Autoimmune Diseases

Cutaneous lupus erythematosus (CLE) is present in 25% of patients with systemic lupus at the time of diagnosis, but it can also occur in up to 85% of cases at some point in their disease course, Eveline Y. Wu, MD, said during the virtual annual meeting of the Society for Pediatric Dermatology.

“CLE can also occur without any systemic disease,” said Dr. Wu, associate professor of pediatrics at the University of North Carolina at Chapel Hill. “It’s been shown that the risk of developing systemic lupus differs according to the type of skin involvement, meaning that cutaneous lupus can be classified into acute, subacute, chronic, and intermittent forms.”

Malar rash is the prototypical acute cutaneous lesion and is associated with active systemic lupus erythematosus (SLE) and anti–double stranded DNA antibody positivity, while discoid lupus erythematosus is the most common chronic lesion. “A small percentage of patients with discoid lupus can develop systemic lupus, particularly when the lesions are more disseminated,” said Dr. Wu, who specializes in pediatric rheumatology as well as allergy and immunology.

In the American College of Rheumatology’s 1997 classification system, mucocutaneous manifestations constitute 4 out of the 11 criteria that clinicians use to make a diagnosis of SLE: malar rash, discoid-lupus rash, photosensitivity, and oral or nasal mucocutaneous ulcerations. Dr. Wu recommends performing an oral exam on suspect cases, “because the oral ulcers that we see in systemic lupus tend to be painless, so oftentimes patients don’t realize they have them.”

Five other organ-specific manifestations of SLE include nonerosive arthritis, nephritis, encephalopathy, pleuritis or pericarditis, and cytopenia. The two other criteria are positive immunoserology and a positive antinuclear antibody test. “If you have any individuals present with one of these [mucocutaneous manifestations criteria], you want to think about getting a CBC to look for cytopenia or a urinalysis to look for evidence of nephritis, and potentially some additional blood studies, depending on your level of suspicion for systemic lupus,” Dr. Wu said.

Other rarer CLE manifestations include lupus pernio or chilblains, lupus panniculitis, livedo reticularis, bullous LE, urticarial vasculitis, neutrophilic dermatoses, and alopecia.

Common treatments for cutaneous manifestations associated pediatric SLE include hydroxychloroquine, low dose corticosteroids, topical steroids, methotrexate, and leflunomide. Other options for increasing severity of systemic disease include lenalidomide/thalidomide, azathioprine, calcineurin inhibitors, belimumab (Benlysta), high-dose corticosteroids, mycophenolate mofetil (CellCept), rituximab (Rituxan), and cyclophosphamide. Cutaneous manifestations of pediatric SLE can often be refractory to treatments.

In 2017, Dr. Wu and associates published a retrospective chart review of 10 adolescents who received lenalidomide for refractory CLE. One of the subjects was a 21-year-old male with a significant malar rash despite being on hydroxychloroquine, azathioprine, and prednisone 40 mg daily. “One month after being on lenalidomide he had a pretty impressive response,” Dr. Wu said. “It’s not quite clear how lenalidomide works in cutaneous lupus. Currently it’s only approved for use in myelodysplastic syndromes, multiple myeloma, as well as certain lymphomas. It’s thought to modulate different parts of the immune system, which collectively result in the cytotoxicity against tumor cells.”

Lenalidomide is supplied in capsule sizes ranging from 2.5 mg to 25 mg and is given once daily. “For a smaller child, I would think about starting 5 mg once a day,” Dr. Wu said. “For an adult-sized adolescent, you could start at 10 mg once a day and then titrate up based on response. Side effects that you need to worry about are cytopenia and GI symptoms. The venous and arterial thromboembolism risk has been seen in patients with multiple myeloma, and it is unclear if this risk is applicable to all indications.” Use of the medication requires enrollment into a safety monitoring program.

She reported having no financial disclosures.

[email protected]

Cutaneous lupus erythematosus (CLE) is present in 25% of patients with systemic lupus at the time of diagnosis, but it can also occur in up to 85% of cases at some point in their disease course, Eveline Y. Wu, MD, said during the virtual annual meeting of the Society for Pediatric Dermatology.

“CLE can also occur without any systemic disease,” said Dr. Wu, associate professor of pediatrics at the University of North Carolina at Chapel Hill. “It’s been shown that the risk of developing systemic lupus differs according to the type of skin involvement, meaning that cutaneous lupus can be classified into acute, subacute, chronic, and intermittent forms.”

Malar rash is the prototypical acute cutaneous lesion and is associated with active systemic lupus erythematosus (SLE) and anti–double stranded DNA antibody positivity, while discoid lupus erythematosus is the most common chronic lesion. “A small percentage of patients with discoid lupus can develop systemic lupus, particularly when the lesions are more disseminated,” said Dr. Wu, who specializes in pediatric rheumatology as well as allergy and immunology.

In the American College of Rheumatology’s 1997 classification system, mucocutaneous manifestations constitute 4 out of the 11 criteria that clinicians use to make a diagnosis of SLE: malar rash, discoid-lupus rash, photosensitivity, and oral or nasal mucocutaneous ulcerations. Dr. Wu recommends performing an oral exam on suspect cases, “because the oral ulcers that we see in systemic lupus tend to be painless, so oftentimes patients don’t realize they have them.”

Five other organ-specific manifestations of SLE include nonerosive arthritis, nephritis, encephalopathy, pleuritis or pericarditis, and cytopenia. The two other criteria are positive immunoserology and a positive antinuclear antibody test. “If you have any individuals present with one of these [mucocutaneous manifestations criteria], you want to think about getting a CBC to look for cytopenia or a urinalysis to look for evidence of nephritis, and potentially some additional blood studies, depending on your level of suspicion for systemic lupus,” Dr. Wu said.

Other rarer CLE manifestations include lupus pernio or chilblains, lupus panniculitis, livedo reticularis, bullous LE, urticarial vasculitis, neutrophilic dermatoses, and alopecia.

Common treatments for cutaneous manifestations associated pediatric SLE include hydroxychloroquine, low dose corticosteroids, topical steroids, methotrexate, and leflunomide. Other options for increasing severity of systemic disease include lenalidomide/thalidomide, azathioprine, calcineurin inhibitors, belimumab (Benlysta), high-dose corticosteroids, mycophenolate mofetil (CellCept), rituximab (Rituxan), and cyclophosphamide. Cutaneous manifestations of pediatric SLE can often be refractory to treatments.

In 2017, Dr. Wu and associates published a retrospective chart review of 10 adolescents who received lenalidomide for refractory CLE. One of the subjects was a 21-year-old male with a significant malar rash despite being on hydroxychloroquine, azathioprine, and prednisone 40 mg daily. “One month after being on lenalidomide he had a pretty impressive response,” Dr. Wu said. “It’s not quite clear how lenalidomide works in cutaneous lupus. Currently it’s only approved for use in myelodysplastic syndromes, multiple myeloma, as well as certain lymphomas. It’s thought to modulate different parts of the immune system, which collectively result in the cytotoxicity against tumor cells.”

Lenalidomide is supplied in capsule sizes ranging from 2.5 mg to 25 mg and is given once daily. “For a smaller child, I would think about starting 5 mg once a day,” Dr. Wu said. “For an adult-sized adolescent, you could start at 10 mg once a day and then titrate up based on response. Side effects that you need to worry about are cytopenia and GI symptoms. The venous and arterial thromboembolism risk has been seen in patients with multiple myeloma, and it is unclear if this risk is applicable to all indications.” Use of the medication requires enrollment into a safety monitoring program.

She reported having no financial disclosures.

[email protected]

Cutaneous lupus erythematosus (CLE) is present in 25% of patients with systemic lupus at the time of diagnosis, but it can also occur in up to 85% of cases at some point in their disease course, Eveline Y. Wu, MD, said during the virtual annual meeting of the Society for Pediatric Dermatology.

“CLE can also occur without any systemic disease,” said Dr. Wu, associate professor of pediatrics at the University of North Carolina at Chapel Hill. “It’s been shown that the risk of developing systemic lupus differs according to the type of skin involvement, meaning that cutaneous lupus can be classified into acute, subacute, chronic, and intermittent forms.”

Malar rash is the prototypical acute cutaneous lesion and is associated with active systemic lupus erythematosus (SLE) and anti–double stranded DNA antibody positivity, while discoid lupus erythematosus is the most common chronic lesion. “A small percentage of patients with discoid lupus can develop systemic lupus, particularly when the lesions are more disseminated,” said Dr. Wu, who specializes in pediatric rheumatology as well as allergy and immunology.

In the American College of Rheumatology’s 1997 classification system, mucocutaneous manifestations constitute 4 out of the 11 criteria that clinicians use to make a diagnosis of SLE: malar rash, discoid-lupus rash, photosensitivity, and oral or nasal mucocutaneous ulcerations. Dr. Wu recommends performing an oral exam on suspect cases, “because the oral ulcers that we see in systemic lupus tend to be painless, so oftentimes patients don’t realize they have them.”

Five other organ-specific manifestations of SLE include nonerosive arthritis, nephritis, encephalopathy, pleuritis or pericarditis, and cytopenia. The two other criteria are positive immunoserology and a positive antinuclear antibody test. “If you have any individuals present with one of these [mucocutaneous manifestations criteria], you want to think about getting a CBC to look for cytopenia or a urinalysis to look for evidence of nephritis, and potentially some additional blood studies, depending on your level of suspicion for systemic lupus,” Dr. Wu said.

Other rarer CLE manifestations include lupus pernio or chilblains, lupus panniculitis, livedo reticularis, bullous LE, urticarial vasculitis, neutrophilic dermatoses, and alopecia.

Common treatments for cutaneous manifestations associated pediatric SLE include hydroxychloroquine, low dose corticosteroids, topical steroids, methotrexate, and leflunomide. Other options for increasing severity of systemic disease include lenalidomide/thalidomide, azathioprine, calcineurin inhibitors, belimumab (Benlysta), high-dose corticosteroids, mycophenolate mofetil (CellCept), rituximab (Rituxan), and cyclophosphamide. Cutaneous manifestations of pediatric SLE can often be refractory to treatments.

In 2017, Dr. Wu and associates published a retrospective chart review of 10 adolescents who received lenalidomide for refractory CLE. One of the subjects was a 21-year-old male with a significant malar rash despite being on hydroxychloroquine, azathioprine, and prednisone 40 mg daily. “One month after being on lenalidomide he had a pretty impressive response,” Dr. Wu said. “It’s not quite clear how lenalidomide works in cutaneous lupus. Currently it’s only approved for use in myelodysplastic syndromes, multiple myeloma, as well as certain lymphomas. It’s thought to modulate different parts of the immune system, which collectively result in the cytotoxicity against tumor cells.”

Lenalidomide is supplied in capsule sizes ranging from 2.5 mg to 25 mg and is given once daily. “For a smaller child, I would think about starting 5 mg once a day,” Dr. Wu said. “For an adult-sized adolescent, you could start at 10 mg once a day and then titrate up based on response. Side effects that you need to worry about are cytopenia and GI symptoms. The venous and arterial thromboembolism risk has been seen in patients with multiple myeloma, and it is unclear if this risk is applicable to all indications.” Use of the medication requires enrollment into a safety monitoring program.

She reported having no financial disclosures.

[email protected]

Clinicians shouldn’t rely on pulmonary function tests (PFTs) alone to screen for interstitial lung disease (ILD). The tests performed poorly in a retrospective study of 212 patients with systemic sclerosis, reinforcing the findings of previous studies.

Any screening algorithm should include high-resolution CT (HRCT), which is good at prognosticating disease, the investigators wrote in Arthritis & Rheumatology. “I think all newly diagnosed systemic sclerosis patients should have a full set of PFTs (spirometry, lung volumes, and diffusion capacity) and an HRCT at baseline to evaluate for ILD,” the study’s lead author, Elana J. Bernstein, MD, said in an interview.

ILD is a leading cause of death in systemic sclerosis (SSc) patients, affecting 40%-60% of those with the disease. HRCT is currently the preferred option for detection of ILD. PFTs are commonly used to screen for ILD but haven’t performed well in previous studies. “Someone can have abnormalities on HRCT that are consistent with ILD but still have PFTs that are in the ‘normal’ range,” explained Dr. Bernstein of Columbia University, New York. One cross-sectional study of 102 SSc patients found that the test’s sensitivity for the detection of ILD on HRCT was just 37.5% when forced vital capacity (FVC) <80% predicted.

Investigators sought to assess performance characteristics of PFTs in patients with early diffuse cutaneous SSc, a cohort at high risk of developing ILD. The study enlisted patients from the Prospective Registry of Early Systemic Sclerosis (PRESS), a multicenter, prospective cohort study of adults with early diffuse cutaneous SSc. Overall, 212 patients at 11 U.S. academic medical centers participated in the study from April 2012 to January 2019.

All patients had spirometry (PFT) and HRCT chest scans. PFTs were conducted per American Thoracic Society/European Respiratory Society guidelines. The investigators calculated test characteristics for single PFT and combinations of PFT parameters for the detection of ILD on HRCT. The HRCTs were ordered at the discretion of treating physicians, and scrutinized for ILD features such as reticular changes, honeycombing, traction bronchiectasis, and ground-glass opacities. The investigators defined the lower limit of normal for FVC, total lung capacity, and diffusion capacity for carbon monoxide (DLCO) as 80% predicted.

Overall, Dr. Bernstein and her colleagues found that PFTs lacked sufficient sensitivity and negative predictive value for the detection of ILD on HRCT in these patients.

An FVC <80% predicted performed at only 63% sensitivity and an false negative rate of 37%. Total lung capacity or DLCO <80% predicted had a sensitivity of 46% and 80%, respectively. The combination of FVC or DLCO <80% predicted raised sensitivity to 85%. However, the addition of total lung capacity to this combination did not improve results.

Overall, PFTs had a positive predictive value of 64%-74% and an negative predictive value of 61%-70%. “This means that PFT alone will not accurately predict the presence of ILD in about 35%, and not be correctly negative in about 35%,” observed Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, and professor of rheumatology at the University of California, Los Angeles.

While the combination of FVC <80% predicted or DLCO <80% predicted performed better than the other parameters, the sensitivity “is inadequate for an ILD screening test as it results in an false negative rate of 15%, thereby falsely reassuring 15% of patients that they do not have ILD when in fact they do,” the investigators observed.

“This study reinforces the notion that PFTs alone are ineffective screening tools for ILD in the presence of systemic sclerosis, particularly for patients with early systemic sclerosis,” said Elizabeth Volkmann, MD, MS, assistant professor and codirector of the CTD-ILD program in the division of rheumatology at the University of California, Los Angeles.

The study’s scope was relatively small, yet the results provide further evidence to show that HRCT should be performed in all SSc patients to screen for the presence of ILD, Dr. Volkmann said in an interview.

Other research has demonstrated the value of baseline HRCT as a prognosticator of ILD outcomes. The method provides useful information about the degree of fibrosis and degree of damage in early-stage disease, said Dr. Furst, also an adjunct professor at the University of Washington, Seattle, and a research professor at the University of Florence (Italy). “If there’s honeycombing, that’s a bad prognosis. If it’s ground glass or reticular changes, the prognosis is better.

“Once there’s a lot of damage, it’s much harder to interpret disease with HRCT,” he added.

HRCT and PFT work well together to assess what’s happening in patients, Dr. Furst explained. HRCT provides an idea of anatomic changes, whereas PFT outlines aspects of functional change to diagnose early ILD in early diffuse SSc. The study results should not apply to patients with later disease who have more developed ILD, he noted.

The investigators acknowledged that they weren’t able to categorize and analyze patients according to disease extent because they didn’t quantify the extent of ILD. Another limitation was that the HRCTs and PFTs were ordered at the discretion of individual physicians, which means that not all participants received the tests.

“Although the tests were done in 90% of the population, there is still a probability of a significant selection bias,” Dr. Furst said.

Dr. Bernstein and several other coauthors in the study received grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases to support their work. Dr. Furst disclosed receiving grant/research support from and/or consulting for AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Corbus, the National Institutes of Health, Novartis, Pfizer, and Roche/Genentech. Dr. Volkmann disclosed consulting for and/or receiving grant support from Boehringer Ingelheim, Corbus, and Forbius.

SOURCE: Bernstein EJ et al. Arthritis Rheumatol. 2020 Jun 25. doi: 10.1002/art.41415.

Clinicians shouldn’t rely on pulmonary function tests (PFTs) alone to screen for interstitial lung disease (ILD). The tests performed poorly in a retrospective study of 212 patients with systemic sclerosis, reinforcing the findings of previous studies.

Any screening algorithm should include high-resolution CT (HRCT), which is good at prognosticating disease, the investigators wrote in Arthritis & Rheumatology. “I think all newly diagnosed systemic sclerosis patients should have a full set of PFTs (spirometry, lung volumes, and diffusion capacity) and an HRCT at baseline to evaluate for ILD,” the study’s lead author, Elana J. Bernstein, MD, said in an interview.

ILD is a leading cause of death in systemic sclerosis (SSc) patients, affecting 40%-60% of those with the disease. HRCT is currently the preferred option for detection of ILD. PFTs are commonly used to screen for ILD but haven’t performed well in previous studies. “Someone can have abnormalities on HRCT that are consistent with ILD but still have PFTs that are in the ‘normal’ range,” explained Dr. Bernstein of Columbia University, New York. One cross-sectional study of 102 SSc patients found that the test’s sensitivity for the detection of ILD on HRCT was just 37.5% when forced vital capacity (FVC) <80% predicted.

Investigators sought to assess performance characteristics of PFTs in patients with early diffuse cutaneous SSc, a cohort at high risk of developing ILD. The study enlisted patients from the Prospective Registry of Early Systemic Sclerosis (PRESS), a multicenter, prospective cohort study of adults with early diffuse cutaneous SSc. Overall, 212 patients at 11 U.S. academic medical centers participated in the study from April 2012 to January 2019.

