutaneous inflammation, as well as histological and molecular signals of the two diseases.
The pathophysiology of both AD and psoriasis is nebulously complex, sharing a similar theme of immune dysregulation, but historically polar opposites based on the different branches of the immune response implicated.
The study is not the only recent work tying TWEAK/Fn14 to dermatologic diseases. Other recent papers have shown evidence of their involvement in chronic cutaneous lupus (J Invest Dermatol. 2015;135[8]:1986-95), UVB irradiation-induced cutaneous lupus (Exp Dermatol. 2016 Dec;25[12]:969-76), and bullous pemphigoid (J Invest Dermatol. 2017 Jul;137[7]:1512-22).
The spate of findings hint that TWEAK/Fn14 could be a novel therapeutic pathway to attack inflammatory disease. Many therapies for autoimmune disease focus on immunosuppressive agents, which are associated with an increased risk of infection. But mice engineered to lack either TWEAK or Fn14 appear normal, and a phase I trial of an anti-TWEAK antibody in patients with rheumatoid arthritis did not reveal any worrisome safety concerns. “It doesn’t seem to have the broad immunosuppressive effects which characterize the therapies we currently use,” said Chaim Putterman, MD, chief of the division of rheumatology and professor of medicine and microbiology & immunology at the Albert Einstein College of Medicine, New York.
Instead, TWEAK seems to be regulating inflammation in target organs. It almost certainly plays a role in healthy functions like wound healing and cell survival, but Dr. Putterman believes there are redundant mechanisms that can pick up the slack, as the healthy knockout mice attest. The evidence suggests that the TWEAK pathway may become overactive in some diseases and, if so, a therapeutic antibody might be able to reset it to a more normal balance. “The utopian vision is that you would block this cytokine and bring its downstream effects back to normal levels, rather than totally abrogating its homeostatic functions,” Dr. Putterman noted.
Because blocking TWEAK has no apparent immunosuppressive effects, it might be a candidate for combination therapy with existing cytotoxic drugs. “If you have a disease like psoriasis where some standard of care medications are immunosuppressive, such as methotrexate, you might not get more risk by adding an antibody targeting TWEAK, as opposed to using immunosuppressives in combination. That, I think, has potential,” he said.
Work remains, however. A proof-of-concept study in lupus nephritis, sponsored by Biogen, failed to show a benefit when an anti-TWEAK antibody was combined with the standard of care.
But the potential impact of this approach holds much promise, and the fact that TWEAK has been linked to multiple diseases should make it a more attractive drug target for drug companies. “Now we have a target, that if you knock it out, or its receptor, you can potentially affect both diseases. This may the start of a whole new direction for biologics to treat inflammatory disease, and cancer as well,” Dr. Friedman said.
Dr. Putterman and Dr. Friedman were among the authors of the 2015 JID study on TWEAK/Fn14 signaling in spontaneous lupus and the Experimental Dermatology study. Dr. Putterman has research funding from Biogen Idec. Dr. Friedman had no related disclosures. The authors of the Nature Communications study were from the La Jolla Institute for Allergy and Immunology, and Biogen.
An immunomodulatory pathway that has been linked to cancer, kidney disease, and other disease processes is becoming a focus of dermatologic research.
New evidence suggests that TNF-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis family (TNF) superfamily, may be involved in both atopic dermatitis (AD) and psoriasis (Nat Commun. 2017 May 22;8:15395. doi: 10.1038/ncomms15395). The research showed that mice engineered to have low TWEAK levels had less severe disease when both AD and psoriasis were induced.
The TWEAK receptor, Fn14, was upregulated in keratinocytes and dermal fibroblasts in mouse disease models of AD and psoriasis, and TWEAK induced production of a range of cytokines associated with both AD and psoriasis. Subcutaneous injection of recombinant TWEAK led to cutaneous inflammation, as well as histological and molecular signals of the two diseases.
