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New insight gained into natural history of interstitial pneumonia with autoimmune features
CHICAGO – than are those with idiopathic interstitial lung disease who don’t meet the criteria, Michail Alevizos, MD, reported at the annual meeting of the American College of Rheumatology.
“We think this is a very novel finding. It means that patients with IPAF [interstitial pneumonia with autoimmune features] should be followed and evaluated by rheumatologists over time,” said Dr. Alevizos, who was a rheumatology fellow at Columbia University in New York at the time of the study.
Interstitial pneumonia with autoimmune features (IPAF) is a term proposed by a joint task force of the American Thoracic Society and European Respiratory Society in 2015 to describe patients diagnosed with idiopathic interstitial lung disease who possess some features of autoimmunity without meeting formal criteria for a full-blown rheumatic disease. The designation requires the presence of interstitial lung disease by imaging or biopsy, exclusion of all other etiologies, and at least one feature from within at least two of three domains: clinical, serologic, and morphologic.
The clinical domain includes Raynaud’s, palmar telangiectasias, distal digital tip ulceration, and other entities. The serologic criteria include any of a dozen possible autoantibodies. And the morphologic domain encompasses a radiographic or histopathologic pattern suggestive of organizing pneumonia, nonspecific interstitial pneumonia, or other specific abnormalities (Eur Respir J. 2015 Oct;46[4]:976-87).
The natural history of IPAF is largely unknown, which was the impetus for Dr. Alevizos’ study. He presented a single-center, retrospective study of 697 patients diagnosed with interstitial lung disease, 174 of whom had idiopathic interstitial lung disease at baseline. Fifty of the 174 met criteria for IPAF, while the other 124 did not.
During a median follow-up of 5.2 years, 8 of the 50 patients with IPAF (16%) were diagnosed with a systemic autoimmune rheumatic disease, as were 2 of the 124 non-IPAF group (1.6%). The average time to diagnosis of a formal rheumatic disease was 3.4 years in the IPAF group and 7.8 years in the comparator arm. The rheumatic diseases that arose in the IPAF group consisted of two cases of rheumatoid arthritis, two of antineutrophil cytoplasmic antibody–associated vasculitis, three of systemic sclerosis, and one of polymyositis.
In an analysis adjusted for age, sex, smoking status, and immunosuppressive therapy at baseline, patients with IPAF were 14.1 times more likely to progress to an autoimmune rheumatic disease.
In terms of distinguishing features, the IPAF patients were on average 10 years younger at baseline and more commonly female. On high-resolution CT, 82% of them displayed a pattern of nonspecific interstitial pneumonia, compared with only 15% of the non-IPAF group. Also, 96% of the IPAF patients were on immunosuppressive therapy at baseline, as were 52% of the non-IPAF group. Usual interstitial pneumonia was evident on high-resolution CT in 18% of the IPAF group, compared with 75% of patients with idiopathic interstitial pneumonia without IPAF.
Dr. Alevizos said he hopes to validate these findings in a prospective study. He reported having no financial conflicts regarding the study, which was conducted free of commercial support.
SOURCE: Alevizos M et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 1305.
CHICAGO – than are those with idiopathic interstitial lung disease who don’t meet the criteria, Michail Alevizos, MD, reported at the annual meeting of the American College of Rheumatology.
“We think this is a very novel finding. It means that patients with IPAF [interstitial pneumonia with autoimmune features] should be followed and evaluated by rheumatologists over time,” said Dr. Alevizos, who was a rheumatology fellow at Columbia University in New York at the time of the study.
Interstitial pneumonia with autoimmune features (IPAF) is a term proposed by a joint task force of the American Thoracic Society and European Respiratory Society in 2015 to describe patients diagnosed with idiopathic interstitial lung disease who possess some features of autoimmunity without meeting formal criteria for a full-blown rheumatic disease. The designation requires the presence of interstitial lung disease by imaging or biopsy, exclusion of all other etiologies, and at least one feature from within at least two of three domains: clinical, serologic, and morphologic.
The clinical domain includes Raynaud’s, palmar telangiectasias, distal digital tip ulceration, and other entities. The serologic criteria include any of a dozen possible autoantibodies. And the morphologic domain encompasses a radiographic or histopathologic pattern suggestive of organizing pneumonia, nonspecific interstitial pneumonia, or other specific abnormalities (Eur Respir J. 2015 Oct;46[4]:976-87).
The natural history of IPAF is largely unknown, which was the impetus for Dr. Alevizos’ study. He presented a single-center, retrospective study of 697 patients diagnosed with interstitial lung disease, 174 of whom had idiopathic interstitial lung disease at baseline. Fifty of the 174 met criteria for IPAF, while the other 124 did not.
During a median follow-up of 5.2 years, 8 of the 50 patients with IPAF (16%) were diagnosed with a systemic autoimmune rheumatic disease, as were 2 of the 124 non-IPAF group (1.6%). The average time to diagnosis of a formal rheumatic disease was 3.4 years in the IPAF group and 7.8 years in the comparator arm. The rheumatic diseases that arose in the IPAF group consisted of two cases of rheumatoid arthritis, two of antineutrophil cytoplasmic antibody–associated vasculitis, three of systemic sclerosis, and one of polymyositis.
In an analysis adjusted for age, sex, smoking status, and immunosuppressive therapy at baseline, patients with IPAF were 14.1 times more likely to progress to an autoimmune rheumatic disease.
In terms of distinguishing features, the IPAF patients were on average 10 years younger at baseline and more commonly female. On high-resolution CT, 82% of them displayed a pattern of nonspecific interstitial pneumonia, compared with only 15% of the non-IPAF group. Also, 96% of the IPAF patients were on immunosuppressive therapy at baseline, as were 52% of the non-IPAF group. Usual interstitial pneumonia was evident on high-resolution CT in 18% of the IPAF group, compared with 75% of patients with idiopathic interstitial pneumonia without IPAF.
Dr. Alevizos said he hopes to validate these findings in a prospective study. He reported having no financial conflicts regarding the study, which was conducted free of commercial support.
SOURCE: Alevizos M et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 1305.
CHICAGO – than are those with idiopathic interstitial lung disease who don’t meet the criteria, Michail Alevizos, MD, reported at the annual meeting of the American College of Rheumatology.
“We think this is a very novel finding. It means that patients with IPAF [interstitial pneumonia with autoimmune features] should be followed and evaluated by rheumatologists over time,” said Dr. Alevizos, who was a rheumatology fellow at Columbia University in New York at the time of the study.
Interstitial pneumonia with autoimmune features (IPAF) is a term proposed by a joint task force of the American Thoracic Society and European Respiratory Society in 2015 to describe patients diagnosed with idiopathic interstitial lung disease who possess some features of autoimmunity without meeting formal criteria for a full-blown rheumatic disease. The designation requires the presence of interstitial lung disease by imaging or biopsy, exclusion of all other etiologies, and at least one feature from within at least two of three domains: clinical, serologic, and morphologic.
The clinical domain includes Raynaud’s, palmar telangiectasias, distal digital tip ulceration, and other entities. The serologic criteria include any of a dozen possible autoantibodies. And the morphologic domain encompasses a radiographic or histopathologic pattern suggestive of organizing pneumonia, nonspecific interstitial pneumonia, or other specific abnormalities (Eur Respir J. 2015 Oct;46[4]:976-87).
The natural history of IPAF is largely unknown, which was the impetus for Dr. Alevizos’ study. He presented a single-center, retrospective study of 697 patients diagnosed with interstitial lung disease, 174 of whom had idiopathic interstitial lung disease at baseline. Fifty of the 174 met criteria for IPAF, while the other 124 did not.
During a median follow-up of 5.2 years, 8 of the 50 patients with IPAF (16%) were diagnosed with a systemic autoimmune rheumatic disease, as were 2 of the 124 non-IPAF group (1.6%). The average time to diagnosis of a formal rheumatic disease was 3.4 years in the IPAF group and 7.8 years in the comparator arm. The rheumatic diseases that arose in the IPAF group consisted of two cases of rheumatoid arthritis, two of antineutrophil cytoplasmic antibody–associated vasculitis, three of systemic sclerosis, and one of polymyositis.