All patients had spirometry (PFT) and HRCT chest scans. PFTs were conducted per American Thoracic Society/European Respiratory Society guidelines. The investigators calculated test characteristics for single PFT and combinations of PFT parameters for the detection of ILD on HRCT. The HRCTs were ordered at the discretion of treating physicians, and scrutinized for ILD features such as reticular changes, honeycombing, traction bronchiectasis, and ground-glass opacities. The investigators defined the lower limit of normal for FVC, total lung capacity, and diffusion capacity for carbon monoxide (DLCO) as 80% predicted.

Overall, Dr. Bernstein and her colleagues found that PFTs lacked sufficient sensitivity and negative predictive value for the detection of ILD on HRCT in these patients.

An FVC <80% predicted performed at only 63% sensitivity and an false negative rate of 37%. Total lung capacity or DLCO <80% predicted had a sensitivity of 46% and 80%, respectively. The combination of FVC or DLCO <80% predicted raised sensitivity to 85%. However, the addition of total lung capacity to this combination did not improve results.

Overall, PFTs had a positive predictive value of 64%-74% and an negative predictive value of 61%-70%. “This means that PFT alone will not accurately predict the presence of ILD in about 35%, and not be correctly negative in about 35%,” observed Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, and professor of rheumatology at the University of California, Los Angeles.

While the combination of FVC <80% predicted or DLCO <80% predicted performed better than the other parameters, the sensitivity “is inadequate for an ILD screening test as it results in an false negative rate of 15%, thereby falsely reassuring 15% of patients that they do not have ILD when in fact they do,” the investigators observed.

“This study reinforces the notion that PFTs alone are ineffective screening tools for ILD in the presence of systemic sclerosis, particularly for patients with early systemic sclerosis,” said Elizabeth Volkmann, MD, MS, assistant professor and codirector of the CTD-ILD program in the division of rheumatology at the University of California, Los Angeles.

The study’s scope was relatively small, yet the results provide further evidence to show that HRCT should be performed in all SSc patients to screen for the presence of ILD, Dr. Volkmann said in an interview.

Other research has demonstrated the value of baseline HRCT as a prognosticator of ILD outcomes. The method provides useful information about the degree of fibrosis and degree of damage in early-stage disease, said Dr. Furst, also an adjunct professor at the University of Washington, Seattle, and a research professor at the University of Florence (Italy). “If there’s honeycombing, that’s a bad prognosis. If it’s ground glass or reticular changes, the prognosis is better.

“Once there’s a lot of damage, it’s much harder to interpret disease with HRCT,” he added.

HRCT and PFT work well together to assess what’s happening in patients, Dr. Furst explained. HRCT provides an idea of anatomic changes, whereas PFT outlines aspects of functional change to diagnose early ILD in early diffuse SSc. The study results should not apply to patients with later disease who have more developed ILD, he noted.

The investigators acknowledged that they weren’t able to categorize and analyze patients according to disease extent because they didn’t quantify the extent of ILD. Another limitation was that the HRCTs and PFTs were ordered at the discretion of individual physicians, which means that not all participants received the tests.

“Although the tests were done in 90% of the population, there is still a probability of a significant selection bias,” Dr. Furst said.

Dr. Bernstein and several other coauthors in the study received grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases to support their work. Dr. Furst disclosed receiving grant/research support from and/or consulting for AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Corbus, the National Institutes of Health, Novartis, Pfizer, and Roche/Genentech. Dr. Volkmann disclosed consulting for and/or receiving grant support from Boehringer Ingelheim, Corbus, and Forbius.

SOURCE: Bernstein EJ et al. Arthritis Rheumatol. 2020 Jun 25. doi: 10.1002/art.41415.

Clinicians shouldn’t rely on pulmonary function tests (PFTs) alone to screen for interstitial lung disease (ILD). The tests performed poorly in a retrospective study of 212 patients with systemic sclerosis, reinforcing the findings of previous studies.

Any screening algorithm should include high-resolution CT (HRCT), which is good at prognosticating disease, the investigators wrote in Arthritis & Rheumatology. “I think all newly diagnosed systemic sclerosis patients should have a full set of PFTs (spirometry, lung volumes, and diffusion capacity) and an HRCT at baseline to evaluate for ILD,” the study’s lead author, Elana J. Bernstein, MD, said in an interview.

ILD is a leading cause of death in systemic sclerosis (SSc) patients, affecting 40%-60% of those with the disease. HRCT is currently the preferred option for detection of ILD. PFTs are commonly used to screen for ILD but haven’t performed well in previous studies. “Someone can have abnormalities on HRCT that are consistent with ILD but still have PFTs that are in the ‘normal’ range,” explained Dr. Bernstein of Columbia University, New York. One cross-sectional study of 102 SSc patients found that the test’s sensitivity for the detection of ILD on HRCT was just 37.5% when forced vital capacity (FVC) <80% predicted.

Investigators sought to assess performance characteristics of PFTs in patients with early diffuse cutaneous SSc, a cohort at high risk of developing ILD. The study enlisted patients from the Prospective Registry of Early Systemic Sclerosis (PRESS), a multicenter, prospective cohort study of adults with early diffuse cutaneous SSc. Overall, 212 patients at 11 U.S. academic medical centers participated in the study from April 2012 to January 2019.

All patients had spirometry (PFT) and HRCT chest scans. PFTs were conducted per American Thoracic Society/European Respiratory Society guidelines. The investigators calculated test characteristics for single PFT and combinations of PFT parameters for the detection of ILD on HRCT. The HRCTs were ordered at the discretion of treating physicians, and scrutinized for ILD features such as reticular changes, honeycombing, traction bronchiectasis, and ground-glass opacities. The investigators defined the lower limit of normal for FVC, total lung capacity, and diffusion capacity for carbon monoxide (DLCO) as 80% predicted.

Overall, Dr. Bernstein and her colleagues found that PFTs lacked sufficient sensitivity and negative predictive value for the detection of ILD on HRCT in these patients.

An FVC <80% predicted performed at only 63% sensitivity and an false negative rate of 37%. Total lung capacity or DLCO <80% predicted had a sensitivity of 46% and 80%, respectively. The combination of FVC or DLCO <80% predicted raised sensitivity to 85%. However, the addition of total lung capacity to this combination did not improve results.

Overall, PFTs had a positive predictive value of 64%-74% and an negative predictive value of 61%-70%. “This means that PFT alone will not accurately predict the presence of ILD in about 35%, and not be correctly negative in about 35%,” observed Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, and professor of rheumatology at the University of California, Los Angeles.

While the combination of FVC <80% predicted or DLCO <80% predicted performed better than the other parameters, the sensitivity “is inadequate for an ILD screening test as it results in an false negative rate of 15%, thereby falsely reassuring 15% of patients that they do not have ILD when in fact they do,” the investigators observed.

“This study reinforces the notion that PFTs alone are ineffective screening tools for ILD in the presence of systemic sclerosis, particularly for patients with early systemic sclerosis,” said Elizabeth Volkmann, MD, MS, assistant professor and codirector of the CTD-ILD program in the division of rheumatology at the University of California, Los Angeles.

The study’s scope was relatively small, yet the results provide further evidence to show that HRCT should be performed in all SSc patients to screen for the presence of ILD, Dr. Volkmann said in an interview.

Other research has demonstrated the value of baseline HRCT as a prognosticator of ILD outcomes. The method provides useful information about the degree of fibrosis and degree of damage in early-stage disease, said Dr. Furst, also an adjunct professor at the University of Washington, Seattle, and a research professor at the University of Florence (Italy). “If there’s honeycombing, that’s a bad prognosis. If it’s ground glass or reticular changes, the prognosis is better.

“Once there’s a lot of damage, it’s much harder to interpret disease with HRCT,” he added.

HRCT and PFT work well together to assess what’s happening in patients, Dr. Furst explained. HRCT provides an idea of anatomic changes, whereas PFT outlines aspects of functional change to diagnose early ILD in early diffuse SSc. The study results should not apply to patients with later disease who have more developed ILD, he noted.

The investigators acknowledged that they weren’t able to categorize and analyze patients according to disease extent because they didn’t quantify the extent of ILD. Another limitation was that the HRCTs and PFTs were ordered at the discretion of individual physicians, which means that not all participants received the tests.

“Although the tests were done in 90% of the population, there is still a probability of a significant selection bias,” Dr. Furst said.

Dr. Bernstein and several other coauthors in the study received grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases to support their work. Dr. Furst disclosed receiving grant/research support from and/or consulting for AbbVie, Actelion, Amgen, Bristol-Myers Squibb, Corbus, the National Institutes of Health, Novartis, Pfizer, and Roche/Genentech. Dr. Volkmann disclosed consulting for and/or receiving grant support from Boehringer Ingelheim, Corbus, and Forbius.

SOURCE: Bernstein EJ et al. Arthritis Rheumatol. 2020 Jun 25. doi: 10.1002/art.41415.

The first validated classification criteria for discoid lupus erythematosus has a sensitivity that ranges between 73.9% and 84.1% and a specificity that ranges between 75.9% and 92.9%.

M. Alexander Otto/MDedge News

“Discoid lupus erythematosus [DLE] is the most common type of chronic cutaneous lupus,” lead study author Scott A. Elman, MD, said during the virtual annual meeting of the American Academy of Dermatology. “It’s one of the most potentially disfiguring forms of cutaneous lupus erythematosus [CLE], which can lead to scarring, hair loss, and dyspigmentation if not treated early or promptly. It has a significant impact on patient quality of life and there are currently no classification criteria for DLE, which has led to problematic heterogeneity in observational and interventional research efforts. As there is increasing interest in drug development programs for CLE and DLE, there is a need to develop classification criteria.”

Dr. Elman, of the Harvard combined medicine-dermatology training program at Brigham and Women’s Hospital, Boston, pointed out that classification criteria are the standard definitions that are primarily intended to enroll uniform cohorts for research. “These emphasize high specificity, whereas diagnostic criteria reflect a more broad and variable set of features of a given disease, and therefore require a higher sensitivity,” he explained. “While classification criteria are not synonymous with diagnostic criteria, they typically mirror the list of criteria that are used for diagnosis.”

In 2017, Dr. Elman and colleagues generated an item list of 12 potential classification criteria using an international Delphi consensus process: 5 criteria represented disease morphology, 2 represented discoid lupus location, and 5 represented histopathology (J Am Acad Dermatol. 2017 Aug 1;77[2]:261-7). The purpose of the current study, which was presented as a late-breaking abstract, was to validate the proposed classification criteria in a multicenter, international trial. “The point is to be able to differentiate between discoid lupus and its disease mimickers, which could be confused in enrollment in clinical trials,” he said.

At nine participating sites, patients were identified at clinical visits as having either DLE or a DLE mimicker. After each visit, dermatologists determined if morphological features were present. One dermatopathologist at each site reviewed pathology, if available, to see if the histopathologic features were present. Diagnosis by clinical features and dermatopathology were tabulated and presented as counts and percentages. Clinical features among those with and without DLE were calculated and compared with chi-square or Fisher’s exact tests. The researchers used best subsets logistic regression analysis to identify candidate models.

A total of 215 patients were enrolled: 94 that were consistent with DLE and 121 that were consistent with a DLE mimicker. Most cases (83%) were from North America, 11% were from Asia, and 6% were from Europe. Only 86 cases (40%) had biopsies for dermatopathology review.

The following clinical features were found to be more commonly associated with DLE, compared with DLE mimickers: atrophic scarring (83% vs. 24%; P < .001), dyspigmentation (84% vs. 55%; P < .001), follicular hyperkeratosis/plugging (43% vs. 11%; P < .001), scarring alopecia (61% vs. 21%; P < .001), location in the conchal bowl (49% vs. 10%; P < .001), preference for the head and neck (87% vs. 49%; P < .001), and erythematous to violaceous in color (93% vs. 85%, a nonsignificant difference; P = .09).

When histopathological items were assessed, the following features were found to be more commonly associated with DLE, compared with DLE mimickers: interface/vacuolar dermatitis (83% vs. 53%; P = .004), perivascular and/or periappendageal lymphohistiocytic infiltrate (95% vs. 84%, a nonsignificant difference; P = .18), follicular keratin plugs (57% vs. 20%; P < .001), mucin deposition (73% vs. 39%; P = .002), and basement membrane thickening (57% vs. 14%; P < .001).

“There was good agreement between the diagnoses made by dermatologists and dermatopathologists, with a Cohen’s kappa statistic of 0.83,” Dr. Elman added. “Similarly, in many of the cases, the dermatopathologists and the dermatologists felt confident in their diagnosis.”

For the final model, the researchers excluded patients who had any missing data as well as those who had a diagnosis that was uncertain. This left 200 cases in the final model. Clinical variables associated with DLE were: atrophic scarring (odds ratio, 8.70; P < .001), location in the conchal bowl (OR, 6.80; P < .001), preference for head and neck (OR, 9.41; P < .001), dyspigmentation (OR, 3.23; P = .020), follicular hyperkeratosis/plugging (OR, 2.94; P = .054), and erythematous to violaceous in color (OR, 3.44; P = .056). The area under the curve for the model was 0.91.

According to Dr. Elman, the final model is a points-based model with 3 points assigned to atrophic scarring, 2 points assigned to location in the conchal bowl, 2 points assigned to preference for head and neck, 1 point assigned to dyspigmentation, 1 point assigned to follicular hyperkeratosis/plugging, and 1 point assigned to erythematous to violaceous in color. A score of 5 or greater yields a classification as DLE with 84.1% sensitivity and 75.9% specificity, while a score of 7 or greater yields a 73.9% sensitivity and 92.9% specificity.

Dr. Elman acknowledged certain limitations of the study, including the fact that information related to histopathology was not included in the final model. “This was a result of having only 40% of cases with relevant dermatopathology,” he said. “This limited our ability to meaningfully incorporate these items into a classification criteria set. However, with the data we’ve collected, efforts are under way to make a DLE-specific histopathology classification criteria.”

Another limitation is that the researchers relied on expert diagnosis as the preferred option. “Similarly, many of the cases came from large referral centers, and no demographic data were obtained, so this limits the generalizability of our study,” he said.

Dr. Elman reported having no financial disclosures.

[email protected]

The first validated classification criteria for discoid lupus erythematosus has a sensitivity that ranges between 73.9% and 84.1% and a specificity that ranges between 75.9% and 92.9%.

M. Alexander Otto/MDedge News

“Discoid lupus erythematosus [DLE] is the most common type of chronic cutaneous lupus,” lead study author Scott A. Elman, MD, said during the virtual annual meeting of the American Academy of Dermatology. “It’s one of the most potentially disfiguring forms of cutaneous lupus erythematosus [CLE], which can lead to scarring, hair loss, and dyspigmentation if not treated early or promptly. It has a significant impact on patient quality of life and there are currently no classification criteria for DLE, which has led to problematic heterogeneity in observational and interventional research efforts. As there is increasing interest in drug development programs for CLE and DLE, there is a need to develop classification criteria.”

Dr. Elman, of the Harvard combined medicine-dermatology training program at Brigham and Women’s Hospital, Boston, pointed out that classification criteria are the standard definitions that are primarily intended to enroll uniform cohorts for research. “These emphasize high specificity, whereas diagnostic criteria reflect a more broad and variable set of features of a given disease, and therefore require a higher sensitivity,” he explained. “While classification criteria are not synonymous with diagnostic criteria, they typically mirror the list of criteria that are used for diagnosis.”

In 2017, Dr. Elman and colleagues generated an item list of 12 potential classification criteria using an international Delphi consensus process: 5 criteria represented disease morphology, 2 represented discoid lupus location, and 5 represented histopathology (J Am Acad Dermatol. 2017 Aug 1;77[2]:261-7). The purpose of the current study, which was presented as a late-breaking abstract, was to validate the proposed classification criteria in a multicenter, international trial. “The point is to be able to differentiate between discoid lupus and its disease mimickers, which could be confused in enrollment in clinical trials,” he said.

At nine participating sites, patients were identified at clinical visits as having either DLE or a DLE mimicker. After each visit, dermatologists determined if morphological features were present. One dermatopathologist at each site reviewed pathology, if available, to see if the histopathologic features were present. Diagnosis by clinical features and dermatopathology were tabulated and presented as counts and percentages. Clinical features among those with and without DLE were calculated and compared with chi-square or Fisher’s exact tests. The researchers used best subsets logistic regression analysis to identify candidate models.

A total of 215 patients were enrolled: 94 that were consistent with DLE and 121 that were consistent with a DLE mimicker. Most cases (83%) were from North America, 11% were from Asia, and 6% were from Europe. Only 86 cases (40%) had biopsies for dermatopathology review.

The following clinical features were found to be more commonly associated with DLE, compared with DLE mimickers: atrophic scarring (83% vs. 24%; P < .001), dyspigmentation (84% vs. 55%; P < .001), follicular hyperkeratosis/plugging (43% vs. 11%; P < .001), scarring alopecia (61% vs. 21%; P < .001), location in the conchal bowl (49% vs. 10%; P < .001), preference for the head and neck (87% vs. 49%; P < .001), and erythematous to violaceous in color (93% vs. 85%, a nonsignificant difference; P = .09).

When histopathological items were assessed, the following features were found to be more commonly associated with DLE, compared with DLE mimickers: interface/vacuolar dermatitis (83% vs. 53%; P = .004), perivascular and/or periappendageal lymphohistiocytic infiltrate (95% vs. 84%, a nonsignificant difference; P = .18), follicular keratin plugs (57% vs. 20%; P < .001), mucin deposition (73% vs. 39%; P = .002), and basement membrane thickening (57% vs. 14%; P < .001).