The pathophysiology of both AD and psoriasis is nebulously complex, sharing a similar theme of immune dysregulation, but historically polar opposites based on the different branches of the immune response implicated.
The study is not the only recent work tying TWEAK/Fn14 to dermatologic diseases. Other recent papers have shown evidence of their involvement in chronic cutaneous lupus (J Invest Dermatol. 2015;135[8]:1986-95), UVB irradiation-induced cutaneous lupus (Exp Dermatol. 2016 Dec;25[12]:969-76), and bullous pemphigoid (J Invest Dermatol. 2017 Jul;137[7]:1512-22).
The spate of findings hint that TWEAK/Fn14 could be a novel therapeutic pathway to attack inflammatory disease. Many therapies for autoimmune disease focus on immunosuppressive agents, which are associated with an increased risk of infection. But mice engineered to lack either TWEAK or Fn14 appear normal, and a phase I trial of an anti-TWEAK antibody in patients with rheumatoid arthritis did not reveal any worrisome safety concerns. “It doesn’t seem to have the broad immunosuppressive effects which characterize the therapies we currently use,” said Chaim Putterman, MD, chief of the division of rheumatology and professor of medicine and microbiology & immunology at the Albert Einstein College of Medicine, New York.
Instead, TWEAK seems to be regulating inflammation in target organs. It almost certainly plays a role in healthy functions like wound healing and cell survival, but Dr. Putterman believes there are redundant mechanisms that can pick up the slack, as the healthy knockout mice attest. The evidence suggests that the TWEAK pathway may become overactive in some diseases and, if so, a therapeutic antibody might be able to reset it to a more normal balance. “The utopian vision is that you would block this cytokine and bring its downstream effects back to normal levels, rather than totally abrogating its homeostatic functions,” Dr. Putterman noted.
Because blocking TWEAK has no apparent immunosuppressive effects, it might be a candidate for combination therapy with existing cytotoxic drugs. “If you have a disease like psoriasis where some standard of care medications are immunosuppressive, such as methotrexate, you might not get more risk by adding an antibody targeting TWEAK, as opposed to using immunosuppressives in combination. That, I think, has potential,” he said.
Work remains, however. A proof-of-concept study in lupus nephritis, sponsored by Biogen, failed to show a benefit when an anti-TWEAK antibody was combined with the standard of care.
But the potential impact of this approach holds much promise, and the fact that TWEAK has been linked to multiple diseases should make it a more attractive drug target for drug companies. “Now we have a target, that if you knock it out, or its receptor, you can potentially affect both diseases. This may the start of a whole new direction for biologics to treat inflammatory disease, and cancer as well,” Dr. Friedman said.
Dr. Putterman and Dr. Friedman were among the authors of the 2015 JID study on TWEAK/Fn14 signaling in spontaneous lupus and the Experimental Dermatology study. Dr. Putterman has research funding from Biogen Idec. Dr. Friedman had no related disclosures. The authors of the Nature Communications study were from the La Jolla Institute for Allergy and Immunology, and Biogen.
VIDEO: Troponin acts as atherosclerotic biomarker in patients with lupus
MADRID – Measuring levels of troponin, a well-known cardiac biomarker, could help identify patients with systemic lupus erythematosus (SLE) at particularly high risk for cardiovascular (CV) events, according to the results of a cross-sectional study presented at the European Congress of Rheumatology.
Karim Sacré, MD, presented the findings of the study that looked for possible biomarkers of atherosclerosis in patients with SLE and provide preliminary evidence that high-sensitivity troponin T (HS-cTnT) was predictive regardless of whether or not patients already had visible atherosclerotic plaques on vascular ultrasound.
“Patients with SLE have been known to be at risk for cardiovascular disease for at least a decade,” Dr. Sacré of Bichat Hospital, University of Paris-Diderot, France, said in an interview at the meeting. Today, SLE is considered an independent risk factor for CV events, much like diabetes, he added.