In an analysis adjusted for age, sex, smoking status, and immunosuppressive therapy at baseline, patients with IPAF were 14.1 times more likely to progress to an autoimmune rheumatic disease.
In terms of distinguishing features, the IPAF patients were on average 10 years younger at baseline and more commonly female. On high-resolution CT, 82% of them displayed a pattern of nonspecific interstitial pneumonia, compared with only 15% of the non-IPAF group. Also, 96% of the IPAF patients were on immunosuppressive therapy at baseline, as were 52% of the non-IPAF group. Usual interstitial pneumonia was evident on high-resolution CT in 18% of the IPAF group, compared with 75% of patients with idiopathic interstitial pneumonia without IPAF.
Dr. Alevizos said he hopes to validate these findings in a prospective study. He reported having no financial conflicts regarding the study, which was conducted free of commercial support.
SOURCE: Alevizos M et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 1305.
REPORTING FROM the ACR ANNUAL MEETING
Key clinical point: The adjusted risk of progression to a systemic autoimmune rheumatic disease is 14.1 times greater in interstitial pneumonia with autoimmune features than in idiopathic interstitial lung disease without such features.
Major finding: A total of 16% of patients with interstitial pneumonia with autoimmune features progressed to a systemic autoimmune rheumatic disease during follow-up, compared with 1.6% of patients with idiopathic interstitial lung disease without such features.
Study details: This retrospective, single-center study included 174 patients with idiopathic interstitial lung disease followed for a median of 5.2 years.
Disclosures: The presenter reported having no financial conflicts regarding the study, which was conducted free of commercial support.
Source: Alevizos M et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 1305.
Drug-drug interactions in rheumatology patients on PPIs: An underappreciated problem?
CHICAGO – posing a distinct danger of unwelcome drug-drug interactions affecting the rate and extent of absorption of selected oral antirheumatic drugs, Nicholas Jones, PharmD, said at the annual meeting of the American College of Rheumatology.
Of particular interest is the fact that the oral Janus kinase inhibitors – a drug class that’s a red hot research topic now in rheumatology – are weak bases whose absorption can be greatly affected by pH-dependent solubility, according to Dr. Jones, a research scientist at Genentech in South San Francisco.
Other commonly prescribed oral antirheumatic drugs whose solubility is affected by the level of stomach acidity include azathioprine, methotrexate, mycophenolate mofetil, and sulfasalazine. On the other hand, solubility is not pH-dependent for apremilast, chloroquine, cyclophosphamide, cyclosporine, hydroxychloroquine, leflunomide, or tacrolimus.
Dr. Jones presented a retrospective analysis of proton pump inhibitor (PPI) utilization patterns during 2012-2015 in 77,034 rheumatoid arthritis and 2,224 systemic lupus erythematosus (SLE) patients included in the national Truven Health MarketScan database.
Thirty-five percent of the rheumatoid arthritis patients and 34% of SLE patients were chronic users of PPIs as defined by continuous daily use for more than a month during 2 years of follow-up. Among the SLE cohort, chronic utilization of PPIs increased stepwise with disease severity: The rate was 27% in those with mild SLE, 39% with moderate disease, and 54% among those with severe SLE.
Omeprazole was far and away the most widely used PPI. It was the one used by 53% of the RA patients who were chronic users of PPIs, followed by pantoprazole at 20% and esomeprazole at 15%. The PPI distribution pattern closely followed suit in SLE patients who were chronic users.
Esomeprazole is 60% more potent and pantoprazole 77% less potent than omeprazole, Dr. Jones noted. The pharmacokinetic clearance routes for omeprazole and esomeprazole involve CYP2C19 and CYP3A4. Clearance of pantoprazole is by those two mechanisms as well as by CYP2D6 and CYP2C9.
Dr. Jones recommended that physicians who treat rheumatoid arthritis and SLE patients be sure to ask them about concomitant use of PPIs, including OTC formulations. And clinical trialists need to be attentive to PPI usage in potential study participants.
Genentech sponsored the study.
SOURCE: Keebler D et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 228
CHICAGO – posing a distinct danger of unwelcome drug-drug interactions affecting the rate and extent of absorption of selected oral antirheumatic drugs, Nicholas Jones, PharmD, said at the annual meeting of the American College of Rheumatology.
Of particular interest is the fact that the oral Janus kinase inhibitors – a drug class that’s a red hot research topic now in rheumatology – are weak bases whose absorption can be greatly affected by pH-dependent solubility, according to Dr. Jones, a research scientist at Genentech in South San Francisco.
Other commonly prescribed oral antirheumatic drugs whose solubility is affected by the level of stomach acidity include azathioprine, methotrexate, mycophenolate mofetil, and sulfasalazine. On the other hand, solubility is not pH-dependent for apremilast, chloroquine, cyclophosphamide, cyclosporine, hydroxychloroquine, leflunomide, or tacrolimus.
Dr. Jones presented a retrospective analysis of proton pump inhibitor (PPI) utilization patterns during 2012-2015 in 77,034 rheumatoid arthritis and 2,224 systemic lupus erythematosus (SLE) patients included in the national Truven Health MarketScan database.
Thirty-five percent of the rheumatoid arthritis patients and 34% of SLE patients were chronic users of PPIs as defined by continuous daily use for more than a month during 2 years of follow-up. Among the SLE cohort, chronic utilization of PPIs increased stepwise with disease severity: The rate was 27% in those with mild SLE, 39% with moderate disease, and 54% among those with severe SLE.
Omeprazole was far and away the most widely used PPI. It was the one used by 53% of the RA patients who were chronic users of PPIs, followed by pantoprazole at 20% and esomeprazole at 15%. The PPI distribution pattern closely followed suit in SLE patients who were chronic users.
Esomeprazole is 60% more potent and pantoprazole 77% less potent than omeprazole, Dr. Jones noted. The pharmacokinetic clearance routes for omeprazole and esomeprazole involve CYP2C19 and CYP3A4. Clearance of pantoprazole is by those two mechanisms as well as by CYP2D6 and CYP2C9.
Dr. Jones recommended that physicians who treat rheumatoid arthritis and SLE patients be sure to ask them about concomitant use of PPIs, including OTC formulations. And clinical trialists need to be attentive to PPI usage in potential study participants.
Genentech sponsored the study.
SOURCE: Keebler D et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 228
CHICAGO – posing a distinct danger of unwelcome drug-drug interactions affecting the rate and extent of absorption of selected oral antirheumatic drugs, Nicholas Jones, PharmD, said at the annual meeting of the American College of Rheumatology.
Of particular interest is the fact that the oral Janus kinase inhibitors – a drug class that’s a red hot research topic now in rheumatology – are weak bases whose absorption can be greatly affected by pH-dependent solubility, according to Dr. Jones, a research scientist at Genentech in South San Francisco.
Other commonly prescribed oral antirheumatic drugs whose solubility is affected by the level of stomach acidity include azathioprine, methotrexate, mycophenolate mofetil, and sulfasalazine. On the other hand, solubility is not pH-dependent for apremilast, chloroquine, cyclophosphamide, cyclosporine, hydroxychloroquine, leflunomide, or tacrolimus.
Dr. Jones presented a retrospective analysis of proton pump inhibitor (PPI) utilization patterns during 2012-2015 in 77,034 rheumatoid arthritis and 2,224 systemic lupus erythematosus (SLE) patients included in the national Truven Health MarketScan database.
Thirty-five percent of the rheumatoid arthritis patients and 34% of SLE patients were chronic users of PPIs as defined by continuous daily use for more than a month during 2 years of follow-up. Among the SLE cohort, chronic utilization of PPIs increased stepwise with disease severity: The rate was 27% in those with mild SLE, 39% with moderate disease, and 54% among those with severe SLE.
Omeprazole was far and away the most widely used PPI. It was the one used by 53% of the RA patients who were chronic users of PPIs, followed by pantoprazole at 20% and esomeprazole at 15%. The PPI distribution pattern closely followed suit in SLE patients who were chronic users.