“There was good agreement between the diagnoses made by dermatologists and dermatopathologists, with a Cohen’s kappa statistic of 0.83,” Dr. Elman added. “Similarly, in many of the cases, the dermatopathologists and the dermatologists felt confident in their diagnosis.”

For the final model, the researchers excluded patients who had any missing data as well as those who had a diagnosis that was uncertain. This left 200 cases in the final model. Clinical variables associated with DLE were: atrophic scarring (odds ratio, 8.70; P < .001), location in the conchal bowl (OR, 6.80; P < .001), preference for head and neck (OR, 9.41; P < .001), dyspigmentation (OR, 3.23; P = .020), follicular hyperkeratosis/plugging (OR, 2.94; P = .054), and erythematous to violaceous in color (OR, 3.44; P = .056). The area under the curve for the model was 0.91.

According to Dr. Elman, the final model is a points-based model with 3 points assigned to atrophic scarring, 2 points assigned to location in the conchal bowl, 2 points assigned to preference for head and neck, 1 point assigned to dyspigmentation, 1 point assigned to follicular hyperkeratosis/plugging, and 1 point assigned to erythematous to violaceous in color. A score of 5 or greater yields a classification as DLE with 84.1% sensitivity and 75.9% specificity, while a score of 7 or greater yields a 73.9% sensitivity and 92.9% specificity.

Dr. Elman acknowledged certain limitations of the study, including the fact that information related to histopathology was not included in the final model. “This was a result of having only 40% of cases with relevant dermatopathology,” he said. “This limited our ability to meaningfully incorporate these items into a classification criteria set. However, with the data we’ve collected, efforts are under way to make a DLE-specific histopathology classification criteria.”

Another limitation is that the researchers relied on expert diagnosis as the preferred option. “Similarly, many of the cases came from large referral centers, and no demographic data were obtained, so this limits the generalizability of our study,” he said.

Dr. Elman reported having no financial disclosures.

[email protected]

The first validated classification criteria for discoid lupus erythematosus has a sensitivity that ranges between 73.9% and 84.1% and a specificity that ranges between 75.9% and 92.9%.

M. Alexander Otto/MDedge News

“Discoid lupus erythematosus [DLE] is the most common type of chronic cutaneous lupus,” lead study author Scott A. Elman, MD, said during the virtual annual meeting of the American Academy of Dermatology. “It’s one of the most potentially disfiguring forms of cutaneous lupus erythematosus [CLE], which can lead to scarring, hair loss, and dyspigmentation if not treated early or promptly. It has a significant impact on patient quality of life and there are currently no classification criteria for DLE, which has led to problematic heterogeneity in observational and interventional research efforts. As there is increasing interest in drug development programs for CLE and DLE, there is a need to develop classification criteria.”

Dr. Elman, of the Harvard combined medicine-dermatology training program at Brigham and Women’s Hospital, Boston, pointed out that classification criteria are the standard definitions that are primarily intended to enroll uniform cohorts for research. “These emphasize high specificity, whereas diagnostic criteria reflect a more broad and variable set of features of a given disease, and therefore require a higher sensitivity,” he explained. “While classification criteria are not synonymous with diagnostic criteria, they typically mirror the list of criteria that are used for diagnosis.”

In 2017, Dr. Elman and colleagues generated an item list of 12 potential classification criteria using an international Delphi consensus process: 5 criteria represented disease morphology, 2 represented discoid lupus location, and 5 represented histopathology (J Am Acad Dermatol. 2017 Aug 1;77[2]:261-7). The purpose of the current study, which was presented as a late-breaking abstract, was to validate the proposed classification criteria in a multicenter, international trial. “The point is to be able to differentiate between discoid lupus and its disease mimickers, which could be confused in enrollment in clinical trials,” he said.

At nine participating sites, patients were identified at clinical visits as having either DLE or a DLE mimicker. After each visit, dermatologists determined if morphological features were present. One dermatopathologist at each site reviewed pathology, if available, to see if the histopathologic features were present. Diagnosis by clinical features and dermatopathology were tabulated and presented as counts and percentages. Clinical features among those with and without DLE were calculated and compared with chi-square or Fisher’s exact tests. The researchers used best subsets logistic regression analysis to identify candidate models.

A total of 215 patients were enrolled: 94 that were consistent with DLE and 121 that were consistent with a DLE mimicker. Most cases (83%) were from North America, 11% were from Asia, and 6% were from Europe. Only 86 cases (40%) had biopsies for dermatopathology review.

The following clinical features were found to be more commonly associated with DLE, compared with DLE mimickers: atrophic scarring (83% vs. 24%; P < .001), dyspigmentation (84% vs. 55%; P < .001), follicular hyperkeratosis/plugging (43% vs. 11%; P < .001), scarring alopecia (61% vs. 21%; P < .001), location in the conchal bowl (49% vs. 10%; P < .001), preference for the head and neck (87% vs. 49%; P < .001), and erythematous to violaceous in color (93% vs. 85%, a nonsignificant difference; P = .09).

When histopathological items were assessed, the following features were found to be more commonly associated with DLE, compared with DLE mimickers: interface/vacuolar dermatitis (83% vs. 53%; P = .004), perivascular and/or periappendageal lymphohistiocytic infiltrate (95% vs. 84%, a nonsignificant difference; P = .18), follicular keratin plugs (57% vs. 20%; P < .001), mucin deposition (73% vs. 39%; P = .002), and basement membrane thickening (57% vs. 14%; P < .001).

“There was good agreement between the diagnoses made by dermatologists and dermatopathologists, with a Cohen’s kappa statistic of 0.83,” Dr. Elman added. “Similarly, in many of the cases, the dermatopathologists and the dermatologists felt confident in their diagnosis.”

For the final model, the researchers excluded patients who had any missing data as well as those who had a diagnosis that was uncertain. This left 200 cases in the final model. Clinical variables associated with DLE were: atrophic scarring (odds ratio, 8.70; P < .001), location in the conchal bowl (OR, 6.80; P < .001), preference for head and neck (OR, 9.41; P < .001), dyspigmentation (OR, 3.23; P = .020), follicular hyperkeratosis/plugging (OR, 2.94; P = .054), and erythematous to violaceous in color (OR, 3.44; P = .056). The area under the curve for the model was 0.91.

According to Dr. Elman, the final model is a points-based model with 3 points assigned to atrophic scarring, 2 points assigned to location in the conchal bowl, 2 points assigned to preference for head and neck, 1 point assigned to dyspigmentation, 1 point assigned to follicular hyperkeratosis/plugging, and 1 point assigned to erythematous to violaceous in color. A score of 5 or greater yields a classification as DLE with 84.1% sensitivity and 75.9% specificity, while a score of 7 or greater yields a 73.9% sensitivity and 92.9% specificity.

Dr. Elman acknowledged certain limitations of the study, including the fact that information related to histopathology was not included in the final model. “This was a result of having only 40% of cases with relevant dermatopathology,” he said. “This limited our ability to meaningfully incorporate these items into a classification criteria set. However, with the data we’ve collected, efforts are under way to make a DLE-specific histopathology classification criteria.”

Another limitation is that the researchers relied on expert diagnosis as the preferred option. “Similarly, many of the cases came from large referral centers, and no demographic data were obtained, so this limits the generalizability of our study,” he said.

Dr. Elman reported having no financial disclosures.

[email protected]

Every rheumatologist ought to be comfortable in using a validated gastrointestinal symptom scale for evaluation of gastroesophageal reflux disease in patients with scleroderma, Tracy M. Frech, MD, declared at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.

copyright nebari/Thinkstock

About 90% of scleroderma patients will develop GI tract involvement during the course of their connective tissue disease. And while any portion of the GI tract from esophagus to anus can be involved, the most common GI manifestation is gastroesophageal reflux disease (GERD), affecting up to 90% of scleroderma patients, observed Dr. Frech, a rheumatologist and director of the systemic sclerosis clinic at the University of Utah and the George E. Wahlen Department of Veterans Affairs Medical Center, both in Salt Lake City.

“It is essential to ask scleroderma patients questions in order to understand their gastrointestinal tract symptoms. The questionnaires are really critical for us to grade the severity and then properly order tests,” she explained. “The goal is symptom identification, ideally with minimal time burden and at no cost, to guide decisions that move our patients’ care forward.”

Three of the most useful validated instruments for assessment of GERD symptoms in scleroderma patients in routine clinical practice are the GerdQ, the University of California, Los Angeles, Scleroderma Clinical Trial Consortium GI Tract Questionnaire (UCLA GIT) 2.0 reflux scale, and the Patient-Reported Outcomes Measurement Information System (PROMIS) reflux scale.

The GerdQ is a six-item, self-administered questionnaire in which patients specify how many days in the past week they have experienced heartburn, regurgitation, nausea, sleep interference, upper abdominal pain, and need for medication. A free online tool is available for calculating the likelihood of having GERD based upon GerdQ score. A score of 8 or more points out of a possible 18 has the highest sensitivity and specificity for diagnosis of GERD.

The UCLA GIT 2.0 – the most commonly used instrument for GI symptom assessment in scleroderma patients – includes 34 items. It takes 6-8 minutes to complete the whole thing, but patients being assessed for GERD only need answer the eight GERD-specific questions. Six of these eight questions are the same as in the GerdQ. One of the two extra questions asks about difficulty in swallowing solid food, which if answered affirmatively warrants early referral to a gastroenterologist. The other question inquires about any food triggers for the reflux, providing an opportunity for a rheumatologist to educate the patient about the importance of avoiding acidic foods, such as tomatoes, and other food and drink generally considered healthy but which actually exacerbate GERD.

The National Institutes of Health PROMIS scale, the newest of the three instruments, is a 60-item questionnaire; however, only 20 questions relate to reflux and dysphagia and are thus germane to a focused GERD assessment in scleroderma.

When a clinical diagnosis of GERD is made in a scleroderma patient based upon symptoms elicited by questionnaire, guidelines recommend a trial of empiric proton pump inhibitor therapy and behavioral interventions, such as raising the head of the bed, in order to confirm the diagnosis. If the patient reports feeling better after these basic interventions, the diagnosis is confirmed. If not, it’s time to make a referral to a gastroenterologist for specialized care, Dr. Frech said.

Dr. Frech was a coinvestigator in an international, prospective, longitudinal study of patient-reported outcomes measures in 116 patients with scleroderma and GERD. All study participants had to complete the UCLA GIT 2.0, the PROMIS reflux scale, and a third patient-reported GERD measure both before and after the therapeutic intervention. The UCLA GIT 2.0 and PROMIS instruments demonstrated similarly robust sensitivity for identifying changes in GERD symptoms after therapeutic intervention.

“It doesn’t really matter what questionnaire we’re using,” according to the rheumatologist. “But I will point out that there is significant overlap in symptoms among GERD, gastroparesis, functional dyspepsia, and eosinophilic esophagitis, all of which cause symptoms of heartburn and regurgitation. So we don’t want to ask these questions just once, we want to make an intervention and then reask the questions to ensure that we’re continuously moving forward with the gastrointestinal tract management plan.”

Dr. Frech reported having no financial conflicts regarding her presentation.

[email protected]

Every rheumatologist ought to be comfortable in using a validated gastrointestinal symptom scale for evaluation of gastroesophageal reflux disease in patients with scleroderma, Tracy M. Frech, MD, declared at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.

copyright nebari/Thinkstock

About 90% of scleroderma patients will develop GI tract involvement during the course of their connective tissue disease. And while any portion of the GI tract from esophagus to anus can be involved, the most common GI manifestation is gastroesophageal reflux disease (GERD), affecting up to 90% of scleroderma patients, observed Dr. Frech, a rheumatologist and director of the systemic sclerosis clinic at the University of Utah and the George E. Wahlen Department of Veterans Affairs Medical Center, both in Salt Lake City.

“It is essential to ask scleroderma patients questions in order to understand their gastrointestinal tract symptoms. The questionnaires are really critical for us to grade the severity and then properly order tests,” she explained. “The goal is symptom identification, ideally with minimal time burden and at no cost, to guide decisions that move our patients’ care forward.”

Three of the most useful validated instruments for assessment of GERD symptoms in scleroderma patients in routine clinical practice are the GerdQ, the University of California, Los Angeles, Scleroderma Clinical Trial Consortium GI Tract Questionnaire (UCLA GIT) 2.0 reflux scale, and the Patient-Reported Outcomes Measurement Information System (PROMIS) reflux scale.

The GerdQ is a six-item, self-administered questionnaire in which patients specify how many days in the past week they have experienced heartburn, regurgitation, nausea, sleep interference, upper abdominal pain, and need for medication. A free online tool is available for calculating the likelihood of having GERD based upon GerdQ score. A score of 8 or more points out of a possible 18 has the highest sensitivity and specificity for diagnosis of GERD.

The UCLA GIT 2.0 – the most commonly used instrument for GI symptom assessment in scleroderma patients – includes 34 items. It takes 6-8 minutes to complete the whole thing, but patients being assessed for GERD only need answer the eight GERD-specific questions. Six of these eight questions are the same as in the GerdQ. One of the two extra questions asks about difficulty in swallowing solid food, which if answered affirmatively warrants early referral to a gastroenterologist. The other question inquires about any food triggers for the reflux, providing an opportunity for a rheumatologist to educate the patient about the importance of avoiding acidic foods, such as tomatoes, and other food and drink generally considered healthy but which actually exacerbate GERD.

The National Institutes of Health PROMIS scale, the newest of the three instruments, is a 60-item questionnaire; however, only 20 questions relate to reflux and dysphagia and are thus germane to a focused GERD assessment in scleroderma.

When a clinical diagnosis of GERD is made in a scleroderma patient based upon symptoms elicited by questionnaire, guidelines recommend a trial of empiric proton pump inhibitor therapy and behavioral interventions, such as raising the head of the bed, in order to confirm the diagnosis. If the patient reports feeling better after these basic interventions, the diagnosis is confirmed. If not, it’s time to make a referral to a gastroenterologist for specialized care, Dr. Frech said.

Dr. Frech was a coinvestigator in an international, prospective, longitudinal study of patient-reported outcomes measures in 116 patients with scleroderma and GERD. All study participants had to complete the UCLA GIT 2.0, the PROMIS reflux scale, and a third patient-reported GERD measure both before and after the therapeutic intervention. The UCLA GIT 2.0 and PROMIS instruments demonstrated similarly robust sensitivity for identifying changes in GERD symptoms after therapeutic intervention.

“It doesn’t really matter what questionnaire we’re using,” according to the rheumatologist. “But I will point out that there is significant overlap in symptoms among GERD, gastroparesis, functional dyspepsia, and eosinophilic esophagitis, all of which cause symptoms of heartburn and regurgitation. So we don’t want to ask these questions just once, we want to make an intervention and then reask the questions to ensure that we’re continuously moving forward with the gastrointestinal tract management plan.”

Dr. Frech reported having no financial conflicts regarding her presentation.

[email protected]

Every rheumatologist ought to be comfortable in using a validated gastrointestinal symptom scale for evaluation of gastroesophageal reflux disease in patients with scleroderma, Tracy M. Frech, MD, declared at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.

copyright nebari/Thinkstock

About 90% of scleroderma patients will develop GI tract involvement during the course of their connective tissue disease. And while any portion of the GI tract from esophagus to anus can be involved, the most common GI manifestation is gastroesophageal reflux disease (GERD), affecting up to 90% of scleroderma patients, observed Dr. Frech, a rheumatologist and director of the systemic sclerosis clinic at the University of Utah and the George E. Wahlen Department of Veterans Affairs Medical Center, both in Salt Lake City.

“It is essential to ask scleroderma patients questions in order to understand their gastrointestinal tract symptoms. The questionnaires are really critical for us to grade the severity and then properly order tests,” she explained. “The goal is symptom identification, ideally with minimal time burden and at no cost, to guide decisions that move our patients’ care forward.”

Three of the most useful validated instruments for assessment of GERD symptoms in scleroderma patients in routine clinical practice are the GerdQ, the University of California, Los Angeles, Scleroderma Clinical Trial Consortium GI Tract Questionnaire (UCLA GIT) 2.0 reflux scale, and the Patient-Reported Outcomes Measurement Information System (PROMIS) reflux scale.

The GerdQ is a six-item, self-administered questionnaire in which patients specify how many days in the past week they have experienced heartburn, regurgitation, nausea, sleep interference, upper abdominal pain, and need for medication. A free online tool is available for calculating the likelihood of having GERD based upon GerdQ score. A score of 8 or more points out of a possible 18 has the highest sensitivity and specificity for diagnosis of GERD.

The UCLA GIT 2.0 – the most commonly used instrument for GI symptom assessment in scleroderma patients – includes 34 items. It takes 6-8 minutes to complete the whole thing, but patients being assessed for GERD only need answer the eight GERD-specific questions. Six of these eight questions are the same as in the GerdQ. One of the two extra questions asks about difficulty in swallowing solid food, which if answered affirmatively warrants early referral to a gastroenterologist. The other question inquires about any food triggers for the reflux, providing an opportunity for a rheumatologist to educate the patient about the importance of avoiding acidic foods, such as tomatoes, and other food and drink generally considered healthy but which actually exacerbate GERD.

The National Institutes of Health PROMIS scale, the newest of the three instruments, is a 60-item questionnaire; however, only 20 questions relate to reflux and dysphagia and are thus germane to a focused GERD assessment in scleroderma.

When a clinical diagnosis of GERD is made in a scleroderma patient based upon symptoms elicited by questionnaire, guidelines recommend a trial of empiric proton pump inhibitor therapy and behavioral interventions, such as raising the head of the bed, in order to confirm the diagnosis. If the patient reports feeling better after these basic interventions, the diagnosis is confirmed. If not, it’s time to make a referral to a gastroenterologist for specialized care, Dr. Frech said.