However, determining which patients with lupus will and which will not develop cardiac problems is still tricky in routine practice. This is because the traditional ways of assessing CV events do not fully account for the increased risk seen in lupus patients. Indeed, the Framingham risk score, which is based on several risk factors such as tobacco use, hypertension, and dyslipidemia, has been shown to underestimate the cardiovascular risk of lupus patients, he observed.
“So, we need something that will help clinicians to better define the real risk of cardiovascular disease in such populations,” he said at an earlier press conference.
Thus, the objective of the study he presented was to try to find a biomarker in the blood that might aid clinicians in identifying which patients who had SLE and no obvious cardiac symptoms might be at risk for future CV events.
The study involved 63 patients with SLE who were consecutively recruited and 18 individuals without SLE who were used as controls. None had any symptoms of cardiovascular disease at recruitment, and all were assessed prospectively by vascular ultrasound for the presence of atherosclerotic plaques in the carotid artery.
The concentration of HS-cTnT was measured in the serum by using an electrochemiluminescence method, which could detect a concentration level greater than 3 ng/L .
At recruitment, the Framingham risk score was low (2.1) in both patients and controls, none of whom showed any signs of already having cardiovascular disease. The results of the carotid ultrasound, however, showed a different story for the SLE patients, with 23 (36.5%) identified as having carotid plaques, compared with just 2 (11.1%) of the control group.
Serum HS-cTNT could be detected in more SLE patients than controls (58.7% vs. 33.3%; P = .057), and the SLE patients who had detectable levels were nine times more likely than controls to have a carotid plaque, Dr. Sacré reported, although the 95% confidence interval was wide (1.55 to 90.07; P = .033).
Interestingly, a higher percentage of SLE patients with carotid plaques than those without had detectable HS-cTNT (87% vs. 42.5%; P less than .001). Conversely, more patients with detectable HS-cTnT than without had a carotid plaque (54.5% vs. 11.5%; P less than .001).
In multivariate analyses, only SLE status and age were significantly associated with having carotid plaques, and body mass index and HS-cTnT (P = .033) were statistically associated with the presence of carotid plaques in SLE patients.
The research is, of course, preliminary, Dr. Sacré emphasized, and further investigation is needed. The study looked at subclinical disease rather than actual CV events, and that is something to look at next in a larger cohort of patients with a longer follow-up period, he said.
Dr. Sacré disclosed that he had received support for travel to the EULAR Congress from Roche Diagnostics France.
*This story was updated 6/20/2017.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
MADRID – Measuring levels of troponin, a well-known cardiac biomarker, could help identify patients with systemic lupus erythematosus (SLE) at particularly high risk for cardiovascular (CV) events, according to the results of a cross-sectional study presented at the European Congress of Rheumatology.
Karim Sacré, MD, presented the findings of the study that looked for possible biomarkers of atherosclerosis in patients with SLE and provide preliminary evidence that high-sensitivity troponin T (HS-cTnT) was predictive regardless of whether or not patients already had visible atherosclerotic plaques on vascular ultrasound.
“Patients with SLE have been known to be at risk for cardiovascular disease for at least a decade,” Dr. Sacré of Bichat Hospital, University of Paris-Diderot, France, said in an interview at the meeting. Today, SLE is considered an independent risk factor for CV events, much like diabetes, he added.
However, determining which patients with lupus will and which will not develop cardiac problems is still tricky in routine practice. This is because the traditional ways of assessing CV events do not fully account for the increased risk seen in lupus patients. Indeed, the Framingham risk score, which is based on several risk factors such as tobacco use, hypertension, and dyslipidemia, has been shown to underestimate the cardiovascular risk of lupus patients, he observed.
“So, we need something that will help clinicians to better define the real risk of cardiovascular disease in such populations,” he said at an earlier press conference.
Thus, the objective of the study he presented was to try to find a biomarker in the blood that might aid clinicians in identifying which patients who had SLE and no obvious cardiac symptoms might be at risk for future CV events.