Esomeprazole is 60% more potent and pantoprazole 77% less potent than omeprazole, Dr. Jones noted. The pharmacokinetic clearance routes for omeprazole and esomeprazole involve CYP2C19 and CYP3A4. Clearance of pantoprazole is by those two mechanisms as well as by CYP2D6 and CYP2C9.
Dr. Jones recommended that physicians who treat rheumatoid arthritis and SLE patients be sure to ask them about concomitant use of PPIs, including OTC formulations. And clinical trialists need to be attentive to PPI usage in potential study participants.
Genentech sponsored the study.
SOURCE: Keebler D et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 228
REPORTING FROM the ACR ANNUAL MEETING
Key clinical point: Ask your RA and SLE patients about concomitant chronic use of PPIs to avoid drug-drug interactions.
Major finding: More than one-third of RA and SLE patients are chronic users of PPIs, which raises potential drug-drug interaction issues for many commonly prescribed oral antirheumatic drugs.
Study details: This retrospective study utilized national claims data to examine chronic use of PPIs among more than 77,000 patients with RA and 2,224 with SLE.
Disclosures: The presenter is employed at Genentech, which sponsored the study.
Source: Keebler D et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 228
Novel SSc classification scheme aims to improve risk stratification
CHICAGO – A simple new classification scheme that combines autoantibody specificity and extent of skin involvement could improve risk stratification of patients with systemic sclerosis, according to researchers at University College London.
“The Le Roy et al. classification of SSc [systemic sclerosis] into limited and diffuse cutaneous subtype remains the most commonly used classification system for systemic sclerosis, but autoantibodies are much better predictors of organ involvement, and while more sophisticated approaches exist, this proposed simple classification using antibodies and skin subset is relevant to clinical practice and could help risk stratification,” Svetlana I. Nihtyanova, MD, said at the annual meeting of the American College of Rheumatology.
Dr. Nihtyanova, a clinical research fellow at University College London, reported how she and her colleagues at UCL divided 1,025 SSc patients into 12 subgroups based on skin subset and autoantibodies and then conducted Kaplan-Meier estimates of survival and cumulative incidence of organ complications to rank these 12 subgroups by endpoint estimates. They merged subgroups with similar ranking in multiple endpoints, ending up with seven groups in the final classification.
Group 1 comprised anti–centromere antibody–positive limited cutaneous SSc (lcSSc) patients and accounted for 29% of patients.
“This was the subgroup with the highest survival (72%) and the lowest incidence of pulmonary fibrosis (13%) and scleroderma renal crisis (no cases) at 20 years from onset,” she said, noting that the incidence of pulmonary hypertension in this group was similar to the average for the whole cohort.
Group 2 comprised all anti–RNA polymerase antibody–positive subjects and accounted for 11% of patients. This group had the highest incidence of scleroderma renal crisis (SRC; 32% at 20 years), but other organ complications and survival were similar to the cohort average.
Group 3 comprised Scl-70–positive lcSSc patients, and accounted for 11% of patients.
“Although incidence of pulmonary fibrosis in this group was the second highest (69% at 20 years), other complications were rare,” Dr. Nihtyanova said, adding that this group had the lowest incidence of pulmonary hypertension (6%) and the second lowest incidence of SRC (3%) at 20 years.
Group 4, conversely, included Scl-70–positive dcSSc patients and accounted for 11% of patients, who had a very poor prognosis; they had the highest incidence of pulmonary fibrosis (91%) and cardiac scleroderma (14%), and the worst survival (41%) at 20 years, she said.
Group 5 included all U3 RNP–positive patients, accounting for 5% of patients.
“Although survival in this group was not bad (70% at 20 years), the group had the highest pulmonary hypertension incidence (40%) and the second highest incidence of cardiac SSc (11%) at 20 years,” she noted.
Groups 6 and 7 (comprising 22% and 11% of study subjects, respectively) included lcSSc and diffuse cutaneous SSc (dcSSc) patients with other antibody specificities. Group 6 had low overall SRC and cardiac SSc risk, while other outcomes were similar to the cohort average. Group 7, however, had poor prognosis, with the second lowest survival (42% at 20 years) and above average rates of organ disease, particularly pulmonary fibrosis and SRC, she said.
Overall, estimated survival for the entire cohort was 60% at 20 years from onset, and in that time frame 44% developed significant pulmonary fibrosis, 25% pulmonary hypertension, 7% SRC, and 6% cardiac SSc. The patients had a mean age of 47 years at disease onset, and 16% were men. Diffuse cutaneous SSc was diagnosed in 35% of the subjects, she noted.
Dr. Nihtyanova reported having no disclosures.
SOURCE: Nihtyanova S et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 2935.
CHICAGO – A simple new classification scheme that combines autoantibody specificity and extent of skin involvement could improve risk stratification of patients with systemic sclerosis, according to researchers at University College London.
“The Le Roy et al. classification of SSc [systemic sclerosis] into limited and diffuse cutaneous subtype remains the most commonly used classification system for systemic sclerosis, but autoantibodies are much better predictors of organ involvement, and while more sophisticated approaches exist, this proposed simple classification using antibodies and skin subset is relevant to clinical practice and could help risk stratification,” Svetlana I. Nihtyanova, MD, said at the annual meeting of the American College of Rheumatology.
Dr. Nihtyanova, a clinical research fellow at University College London, reported how she and her colleagues at UCL divided 1,025 SSc patients into 12 subgroups based on skin subset and autoantibodies and then conducted Kaplan-Meier estimates of survival and cumulative incidence of organ complications to rank these 12 subgroups by endpoint estimates. They merged subgroups with similar ranking in multiple endpoints, ending up with seven groups in the final classification.
Group 1 comprised anti–centromere antibody–positive limited cutaneous SSc (lcSSc) patients and accounted for 29% of patients.
“This was the subgroup with the highest survival (72%) and the lowest incidence of pulmonary fibrosis (13%) and scleroderma renal crisis (no cases) at 20 years from onset,” she said, noting that the incidence of pulmonary hypertension in this group was similar to the average for the whole cohort.
Group 2 comprised all anti–RNA polymerase antibody–positive subjects and accounted for 11% of patients. This group had the highest incidence of scleroderma renal crisis (SRC; 32% at 20 years), but other organ complications and survival were similar to the cohort average.
Group 3 comprised Scl-70–positive lcSSc patients, and accounted for 11% of patients.
“Although incidence of pulmonary fibrosis in this group was the second highest (69% at 20 years), other complications were rare,” Dr. Nihtyanova said, adding that this group had the lowest incidence of pulmonary hypertension (6%) and the second lowest incidence of SRC (3%) at 20 years.
Group 4, conversely, included Scl-70–positive dcSSc patients and accounted for 11% of patients, who had a very poor prognosis; they had the highest incidence of pulmonary fibrosis (91%) and cardiac scleroderma (14%), and the worst survival (41%) at 20 years, she said.
Group 5 included all U3 RNP–positive patients, accounting for 5% of patients.
“Although survival in this group was not bad (70% at 20 years), the group had the highest pulmonary hypertension incidence (40%) and the second highest incidence of cardiac SSc (11%) at 20 years,” she noted.
Groups 6 and 7 (comprising 22% and 11% of study subjects, respectively) included lcSSc and diffuse cutaneous SSc (dcSSc) patients with other antibody specificities. Group 6 had low overall SRC and cardiac SSc risk, while other outcomes were similar to the cohort average. Group 7, however, had poor prognosis, with the second lowest survival (42% at 20 years) and above average rates of organ disease, particularly pulmonary fibrosis and SRC, she said.
Overall, estimated survival for the entire cohort was 60% at 20 years from onset, and in that time frame 44% developed significant pulmonary fibrosis, 25% pulmonary hypertension, 7% SRC, and 6% cardiac SSc. The patients had a mean age of 47 years at disease onset, and 16% were men. Diffuse cutaneous SSc was diagnosed in 35% of the subjects, she noted.