Dr. Frech was a coinvestigator in an international, prospective, longitudinal study of patient-reported outcomes measures in 116 patients with scleroderma and GERD. All study participants had to complete the UCLA GIT 2.0, the PROMIS reflux scale, and a third patient-reported GERD measure both before and after the therapeutic intervention. The UCLA GIT 2.0 and PROMIS instruments demonstrated similarly robust sensitivity for identifying changes in GERD symptoms after therapeutic intervention.

“It doesn’t really matter what questionnaire we’re using,” according to the rheumatologist. “But I will point out that there is significant overlap in symptoms among GERD, gastroparesis, functional dyspepsia, and eosinophilic esophagitis, all of which cause symptoms of heartburn and regurgitation. So we don’t want to ask these questions just once, we want to make an intervention and then reask the questions to ensure that we’re continuously moving forward with the gastrointestinal tract management plan.”

Dr. Frech reported having no financial conflicts regarding her presentation.

[email protected]

Treatment of patients with systemic lupus erythematosus and active lupus nephritis with belimumab (Benlysta) for 2 years with minimized background glucocorticoid treatment produced significantly better renal function, compared with control patients who only received standard therapy, in a randomized, multicenter trial with 446 evaluable patients, a finding that may help extend this treatment to a new group of lupus patients.

Sara Freeman/MDedge News

“The largest” treatment study of lupus nephritis reported to date showed that belimumab, approved by the Food and Drug Administration in 2011 for treating patients with systemic lupus erythematosus (SLE), administered at a standard dosage of 10 mg intravenously every 4 weeks, “significantly improved multiple lupus nephritis renal responses versus standard therapy alone while maintaining an acceptable safety profile,” Richard A. Furie, MD, said at the annual European Congress of Rheumatology, held online this year due to COVID-19.

The study’s primary endpoint was a composite measure that Dr. Furie and associates called the Primary Endpoint Renal Response, which required patients to have achieved a urinary protein-to-creatinine ratio of 0.7 or less (compared with an enrollment level of 1.0 or greater), an estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 kg/m² and no more than 20% below its preflare level, and continuation on the assigned treatment regimen. After 104 weeks on this treatment, which followed a 60-day induction phase that included treatment with a high-dose glucocorticoid, the percentages of patients who met the Primary Endpoint Renal Response criteria were 32% in the control arm who received standard treatment at the discretion of their treating clinicians plus placebo infusions and 43% in patients who received belimumab infusions in addition to their standard care. This calculated out to a 55% relative increase in this response with belimumab, a statistically significant result, reported Dr. Furie, professor of medicine at Hofstra University, Hempstead, N.Y., and chief of rheumatology at Northwell Health in Manhasset, N.Y.

Patients who received belimumab also had similar and statistically significant levels of improvement for several secondary endpoints, including one called Complete Renal Response, which required a protein-to-creatinine ratio of no greater than 0.5, an eGFR of at least 90 mL/min per 1.73 kg/m² and no more than 10% below its preflare level, and maintaining the assigned treatment. The Complete Renal Response after 104 weeks was 20% among control patients and 30% among those maintained on belimumab, a 74% relative improvement that was statistically significant. The total percentage of patients with any renal-related event after 104 weeks was 28% among the control patients and 16% among those who received belimumab, a statistically significant difference.

“The fact that the primary and all key secondary endpoints were successfully attained is a major accomplishment in lupus nephritis as well as in any SLE study,” Dr. Furie said in an interview. The study’s 2-year design “provided insight into the durability of the response,” and the steady divergence of the endpoint events in the two study arms beginning after about 24 weeks into the randomized phase “provided data regarding the rapidity of onset of action.” Collectively, the endpoints “mimic our real-life treatment goals: reduce disease activity, prevent flares, preserve renal function, lower steroid treatment, and do it all safely,” he concluded.

Results confirm benefit to subset of patients

“Belimumab is a safe and effective treatment for a significant subset of patients with lupus. We already knew that. Now we have even more confirmation,” commented Joan T. Merrill, MD, a professor of medicine at the University of Oklahoma Health Sciences Center and a rheumatologist who specializes in SLE at the Oklahoma Medical Research Foundation, both in Oklahoma City. “There have already been at least four international trials demonstrating belimumab’s efficacy in general lupus. Some patients in these earlier trials had nephritis, so it should not be surprising to see similar results in a trial restricted to patients with active nephritis, given the drug’s mechanism of action. Belimumab has repeatedly shown early and sustained benefits above what background treatments achieve, and belimumab has also proven to be safe to add to standard-of-care treatments,” she said in an interview.

The BLISS-LN (Efficacy and Safety of Belimumab in Patients With Active Lupus Nephritis) study enrolled patients at any of 118 centers in 20 countries, including the United States. All patients enrolled in the trial were adults with biopsy-confirmed, clinically active lupus nephritis and a urinary protein-to-creatinine ratio of at least 1.0, and need for induction therapy. The 60-day induction run-in phase began with high-dose glucocorticoids plus either cyclophosphamide or mycophenolate mofetil (CellCept), followed by maintenance on low-dose glucocorticoids and either azathioprine or mycophenolate mofetil. Nearly three-quarters of patients received mycophenolate mofetil–based induction. Once treatment with either belimumab or placebo began in the study’s main phase, the glucocorticoid dosage had to drop with tapering to no more than 10 mg/day within 24 weeks or the patient was considered a treatment failure.
 

Thoughts on current and future use of belimumab

The current labeled indication for belimumab is for “treatment of patients aged 5 years and older with active, autoantibody-positive systemic lupus erythematosus who are receiving standard therapy,” an inclusive SLE population, but the label also adds this caveat: “Limitations of use: The efficacy of Benlysta has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus.” According to Dr. Furie’s report, GlaxoSmithKline, the company that markets belimumab, plans to seek a labeled indication for lupus nephritis for the drug during 2020.

“I doubt the drug is widely used as yet in clinical practice for lupus nephritis,” although it is being prescribed to selected SLE patients in current, routine practice, said Dr. Merrill, a coinvestigator on some belimumab studies. What also remains unknown is the efficacy of belimumab monotherapy. “We don’t know which subset of patients might benefit from belimumab alone,” she noted. Nor is it known whether belimumab treatment of patients with SLE but without lupus nephritis will forestall later development of lupus nephritis.

“With the introduction of the subcutaneous formulation a few years ago, there has been greater belimumab use” overall in patients with SLE, said Dr. Furie, and with a safety and efficacy record now established in five separate, reported studies in addition to the new BLISS-LN study: BLISS-52, BLISS-76, BLISS-SC, BLISS-NE ASIA, and PLUTO. “The pivotal studies [BLISS-52 and BLISS-76] were done in patients with SLE but without nephritis in need of aggressive induction therapy. About 15% of the trial cohorts had low-level renal involvement,” and post hoc analyses suggested that the benefit in those patients was similar to patients without renal involvement, which led to the BLISS-LN study. “In theory, no SLE patients with high-level nephritis should be on belimumab at this time,” based on its labeling, although some SLE patients with low-level renal disease may now receive the drug because they also have other affected organs, such as skin and joints, Dr. Furie said.

“These are encouraging results,” commented George K. Bertsias, MD, a rheumatologist and SLE specialist at the University of Crete in Heraklion, Greece. He particularly cited the “significant effect from add-on belimumab” on top of treatment with mycophenolate mofetil, an “established and effective treatment for lupus nephritis. The data provide additional evidence for the efficacy of belimumab in SLE, and also in lupus nephritis,” he said in an interview, and “having an official labeled indication for active nephritis will enhance use of the drug” in such patients. “Considering the favorable effects of the drug on SLE, especially preventing major flares, and on lupus nephritis it is possible that the drug will be particularly suitable for SLE patients who are at high risk for developing lupus nephritis, although such an effect remains to be determined.” Until now, belimumab has generally been prescribed to SLE patients who have disease manifestations in organs outside of the kidneys, he noted.

BLISS-LN was sponsored by GlaxoSmithKline. Dr. Furie is a consultant to and has received research funding from GlaxoSmithKline, and several of the study’s coauthors are employees of the company. Dr. Merrill has been a consultant to GlaxoSmithKline as well as to several other companies and has been a coinvestigator on belimumab studies. Dr. Bertsias has been a consultant to Novartis and has received research funding from GlaxoSmithKline.

[email protected]

SOURCE: Furie RA et al. Ann Rheum Dis. 2020 Jun;79[suppl 1]:103, Abstract OP0164.

Treatment of patients with systemic lupus erythematosus and active lupus nephritis with belimumab (Benlysta) for 2 years with minimized background glucocorticoid treatment produced significantly better renal function, compared with control patients who only received standard therapy, in a randomized, multicenter trial with 446 evaluable patients, a finding that may help extend this treatment to a new group of lupus patients.

Sara Freeman/MDedge News

“The largest” treatment study of lupus nephritis reported to date showed that belimumab, approved by the Food and Drug Administration in 2011 for treating patients with systemic lupus erythematosus (SLE), administered at a standard dosage of 10 mg intravenously every 4 weeks, “significantly improved multiple lupus nephritis renal responses versus standard therapy alone while maintaining an acceptable safety profile,” Richard A. Furie, MD, said at the annual European Congress of Rheumatology, held online this year due to COVID-19.

The study’s primary endpoint was a composite measure that Dr. Furie and associates called the Primary Endpoint Renal Response, which required patients to have achieved a urinary protein-to-creatinine ratio of 0.7 or less (compared with an enrollment level of 1.0 or greater), an estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 kg/m² and no more than 20% below its preflare level, and continuation on the assigned treatment regimen. After 104 weeks on this treatment, which followed a 60-day induction phase that included treatment with a high-dose glucocorticoid, the percentages of patients who met the Primary Endpoint Renal Response criteria were 32% in the control arm who received standard treatment at the discretion of their treating clinicians plus placebo infusions and 43% in patients who received belimumab infusions in addition to their standard care. This calculated out to a 55% relative increase in this response with belimumab, a statistically significant result, reported Dr. Furie, professor of medicine at Hofstra University, Hempstead, N.Y., and chief of rheumatology at Northwell Health in Manhasset, N.Y.

Patients who received belimumab also had similar and statistically significant levels of improvement for several secondary endpoints, including one called Complete Renal Response, which required a protein-to-creatinine ratio of no greater than 0.5, an eGFR of at least 90 mL/min per 1.73 kg/m² and no more than 10% below its preflare level, and maintaining the assigned treatment. The Complete Renal Response after 104 weeks was 20% among control patients and 30% among those maintained on belimumab, a 74% relative improvement that was statistically significant. The total percentage of patients with any renal-related event after 104 weeks was 28% among the control patients and 16% among those who received belimumab, a statistically significant difference.

“The fact that the primary and all key secondary endpoints were successfully attained is a major accomplishment in lupus nephritis as well as in any SLE study,” Dr. Furie said in an interview. The study’s 2-year design “provided insight into the durability of the response,” and the steady divergence of the endpoint events in the two study arms beginning after about 24 weeks into the randomized phase “provided data regarding the rapidity of onset of action.” Collectively, the endpoints “mimic our real-life treatment goals: reduce disease activity, prevent flares, preserve renal function, lower steroid treatment, and do it all safely,” he concluded.

Results confirm benefit to subset of patients

“Belimumab is a safe and effective treatment for a significant subset of patients with lupus. We already knew that. Now we have even more confirmation,” commented Joan T. Merrill, MD, a professor of medicine at the University of Oklahoma Health Sciences Center and a rheumatologist who specializes in SLE at the Oklahoma Medical Research Foundation, both in Oklahoma City. “There have already been at least four international trials demonstrating belimumab’s efficacy in general lupus. Some patients in these earlier trials had nephritis, so it should not be surprising to see similar results in a trial restricted to patients with active nephritis, given the drug’s mechanism of action. Belimumab has repeatedly shown early and sustained benefits above what background treatments achieve, and belimumab has also proven to be safe to add to standard-of-care treatments,” she said in an interview.

The BLISS-LN (Efficacy and Safety of Belimumab in Patients With Active Lupus Nephritis) study enrolled patients at any of 118 centers in 20 countries, including the United States. All patients enrolled in the trial were adults with biopsy-confirmed, clinically active lupus nephritis and a urinary protein-to-creatinine ratio of at least 1.0, and need for induction therapy. The 60-day induction run-in phase began with high-dose glucocorticoids plus either cyclophosphamide or mycophenolate mofetil (CellCept), followed by maintenance on low-dose glucocorticoids and either azathioprine or mycophenolate mofetil. Nearly three-quarters of patients received mycophenolate mofetil–based induction. Once treatment with either belimumab or placebo began in the study’s main phase, the glucocorticoid dosage had to drop with tapering to no more than 10 mg/day within 24 weeks or the patient was considered a treatment failure.
 

Thoughts on current and future use of belimumab

The current labeled indication for belimumab is for “treatment of patients aged 5 years and older with active, autoantibody-positive systemic lupus erythematosus who are receiving standard therapy,” an inclusive SLE population, but the label also adds this caveat: “Limitations of use: The efficacy of Benlysta has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus.” According to Dr. Furie’s report, GlaxoSmithKline, the company that markets belimumab, plans to seek a labeled indication for lupus nephritis for the drug during 2020.

“I doubt the drug is widely used as yet in clinical practice for lupus nephritis,” although it is being prescribed to selected SLE patients in current, routine practice, said Dr. Merrill, a coinvestigator on some belimumab studies. What also remains unknown is the efficacy of belimumab monotherapy. “We don’t know which subset of patients might benefit from belimumab alone,” she noted. Nor is it known whether belimumab treatment of patients with SLE but without lupus nephritis will forestall later development of lupus nephritis.

“With the introduction of the subcutaneous formulation a few years ago, there has been greater belimumab use” overall in patients with SLE, said Dr. Furie, and with a safety and efficacy record now established in five separate, reported studies in addition to the new BLISS-LN study: BLISS-52, BLISS-76, BLISS-SC, BLISS-NE ASIA, and PLUTO. “The pivotal studies [BLISS-52 and BLISS-76] were done in patients with SLE but without nephritis in need of aggressive induction therapy. About 15% of the trial cohorts had low-level renal involvement,” and post hoc analyses suggested that the benefit in those patients was similar to patients without renal involvement, which led to the BLISS-LN study. “In theory, no SLE patients with high-level nephritis should be on belimumab at this time,” based on its labeling, although some SLE patients with low-level renal disease may now receive the drug because they also have other affected organs, such as skin and joints, Dr. Furie said.

“These are encouraging results,” commented George K. Bertsias, MD, a rheumatologist and SLE specialist at the University of Crete in Heraklion, Greece. He particularly cited the “significant effect from add-on belimumab” on top of treatment with mycophenolate mofetil, an “established and effective treatment for lupus nephritis. The data provide additional evidence for the efficacy of belimumab in SLE, and also in lupus nephritis,” he said in an interview, and “having an official labeled indication for active nephritis will enhance use of the drug” in such patients. “Considering the favorable effects of the drug on SLE, especially preventing major flares, and on lupus nephritis it is possible that the drug will be particularly suitable for SLE patients who are at high risk for developing lupus nephritis, although such an effect remains to be determined.” Until now, belimumab has generally been prescribed to SLE patients who have disease manifestations in organs outside of the kidneys, he noted.

BLISS-LN was sponsored by GlaxoSmithKline. Dr. Furie is a consultant to and has received research funding from GlaxoSmithKline, and several of the study’s coauthors are employees of the company. Dr. Merrill has been a consultant to GlaxoSmithKline as well as to several other companies and has been a coinvestigator on belimumab studies. Dr. Bertsias has been a consultant to Novartis and has received research funding from GlaxoSmithKline.

[email protected]

SOURCE: Furie RA et al. Ann Rheum Dis. 2020 Jun;79[suppl 1]:103, Abstract OP0164.

Treatment of patients with systemic lupus erythematosus and active lupus nephritis with belimumab (Benlysta) for 2 years with minimized background glucocorticoid treatment produced significantly better renal function, compared with control patients who only received standard therapy, in a randomized, multicenter trial with 446 evaluable patients, a finding that may help extend this treatment to a new group of lupus patients.

Sara Freeman/MDedge News

“The largest” treatment study of lupus nephritis reported to date showed that belimumab, approved by the Food and Drug Administration in 2011 for treating patients with systemic lupus erythematosus (SLE), administered at a standard dosage of 10 mg intravenously every 4 weeks, “significantly improved multiple lupus nephritis renal responses versus standard therapy alone while maintaining an acceptable safety profile,” Richard A. Furie, MD, said at the annual European Congress of Rheumatology, held online this year due to COVID-19.

The study’s primary endpoint was a composite measure that Dr. Furie and associates called the Primary Endpoint Renal Response, which required patients to have achieved a urinary protein-to-creatinine ratio of 0.7 or less (compared with an enrollment level of 1.0 or greater), an estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 kg/m² and no more than 20% below its preflare level, and continuation on the assigned treatment regimen. After 104 weeks on this treatment, which followed a 60-day induction phase that included treatment with a high-dose glucocorticoid, the percentages of patients who met the Primary Endpoint Renal Response criteria were 32% in the control arm who received standard treatment at the discretion of their treating clinicians plus placebo infusions and 43% in patients who received belimumab infusions in addition to their standard care. This calculated out to a 55% relative increase in this response with belimumab, a statistically significant result, reported Dr. Furie, professor of medicine at Hofstra University, Hempstead, N.Y., and chief of rheumatology at Northwell Health in Manhasset, N.Y.

Patients who received belimumab also had similar and statistically significant levels of improvement for several secondary endpoints, including one called Complete Renal Response, which required a protein-to-creatinine ratio of no greater than 0.5, an eGFR of at least 90 mL/min per 1.73 kg/m² and no more than 10% below its preflare level, and maintaining the assigned treatment. The Complete Renal Response after 104 weeks was 20% among control patients and 30% among those maintained on belimumab, a 74% relative improvement that was statistically significant. The total percentage of patients with any renal-related event after 104 weeks was 28% among the control patients and 16% among those who received belimumab, a statistically significant difference.