The study involved 63 patients with SLE who were consecutively recruited and 18 individuals without SLE who were used as controls. None had any symptoms of cardiovascular disease at recruitment, and all were assessed prospectively by vascular ultrasound for the presence of atherosclerotic plaques in the carotid artery.
The concentration of HS-cTnT was measured in the serum by using an electrochemiluminescence method, which could detect a concentration level greater than 3 ng/L .
At recruitment, the Framingham risk score was low (2.1) in both patients and controls, none of whom showed any signs of already having cardiovascular disease. The results of the carotid ultrasound, however, showed a different story for the SLE patients, with 23 (36.5%) identified as having carotid plaques, compared with just 2 (11.1%) of the control group.
Serum HS-cTNT could be detected in more SLE patients than controls (58.7% vs. 33.3%; P = .057), and the SLE patients who had detectable levels were nine times more likely than controls to have a carotid plaque, Dr. Sacré reported, although the 95% confidence interval was wide (1.55 to 90.07; P = .033).
Interestingly, a higher percentage of SLE patients with carotid plaques than those without had detectable HS-cTNT (87% vs. 42.5%; P less than .001). Conversely, more patients with detectable HS-cTnT than without had a carotid plaque (54.5% vs. 11.5%; P less than .001).
In multivariate analyses, only SLE status and age were significantly associated with having carotid plaques, and body mass index and HS-cTnT (P = .033) were statistically associated with the presence of carotid plaques in SLE patients.
The research is, of course, preliminary, Dr. Sacré emphasized, and further investigation is needed. The study looked at subclinical disease rather than actual CV events, and that is something to look at next in a larger cohort of patients with a longer follow-up period, he said.
Dr. Sacré disclosed that he had received support for travel to the EULAR Congress from Roche Diagnostics France.
*This story was updated 6/20/2017.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
MADRID – Measuring levels of troponin, a well-known cardiac biomarker, could help identify patients with systemic lupus erythematosus (SLE) at particularly high risk for cardiovascular (CV) events, according to the results of a cross-sectional study presented at the European Congress of Rheumatology.
Karim Sacré, MD, presented the findings of the study that looked for possible biomarkers of atherosclerosis in patients with SLE and provide preliminary evidence that high-sensitivity troponin T (HS-cTnT) was predictive regardless of whether or not patients already had visible atherosclerotic plaques on vascular ultrasound.
“Patients with SLE have been known to be at risk for cardiovascular disease for at least a decade,” Dr. Sacré of Bichat Hospital, University of Paris-Diderot, France, said in an interview at the meeting. Today, SLE is considered an independent risk factor for CV events, much like diabetes, he added.
However, determining which patients with lupus will and which will not develop cardiac problems is still tricky in routine practice. This is because the traditional ways of assessing CV events do not fully account for the increased risk seen in lupus patients. Indeed, the Framingham risk score, which is based on several risk factors such as tobacco use, hypertension, and dyslipidemia, has been shown to underestimate the cardiovascular risk of lupus patients, he observed.
“So, we need something that will help clinicians to better define the real risk of cardiovascular disease in such populations,” he said at an earlier press conference.
Thus, the objective of the study he presented was to try to find a biomarker in the blood that might aid clinicians in identifying which patients who had SLE and no obvious cardiac symptoms might be at risk for future CV events.
The study involved 63 patients with SLE who were consecutively recruited and 18 individuals without SLE who were used as controls. None had any symptoms of cardiovascular disease at recruitment, and all were assessed prospectively by vascular ultrasound for the presence of atherosclerotic plaques in the carotid artery.
The concentration of HS-cTnT was measured in the serum by using an electrochemiluminescence method, which could detect a concentration level greater than 3 ng/L .