Dr. Nihtyanova reported having no disclosures.
SOURCE: Nihtyanova S et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 2935.
CHICAGO – A simple new classification scheme that combines autoantibody specificity and extent of skin involvement could improve risk stratification of patients with systemic sclerosis, according to researchers at University College London.
“The Le Roy et al. classification of SSc [systemic sclerosis] into limited and diffuse cutaneous subtype remains the most commonly used classification system for systemic sclerosis, but autoantibodies are much better predictors of organ involvement, and while more sophisticated approaches exist, this proposed simple classification using antibodies and skin subset is relevant to clinical practice and could help risk stratification,” Svetlana I. Nihtyanova, MD, said at the annual meeting of the American College of Rheumatology.
Dr. Nihtyanova, a clinical research fellow at University College London, reported how she and her colleagues at UCL divided 1,025 SSc patients into 12 subgroups based on skin subset and autoantibodies and then conducted Kaplan-Meier estimates of survival and cumulative incidence of organ complications to rank these 12 subgroups by endpoint estimates. They merged subgroups with similar ranking in multiple endpoints, ending up with seven groups in the final classification.
Group 1 comprised anti–centromere antibody–positive limited cutaneous SSc (lcSSc) patients and accounted for 29% of patients.
“This was the subgroup with the highest survival (72%) and the lowest incidence of pulmonary fibrosis (13%) and scleroderma renal crisis (no cases) at 20 years from onset,” she said, noting that the incidence of pulmonary hypertension in this group was similar to the average for the whole cohort.
Group 2 comprised all anti–RNA polymerase antibody–positive subjects and accounted for 11% of patients. This group had the highest incidence of scleroderma renal crisis (SRC; 32% at 20 years), but other organ complications and survival were similar to the cohort average.
Group 3 comprised Scl-70–positive lcSSc patients, and accounted for 11% of patients.
“Although incidence of pulmonary fibrosis in this group was the second highest (69% at 20 years), other complications were rare,” Dr. Nihtyanova said, adding that this group had the lowest incidence of pulmonary hypertension (6%) and the second lowest incidence of SRC (3%) at 20 years.
Group 4, conversely, included Scl-70–positive dcSSc patients and accounted for 11% of patients, who had a very poor prognosis; they had the highest incidence of pulmonary fibrosis (91%) and cardiac scleroderma (14%), and the worst survival (41%) at 20 years, she said.
Group 5 included all U3 RNP–positive patients, accounting for 5% of patients.
“Although survival in this group was not bad (70% at 20 years), the group had the highest pulmonary hypertension incidence (40%) and the second highest incidence of cardiac SSc (11%) at 20 years,” she noted.
Groups 6 and 7 (comprising 22% and 11% of study subjects, respectively) included lcSSc and diffuse cutaneous SSc (dcSSc) patients with other antibody specificities. Group 6 had low overall SRC and cardiac SSc risk, while other outcomes were similar to the cohort average. Group 7, however, had poor prognosis, with the second lowest survival (42% at 20 years) and above average rates of organ disease, particularly pulmonary fibrosis and SRC, she said.
Overall, estimated survival for the entire cohort was 60% at 20 years from onset, and in that time frame 44% developed significant pulmonary fibrosis, 25% pulmonary hypertension, 7% SRC, and 6% cardiac SSc. The patients had a mean age of 47 years at disease onset, and 16% were men. Diffuse cutaneous SSc was diagnosed in 35% of the subjects, she noted.
Dr. Nihtyanova reported having no disclosures.
SOURCE: Nihtyanova S et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 2935.
REPORTING FROM THE ACR ANNUAL MEETING
Key clinical point:
Major finding: The classification scheme for SSc risk stratification identified seven distinct SSc subgroups.
Study details: Development and testing of a novel risk classification scheme in 1,025 SSc patients.
Disclosures: Dr. Nihtyanova reported having no disclosures.
Source: Nihtyanova S et al. Arthritis Rheumatol. 2018;70(Suppl 10):Abstract 2935.
Increased cancer risk in dermatomyositis has temporal limits
The increased risk of cancer associated with anti-TIF1-Ab-positive dermatomyositis is limited almost exclusively to 3 years on either side of the onset of dermatomyositis, new research suggests.
Idiopathic inflammatory myopathy have been associated with malignancy, in particular dermatomyositis (DM) and the DM-specific antitranscriptional intermediary factor 1 antibody (anti-TIF1-Ab).
Around one-fifth of the 236 patients diagnosed with DM in the current study, published online Dec. 7 in Rheumatology, were anti-TIF1-Ab positive, and these patients had a more than threefold higher risk of developing cancer comapared with patients who were anti-TIF1-Ab negative (hazard ratio = 3.4, 95% confidence interval, 2.2-5.4; P less than .01).
Overall, 38% of patients in the anti-TIF1-Ab-positive group developed cancer during the 10-year follow-up, compared with 15% of patients with anti-TIF1-Ab-negative DM.
However, all the cancers in the anti-TIF1-Ab-positive group occurred within the 3 years before the onset of DM or within 2.5 years after onset. No anti-TIF1-Ab-positive patients developed cancers after this time, but some patients in the anti-TIF1-Ab-negative group did.
“This finding is not likely to be due to a disparity in follow-up time between anti-TIF1-Ab-positive and -negative cases, as the median follow-up times were similar for both groups: 10 years and 12 years, respectively,” wrote Alexander Oldroyd, MBChB, a clinical research fellow in the Centre for Musculoskeletal Research at the University of Manchester (England), and his coauthors. “Further, this finding is unlikely to be due to differences in cancer detection methods, as both cohorts’ cancer diagnoses were identified through HSCIC [U.K. Health and Social Care Information Centre] data, ensuring capture of all incident cancers during the follow-up period.”
Anti-TIF1-Ab-positive patients were more likely to develop cancer if they were older. None of the 15 anti-TIF1-Ab-positive patients who were aged under 39 when they developed DM went on to develop cancer. But cancer developed in around half of the anti-TIF1-Ab-positive patients who were aged 39 years or older when their DM began.
The anti-TIF1 antibody is commonly found in juvenile DM, but previous research has not found an association with an increased risk of cancer in this younger patient population.
“Our findings add strength to the hypothesis that there exists a subset of young adult anti-TIF1-Ab-positive cases who do not have a discernible increased risk of cancer, similar to that observed in TIF1-Ab-positive juvenile DM,” the authors wrote. They suggested that given the increased risk of malignancy in older patients who were anti-TIF1-Ab positive, this group should be subject to more detailed cancer screening.
Breast cancer was the most common malignancy among both anti-TIF1-Ab-positive and anti-TIF1-Ab-negative patients (33% and 25%, respectively). However, ovarian cancer was significantly more common among the anti-TIF1-Ab-positive patients than among the anti-TIF1-Ab-negative patients (19% vs. 2%; P less than .05); four of the five ovarian cancers in the entire cohort occurred in the anti-TIF1-Ab-positive group.
The authors noted that this confirmed the finding of a number of previous studies suggesting an increased risk of ovarian cancer with DM.
“However, this is the first large study to identify that ovarian cancer is overrepresented in anti-TIF1-Ab-positive individuals, suggesting that the true association between DM and ovarian cancer may be through possession of anti-TIF1-Abs,” they noted.
The authors wrote that they had aimed to inform cancer screening strategies among patients with DM.
“It may be that a focus on screening for cancer within the first 3 years after DM onset and particularly screening for ovarian cancer in anti-TIF1-Ab-positive female patients may be required,” they wrote. “Our findings also strengthen the hypothesis that inflammatory myopathies represent a paraneoplastic reaction initiated by attempted immune-mediated clearance of a cancer.”
The study was supported by Arthritis Research UK, Myositis UK, the European Science Foundation for EuMyoNet, Association Francaise Contre Les Myopathies, the Medical Research Council, and the Manchester Academic Health Science Centre. No conflicts of interest were declared.
SOURCE: Oldroyd A et al. Rheumatology. 2018 Dec 7. doi: 10.1093/rheumatology/key357.