“The fact that the primary and all key secondary endpoints were successfully attained is a major accomplishment in lupus nephritis as well as in any SLE study,” Dr. Furie said in an interview. The study’s 2-year design “provided insight into the durability of the response,” and the steady divergence of the endpoint events in the two study arms beginning after about 24 weeks into the randomized phase “provided data regarding the rapidity of onset of action.” Collectively, the endpoints “mimic our real-life treatment goals: reduce disease activity, prevent flares, preserve renal function, lower steroid treatment, and do it all safely,” he concluded.

Results confirm benefit to subset of patients

“Belimumab is a safe and effective treatment for a significant subset of patients with lupus. We already knew that. Now we have even more confirmation,” commented Joan T. Merrill, MD, a professor of medicine at the University of Oklahoma Health Sciences Center and a rheumatologist who specializes in SLE at the Oklahoma Medical Research Foundation, both in Oklahoma City. “There have already been at least four international trials demonstrating belimumab’s efficacy in general lupus. Some patients in these earlier trials had nephritis, so it should not be surprising to see similar results in a trial restricted to patients with active nephritis, given the drug’s mechanism of action. Belimumab has repeatedly shown early and sustained benefits above what background treatments achieve, and belimumab has also proven to be safe to add to standard-of-care treatments,” she said in an interview.

The BLISS-LN (Efficacy and Safety of Belimumab in Patients With Active Lupus Nephritis) study enrolled patients at any of 118 centers in 20 countries, including the United States. All patients enrolled in the trial were adults with biopsy-confirmed, clinically active lupus nephritis and a urinary protein-to-creatinine ratio of at least 1.0, and need for induction therapy. The 60-day induction run-in phase began with high-dose glucocorticoids plus either cyclophosphamide or mycophenolate mofetil (CellCept), followed by maintenance on low-dose glucocorticoids and either azathioprine or mycophenolate mofetil. Nearly three-quarters of patients received mycophenolate mofetil–based induction. Once treatment with either belimumab or placebo began in the study’s main phase, the glucocorticoid dosage had to drop with tapering to no more than 10 mg/day within 24 weeks or the patient was considered a treatment failure.
 

Thoughts on current and future use of belimumab

The current labeled indication for belimumab is for “treatment of patients aged 5 years and older with active, autoantibody-positive systemic lupus erythematosus who are receiving standard therapy,” an inclusive SLE population, but the label also adds this caveat: “Limitations of use: The efficacy of Benlysta has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus.” According to Dr. Furie’s report, GlaxoSmithKline, the company that markets belimumab, plans to seek a labeled indication for lupus nephritis for the drug during 2020.

“I doubt the drug is widely used as yet in clinical practice for lupus nephritis,” although it is being prescribed to selected SLE patients in current, routine practice, said Dr. Merrill, a coinvestigator on some belimumab studies. What also remains unknown is the efficacy of belimumab monotherapy. “We don’t know which subset of patients might benefit from belimumab alone,” she noted. Nor is it known whether belimumab treatment of patients with SLE but without lupus nephritis will forestall later development of lupus nephritis.

“With the introduction of the subcutaneous formulation a few years ago, there has been greater belimumab use” overall in patients with SLE, said Dr. Furie, and with a safety and efficacy record now established in five separate, reported studies in addition to the new BLISS-LN study: BLISS-52, BLISS-76, BLISS-SC, BLISS-NE ASIA, and PLUTO. “The pivotal studies [BLISS-52 and BLISS-76] were done in patients with SLE but without nephritis in need of aggressive induction therapy. About 15% of the trial cohorts had low-level renal involvement,” and post hoc analyses suggested that the benefit in those patients was similar to patients without renal involvement, which led to the BLISS-LN study. “In theory, no SLE patients with high-level nephritis should be on belimumab at this time,” based on its labeling, although some SLE patients with low-level renal disease may now receive the drug because they also have other affected organs, such as skin and joints, Dr. Furie said.

“These are encouraging results,” commented George K. Bertsias, MD, a rheumatologist and SLE specialist at the University of Crete in Heraklion, Greece. He particularly cited the “significant effect from add-on belimumab” on top of treatment with mycophenolate mofetil, an “established and effective treatment for lupus nephritis. The data provide additional evidence for the efficacy of belimumab in SLE, and also in lupus nephritis,” he said in an interview, and “having an official labeled indication for active nephritis will enhance use of the drug” in such patients. “Considering the favorable effects of the drug on SLE, especially preventing major flares, and on lupus nephritis it is possible that the drug will be particularly suitable for SLE patients who are at high risk for developing lupus nephritis, although such an effect remains to be determined.” Until now, belimumab has generally been prescribed to SLE patients who have disease manifestations in organs outside of the kidneys, he noted.

BLISS-LN was sponsored by GlaxoSmithKline. Dr. Furie is a consultant to and has received research funding from GlaxoSmithKline, and several of the study’s coauthors are employees of the company. Dr. Merrill has been a consultant to GlaxoSmithKline as well as to several other companies and has been a coinvestigator on belimumab studies. Dr. Bertsias has been a consultant to Novartis and has received research funding from GlaxoSmithKline.

[email protected]

SOURCE: Furie RA et al. Ann Rheum Dis. 2020 Jun;79[suppl 1]:103, Abstract OP0164.

New recommendations from the European League Against Rheumatism on interpreting the results of antinuclear antibody (ANA) testing advised taking the test methodology into account because of differences in performance.

copyright Martynasfoto/Thinkstock

ANA results vary not only by the test being used but also by the underlying disease they are being used to assess, warned Pier Luigi Meroni, MD, director of the Immunorheumatology Research Laboratory at the IRCCS Istituto Auxologico Italiano in Milan.

“Antinuclear antibody testing is a known diagnostic tool. But the recent advances in methodologies strongly suggests that we have to update our knowledge for a better interpretation of the results,” Dr. Meroni said in his presentation at the annual European Congress of Rheumatology, held online this year due to COVID-19.

There is “no doubt that ANA testing is useful,” he continued, adding that ANA is used as a primary screening tool in many rheumatic diseases, notably systemic lupus erythematosus (SLE), primary Sjögren’s syndrome, and systemic sclerosis. It’s also recently been suggested as an important entry criterion for the classification of SLE.

In fact, the 2019 SLE classification criteria – developed by EULAR in collaboration with the American College of Rheumatology – state that “testing by immunofluorescence on HEp-2 cells or a solid-phase ANA screening immunoassay with at least equivalent performance is highly recommended,” Dr. Meroni said.

The ideas underpinning that recommendation was that “ANA expression is invariable in SLE, and that ANA-negative lupus is quite rare,” he explained. Also, as SLE expression persists over time, ANA testing could be used for classification at any point in the disease course. These assumptions have been borne out in several studies, with very small percentages of patients (6% or less) having ANA-negative lupus, and more than 80% having a positive HEp-2 test over time, even with immunosuppressive treatment.

Which test methodology to use?

There are several methods that can be used to detect ANA, including the preferred HEp-2 indirect fluorescence assay (IFA), several solid-phase assays (SpA), and line- or dot-blot immunoassays. The issue is which assay should be used in which disease?

The performance of a particular assay can depend on the disease in which they are used. For instance, while the HEp-2 IFA and SpA are equivalent in SLE and in other connective tissue diseases, “this is not the case for other autoimmune diseases in which basically we don’t know exactly all the autoantigens,” Dr. Meroni explained. “Most of the autoantigens are undefined. They cannot be found in solid-phase kits, and we have to use the IFA for detecting all these autoantibodies.”

Importantly, neither the IFA nor the SpA is superior to the other. “We just say that one technique can detect relevant antibodies that are not detectable by the other one, and maybe the combination of the two techniques can be the right strategy to get the highest sensitivity,” Dr. Meroni said.

“Clinicians should be aware of the type of assay used for ANA detection,” he said, “because there are strong differences in the performance, for example between IFA and SpA, and such differences can have important clinical and relevant consequences.”

The test selected will depend on if the aim is to exclude or confirm a disease, and the optimal strategy will depend on pretest probability. For instance, IFA is more sensitive than SpA for SLE and scleroderma, whereas IFA is less sensitive than SpA for Sjögren’s. For SLE, it is suggested to use both the IFA and SpA. A combination of both tests is also considered optimal for scleroderma. SpA testing offers the best sensitivity for Sjögren’s.

“The story is a little bit more complicated for inflammatory myopathies in which we don’t have assays able to detect all the autoantibodies,” Dr. Meroni said. In that situation, several different techniques have to be used to check if the SpA results fit with the IFA pattern.

In 2019, the ACR released its own position statement on ANA testing, highlighting that it supported the use of the HEp-2 IFA assay as the preferred option for ANA testing and that labs should specify the methods being used to test for ANA when reporting their results. The ACR position statement also noted that “ordering health care professionals should select specific ANA subserologies based on a patient’s signs and symptoms and when there is a high pretest suspicion for a specific condition.”

Dr. Meroni disclosed serving as a consultant to Inova Diagnostics, Thermo Fisher Scientific, Pfizer, AbbVie, Merck Sharp & Dohme, and UCB.

New recommendations from the European League Against Rheumatism on interpreting the results of antinuclear antibody (ANA) testing advised taking the test methodology into account because of differences in performance.

copyright Martynasfoto/Thinkstock

ANA results vary not only by the test being used but also by the underlying disease they are being used to assess, warned Pier Luigi Meroni, MD, director of the Immunorheumatology Research Laboratory at the IRCCS Istituto Auxologico Italiano in Milan.

“Antinuclear antibody testing is a known diagnostic tool. But the recent advances in methodologies strongly suggests that we have to update our knowledge for a better interpretation of the results,” Dr. Meroni said in his presentation at the annual European Congress of Rheumatology, held online this year due to COVID-19.

There is “no doubt that ANA testing is useful,” he continued, adding that ANA is used as a primary screening tool in many rheumatic diseases, notably systemic lupus erythematosus (SLE), primary Sjögren’s syndrome, and systemic sclerosis. It’s also recently been suggested as an important entry criterion for the classification of SLE.

In fact, the 2019 SLE classification criteria – developed by EULAR in collaboration with the American College of Rheumatology – state that “testing by immunofluorescence on HEp-2 cells or a solid-phase ANA screening immunoassay with at least equivalent performance is highly recommended,” Dr. Meroni said.

The ideas underpinning that recommendation was that “ANA expression is invariable in SLE, and that ANA-negative lupus is quite rare,” he explained. Also, as SLE expression persists over time, ANA testing could be used for classification at any point in the disease course. These assumptions have been borne out in several studies, with very small percentages of patients (6% or less) having ANA-negative lupus, and more than 80% having a positive HEp-2 test over time, even with immunosuppressive treatment.

Which test methodology to use?

There are several methods that can be used to detect ANA, including the preferred HEp-2 indirect fluorescence assay (IFA), several solid-phase assays (SpA), and line- or dot-blot immunoassays. The issue is which assay should be used in which disease?

The performance of a particular assay can depend on the disease in which they are used. For instance, while the HEp-2 IFA and SpA are equivalent in SLE and in other connective tissue diseases, “this is not the case for other autoimmune diseases in which basically we don’t know exactly all the autoantigens,” Dr. Meroni explained. “Most of the autoantigens are undefined. They cannot be found in solid-phase kits, and we have to use the IFA for detecting all these autoantibodies.”

Importantly, neither the IFA nor the SpA is superior to the other. “We just say that one technique can detect relevant antibodies that are not detectable by the other one, and maybe the combination of the two techniques can be the right strategy to get the highest sensitivity,” Dr. Meroni said.

“Clinicians should be aware of the type of assay used for ANA detection,” he said, “because there are strong differences in the performance, for example between IFA and SpA, and such differences can have important clinical and relevant consequences.”

The test selected will depend on if the aim is to exclude or confirm a disease, and the optimal strategy will depend on pretest probability. For instance, IFA is more sensitive than SpA for SLE and scleroderma, whereas IFA is less sensitive than SpA for Sjögren’s. For SLE, it is suggested to use both the IFA and SpA. A combination of both tests is also considered optimal for scleroderma. SpA testing offers the best sensitivity for Sjögren’s.

“The story is a little bit more complicated for inflammatory myopathies in which we don’t have assays able to detect all the autoantibodies,” Dr. Meroni said. In that situation, several different techniques have to be used to check if the SpA results fit with the IFA pattern.

In 2019, the ACR released its own position statement on ANA testing, highlighting that it supported the use of the HEp-2 IFA assay as the preferred option for ANA testing and that labs should specify the methods being used to test for ANA when reporting their results. The ACR position statement also noted that “ordering health care professionals should select specific ANA subserologies based on a patient’s signs and symptoms and when there is a high pretest suspicion for a specific condition.”

Dr. Meroni disclosed serving as a consultant to Inova Diagnostics, Thermo Fisher Scientific, Pfizer, AbbVie, Merck Sharp & Dohme, and UCB.

New recommendations from the European League Against Rheumatism on interpreting the results of antinuclear antibody (ANA) testing advised taking the test methodology into account because of differences in performance.

copyright Martynasfoto/Thinkstock

ANA results vary not only by the test being used but also by the underlying disease they are being used to assess, warned Pier Luigi Meroni, MD, director of the Immunorheumatology Research Laboratory at the IRCCS Istituto Auxologico Italiano in Milan.

“Antinuclear antibody testing is a known diagnostic tool. But the recent advances in methodologies strongly suggests that we have to update our knowledge for a better interpretation of the results,” Dr. Meroni said in his presentation at the annual European Congress of Rheumatology, held online this year due to COVID-19.

There is “no doubt that ANA testing is useful,” he continued, adding that ANA is used as a primary screening tool in many rheumatic diseases, notably systemic lupus erythematosus (SLE), primary Sjögren’s syndrome, and systemic sclerosis. It’s also recently been suggested as an important entry criterion for the classification of SLE.

In fact, the 2019 SLE classification criteria – developed by EULAR in collaboration with the American College of Rheumatology – state that “testing by immunofluorescence on HEp-2 cells or a solid-phase ANA screening immunoassay with at least equivalent performance is highly recommended,” Dr. Meroni said.

The ideas underpinning that recommendation was that “ANA expression is invariable in SLE, and that ANA-negative lupus is quite rare,” he explained. Also, as SLE expression persists over time, ANA testing could be used for classification at any point in the disease course. These assumptions have been borne out in several studies, with very small percentages of patients (6% or less) having ANA-negative lupus, and more than 80% having a positive HEp-2 test over time, even with immunosuppressive treatment.

Which test methodology to use?

There are several methods that can be used to detect ANA, including the preferred HEp-2 indirect fluorescence assay (IFA), several solid-phase assays (SpA), and line- or dot-blot immunoassays. The issue is which assay should be used in which disease?

The performance of a particular assay can depend on the disease in which they are used. For instance, while the HEp-2 IFA and SpA are equivalent in SLE and in other connective tissue diseases, “this is not the case for other autoimmune diseases in which basically we don’t know exactly all the autoantigens,” Dr. Meroni explained. “Most of the autoantigens are undefined. They cannot be found in solid-phase kits, and we have to use the IFA for detecting all these autoantibodies.”

Importantly, neither the IFA nor the SpA is superior to the other. “We just say that one technique can detect relevant antibodies that are not detectable by the other one, and maybe the combination of the two techniques can be the right strategy to get the highest sensitivity,” Dr. Meroni said.

“Clinicians should be aware of the type of assay used for ANA detection,” he said, “because there are strong differences in the performance, for example between IFA and SpA, and such differences can have important clinical and relevant consequences.”

The test selected will depend on if the aim is to exclude or confirm a disease, and the optimal strategy will depend on pretest probability. For instance, IFA is more sensitive than SpA for SLE and scleroderma, whereas IFA is less sensitive than SpA for Sjögren’s. For SLE, it is suggested to use both the IFA and SpA. A combination of both tests is also considered optimal for scleroderma. SpA testing offers the best sensitivity for Sjögren’s.

“The story is a little bit more complicated for inflammatory myopathies in which we don’t have assays able to detect all the autoantibodies,” Dr. Meroni said. In that situation, several different techniques have to be used to check if the SpA results fit with the IFA pattern.

In 2019, the ACR released its own position statement on ANA testing, highlighting that it supported the use of the HEp-2 IFA assay as the preferred option for ANA testing and that labs should specify the methods being used to test for ANA when reporting their results. The ACR position statement also noted that “ordering health care professionals should select specific ANA subserologies based on a patient’s signs and symptoms and when there is a high pretest suspicion for a specific condition.”

Dr. Meroni disclosed serving as a consultant to Inova Diagnostics, Thermo Fisher Scientific, Pfizer, AbbVie, Merck Sharp & Dohme, and UCB.

Scleroderma renal crisis is often the most challenging type of scleroderma emergency to identify promptly, according to Francesco Boin, MD, professor of medicine and director of the scleroderma center at the University of California, San Francisco.

“Fortunately, it’s not a frequent event. But it’s severe enough that all rheumatologists should be aware of it,” he said at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.
 

Atypical presentations occur in 30%

Scleroderma renal crisis (SRC) occurs in 5%-10% of scleroderma patients. A vexing feature of this emergency is that not uncommonly it actually precedes the diagnosis of scleroderma. Indeed, 20% of patients with SRC present with sine scleroderma – that is, they have no skin disease and their renal crisis is their first symptom of scleroderma. In contrast, critical digital ischemia – the most common scleroderma emergency – is invariably preceded by worsening episodes of Raynaud’s, and impending intestinal pseudo-obstruction – also among the most common scleroderma emergencies – is heralded by an established history of dysmotility, loss of appetite, abdominal bloating, small intestinal bacterial overgrowth, and bowel distension.