At recruitment, the Framingham risk score was low (2.1) in both patients and controls, none of whom showed any signs of already having cardiovascular disease. The results of the carotid ultrasound, however, showed a different story for the SLE patients, with 23 (36.5%) identified as having carotid plaques, compared with just 2 (11.1%) of the control group.
Serum HS-cTNT could be detected in more SLE patients than controls (58.7% vs. 33.3%; P = .057), and the SLE patients who had detectable levels were nine times more likely than controls to have a carotid plaque, Dr. Sacré reported, although the 95% confidence interval was wide (1.55 to 90.07; P = .033).
Interestingly, a higher percentage of SLE patients with carotid plaques than those without had detectable HS-cTNT (87% vs. 42.5%; P less than .001). Conversely, more patients with detectable HS-cTnT than without had a carotid plaque (54.5% vs. 11.5%; P less than .001).
In multivariate analyses, only SLE status and age were significantly associated with having carotid plaques, and body mass index and HS-cTnT (P = .033) were statistically associated with the presence of carotid plaques in SLE patients.
The research is, of course, preliminary, Dr. Sacré emphasized, and further investigation is needed. The study looked at subclinical disease rather than actual CV events, and that is something to look at next in a larger cohort of patients with a longer follow-up period, he said.
Dr. Sacré disclosed that he had received support for travel to the EULAR Congress from Roche Diagnostics France.
*This story was updated 6/20/2017.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE EULAR 2017 CONGRESS
CC-220 shows efficacy, safety concerns in phase II SLE trial
PORTLAND – The investigational agent CC-220 showed some efficacy but important safety signals in a 12-week, phase II, dose-escalation study of 42 patients with systemic lupus erythematosus (SLE).
In all, 14% of patients stopped treatment because of adverse effects, including five patients who were receiving CC-220 and one patient on placebo, Victoria Werth, MD, of the University of Pennsylvania, Philadelphia, said during a poster presentation at the annual meeting of the Society for Investigative Dermatology. Higher doses of CC-220 were associated with neutropenia, pneumonia, and dermatitis, she reported.
About 79% of patients completed the study, and none stopped because of lack of efficacy, Dr. Werth said. The most common treatment-emergent adverse effects were mild to moderate nausea and diarrhea. However, four patients experienced serious adverse events, including two patients in the placebo group and two patients who developed pneumonia at the highest (0.6 mg per day) CC-220 dose. In the two highest-dose groups, two patients also developed grade 3 neutropenia, one patient developed grade 1 neutropenia, and there were two cases each of dermatitis and urticaria.
CC-220 appeared to improve scores on the CLASI, SELENA-SENDAI, and PGA, Dr. Werth said. Average drops from baseline on the CLASI ranged from 0 (placebo group) to 7 points (0.3 mg every other day), and were 5 points at 0.3 mg daily, 4 points at alternating doses of 0.3 mg and 0.6 mg, and 6 points at the highest dose of 0.6 mg daily. Among patients whose baseline CLASI score was at least 10, mean decreases ranged between 0 (placebo) and 26 points (0.3 mg daily), and average decreases for the other groups were 9 points (0.3 mg every other day and 0.3 mg alternating with 0.6 mg) or 13 points (0.6 mg daily).
Compared with the placebo group, a greater proportion of CC-220 recipients also had at least a 4-point drop on SELENA-SENDAI and tended to improve more on the tender joint count and the swollen joint count, said Dr. Werth. The average drop in mean PGA score ranged between 0 (placebo group) and 0.9 (0.3 mg per day) and did not show a dose-response trend. The relatively small number of patients in this study and some variability in baseline SLE disease activity made it difficult to draw conclusions about dose-response relationships, Dr. Werth noted. However, there were signs of an overall dose-response trend when pooling mean changes in CLASI, tender and swollen joint counts, SELENA-SLEDAI, and PGA scores.