The increased risk of cancer associated with anti-TIF1-Ab-positive dermatomyositis is limited almost exclusively to 3 years on either side of the onset of dermatomyositis, new research suggests.
Idiopathic inflammatory myopathy have been associated with malignancy, in particular dermatomyositis (DM) and the DM-specific antitranscriptional intermediary factor 1 antibody (anti-TIF1-Ab).
Around one-fifth of the 236 patients diagnosed with DM in the current study, published online Dec. 7 in Rheumatology, were anti-TIF1-Ab positive, and these patients had a more than threefold higher risk of developing cancer comapared with patients who were anti-TIF1-Ab negative (hazard ratio = 3.4, 95% confidence interval, 2.2-5.4; P less than .01).
Overall, 38% of patients in the anti-TIF1-Ab-positive group developed cancer during the 10-year follow-up, compared with 15% of patients with anti-TIF1-Ab-negative DM.
However, all the cancers in the anti-TIF1-Ab-positive group occurred within the 3 years before the onset of DM or within 2.5 years after onset. No anti-TIF1-Ab-positive patients developed cancers after this time, but some patients in the anti-TIF1-Ab-negative group did.
“This finding is not likely to be due to a disparity in follow-up time between anti-TIF1-Ab-positive and -negative cases, as the median follow-up times were similar for both groups: 10 years and 12 years, respectively,” wrote Alexander Oldroyd, MBChB, a clinical research fellow in the Centre for Musculoskeletal Research at the University of Manchester (England), and his coauthors. “Further, this finding is unlikely to be due to differences in cancer detection methods, as both cohorts’ cancer diagnoses were identified through HSCIC [U.K. Health and Social Care Information Centre] data, ensuring capture of all incident cancers during the follow-up period.”
Anti-TIF1-Ab-positive patients were more likely to develop cancer if they were older. None of the 15 anti-TIF1-Ab-positive patients who were aged under 39 when they developed DM went on to develop cancer. But cancer developed in around half of the anti-TIF1-Ab-positive patients who were aged 39 years or older when their DM began.
The anti-TIF1 antibody is commonly found in juvenile DM, but previous research has not found an association with an increased risk of cancer in this younger patient population.
“Our findings add strength to the hypothesis that there exists a subset of young adult anti-TIF1-Ab-positive cases who do not have a discernible increased risk of cancer, similar to that observed in TIF1-Ab-positive juvenile DM,” the authors wrote. They suggested that given the increased risk of malignancy in older patients who were anti-TIF1-Ab positive, this group should be subject to more detailed cancer screening.
Breast cancer was the most common malignancy among both anti-TIF1-Ab-positive and anti-TIF1-Ab-negative patients (33% and 25%, respectively). However, ovarian cancer was significantly more common among the anti-TIF1-Ab-positive patients than among the anti-TIF1-Ab-negative patients (19% vs. 2%; P less than .05); four of the five ovarian cancers in the entire cohort occurred in the anti-TIF1-Ab-positive group.
The authors noted that this confirmed the finding of a number of previous studies suggesting an increased risk of ovarian cancer with DM.
“However, this is the first large study to identify that ovarian cancer is overrepresented in anti-TIF1-Ab-positive individuals, suggesting that the true association between DM and ovarian cancer may be through possession of anti-TIF1-Abs,” they noted.
The authors wrote that they had aimed to inform cancer screening strategies among patients with DM.
“It may be that a focus on screening for cancer within the first 3 years after DM onset and particularly screening for ovarian cancer in anti-TIF1-Ab-positive female patients may be required,” they wrote. “Our findings also strengthen the hypothesis that inflammatory myopathies represent a paraneoplastic reaction initiated by attempted immune-mediated clearance of a cancer.”
The study was supported by Arthritis Research UK, Myositis UK, the European Science Foundation for EuMyoNet, Association Francaise Contre Les Myopathies, the Medical Research Council, and the Manchester Academic Health Science Centre. No conflicts of interest were declared.
SOURCE: Oldroyd A et al. Rheumatology. 2018 Dec 7. doi: 10.1093/rheumatology/key357.
The increased risk of cancer associated with anti-TIF1-Ab-positive dermatomyositis is limited almost exclusively to 3 years on either side of the onset of dermatomyositis, new research suggests.
Idiopathic inflammatory myopathy have been associated with malignancy, in particular dermatomyositis (DM) and the DM-specific antitranscriptional intermediary factor 1 antibody (anti-TIF1-Ab).
Around one-fifth of the 236 patients diagnosed with DM in the current study, published online Dec. 7 in Rheumatology, were anti-TIF1-Ab positive, and these patients had a more than threefold higher risk of developing cancer comapared with patients who were anti-TIF1-Ab negative (hazard ratio = 3.4, 95% confidence interval, 2.2-5.4; P less than .01).
Overall, 38% of patients in the anti-TIF1-Ab-positive group developed cancer during the 10-year follow-up, compared with 15% of patients with anti-TIF1-Ab-negative DM.
However, all the cancers in the anti-TIF1-Ab-positive group occurred within the 3 years before the onset of DM or within 2.5 years after onset. No anti-TIF1-Ab-positive patients developed cancers after this time, but some patients in the anti-TIF1-Ab-negative group did.
“This finding is not likely to be due to a disparity in follow-up time between anti-TIF1-Ab-positive and -negative cases, as the median follow-up times were similar for both groups: 10 years and 12 years, respectively,” wrote Alexander Oldroyd, MBChB, a clinical research fellow in the Centre for Musculoskeletal Research at the University of Manchester (England), and his coauthors. “Further, this finding is unlikely to be due to differences in cancer detection methods, as both cohorts’ cancer diagnoses were identified through HSCIC [U.K. Health and Social Care Information Centre] data, ensuring capture of all incident cancers during the follow-up period.”
Anti-TIF1-Ab-positive patients were more likely to develop cancer if they were older. None of the 15 anti-TIF1-Ab-positive patients who were aged under 39 when they developed DM went on to develop cancer. But cancer developed in around half of the anti-TIF1-Ab-positive patients who were aged 39 years or older when their DM began.
The anti-TIF1 antibody is commonly found in juvenile DM, but previous research has not found an association with an increased risk of cancer in this younger patient population.
“Our findings add strength to the hypothesis that there exists a subset of young adult anti-TIF1-Ab-positive cases who do not have a discernible increased risk of cancer, similar to that observed in TIF1-Ab-positive juvenile DM,” the authors wrote. They suggested that given the increased risk of malignancy in older patients who were anti-TIF1-Ab positive, this group should be subject to more detailed cancer screening.
Breast cancer was the most common malignancy among both anti-TIF1-Ab-positive and anti-TIF1-Ab-negative patients (33% and 25%, respectively). However, ovarian cancer was significantly more common among the anti-TIF1-Ab-positive patients than among the anti-TIF1-Ab-negative patients (19% vs. 2%; P less than .05); four of the five ovarian cancers in the entire cohort occurred in the anti-TIF1-Ab-positive group.
The authors noted that this confirmed the finding of a number of previous studies suggesting an increased risk of ovarian cancer with DM.
“However, this is the first large study to identify that ovarian cancer is overrepresented in anti-TIF1-Ab-positive individuals, suggesting that the true association between DM and ovarian cancer may be through possession of anti-TIF1-Abs,” they noted.
The authors wrote that they had aimed to inform cancer screening strategies among patients with DM.
“It may be that a focus on screening for cancer within the first 3 years after DM onset and particularly screening for ovarian cancer in anti-TIF1-Ab-positive female patients may be required,” they wrote. “Our findings also strengthen the hypothesis that inflammatory myopathies represent a paraneoplastic reaction initiated by attempted immune-mediated clearance of a cancer.”
The study was supported by Arthritis Research UK, Myositis UK, the European Science Foundation for EuMyoNet, Association Francaise Contre Les Myopathies, the Medical Research Council, and the Manchester Academic Health Science Centre. No conflicts of interest were declared.