While sine SRC often poses a formidable diagnostic challenge, SRC occurs most often in patients with early, rapidly progressing diffuse scleroderma skin disease. Indeed, the median duration of scleroderma when SRC strikes is just 8 months. The use of glucocorticoids at 15 mg or more per day, or at lower doses for a lengthy period, is an independent risk factor for SRC. Detection of anti–RNA polymerase III antibodies warrants increased vigilance, since 60% of patients with SRC are anti–RNA polymerase III antibody positive. Other autoantibodies are not a risk factor. Neither is preexisting hypertension nor a high baseline serum creatinine.

The classic textbook presentation of SRC is abrupt onset of blood pressures greater than 20 mm Hg above normal for that individual, along with sudden renal failure; a climbing creatinine; proteinuria; and expressions of malignant hypertension such as pulmonary edema, new-onset heart failure, encephalopathy, and/or development of a thrombotic microangiopathy.

Notably, however, 30% of individuals with SRC don’t fit this picture at all. They may present with abrupt-onset severe hypertension but no evidence of renal failure, at least early on. Or they may have sudden renal failure without a hypertensive crisis. Alternatively, they may have no signs of malignant hypertension, just an asymptomatic pericardial effusion or mild arrhythmias.

“Also, the thrombotic microangiopathy can be present without the other features of scleroderma renal crisis, so no renal failure or hypertensive emergency. Be aware of the possibility of atypical presentations, and always suspect this unfolding problem in the right individuals,” the rheumatologist urged.

Anyone with scleroderma who presents with new-onset hypertension needs to begin keeping a careful home blood pressure diary. If the blood pressure shoots up, or symptoms of malignant hypertension develop, or laboratory monitoring reveals evidence of thrombotic microangiopathy, the patient should immediately go to the ED because these events are often followed by accelerated progression to renal crisis.

Inpatient management of SRC is critical. “In the hospital we can monitor renal function in a more refined way, we can manage the malignant hypertension, and early on, hospitalization provides the opportunity to do a renal biopsy. I always consider doing this early. The pathologist often pushes back, but I think it’s relevant. It confirms the diagnosis. We’ve had patients where we were surprised: We thought it was scleroderma renal crisis, but instead they had interstitial nephritis or glomerulonephritis. Most important, biopsy has major prognostic implications: You can measure the extent of damage and therefore have a sense of whether the patient will be able to recover renal function,” Dr. Boin explained.

Prognosis and predictors

Outcome of SRC is often poor: the 1-year mortality is 20%-30%, with a 5-year mortality of 30%-50%. Normotensive SRC with renal crisis, which accounts for about 10% of all cases of SRC, is particularly serious in its implication, with a 1-year mortality of 60%. Half of patients with SRC require hemodialysis, and only one-quarter of them recover spontaneous renal function.

Predictors of worse outcome include older age at onset of SRC, male gender, a serum creatinine level above 3 mg/dL at presentation, incomplete blood pressure control within the first 3 days of the crisis, and normotensive SRC. Use of an ACE inhibitor prior to SRC is also an independent predictor of poor outcome, possibly because by keeping the blood pressure under control the medication blunts recognition of the unfolding renal crisis.

“This is why experts don’t recommend prophylactic ACE inhibitors in patients who are at risk for SRC,” according to Dr. Boin.

He reported having no financial conflicts regarding his presentation.

[email protected]

Scleroderma renal crisis is often the most challenging type of scleroderma emergency to identify promptly, according to Francesco Boin, MD, professor of medicine and director of the scleroderma center at the University of California, San Francisco.

“Fortunately, it’s not a frequent event. But it’s severe enough that all rheumatologists should be aware of it,” he said at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.
 

Atypical presentations occur in 30%

Scleroderma renal crisis (SRC) occurs in 5%-10% of scleroderma patients. A vexing feature of this emergency is that not uncommonly it actually precedes the diagnosis of scleroderma. Indeed, 20% of patients with SRC present with sine scleroderma – that is, they have no skin disease and their renal crisis is their first symptom of scleroderma. In contrast, critical digital ischemia – the most common scleroderma emergency – is invariably preceded by worsening episodes of Raynaud’s, and impending intestinal pseudo-obstruction – also among the most common scleroderma emergencies – is heralded by an established history of dysmotility, loss of appetite, abdominal bloating, small intestinal bacterial overgrowth, and bowel distension.

While sine SRC often poses a formidable diagnostic challenge, SRC occurs most often in patients with early, rapidly progressing diffuse scleroderma skin disease. Indeed, the median duration of scleroderma when SRC strikes is just 8 months. The use of glucocorticoids at 15 mg or more per day, or at lower doses for a lengthy period, is an independent risk factor for SRC. Detection of anti–RNA polymerase III antibodies warrants increased vigilance, since 60% of patients with SRC are anti–RNA polymerase III antibody positive. Other autoantibodies are not a risk factor. Neither is preexisting hypertension nor a high baseline serum creatinine.

The classic textbook presentation of SRC is abrupt onset of blood pressures greater than 20 mm Hg above normal for that individual, along with sudden renal failure; a climbing creatinine; proteinuria; and expressions of malignant hypertension such as pulmonary edema, new-onset heart failure, encephalopathy, and/or development of a thrombotic microangiopathy.

Notably, however, 30% of individuals with SRC don’t fit this picture at all. They may present with abrupt-onset severe hypertension but no evidence of renal failure, at least early on. Or they may have sudden renal failure without a hypertensive crisis. Alternatively, they may have no signs of malignant hypertension, just an asymptomatic pericardial effusion or mild arrhythmias.

“Also, the thrombotic microangiopathy can be present without the other features of scleroderma renal crisis, so no renal failure or hypertensive emergency. Be aware of the possibility of atypical presentations, and always suspect this unfolding problem in the right individuals,” the rheumatologist urged.

Anyone with scleroderma who presents with new-onset hypertension needs to begin keeping a careful home blood pressure diary. If the blood pressure shoots up, or symptoms of malignant hypertension develop, or laboratory monitoring reveals evidence of thrombotic microangiopathy, the patient should immediately go to the ED because these events are often followed by accelerated progression to renal crisis.

Inpatient management of SRC is critical. “In the hospital we can monitor renal function in a more refined way, we can manage the malignant hypertension, and early on, hospitalization provides the opportunity to do a renal biopsy. I always consider doing this early. The pathologist often pushes back, but I think it’s relevant. It confirms the diagnosis. We’ve had patients where we were surprised: We thought it was scleroderma renal crisis, but instead they had interstitial nephritis or glomerulonephritis. Most important, biopsy has major prognostic implications: You can measure the extent of damage and therefore have a sense of whether the patient will be able to recover renal function,” Dr. Boin explained.

Prognosis and predictors

Outcome of SRC is often poor: the 1-year mortality is 20%-30%, with a 5-year mortality of 30%-50%. Normotensive SRC with renal crisis, which accounts for about 10% of all cases of SRC, is particularly serious in its implication, with a 1-year mortality of 60%. Half of patients with SRC require hemodialysis, and only one-quarter of them recover spontaneous renal function.

Predictors of worse outcome include older age at onset of SRC, male gender, a serum creatinine level above 3 mg/dL at presentation, incomplete blood pressure control within the first 3 days of the crisis, and normotensive SRC. Use of an ACE inhibitor prior to SRC is also an independent predictor of poor outcome, possibly because by keeping the blood pressure under control the medication blunts recognition of the unfolding renal crisis.

“This is why experts don’t recommend prophylactic ACE inhibitors in patients who are at risk for SRC,” according to Dr. Boin.

He reported having no financial conflicts regarding his presentation.

[email protected]

Scleroderma renal crisis is often the most challenging type of scleroderma emergency to identify promptly, according to Francesco Boin, MD, professor of medicine and director of the scleroderma center at the University of California, San Francisco.

“Fortunately, it’s not a frequent event. But it’s severe enough that all rheumatologists should be aware of it,” he said at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.
 

Atypical presentations occur in 30%

Scleroderma renal crisis (SRC) occurs in 5%-10% of scleroderma patients. A vexing feature of this emergency is that not uncommonly it actually precedes the diagnosis of scleroderma. Indeed, 20% of patients with SRC present with sine scleroderma – that is, they have no skin disease and their renal crisis is their first symptom of scleroderma. In contrast, critical digital ischemia – the most common scleroderma emergency – is invariably preceded by worsening episodes of Raynaud’s, and impending intestinal pseudo-obstruction – also among the most common scleroderma emergencies – is heralded by an established history of dysmotility, loss of appetite, abdominal bloating, small intestinal bacterial overgrowth, and bowel distension.

While sine SRC often poses a formidable diagnostic challenge, SRC occurs most often in patients with early, rapidly progressing diffuse scleroderma skin disease. Indeed, the median duration of scleroderma when SRC strikes is just 8 months. The use of glucocorticoids at 15 mg or more per day, or at lower doses for a lengthy period, is an independent risk factor for SRC. Detection of anti–RNA polymerase III antibodies warrants increased vigilance, since 60% of patients with SRC are anti–RNA polymerase III antibody positive. Other autoantibodies are not a risk factor. Neither is preexisting hypertension nor a high baseline serum creatinine.

The classic textbook presentation of SRC is abrupt onset of blood pressures greater than 20 mm Hg above normal for that individual, along with sudden renal failure; a climbing creatinine; proteinuria; and expressions of malignant hypertension such as pulmonary edema, new-onset heart failure, encephalopathy, and/or development of a thrombotic microangiopathy.

Notably, however, 30% of individuals with SRC don’t fit this picture at all. They may present with abrupt-onset severe hypertension but no evidence of renal failure, at least early on. Or they may have sudden renal failure without a hypertensive crisis. Alternatively, they may have no signs of malignant hypertension, just an asymptomatic pericardial effusion or mild arrhythmias.

“Also, the thrombotic microangiopathy can be present without the other features of scleroderma renal crisis, so no renal failure or hypertensive emergency. Be aware of the possibility of atypical presentations, and always suspect this unfolding problem in the right individuals,” the rheumatologist urged.

Anyone with scleroderma who presents with new-onset hypertension needs to begin keeping a careful home blood pressure diary. If the blood pressure shoots up, or symptoms of malignant hypertension develop, or laboratory monitoring reveals evidence of thrombotic microangiopathy, the patient should immediately go to the ED because these events are often followed by accelerated progression to renal crisis.

Inpatient management of SRC is critical. “In the hospital we can monitor renal function in a more refined way, we can manage the malignant hypertension, and early on, hospitalization provides the opportunity to do a renal biopsy. I always consider doing this early. The pathologist often pushes back, but I think it’s relevant. It confirms the diagnosis. We’ve had patients where we were surprised: We thought it was scleroderma renal crisis, but instead they had interstitial nephritis or glomerulonephritis. Most important, biopsy has major prognostic implications: You can measure the extent of damage and therefore have a sense of whether the patient will be able to recover renal function,” Dr. Boin explained.

Prognosis and predictors

Outcome of SRC is often poor: the 1-year mortality is 20%-30%, with a 5-year mortality of 30%-50%. Normotensive SRC with renal crisis, which accounts for about 10% of all cases of SRC, is particularly serious in its implication, with a 1-year mortality of 60%. Half of patients with SRC require hemodialysis, and only one-quarter of them recover spontaneous renal function.

Predictors of worse outcome include older age at onset of SRC, male gender, a serum creatinine level above 3 mg/dL at presentation, incomplete blood pressure control within the first 3 days of the crisis, and normotensive SRC. Use of an ACE inhibitor prior to SRC is also an independent predictor of poor outcome, possibly because by keeping the blood pressure under control the medication blunts recognition of the unfolding renal crisis.

“This is why experts don’t recommend prophylactic ACE inhibitors in patients who are at risk for SRC,” according to Dr. Boin.

He reported having no financial conflicts regarding his presentation.

[email protected]

An alternative disease activity index for patients with systemic lupus erythematosus called the SLE-DAS (Disease Activity Score) has shown similar results to the Lupus Low Disease Activity State (LLDAS) in classifying low disease activity but may be easier to potentially apply in daily clinical practice in treat-to-target strategies, according to research presented at the annual European Congress of Rheumatology, held online this year because of COVID-19.

A treat-to-target approach, in which therapies are adjusted and the patient monitored to achieve the desired endpoint, has been proposed for patients with SLE. Clinical remission is the ideal goal, followed by achieving low disease activity (LDA) when clinical remission is unattainable, the first author of the SLE-DAS study, Helena Assunção, MD, of the department of rheumatology at Centro Hospitalar e Universitário de Coimbra (Portugal), said in an interview prior to the presentation of the study at the e-congress.

But to conduct a treat-to-target approach in the clinical setting, clinicians must have reliable, user-friendly targets to assess a patient’s progress, she said. But that’s not available right now. Proposed definitions of LDA, such as the LLDAS, are based on the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). This index doesn’t address some important manifestations of SLE and it is scored dichotomously – for example, giving a similar score for thrombocytopenia when platelet count is reduced to 100,000 or to 10,000.

To compensate for these limitations, the current LLDAS definition also requires the Physician Global Assessment and other steps, including a review of medication and changes to treatment or clinical status since the previous visit.

“It is not easy to apply,” Dr. Assunção said.

The SLE-DAS is a continuous index involving 17 parameters (4 continuous: arthritis, proteinuria, thrombocytopenia, and leukopenia), assigning higher scores when a manifestation is more severe, and has manifestation information that SLEDAI-2K lacks (cardiopulmonary involvement, lupus enteritis, and hemolytic anemia).

In contrast, the LLDAS is defined as:
 

• A SLEDAI-2k score of 4 or less with no major organ involvement
• No new disease activity
• A physician global assessment of the patient of 1 or less on a 0-3 scale
• Maintenance on a prednisolone dosage of 7.5 mg/day or less
• Maintenance on a standard immunosuppressive regimen

A previous study validated the SLE-DAS (Ann Rheum Dis. 2019 Mar;78[3]:365-71), and another exploratory study identified a cutoff SLE-DAS value of 3.77 or lower for LDA with SLE-DAS (Ann Rheum Dis. 2019;78:411-2).

Her group compared LDA status as measured with LLDAS versus the SLE-DAS in a cross-sectional study of 292 consecutive patients at their hospital. LDA on the SLE-DAS was defined as a score 3.77 or lower and a prednisolone dose of 7.5 mg/day or less. A total of 85% of patients were in LDA with SLE-DAS and 83.9% with LLDAS, and the agreement between LLDAS and SLE-DAS LDA was very high (Cohen’s kappa coefficient test; kappa = 0.831; P < .01). Out of 292 patients, only 13 were classified differently by the two definitions, 8 of which were classified as LDA by SLE-DAS, and 5 by LLDAS. Overall, 87% of patients were women and had a mean age of nearly 49 years, with a mean disease duration of about 14 years.

Dr. Assunção feels that the SLE-DAS LDA should be sufficient to monitor disease activity without adding the Physician Global Assessment and other steps, which would make it easier to apply than LLDAS. The fact that it is based on a continuous index is also an important difference. “Especially for low disease activity, it’s very good to be able to define it with a continuous index, because you are not that bad, but not that good, you’re in the middle,” she said.

The study should be regarded as exploratory, she said, but the results were encouraging. “We got similar results, and it’s definitely easier to apply.” She can also personally attest that the new model is easier to use, since she personally collected data for LLDAS assignment. “I had to check this, and this, and this … [SLE-DAS] is easier.”

Future work from her group will aim at deriving and validating a more robust definition of LDA, which will again be compared with the current LLDAS definition.

Her colleagues have already developed and validated a definition for clinical remission using SLE-DAS, although those results have not yet been published. They hope to define activity states using SLE-DAS, including mild, moderate, and high disease activity.

The team has produced an online SLE-DAS calculator (http://sle-das.eu/) where clinicians can score the 17 parameters. “You just input the values and it gives a number reflecting disease activity. Using this definition of SLE-DAS LDA you only need that number and to verify that the prednisolone dose is equal to or inferior to 7.5 mg/day,” said Dr. Assunção.

The study received no funding. Dr. Assunção has no financial disclosures, but one coauthor reported receiving grant/research support from Pfizer and AbbVie and serving as a consultant to Pfizer, AbbVie, Roche, Lilly, and Novartis.

SOURCE: Assunção H et al. Ann Rheum Dis 2020;79[suppl 1]:60, Abstract OP0092.

An alternative disease activity index for patients with systemic lupus erythematosus called the SLE-DAS (Disease Activity Score) has shown similar results to the Lupus Low Disease Activity State (LLDAS) in classifying low disease activity but may be easier to potentially apply in daily clinical practice in treat-to-target strategies, according to research presented at the annual European Congress of Rheumatology, held online this year because of COVID-19.

A treat-to-target approach, in which therapies are adjusted and the patient monitored to achieve the desired endpoint, has been proposed for patients with SLE. Clinical remission is the ideal goal, followed by achieving low disease activity (LDA) when clinical remission is unattainable, the first author of the SLE-DAS study, Helena Assunção, MD, of the department of rheumatology at Centro Hospitalar e Universitário de Coimbra (Portugal), said in an interview prior to the presentation of the study at the e-congress.

But to conduct a treat-to-target approach in the clinical setting, clinicians must have reliable, user-friendly targets to assess a patient’s progress, she said. But that’s not available right now. Proposed definitions of LDA, such as the LLDAS, are based on the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). This index doesn’t address some important manifestations of SLE and it is scored dichotomously – for example, giving a similar score for thrombocytopenia when platelet count is reduced to 100,000 or to 10,000.

To compensate for these limitations, the current LLDAS definition also requires the Physician Global Assessment and other steps, including a review of medication and changes to treatment or clinical status since the previous visit.

“It is not easy to apply,” Dr. Assunção said.