In terms of pharmacodynamics, doses of at least 0.3 mg CC-220 per day were associated with marked decreases in circulating plasmacytoid dendritic cells and B-cell subsets, which began as early as day 29, Dr. Werth said. Cereblon is part of the cullin-ring finger ligase-4 complex, she explained. Previous work has shown that CC-220 binds with high affinity to cereblon, inducing ubiquitination and increased breakdown of the transcription factors IKZF1 and IKZF3. The end result is an altered immune response.
This study includes an optional 2-year extension phase at the three highest doses of CC-220. Celgene also plans a phase IIb proof-of-concept study in a “broader SLE population,” Dr. Werth said.
Celgene funded the study. Dr. Werth disclosed grant or research support from Celgene, Janssen, Biogen, Roche, and Corbus Pharmaceuticals, and consulting or advisory fees from Celgene, Janssen, Genentech, and several other pharmaceutical companies.
PORTLAND – The investigational agent CC-220 showed some efficacy but important safety signals in a 12-week, phase II, dose-escalation study of 42 patients with systemic lupus erythematosus (SLE).
In all, 14% of patients stopped treatment because of adverse effects, including five patients who were receiving CC-220 and one patient on placebo, Victoria Werth, MD, of the University of Pennsylvania, Philadelphia, said during a poster presentation at the annual meeting of the Society for Investigative Dermatology. Higher doses of CC-220 were associated with neutropenia, pneumonia, and dermatitis, she reported.
About 79% of patients completed the study, and none stopped because of lack of efficacy, Dr. Werth said. The most common treatment-emergent adverse effects were mild to moderate nausea and diarrhea. However, four patients experienced serious adverse events, including two patients in the placebo group and two patients who developed pneumonia at the highest (0.6 mg per day) CC-220 dose. In the two highest-dose groups, two patients also developed grade 3 neutropenia, one patient developed grade 1 neutropenia, and there were two cases each of dermatitis and urticaria.
CC-220 appeared to improve scores on the CLASI, SELENA-SENDAI, and PGA, Dr. Werth said. Average drops from baseline on the CLASI ranged from 0 (placebo group) to 7 points (0.3 mg every other day), and were 5 points at 0.3 mg daily, 4 points at alternating doses of 0.3 mg and 0.6 mg, and 6 points at the highest dose of 0.6 mg daily. Among patients whose baseline CLASI score was at least 10, mean decreases ranged between 0 (placebo) and 26 points (0.3 mg daily), and average decreases for the other groups were 9 points (0.3 mg every other day and 0.3 mg alternating with 0.6 mg) or 13 points (0.6 mg daily).
Compared with the placebo group, a greater proportion of CC-220 recipients also had at least a 4-point drop on SELENA-SENDAI and tended to improve more on the tender joint count and the swollen joint count, said Dr. Werth. The average drop in mean PGA score ranged between 0 (placebo group) and 0.9 (0.3 mg per day) and did not show a dose-response trend. The relatively small number of patients in this study and some variability in baseline SLE disease activity made it difficult to draw conclusions about dose-response relationships, Dr. Werth noted. However, there were signs of an overall dose-response trend when pooling mean changes in CLASI, tender and swollen joint counts, SELENA-SLEDAI, and PGA scores.
In terms of pharmacodynamics, doses of at least 0.3 mg CC-220 per day were associated with marked decreases in circulating plasmacytoid dendritic cells and B-cell subsets, which began as early as day 29, Dr. Werth said. Cereblon is part of the cullin-ring finger ligase-4 complex, she explained. Previous work has shown that CC-220 binds with high affinity to cereblon, inducing ubiquitination and increased breakdown of the transcription factors IKZF1 and IKZF3. The end result is an altered immune response.
This study includes an optional 2-year extension phase at the three highest doses of CC-220. Celgene also plans a phase IIb proof-of-concept study in a “broader SLE population,” Dr. Werth said.
Celgene funded the study. Dr. Werth disclosed grant or research support from Celgene, Janssen, Biogen, Roche, and Corbus Pharmaceuticals, and consulting or advisory fees from Celgene, Janssen, Genentech, and several other pharmaceutical companies.