SOURCE: Oldroyd A et al. Rheumatology. 2018 Dec 7. doi: 10.1093/rheumatology/key357.
FROM RHEUMATOLOGY
Key clinical point: Patients with dermatomyositis are at increased risk of cancer only in the 3-year periods before and after the onset of dermatomyositis.
Major finding: Overall, 38% of patients in the anti-TIF1-Ab-positive group developed cancer during the 10-year follow-up, compared with 15% of patients with anti-TIF1-Ab-negative DM.
Study details: Cohort study of 236 people with dermatomyositis.
Disclosures: The study was supported by Arthritis Research UK, Myositis UK, the European Science Foundation for EuMyoNet, Association Francaise Contre Les Myopathies, the Medical Research Council, and the Manchester Academic Health Science Centre. No conflicts of interest were declared.
Source: Oldroyd A et al. Rheumatology. 2018 Dec 7. doi: 10.1093/rheumatology/key357.
Combination immunotherapy ups survival in ILD patients with anti-MDA5–positive dermatomyositis
CHICAGO – Early treatment with combined high-dose glucocorticoids, tacrolimus, and intravenous cyclophosphamide therapy significantly improves survival vs. step-up therapy in interstitial lung disease patients with anti–melanoma differentiation–associated gene 5 (anti-MDA5)–positive dermatomyositis, according to findings from a prospective, multicenter study.
However, the combination therapy was associated with a high risk of cytomegalovirus reactivation and other opportunistic infections that warrants careful monitoring of treated patients, Hideaki Tsuji, MD, reported at the annual meeting of the American College of Rheumatology.
ILD accompanied by anti-MDA5–positive dermatomyositis (DM) is often intractable and associated with high mortality in Japanese patients. Case reports have suggested improved outcomes with combined immunosuppressive therapy, but a standard treatment has not been established, said Dr. Tsuji of Kyoto University.
“Therefore, we evaluated the efficacy and safety of combined immunosuppressive therapy for anti-MDA5–positive DM with ILD in a prospective single-arm study,” he said, adding that early administration, a short interval of intravenous cyclophosphamide, use of plasmapheresis as an additional therapy, and control of opportunistic infections may contribute to the improved outcomes seen with the regimen in this study.
The primary endpoint of 6-month survival was reached by 24 (89%) of 27 patients treated with the combination regimen for 52 weeks, compared with 5 (33%) of 15 historical controls who received high-dose glucocorticoids followed by step-wise addition of immunosuppressants. At 12 months, the survival rates were 85% and 33%, respectively, Dr. Tsuji said.
Additionally, anti-MDA5 titer, serum ferritin level, C-reactive protein level, lactate dehydrogenase, and KL-6 level gradually decreased over the 52 months, and percent vital capacity increased with combination vs. step-up therapy, he noted.
Cytomegalovirus reactivation occurred in 90% of combination regimen patients vs. 33% of controls over the 52-week study period, he said, adding that pneumocystic pneumonia and sepsis also occurred in combination regimen group patients, and were associated with death in four patients.
When the 23 surviving patients in the combination regimen group were compared with the 4 in the group who died, it was noted that the deceased patients were significantly more likely to have cutaneous ulcers (75% vs. 13%), higher mean C-reactive protein level (2.7 vs. 0.77 mg/dL), and higher creatine kinase level (644.3 vs. 219.3 IU/L), respectively, before treatment, he said.
Study subjects were Japanese adults with new-onset anti-MDA5–positive dermatomyositis with interstitial lung disease (ILD) who were enrolled between July 2014 and September 2017.
They were treated with 1 mg/kg/day of prednisolone for 4 weeks with reduced doses thereafter, 500-1,000 mg/m2 of IV cyclophosphamide every 2 weeks for six cycles then every 4 weeks for up to a total of 10-15 treatments, and 10-12 ng/mL of tacrolimus (12-hour trough). Plasmapheresis was allowed in patients who progressed and needed oxygenation after the regimen was initiated, and it was administered in nine patients (31%) in the combination regimen group vs. one (7%) of the historical controls.
Given the different frequencies of rapidly progressive ILD in Asian vs. Western countries (39%-71% vs. 22%-57%, respectively), it is unclear whether the results seen in this study can be extrapolated to patients from the United States and Europe. Therefore, it is necessary to analyze the efficacy of the regimen in those patient populations, Dr. Tsuji said, also noting that future studies should evaluate risk-based modifications of the regimen to identify the optimal treatment for individuals based on factors such as age, respiratory dysfunction, hyperferritinemia, and treatment delay.
Dr. Tsuji reported having no disclosures.
SOURCE: Tsuji H et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 838.
CHICAGO – Early treatment with combined high-dose glucocorticoids, tacrolimus, and intravenous cyclophosphamide therapy significantly improves survival vs. step-up therapy in interstitial lung disease patients with anti–melanoma differentiation–associated gene 5 (anti-MDA5)–positive dermatomyositis, according to findings from a prospective, multicenter study.
However, the combination therapy was associated with a high risk of cytomegalovirus reactivation and other opportunistic infections that warrants careful monitoring of treated patients, Hideaki Tsuji, MD, reported at the annual meeting of the American College of Rheumatology.
ILD accompanied by anti-MDA5–positive dermatomyositis (DM) is often intractable and associated with high mortality in Japanese patients. Case reports have suggested improved outcomes with combined immunosuppressive therapy, but a standard treatment has not been established, said Dr. Tsuji of Kyoto University.
“Therefore, we evaluated the efficacy and safety of combined immunosuppressive therapy for anti-MDA5–positive DM with ILD in a prospective single-arm study,” he said, adding that early administration, a short interval of intravenous cyclophosphamide, use of plasmapheresis as an additional therapy, and control of opportunistic infections may contribute to the improved outcomes seen with the regimen in this study.
The primary endpoint of 6-month survival was reached by 24 (89%) of 27 patients treated with the combination regimen for 52 weeks, compared with 5 (33%) of 15 historical controls who received high-dose glucocorticoids followed by step-wise addition of immunosuppressants. At 12 months, the survival rates were 85% and 33%, respectively, Dr. Tsuji said.
Additionally, anti-MDA5 titer, serum ferritin level, C-reactive protein level, lactate dehydrogenase, and KL-6 level gradually decreased over the 52 months, and percent vital capacity increased with combination vs. step-up therapy, he noted.
Cytomegalovirus reactivation occurred in 90% of combination regimen patients vs. 33% of controls over the 52-week study period, he said, adding that pneumocystic pneumonia and sepsis also occurred in combination regimen group patients, and were associated with death in four patients.
When the 23 surviving patients in the combination regimen group were compared with the 4 in the group who died, it was noted that the deceased patients were significantly more likely to have cutaneous ulcers (75% vs. 13%), higher mean C-reactive protein level (2.7 vs. 0.77 mg/dL), and higher creatine kinase level (644.3 vs. 219.3 IU/L), respectively, before treatment, he said.
Study subjects were Japanese adults with new-onset anti-MDA5–positive dermatomyositis with interstitial lung disease (ILD) who were enrolled between July 2014 and September 2017.
They were treated with 1 mg/kg/day of prednisolone for 4 weeks with reduced doses thereafter, 500-1,000 mg/m2 of IV cyclophosphamide every 2 weeks for six cycles then every 4 weeks for up to a total of 10-15 treatments, and 10-12 ng/mL of tacrolimus (12-hour trough). Plasmapheresis was allowed in patients who progressed and needed oxygenation after the regimen was initiated, and it was administered in nine patients (31%) in the combination regimen group vs. one (7%) of the historical controls.
Given the different frequencies of rapidly progressive ILD in Asian vs. Western countries (39%-71% vs. 22%-57%, respectively), it is unclear whether the results seen in this study can be extrapolated to patients from the United States and Europe. Therefore, it is necessary to analyze the efficacy of the regimen in those patient populations, Dr. Tsuji said, also noting that future studies should evaluate risk-based modifications of the regimen to identify the optimal treatment for individuals based on factors such as age, respiratory dysfunction, hyperferritinemia, and treatment delay.