The SLE-DAS is a continuous index involving 17 parameters (4 continuous: arthritis, proteinuria, thrombocytopenia, and leukopenia), assigning higher scores when a manifestation is more severe, and has manifestation information that SLEDAI-2K lacks (cardiopulmonary involvement, lupus enteritis, and hemolytic anemia).

In contrast, the LLDAS is defined as:
 

• A SLEDAI-2k score of 4 or less with no major organ involvement
• No new disease activity
• A physician global assessment of the patient of 1 or less on a 0-3 scale
• Maintenance on a prednisolone dosage of 7.5 mg/day or less
• Maintenance on a standard immunosuppressive regimen

A previous study validated the SLE-DAS (Ann Rheum Dis. 2019 Mar;78[3]:365-71), and another exploratory study identified a cutoff SLE-DAS value of 3.77 or lower for LDA with SLE-DAS (Ann Rheum Dis. 2019;78:411-2).

Her group compared LDA status as measured with LLDAS versus the SLE-DAS in a cross-sectional study of 292 consecutive patients at their hospital. LDA on the SLE-DAS was defined as a score 3.77 or lower and a prednisolone dose of 7.5 mg/day or less. A total of 85% of patients were in LDA with SLE-DAS and 83.9% with LLDAS, and the agreement between LLDAS and SLE-DAS LDA was very high (Cohen’s kappa coefficient test; kappa = 0.831; P < .01). Out of 292 patients, only 13 were classified differently by the two definitions, 8 of which were classified as LDA by SLE-DAS, and 5 by LLDAS. Overall, 87% of patients were women and had a mean age of nearly 49 years, with a mean disease duration of about 14 years.

Dr. Assunção feels that the SLE-DAS LDA should be sufficient to monitor disease activity without adding the Physician Global Assessment and other steps, which would make it easier to apply than LLDAS. The fact that it is based on a continuous index is also an important difference. “Especially for low disease activity, it’s very good to be able to define it with a continuous index, because you are not that bad, but not that good, you’re in the middle,” she said.

The study should be regarded as exploratory, she said, but the results were encouraging. “We got similar results, and it’s definitely easier to apply.” She can also personally attest that the new model is easier to use, since she personally collected data for LLDAS assignment. “I had to check this, and this, and this … [SLE-DAS] is easier.”

Future work from her group will aim at deriving and validating a more robust definition of LDA, which will again be compared with the current LLDAS definition.

Her colleagues have already developed and validated a definition for clinical remission using SLE-DAS, although those results have not yet been published. They hope to define activity states using SLE-DAS, including mild, moderate, and high disease activity.

The team has produced an online SLE-DAS calculator (http://sle-das.eu/) where clinicians can score the 17 parameters. “You just input the values and it gives a number reflecting disease activity. Using this definition of SLE-DAS LDA you only need that number and to verify that the prednisolone dose is equal to or inferior to 7.5 mg/day,” said Dr. Assunção.

The study received no funding. Dr. Assunção has no financial disclosures, but one coauthor reported receiving grant/research support from Pfizer and AbbVie and serving as a consultant to Pfizer, AbbVie, Roche, Lilly, and Novartis.

SOURCE: Assunção H et al. Ann Rheum Dis 2020;79[suppl 1]:60, Abstract OP0092.

An alternative disease activity index for patients with systemic lupus erythematosus called the SLE-DAS (Disease Activity Score) has shown similar results to the Lupus Low Disease Activity State (LLDAS) in classifying low disease activity but may be easier to potentially apply in daily clinical practice in treat-to-target strategies, according to research presented at the annual European Congress of Rheumatology, held online this year because of COVID-19.

A treat-to-target approach, in which therapies are adjusted and the patient monitored to achieve the desired endpoint, has been proposed for patients with SLE. Clinical remission is the ideal goal, followed by achieving low disease activity (LDA) when clinical remission is unattainable, the first author of the SLE-DAS study, Helena Assunção, MD, of the department of rheumatology at Centro Hospitalar e Universitário de Coimbra (Portugal), said in an interview prior to the presentation of the study at the e-congress.

But to conduct a treat-to-target approach in the clinical setting, clinicians must have reliable, user-friendly targets to assess a patient’s progress, she said. But that’s not available right now. Proposed definitions of LDA, such as the LLDAS, are based on the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). This index doesn’t address some important manifestations of SLE and it is scored dichotomously – for example, giving a similar score for thrombocytopenia when platelet count is reduced to 100,000 or to 10,000.

To compensate for these limitations, the current LLDAS definition also requires the Physician Global Assessment and other steps, including a review of medication and changes to treatment or clinical status since the previous visit.

“It is not easy to apply,” Dr. Assunção said.

The SLE-DAS is a continuous index involving 17 parameters (4 continuous: arthritis, proteinuria, thrombocytopenia, and leukopenia), assigning higher scores when a manifestation is more severe, and has manifestation information that SLEDAI-2K lacks (cardiopulmonary involvement, lupus enteritis, and hemolytic anemia).

In contrast, the LLDAS is defined as:
 

• A SLEDAI-2k score of 4 or less with no major organ involvement
• No new disease activity
• A physician global assessment of the patient of 1 or less on a 0-3 scale
• Maintenance on a prednisolone dosage of 7.5 mg/day or less
• Maintenance on a standard immunosuppressive regimen

A previous study validated the SLE-DAS (Ann Rheum Dis. 2019 Mar;78[3]:365-71), and another exploratory study identified a cutoff SLE-DAS value of 3.77 or lower for LDA with SLE-DAS (Ann Rheum Dis. 2019;78:411-2).

Her group compared LDA status as measured with LLDAS versus the SLE-DAS in a cross-sectional study of 292 consecutive patients at their hospital. LDA on the SLE-DAS was defined as a score 3.77 or lower and a prednisolone dose of 7.5 mg/day or less. A total of 85% of patients were in LDA with SLE-DAS and 83.9% with LLDAS, and the agreement between LLDAS and SLE-DAS LDA was very high (Cohen’s kappa coefficient test; kappa = 0.831; P < .01). Out of 292 patients, only 13 were classified differently by the two definitions, 8 of which were classified as LDA by SLE-DAS, and 5 by LLDAS. Overall, 87% of patients were women and had a mean age of nearly 49 years, with a mean disease duration of about 14 years.

Dr. Assunção feels that the SLE-DAS LDA should be sufficient to monitor disease activity without adding the Physician Global Assessment and other steps, which would make it easier to apply than LLDAS. The fact that it is based on a continuous index is also an important difference. “Especially for low disease activity, it’s very good to be able to define it with a continuous index, because you are not that bad, but not that good, you’re in the middle,” she said.

The study should be regarded as exploratory, she said, but the results were encouraging. “We got similar results, and it’s definitely easier to apply.” She can also personally attest that the new model is easier to use, since she personally collected data for LLDAS assignment. “I had to check this, and this, and this … [SLE-DAS] is easier.”

Future work from her group will aim at deriving and validating a more robust definition of LDA, which will again be compared with the current LLDAS definition.

Her colleagues have already developed and validated a definition for clinical remission using SLE-DAS, although those results have not yet been published. They hope to define activity states using SLE-DAS, including mild, moderate, and high disease activity.

The team has produced an online SLE-DAS calculator (http://sle-das.eu/) where clinicians can score the 17 parameters. “You just input the values and it gives a number reflecting disease activity. Using this definition of SLE-DAS LDA you only need that number and to verify that the prednisolone dose is equal to or inferior to 7.5 mg/day,” said Dr. Assunção.

The study received no funding. Dr. Assunção has no financial disclosures, but one coauthor reported receiving grant/research support from Pfizer and AbbVie and serving as a consultant to Pfizer, AbbVie, Roche, Lilly, and Novartis.

SOURCE: Assunção H et al. Ann Rheum Dis 2020;79[suppl 1]:60, Abstract OP0092.

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease that can have devastating effects on many organs. Despite the considerable morbidity and mortality associated with SLE, treatment options have been largely unchanged since the 1950s.¹ It was not until the last decade that a new biologic medication was approved, and several other promising treatments currently are being evaluated in clinical trials. Dermatologists are most likely to encounter cutaneous lupus erythematosus (CLE) with or without SLE, which can present with a variety of skin manifestations. Cutaneous lupus erythematosus can have devastating effects on quality of life and can be a visible sign of the internal activity and damage of SLE.^2,3 Although many trials have been completed evaluating SLE treatments, few medications have been evaluated specifically for CLE despite the availability of validated measures of CLE skin activity.⁴ There is a recent shortage of antimalarial medications, the current first-line therapy for CLE, due to both an import alert in the United States on quinacrine placed in 2019 as well as the use of hydroxychloroquine and chloroquine in treating coronavirus disease 2019.^5,6 Due to this shortage, the need for new and effective treatments is more critical than ever, as alternatives to first-line therapy frequently require immunosuppression. We review recent drug approvals for SLE and their efficacy in CLE. We also provide an update on new agents currently being studied to treat this disease.

Belimumab

Belimumab is a B-lymphocyte stimulator–specific inhibitor that was first approved for treatment of SLE in 2011. It was the first monoclonal antibody approved to treat SLE.⁷ B-lymphocyte stimulator plays a critical role in B-cell survival; thus, its inhibition increases apoptosis of autoreactive B cells involved in the pathogenesis of SLE. More recently, belimumab was approved for pediatric SLE in April 2019 based on the PLUTO study, a phase 2 randomized, double-blind study of 93 patients.⁸ Although patients with cutaneous manifestations of lupus were included in trials for belimumab, they lacked CLE-specific outcome measurements to truly evaluate the efficacy in treating skin disease.⁹ This medication currently is not approved by the US Food and Drug Administration (FDA) for CLE; however, it is used off label in some cases for recalcitrant disease.¹⁰

Baricitinib

Baricitinib is a selective and reversible inhibitor of JAK1 and JAK2 that was granted fast-track status by the FDA in December 2018. In a phase 2 trial, baricitinib was superior to placebo plus standard of care, primarily for arthritis and lupus nephritis.¹¹ Although improvement of cutaneous disease was measured as an end point, it did not show significant improvement in disease. The presence of skin disease was high, but the activity of disease was low, which can make it difficult to show meaningful improvement, as there is not much room for patients to objectively improve.¹² Showing meaningful improvement in skin disease often is difficult in phase 2 trials, especially when the trial design is focused on SLE rather than CLE activity. Further studies of baricitinib that include more severe patients with CLE disease are needed to truly understand its effects on the skin.

Lenalidomide

There have been several CLE studies in the last several years surrounding lenalidomide, an analog of thalidomide.^13-15 This molecule has a number of immunomodulatory effects including antiangiogenic effects, increased natural killer cell–dependent cytotoxicity, and cytokine and interleukin inhibition. Lenalidomide is of particular interest in treating CLE, as it was shown to be more potent than thalidomide at low doses and with a better side-effect profile. Multiple small, open-label trials have shown lenalidomide to be both safe and efficacious in the treatment of CLE.^13,14 In addition, iberdomide, a derivative of lenalidomide, recently completed a phase 2 dose-escalation study showing improvement in both SLE and CLE end points.¹⁶ A phase 2b proof-of-concept study currently is underway (ClinicalTrials.gov Identifier NCT03161483).

Monoclonal Antibodies

Many developing therapies target specific components of the type I interferon pathway, which is a primary driver of CLE lesions. Innate immune system pathways involving type I interferon were shown to be active in the pathogenesis of CLE, and levels of interferon correlate with skin disease activity.¹⁷ One molecule in development that targets this pathway is BIIB059, a humanized IgG1 monoclonal antibody that binds to blood dendritic cell antigen 2. This cell surface protein is uniquely expressed on plasmacytoid dendritic cells, which are the main source of type I interferon overproduction in SLE. The binding of this antibody to the blood dendritic cell antigen 2 receptor both blocks type I interferon production and decreases the overall number of active plasmacytoid dendritic cells present.¹⁸ In the completed phase 1b study, a response in cutaneous disease was shown through a reduction in the CLE disease area and severity index score following single-dose administration.¹⁹ More recently, a phase 2 study met primary end points in both SLE and CLE compared to placebo.²⁰

Anifrolumab is a human IgG1k monoclonal antibody that binds to type I interferon receptor, blocking all type I interferon signaling. Following a successful phase 2 trial, it failed to meet its primary end point in its first phase 3 trial.²¹ Several secondary end points suggested a clinical benefit. A second phase 3 trial of 362 patients randomized to treatment with anifrolumab or placebo over 48 weeks showed anifrolumab to be superior to placebo for multiple end points, including the overall disease primary end point as well as a notable reduction in skin activity.²²

Final Thoughts

Outside of the approval of belimumab, there have been no new FDA-approved treatments for SLE since the approval of antimalarial agents nearly 50 years ago. For CLE specifically, there is an even greater scarcity of evidence-based treatments. Recently studied medications, such as belimumab and lenalidomide, are available off label for CLE patients when other options have failed. Recent studies have evaluated the efficacy of these agents in the treatment of CLE using the CLE disease area and severity index.^10,13,14 Enrollment in CLE trials is difficult due to the rarity of the disease, and careful attention must be paid to evaluating skin end points. As experts in CLE and the nuances of these assessments, it is critical that dermatologists be involved in clinical trials. Future SLE trials must consider CLE as an important end point for CLE patients to get access to much-needed novel therapies.

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease that can have devastating effects on many organs. Despite the considerable morbidity and mortality associated with SLE, treatment options have been largely unchanged since the 1950s.¹ It was not until the last decade that a new biologic medication was approved, and several other promising treatments currently are being evaluated in clinical trials. Dermatologists are most likely to encounter cutaneous lupus erythematosus (CLE) with or without SLE, which can present with a variety of skin manifestations. Cutaneous lupus erythematosus can have devastating effects on quality of life and can be a visible sign of the internal activity and damage of SLE.^2,3 Although many trials have been completed evaluating SLE treatments, few medications have been evaluated specifically for CLE despite the availability of validated measures of CLE skin activity.⁴ There is a recent shortage of antimalarial medications, the current first-line therapy for CLE, due to both an import alert in the United States on quinacrine placed in 2019 as well as the use of hydroxychloroquine and chloroquine in treating coronavirus disease 2019.^5,6 Due to this shortage, the need for new and effective treatments is more critical than ever, as alternatives to first-line therapy frequently require immunosuppression. We review recent drug approvals for SLE and their efficacy in CLE. We also provide an update on new agents currently being studied to treat this disease.

Belimumab

Belimumab is a B-lymphocyte stimulator–specific inhibitor that was first approved for treatment of SLE in 2011. It was the first monoclonal antibody approved to treat SLE.⁷ B-lymphocyte stimulator plays a critical role in B-cell survival; thus, its inhibition increases apoptosis of autoreactive B cells involved in the pathogenesis of SLE. More recently, belimumab was approved for pediatric SLE in April 2019 based on the PLUTO study, a phase 2 randomized, double-blind study of 93 patients.⁸ Although patients with cutaneous manifestations of lupus were included in trials for belimumab, they lacked CLE-specific outcome measurements to truly evaluate the efficacy in treating skin disease.⁹ This medication currently is not approved by the US Food and Drug Administration (FDA) for CLE; however, it is used off label in some cases for recalcitrant disease.¹⁰

Baricitinib

Baricitinib is a selective and reversible inhibitor of JAK1 and JAK2 that was granted fast-track status by the FDA in December 2018. In a phase 2 trial, baricitinib was superior to placebo plus standard of care, primarily for arthritis and lupus nephritis.¹¹ Although improvement of cutaneous disease was measured as an end point, it did not show significant improvement in disease. The presence of skin disease was high, but the activity of disease was low, which can make it difficult to show meaningful improvement, as there is not much room for patients to objectively improve.¹² Showing meaningful improvement in skin disease often is difficult in phase 2 trials, especially when the trial design is focused on SLE rather than CLE activity. Further studies of baricitinib that include more severe patients with CLE disease are needed to truly understand its effects on the skin.

Lenalidomide

There have been several CLE studies in the last several years surrounding lenalidomide, an analog of thalidomide.^13-15 This molecule has a number of immunomodulatory effects including antiangiogenic effects, increased natural killer cell–dependent cytotoxicity, and cytokine and interleukin inhibition. Lenalidomide is of particular interest in treating CLE, as it was shown to be more potent than thalidomide at low doses and with a better side-effect profile. Multiple small, open-label trials have shown lenalidomide to be both safe and efficacious in the treatment of CLE.^13,14 In addition, iberdomide, a derivative of lenalidomide, recently completed a phase 2 dose-escalation study showing improvement in both SLE and CLE end points.¹⁶ A phase 2b proof-of-concept study currently is underway (ClinicalTrials.gov Identifier NCT03161483).

Monoclonal Antibodies

Many developing therapies target specific components of the type I interferon pathway, which is a primary driver of CLE lesions. Innate immune system pathways involving type I interferon were shown to be active in the pathogenesis of CLE, and levels of interferon correlate with skin disease activity.¹⁷ One molecule in development that targets this pathway is BIIB059, a humanized IgG1 monoclonal antibody that binds to blood dendritic cell antigen 2. This cell surface protein is uniquely expressed on plasmacytoid dendritic cells, which are the main source of type I interferon overproduction in SLE. The binding of this antibody to the blood dendritic cell antigen 2 receptor both blocks type I interferon production and decreases the overall number of active plasmacytoid dendritic cells present.¹⁸ In the completed phase 1b study, a response in cutaneous disease was shown through a reduction in the CLE disease area and severity index score following single-dose administration.¹⁹ More recently, a phase 2 study met primary end points in both SLE and CLE compared to placebo.²⁰

Anifrolumab is a human IgG1k monoclonal antibody that binds to type I interferon receptor, blocking all type I interferon signaling. Following a successful phase 2 trial, it failed to meet its primary end point in its first phase 3 trial.²¹ Several secondary end points suggested a clinical benefit. A second phase 3 trial of 362 patients randomized to treatment with anifrolumab or placebo over 48 weeks showed anifrolumab to be superior to placebo for multiple end points, including the overall disease primary end point as well as a notable reduction in skin activity.²²

Final Thoughts

Outside of the approval of belimumab, there have been no new FDA-approved treatments for SLE since the approval of antimalarial agents nearly 50 years ago. For CLE specifically, there is an even greater scarcity of evidence-based treatments. Recently studied medications, such as belimumab and lenalidomide, are available off label for CLE patients when other options have failed. Recent studies have evaluated the efficacy of these agents in the treatment of CLE using the CLE disease area and severity index.^10,13,14 Enrollment in CLE trials is difficult due to the rarity of the disease, and careful attention must be paid to evaluating skin end points. As experts in CLE and the nuances of these assessments, it is critical that dermatologists be involved in clinical trials. Future SLE trials must consider CLE as an important end point for CLE patients to get access to much-needed novel therapies.