PORTLAND – The investigational agent CC-220 showed some efficacy but important safety signals in a 12-week, phase II, dose-escalation study of 42 patients with systemic lupus erythematosus (SLE).
In all, 14% of patients stopped treatment because of adverse effects, including five patients who were receiving CC-220 and one patient on placebo, Victoria Werth, MD, of the University of Pennsylvania, Philadelphia, said during a poster presentation at the annual meeting of the Society for Investigative Dermatology. Higher doses of CC-220 were associated with neutropenia, pneumonia, and dermatitis, she reported.
About 79% of patients completed the study, and none stopped because of lack of efficacy, Dr. Werth said. The most common treatment-emergent adverse effects were mild to moderate nausea and diarrhea. However, four patients experienced serious adverse events, including two patients in the placebo group and two patients who developed pneumonia at the highest (0.6 mg per day) CC-220 dose. In the two highest-dose groups, two patients also developed grade 3 neutropenia, one patient developed grade 1 neutropenia, and there were two cases each of dermatitis and urticaria.
CC-220 appeared to improve scores on the CLASI, SELENA-SENDAI, and PGA, Dr. Werth said. Average drops from baseline on the CLASI ranged from 0 (placebo group) to 7 points (0.3 mg every other day), and were 5 points at 0.3 mg daily, 4 points at alternating doses of 0.3 mg and 0.6 mg, and 6 points at the highest dose of 0.6 mg daily. Among patients whose baseline CLASI score was at least 10, mean decreases ranged between 0 (placebo) and 26 points (0.3 mg daily), and average decreases for the other groups were 9 points (0.3 mg every other day and 0.3 mg alternating with 0.6 mg) or 13 points (0.6 mg daily).
Compared with the placebo group, a greater proportion of CC-220 recipients also had at least a 4-point drop on SELENA-SENDAI and tended to improve more on the tender joint count and the swollen joint count, said Dr. Werth. The average drop in mean PGA score ranged between 0 (placebo group) and 0.9 (0.3 mg per day) and did not show a dose-response trend. The relatively small number of patients in this study and some variability in baseline SLE disease activity made it difficult to draw conclusions about dose-response relationships, Dr. Werth noted. However, there were signs of an overall dose-response trend when pooling mean changes in CLASI, tender and swollen joint counts, SELENA-SLEDAI, and PGA scores.
In terms of pharmacodynamics, doses of at least 0.3 mg CC-220 per day were associated with marked decreases in circulating plasmacytoid dendritic cells and B-cell subsets, which began as early as day 29, Dr. Werth said. Cereblon is part of the cullin-ring finger ligase-4 complex, she explained. Previous work has shown that CC-220 binds with high affinity to cereblon, inducing ubiquitination and increased breakdown of the transcription factors IKZF1 and IKZF3. The end result is an altered immune response.
This study includes an optional 2-year extension phase at the three highest doses of CC-220. Celgene also plans a phase IIb proof-of-concept study in a “broader SLE population,” Dr. Werth said.
Celgene funded the study. Dr. Werth disclosed grant or research support from Celgene, Janssen, Biogen, Roche, and Corbus Pharmaceuticals, and consulting or advisory fees from Celgene, Janssen, Genentech, and several other pharmaceutical companies.
AT SID 2017
Key clinical point:
Major finding: Among patients whose baseline CLASI score was at least 10, mean decreases ranged between 0 (placebo), and 26 points (0.3 mg daily).
Data source: A 12-week, phase II, placebo-controlled dose-escalation study of 42 patients with systemic lupus erythematosus.
Disclosures: Celgene funded the study. Dr. Werth disclosed grant or research support from Celgene, Janssen, Biogen, Roche, and Corbus Pharmaceuticals, and consulting or advisory fees from Celgene, Janssen, Genentech, and several other pharmaceutical companies.