Dr. Tsuji reported having no disclosures.
SOURCE: Tsuji H et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 838.
CHICAGO – Early treatment with combined high-dose glucocorticoids, tacrolimus, and intravenous cyclophosphamide therapy significantly improves survival vs. step-up therapy in interstitial lung disease patients with anti–melanoma differentiation–associated gene 5 (anti-MDA5)–positive dermatomyositis, according to findings from a prospective, multicenter study.
However, the combination therapy was associated with a high risk of cytomegalovirus reactivation and other opportunistic infections that warrants careful monitoring of treated patients, Hideaki Tsuji, MD, reported at the annual meeting of the American College of Rheumatology.
ILD accompanied by anti-MDA5–positive dermatomyositis (DM) is often intractable and associated with high mortality in Japanese patients. Case reports have suggested improved outcomes with combined immunosuppressive therapy, but a standard treatment has not been established, said Dr. Tsuji of Kyoto University.
“Therefore, we evaluated the efficacy and safety of combined immunosuppressive therapy for anti-MDA5–positive DM with ILD in a prospective single-arm study,” he said, adding that early administration, a short interval of intravenous cyclophosphamide, use of plasmapheresis as an additional therapy, and control of opportunistic infections may contribute to the improved outcomes seen with the regimen in this study.
The primary endpoint of 6-month survival was reached by 24 (89%) of 27 patients treated with the combination regimen for 52 weeks, compared with 5 (33%) of 15 historical controls who received high-dose glucocorticoids followed by step-wise addition of immunosuppressants. At 12 months, the survival rates were 85% and 33%, respectively, Dr. Tsuji said.
Additionally, anti-MDA5 titer, serum ferritin level, C-reactive protein level, lactate dehydrogenase, and KL-6 level gradually decreased over the 52 months, and percent vital capacity increased with combination vs. step-up therapy, he noted.
Cytomegalovirus reactivation occurred in 90% of combination regimen patients vs. 33% of controls over the 52-week study period, he said, adding that pneumocystic pneumonia and sepsis also occurred in combination regimen group patients, and were associated with death in four patients.
When the 23 surviving patients in the combination regimen group were compared with the 4 in the group who died, it was noted that the deceased patients were significantly more likely to have cutaneous ulcers (75% vs. 13%), higher mean C-reactive protein level (2.7 vs. 0.77 mg/dL), and higher creatine kinase level (644.3 vs. 219.3 IU/L), respectively, before treatment, he said.
Study subjects were Japanese adults with new-onset anti-MDA5–positive dermatomyositis with interstitial lung disease (ILD) who were enrolled between July 2014 and September 2017.
They were treated with 1 mg/kg/day of prednisolone for 4 weeks with reduced doses thereafter, 500-1,000 mg/m2 of IV cyclophosphamide every 2 weeks for six cycles then every 4 weeks for up to a total of 10-15 treatments, and 10-12 ng/mL of tacrolimus (12-hour trough). Plasmapheresis was allowed in patients who progressed and needed oxygenation after the regimen was initiated, and it was administered in nine patients (31%) in the combination regimen group vs. one (7%) of the historical controls.
Given the different frequencies of rapidly progressive ILD in Asian vs. Western countries (39%-71% vs. 22%-57%, respectively), it is unclear whether the results seen in this study can be extrapolated to patients from the United States and Europe. Therefore, it is necessary to analyze the efficacy of the regimen in those patient populations, Dr. Tsuji said, also noting that future studies should evaluate risk-based modifications of the regimen to identify the optimal treatment for individuals based on factors such as age, respiratory dysfunction, hyperferritinemia, and treatment delay.
Dr. Tsuji reported having no disclosures.
SOURCE: Tsuji H et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 838.
REPORTING FROM THE ACR ANNUAL MEETING
Key clinical point:
Major finding: 6-month survival was 89% vs. 33% with combination immunotherapy vs. step-up therapy.
Study details: A prospective, multicenter study of 27 patients and 15 historical controls.
Disclosures: Dr. Tsuji reported having no disclosures.
Source: Tsuji H et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 838.
Composite screening measures advocated for asymptomatic PAH
In patients at risk for pulmonary arterial hypertension (PAH) due to a connective tissue disease, composite novel screening methods are improving early detection when employed in the context of traditional tools, such as transthoracic echocardiography (TTE), according to a systematic review of studies published over the last 5 years.
The review was conducted to prepare for a guideline update, according to the authors of this recently published summary in Seminars in Arthritis and Rheumatism.
In a literature review for 2012-2015, the authors evaluated whether new tools or strategies have improved PAH screening in patients with connective tissue disease since the last review was undertaken (Semin Arthritis Rheum 2014;43:536-41).
The latest review found that although TTE and pulmonary function tests (PFT) remain a mainstay of screening, there is growing evidence that composite measures, such as the DETECT and ASIG algorithms, add sensitivity and specificity, compared with guidelines that rely on TTE and PFT alone.
After a literature search, the systematic review included 16 cohort studies and 6 case-control studies. Most of these evaluated PAH screening strategies for patients with systemic sclerosis specifically despite the potential for other connective tissue disease etiologies to lead to PAH.
“We need more longitudinal observational studies to develop and validate screening algorithms for non–systemic sclerosis connective tissue diseases,” stated the authors, led by senior investigator Dinesh Khanna, MD, medical director of ambulatory and chronic disease in the University of Michigan’s Office of Research, Ann Arbor.
Relative to screening primarily based on TTE and PFT as advocated in 2009 joint guidelines from the European Society of Cardiology and the European Respiratory Society (ESC/ERS), the preponderance of data supported the addition of DIRECT and ASIG algorithms to improve the sensitivity and specificity of traditional screening and diagnostic tools, according to the data reviewed.
Several of the studies evaluating DETECT and ASIG compared their sensitivities and specificities to the screening strategy recommended in the 2009 ESC/ERS guidelines because the 2015 ESC/ERS guidelines were not yet available at the time these studies were taking place.
In fact, the advantage of these algorithms has been acknowledged in a set of subsequent ESC/ERS guidelines issued in 2015. These specifically recommend DETECT in selected populations, such as adults with more than a 3-year history of systemic sclerosis and less than 60% diffusing capacity of the lung for carbon monoxide.
Based on the systematic review, the authors did not conclude that there is a single set of optimal tests for PAH screening whether in patients with systemic sclerosis or another connective tissue disease, but the authors did conclude that there has been progress in strategies for early PAH detection.
They also speculated that more progress might be coming. They noted that several newer tests, such as stress TTE to assess cardiopulmonary function during exercise, might further improve PAH detection at early stages.
According to the authors, this work is important, because better screening that results in earlier PAH detection means earlier treatment, which, in turn, “may improve survival.”
SOURCE: Young A et al. Semin Arthritis Rheum. 2018; Oct 14. doi: 10.1016/j.semarthrit.2018.10.010.
In patients at risk for pulmonary arterial hypertension (PAH) due to a connective tissue disease, composite novel screening methods are improving early detection when employed in the context of traditional tools, such as transthoracic echocardiography (TTE), according to a systematic review of studies published over the last 5 years.
The review was conducted to prepare for a guideline update, according to the authors of this recently published summary in Seminars in Arthritis and Rheumatism.
In a literature review for 2012-2015, the authors evaluated whether new tools or strategies have improved PAH screening in patients with connective tissue disease since the last review was undertaken (Semin Arthritis Rheum 2014;43:536-41).
The latest review found that although TTE and pulmonary function tests (PFT) remain a mainstay of screening, there is growing evidence that composite measures, such as the DETECT and ASIG algorithms, add sensitivity and specificity, compared with guidelines that rely on TTE and PFT alone.
After a literature search, the systematic review included 16 cohort studies and 6 case-control studies. Most of these evaluated PAH screening strategies for patients with systemic sclerosis specifically despite the potential for other connective tissue disease etiologies to lead to PAH.