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease that can have devastating effects on many organs. Despite the considerable morbidity and mortality associated with SLE, treatment options have been largely unchanged since the 1950s.¹ It was not until the last decade that a new biologic medication was approved, and several other promising treatments currently are being evaluated in clinical trials. Dermatologists are most likely to encounter cutaneous lupus erythematosus (CLE) with or without SLE, which can present with a variety of skin manifestations. Cutaneous lupus erythematosus can have devastating effects on quality of life and can be a visible sign of the internal activity and damage of SLE.^2,3 Although many trials have been completed evaluating SLE treatments, few medications have been evaluated specifically for CLE despite the availability of validated measures of CLE skin activity.⁴ There is a recent shortage of antimalarial medications, the current first-line therapy for CLE, due to both an import alert in the United States on quinacrine placed in 2019 as well as the use of hydroxychloroquine and chloroquine in treating coronavirus disease 2019.^5,6 Due to this shortage, the need for new and effective treatments is more critical than ever, as alternatives to first-line therapy frequently require immunosuppression. We review recent drug approvals for SLE and their efficacy in CLE. We also provide an update on new agents currently being studied to treat this disease.

Belimumab

Belimumab is a B-lymphocyte stimulator–specific inhibitor that was first approved for treatment of SLE in 2011. It was the first monoclonal antibody approved to treat SLE.⁷ B-lymphocyte stimulator plays a critical role in B-cell survival; thus, its inhibition increases apoptosis of autoreactive B cells involved in the pathogenesis of SLE. More recently, belimumab was approved for pediatric SLE in April 2019 based on the PLUTO study, a phase 2 randomized, double-blind study of 93 patients.⁸ Although patients with cutaneous manifestations of lupus were included in trials for belimumab, they lacked CLE-specific outcome measurements to truly evaluate the efficacy in treating skin disease.⁹ This medication currently is not approved by the US Food and Drug Administration (FDA) for CLE; however, it is used off label in some cases for recalcitrant disease.¹⁰

Baricitinib

Baricitinib is a selective and reversible inhibitor of JAK1 and JAK2 that was granted fast-track status by the FDA in December 2018. In a phase 2 trial, baricitinib was superior to placebo plus standard of care, primarily for arthritis and lupus nephritis.¹¹ Although improvement of cutaneous disease was measured as an end point, it did not show significant improvement in disease. The presence of skin disease was high, but the activity of disease was low, which can make it difficult to show meaningful improvement, as there is not much room for patients to objectively improve.¹² Showing meaningful improvement in skin disease often is difficult in phase 2 trials, especially when the trial design is focused on SLE rather than CLE activity. Further studies of baricitinib that include more severe patients with CLE disease are needed to truly understand its effects on the skin.

Lenalidomide

There have been several CLE studies in the last several years surrounding lenalidomide, an analog of thalidomide.^13-15 This molecule has a number of immunomodulatory effects including antiangiogenic effects, increased natural killer cell–dependent cytotoxicity, and cytokine and interleukin inhibition. Lenalidomide is of particular interest in treating CLE, as it was shown to be more potent than thalidomide at low doses and with a better side-effect profile. Multiple small, open-label trials have shown lenalidomide to be both safe and efficacious in the treatment of CLE.^13,14 In addition, iberdomide, a derivative of lenalidomide, recently completed a phase 2 dose-escalation study showing improvement in both SLE and CLE end points.¹⁶ A phase 2b proof-of-concept study currently is underway (ClinicalTrials.gov Identifier NCT03161483).

Monoclonal Antibodies

Many developing therapies target specific components of the type I interferon pathway, which is a primary driver of CLE lesions. Innate immune system pathways involving type I interferon were shown to be active in the pathogenesis of CLE, and levels of interferon correlate with skin disease activity.¹⁷ One molecule in development that targets this pathway is BIIB059, a humanized IgG1 monoclonal antibody that binds to blood dendritic cell antigen 2. This cell surface protein is uniquely expressed on plasmacytoid dendritic cells, which are the main source of type I interferon overproduction in SLE. The binding of this antibody to the blood dendritic cell antigen 2 receptor both blocks type I interferon production and decreases the overall number of active plasmacytoid dendritic cells present.¹⁸ In the completed phase 1b study, a response in cutaneous disease was shown through a reduction in the CLE disease area and severity index score following single-dose administration.¹⁹ More recently, a phase 2 study met primary end points in both SLE and CLE compared to placebo.²⁰

Anifrolumab is a human IgG1k monoclonal antibody that binds to type I interferon receptor, blocking all type I interferon signaling. Following a successful phase 2 trial, it failed to meet its primary end point in its first phase 3 trial.²¹ Several secondary end points suggested a clinical benefit. A second phase 3 trial of 362 patients randomized to treatment with anifrolumab or placebo over 48 weeks showed anifrolumab to be superior to placebo for multiple end points, including the overall disease primary end point as well as a notable reduction in skin activity.²²

Final Thoughts

Outside of the approval of belimumab, there have been no new FDA-approved treatments for SLE since the approval of antimalarial agents nearly 50 years ago. For CLE specifically, there is an even greater scarcity of evidence-based treatments. Recently studied medications, such as belimumab and lenalidomide, are available off label for CLE patients when other options have failed. Recent studies have evaluated the efficacy of these agents in the treatment of CLE using the CLE disease area and severity index.^10,13,14 Enrollment in CLE trials is difficult due to the rarity of the disease, and careful attention must be paid to evaluating skin end points. As experts in CLE and the nuances of these assessments, it is critical that dermatologists be involved in clinical trials. Future SLE trials must consider CLE as an important end point for CLE patients to get access to much-needed novel therapies.

Kawasaki disease

Given the presentation of persistent fever, nonpurulent conjunctivitis, cracked lips, erythematous tongue, desquamating perianal rash, and acral edema and erythema, suspicion was high for Kawasaki disease (KD). An echocardiogram revealed diffuse dilation of the left anterior descending artery without evidence of an aneurysm. The patient was promptly started on 2 g/kg IVIG and high-dose aspirin. She was later transitioned to low-dose aspirin. Long-term follow-up thus far has revealed no cardiac sequelae.

KD, or mucocutaneous lymph node syndrome, is a multisystem vasculitis with predilection for the coronary arteries that most commonly affects children between 6 months and 5 years of age.¹ While the etiology remains unclear, the pathogenesis is thought to be the result of an immune response to an infection in the setting of genetic susceptibility.¹ Approximately 90% of patients have mucocutaneous manifestations, highlighting the important role dermatologists play in the diagnosis and early intervention to prevent cardiovascular morbidity.

The diagnostic criteria include fever for at least 5 days accompanied by at least four of the following:

• Bilateral bulbar conjunctival injection without exudate that is classically limbal sparing.
• Oral mucosal changes with cracked fissured lips, “strawberry tongue,” or erythema of the lips and mucosa.
• Changes in the extremities: erythema, swelling, or periungual peeling.
• Polymorphous exanthem.
• Cervical lymphadenopathy, often unilateral (greater than 1.5 cm).

Courtesy Dr. Elizabeth H. Cusick and Dr. Molly E. Plovanich, department of dermatology at the University of Rochester (N.Y.)

Although nonspecific for diagnosis, laboratory abnormalities are common, including anemia, thrombocytosis, leukocytosis, elevated inflammatory markers, elevated alanine aminotransferase (ALT), hypoalbuminemia, and sterile pyuria on urine analysis.¹

Notably, a classic finding of KD is perineal dermatitis with desquamation occurring in the acute phase of disease in 80%-90% of patients.^2-5 In a retrospective review, up to 67% of patients with KD developed a perineal rash in the first week, most often beginning in the diaper area.² The perineal rash classically desquamates early during the acute phase of the disease.¹

While most individuals with KD follow a benign disease course, it is the most common cause of acquired heart disease in the United States.¹ Treatment is aimed at decreasing the risk of developing coronary abnormalities through the prompt administration of IVIG and high-dose aspirin initiated early in the acute phase.⁶ A second dose of IVIG may be given to patients who remain febrile within 24-48 hours after treatment.⁶ Infliximab has been used safely and effectively in patients with refractory KD.⁷ Long-term cardiac follow-up of KD patients is recommended.

Recently, there has been an emerging association between COVID-19 and pediatric multi-system inflammatory syndrome, which shares features with KD. Patients with pediatric multi-system inflammatory syndrome who meet clinical criteria for KD should be promptly treated with IVIG and aspirin to avoid long-term cardiac sequelae.

This case and the photos were submitted by Dr. Elizabeth H. Cusick and Dr. Molly E. Plovanich, both with the department of dermatology at the University of Rochester (N.Y.). Dr. Donna Bilu Martin edited the case.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

1. Bayers S et al. (2013). J Am Acad Dermatol. 2013 Oct;69(4):501.e1-11.

2. Friter BS and Lucky AW. Arch Dermatol. 1988 Dec;124(12):1805-10.

3. Urbach AH et al. Am J Dis Child. 1988 Nov;142(11):1174-6.

4. Fink CW. Pediatr Infect Dis. 1983 Mar-Apr; 2(2):140-1.

5. Aballi A J and Bisken LC. Pediatr Infect Dis. 1984 Mar-Apr;3(2):187.

6. McCrindle BW et al. Circulation. 2017 Apr 25;135(17):e927-e99.

7.Sauvaget E et al. J Pediatr. 2012 May; 160(5),875-6.


 

Kawasaki disease

Given the presentation of persistent fever, nonpurulent conjunctivitis, cracked lips, erythematous tongue, desquamating perianal rash, and acral edema and erythema, suspicion was high for Kawasaki disease (KD). An echocardiogram revealed diffuse dilation of the left anterior descending artery without evidence of an aneurysm. The patient was promptly started on 2 g/kg IVIG and high-dose aspirin. She was later transitioned to low-dose aspirin. Long-term follow-up thus far has revealed no cardiac sequelae.

KD, or mucocutaneous lymph node syndrome, is a multisystem vasculitis with predilection for the coronary arteries that most commonly affects children between 6 months and 5 years of age.¹ While the etiology remains unclear, the pathogenesis is thought to be the result of an immune response to an infection in the setting of genetic susceptibility.¹ Approximately 90% of patients have mucocutaneous manifestations, highlighting the important role dermatologists play in the diagnosis and early intervention to prevent cardiovascular morbidity.

The diagnostic criteria include fever for at least 5 days accompanied by at least four of the following:

• Bilateral bulbar conjunctival injection without exudate that is classically limbal sparing.
• Oral mucosal changes with cracked fissured lips, “strawberry tongue,” or erythema of the lips and mucosa.
• Changes in the extremities: erythema, swelling, or periungual peeling.
• Polymorphous exanthem.
• Cervical lymphadenopathy, often unilateral (greater than 1.5 cm).

Courtesy Dr. Elizabeth H. Cusick and Dr. Molly E. Plovanich, department of dermatology at the University of Rochester (N.Y.)

Although nonspecific for diagnosis, laboratory abnormalities are common, including anemia, thrombocytosis, leukocytosis, elevated inflammatory markers, elevated alanine aminotransferase (ALT), hypoalbuminemia, and sterile pyuria on urine analysis.¹

Notably, a classic finding of KD is perineal dermatitis with desquamation occurring in the acute phase of disease in 80%-90% of patients.^2-5 In a retrospective review, up to 67% of patients with KD developed a perineal rash in the first week, most often beginning in the diaper area.² The perineal rash classically desquamates early during the acute phase of the disease.¹

While most individuals with KD follow a benign disease course, it is the most common cause of acquired heart disease in the United States.¹ Treatment is aimed at decreasing the risk of developing coronary abnormalities through the prompt administration of IVIG and high-dose aspirin initiated early in the acute phase.⁶ A second dose of IVIG may be given to patients who remain febrile within 24-48 hours after treatment.⁶ Infliximab has been used safely and effectively in patients with refractory KD.⁷ Long-term cardiac follow-up of KD patients is recommended.

Recently, there has been an emerging association between COVID-19 and pediatric multi-system inflammatory syndrome, which shares features with KD. Patients with pediatric multi-system inflammatory syndrome who meet clinical criteria for KD should be promptly treated with IVIG and aspirin to avoid long-term cardiac sequelae.

This case and the photos were submitted by Dr. Elizabeth H. Cusick and Dr. Molly E. Plovanich, both with the department of dermatology at the University of Rochester (N.Y.). Dr. Donna Bilu Martin edited the case.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

1. Bayers S et al. (2013). J Am Acad Dermatol. 2013 Oct;69(4):501.e1-11.

2. Friter BS and Lucky AW. Arch Dermatol. 1988 Dec;124(12):1805-10.

3. Urbach AH et al. Am J Dis Child. 1988 Nov;142(11):1174-6.

4. Fink CW. Pediatr Infect Dis. 1983 Mar-Apr; 2(2):140-1.

5. Aballi A J and Bisken LC. Pediatr Infect Dis. 1984 Mar-Apr;3(2):187.

6. McCrindle BW et al. Circulation. 2017 Apr 25;135(17):e927-e99.

7.Sauvaget E et al. J Pediatr. 2012 May; 160(5),875-6.


 

Kawasaki disease

Given the presentation of persistent fever, nonpurulent conjunctivitis, cracked lips, erythematous tongue, desquamating perianal rash, and acral edema and erythema, suspicion was high for Kawasaki disease (KD). An echocardiogram revealed diffuse dilation of the left anterior descending artery without evidence of an aneurysm. The patient was promptly started on 2 g/kg IVIG and high-dose aspirin. She was later transitioned to low-dose aspirin. Long-term follow-up thus far has revealed no cardiac sequelae.

KD, or mucocutaneous lymph node syndrome, is a multisystem vasculitis with predilection for the coronary arteries that most commonly affects children between 6 months and 5 years of age.¹ While the etiology remains unclear, the pathogenesis is thought to be the result of an immune response to an infection in the setting of genetic susceptibility.¹ Approximately 90% of patients have mucocutaneous manifestations, highlighting the important role dermatologists play in the diagnosis and early intervention to prevent cardiovascular morbidity.

The diagnostic criteria include fever for at least 5 days accompanied by at least four of the following:

• Bilateral bulbar conjunctival injection without exudate that is classically limbal sparing.
• Oral mucosal changes with cracked fissured lips, “strawberry tongue,” or erythema of the lips and mucosa.
• Changes in the extremities: erythema, swelling, or periungual peeling.
• Polymorphous exanthem.
• Cervical lymphadenopathy, often unilateral (greater than 1.5 cm).

Courtesy Dr. Elizabeth H. Cusick and Dr. Molly E. Plovanich, department of dermatology at the University of Rochester (N.Y.)

Although nonspecific for diagnosis, laboratory abnormalities are common, including anemia, thrombocytosis, leukocytosis, elevated inflammatory markers, elevated alanine aminotransferase (ALT), hypoalbuminemia, and sterile pyuria on urine analysis.¹

Notably, a classic finding of KD is perineal dermatitis with desquamation occurring in the acute phase of disease in 80%-90% of patients.^2-5 In a retrospective review, up to 67% of patients with KD developed a perineal rash in the first week, most often beginning in the diaper area.² The perineal rash classically desquamates early during the acute phase of the disease.¹

While most individuals with KD follow a benign disease course, it is the most common cause of acquired heart disease in the United States.¹ Treatment is aimed at decreasing the risk of developing coronary abnormalities through the prompt administration of IVIG and high-dose aspirin initiated early in the acute phase.⁶ A second dose of IVIG may be given to patients who remain febrile within 24-48 hours after treatment.⁶ Infliximab has been used safely and effectively in patients with refractory KD.⁷ Long-term cardiac follow-up of KD patients is recommended.

Recently, there has been an emerging association between COVID-19 and pediatric multi-system inflammatory syndrome, which shares features with KD. Patients with pediatric multi-system inflammatory syndrome who meet clinical criteria for KD should be promptly treated with IVIG and aspirin to avoid long-term cardiac sequelae.

This case and the photos were submitted by Dr. Elizabeth H. Cusick and Dr. Molly E. Plovanich, both with the department of dermatology at the University of Rochester (N.Y.). Dr. Donna Bilu Martin edited the case.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

1. Bayers S et al. (2013). J Am Acad Dermatol. 2013 Oct;69(4):501.e1-11.

2. Friter BS and Lucky AW. Arch Dermatol. 1988 Dec;124(12):1805-10.

3. Urbach AH et al. Am J Dis Child. 1988 Nov;142(11):1174-6.

4. Fink CW. Pediatr Infect Dis. 1983 Mar-Apr; 2(2):140-1.

5. Aballi A J and Bisken LC. Pediatr Infect Dis. 1984 Mar-Apr;3(2):187.

6. McCrindle BW et al. Circulation. 2017 Apr 25;135(17):e927-e99.

7.Sauvaget E et al. J Pediatr. 2012 May; 160(5),875-6.