“We need more longitudinal observational studies to develop and validate screening algorithms for non–systemic sclerosis connective tissue diseases,” stated the authors, led by senior investigator Dinesh Khanna, MD, medical director of ambulatory and chronic disease in the University of Michigan’s Office of Research, Ann Arbor.
Relative to screening primarily based on TTE and PFT as advocated in 2009 joint guidelines from the European Society of Cardiology and the European Respiratory Society (ESC/ERS), the preponderance of data supported the addition of DIRECT and ASIG algorithms to improve the sensitivity and specificity of traditional screening and diagnostic tools, according to the data reviewed.
Several of the studies evaluating DETECT and ASIG compared their sensitivities and specificities to the screening strategy recommended in the 2009 ESC/ERS guidelines because the 2015 ESC/ERS guidelines were not yet available at the time these studies were taking place.
In fact, the advantage of these algorithms has been acknowledged in a set of subsequent ESC/ERS guidelines issued in 2015. These specifically recommend DETECT in selected populations, such as adults with more than a 3-year history of systemic sclerosis and less than 60% diffusing capacity of the lung for carbon monoxide.
Based on the systematic review, the authors did not conclude that there is a single set of optimal tests for PAH screening whether in patients with systemic sclerosis or another connective tissue disease, but the authors did conclude that there has been progress in strategies for early PAH detection.
They also speculated that more progress might be coming. They noted that several newer tests, such as stress TTE to assess cardiopulmonary function during exercise, might further improve PAH detection at early stages.
According to the authors, this work is important, because better screening that results in earlier PAH detection means earlier treatment, which, in turn, “may improve survival.”
SOURCE: Young A et al. Semin Arthritis Rheum. 2018; Oct 14. doi: 10.1016/j.semarthrit.2018.10.010.
In patients at risk for pulmonary arterial hypertension (PAH) due to a connective tissue disease, composite novel screening methods are improving early detection when employed in the context of traditional tools, such as transthoracic echocardiography (TTE), according to a systematic review of studies published over the last 5 years.
The review was conducted to prepare for a guideline update, according to the authors of this recently published summary in Seminars in Arthritis and Rheumatism.
In a literature review for 2012-2015, the authors evaluated whether new tools or strategies have improved PAH screening in patients with connective tissue disease since the last review was undertaken (Semin Arthritis Rheum 2014;43:536-41).
The latest review found that although TTE and pulmonary function tests (PFT) remain a mainstay of screening, there is growing evidence that composite measures, such as the DETECT and ASIG algorithms, add sensitivity and specificity, compared with guidelines that rely on TTE and PFT alone.
After a literature search, the systematic review included 16 cohort studies and 6 case-control studies. Most of these evaluated PAH screening strategies for patients with systemic sclerosis specifically despite the potential for other connective tissue disease etiologies to lead to PAH.
“We need more longitudinal observational studies to develop and validate screening algorithms for non–systemic sclerosis connective tissue diseases,” stated the authors, led by senior investigator Dinesh Khanna, MD, medical director of ambulatory and chronic disease in the University of Michigan’s Office of Research, Ann Arbor.
Relative to screening primarily based on TTE and PFT as advocated in 2009 joint guidelines from the European Society of Cardiology and the European Respiratory Society (ESC/ERS), the preponderance of data supported the addition of DIRECT and ASIG algorithms to improve the sensitivity and specificity of traditional screening and diagnostic tools, according to the data reviewed.
Several of the studies evaluating DETECT and ASIG compared their sensitivities and specificities to the screening strategy recommended in the 2009 ESC/ERS guidelines because the 2015 ESC/ERS guidelines were not yet available at the time these studies were taking place.
In fact, the advantage of these algorithms has been acknowledged in a set of subsequent ESC/ERS guidelines issued in 2015. These specifically recommend DETECT in selected populations, such as adults with more than a 3-year history of systemic sclerosis and less than 60% diffusing capacity of the lung for carbon monoxide.
Based on the systematic review, the authors did not conclude that there is a single set of optimal tests for PAH screening whether in patients with systemic sclerosis or another connective tissue disease, but the authors did conclude that there has been progress in strategies for early PAH detection.
They also speculated that more progress might be coming. They noted that several newer tests, such as stress TTE to assess cardiopulmonary function during exercise, might further improve PAH detection at early stages.
According to the authors, this work is important, because better screening that results in earlier PAH detection means earlier treatment, which, in turn, “may improve survival.”
SOURCE: Young A et al. Semin Arthritis Rheum. 2018; Oct 14. doi: 10.1016/j.semarthrit.2018.10.010.
FROM SEMINARS IN ARTHRITIS AND RHEUMATISM
Key clinical point: Strategies for early detection of pulmonary arterial hypertension (PAH) are improving with new tools.
Major finding: Screening algorithms are improving sensitivity and specificity for PAH in patients with connective tissue diseases.
Study details: Systematic literature review.
Disclosures: Dr. Khanna has financial relationships with many companies that produce drugs for PAH but no conflicts relative to this study.
Source: Young A et al. Semin Arthritis Rheum. 2018 Oct 14. doi. 10.1016/j.semarthrit.2018.10.010.
IgA vasculitis increases risks for hypertension, chronic kidney disease
IgA vasculitis, also called Henoch-Schönlein purpura, increases risks for hypertension and chronic kidney disease (CKD), according to a retrospective study of more than 13,000 patients with IgAV.
In patients with adult-onset IgA vasculitis (IgAV), mortality risk is also increased, reported first author Alexander Tracy and his colleagues at the University of Birmingham (England).
“Long-term health outcomes of adult-onset IgAV are not well characterized,” the investigators wrote in Annals of Rheumatic Disease. “Most evidence regarding complications of IgAV in adults derives from case reports and case series; there is need for controlled epidemiological studies to address this question.”
The retrospective study compared 2,828 patients with adult-onset IgAV and 10,405 patients with childhood-onset IgAV against sex- and age-matched controls. Patients diagnosed at age 16 years or older were classified as having adult-onset disease. The investigators drew their data from The Health Improvement Network database, which includes 3.6 million active patients from more than 675 general practices in the United Kingdom. Patients in the present study were diagnosed with IgAV between 2005 and 2016. After diagnosis, participant follow-up continued until any of the following occurred: outcome event, patient left practice, death, the practice stopped contributing data, or the study ended. Primary outcomes for adult-onset patients were venous thromboembolism (VTE), ischemic heart disease, hypertension, stage 3-5 CKD, stroke/transient ischemic attack, and all-cause mortality. Primary outcomes for patients with childhood-onset disease were limited to CKD, hypertension, and VTE.
The incidence of childhood-onset IgAV was 27.22 per 100,000 person-years, whereas adult-onset disease was much less common at 2.20 per 100,000 person-years. Mean age at onset of childhood IgAV was 6.68 years. The adult-onset group had a mean age at diagnosis of 38.1 years.
Compared with controls, all patients with IgAV, regardless of onset age, had increased risks of hypertension (adult-onset adjusted hazard ratio, 1.42; P less than .001; childhood-onset aHR, 1.52; P less than .001) and CKD (adult-onset aHR, 1.54; P less than .001; childhood-onset aHR, 1.89; P = .01). Patients with adult-onset IgAV showed increased risk of death, compared with controls (aHR, 1.27; P = .006). No associations were found between IgAV and stroke/transient ischemic attack, VTE, or ischemic heart disease.
“These findings emphasize the importance of blood pressure and renal function monitoring in patients with IgAV,” the investigators concluded. “Our data also suggest that IgAV should not be considered a ‘single-hit’ disease, but that clinicians should monitor for long-term sequelae. Further research is required to clarify the cause of hypertension in patients with IgAV, and to investigate whether such patients suffer from additional long-term sequelae than that are currently unrecognized.”
The investigators reported no funding sources or conflicts or interest.
SOURCE: Tracy A et al. Ann Rheum Dis. 2018 Nov 28. doi: 10.1136/annrheumdis-2018-214142.
IgA vasculitis, also called Henoch-Schönlein purpura, increases risks for hypertension and chronic kidney disease (CKD), according to a retrospective study of more than 13,000 patients with IgAV.
In patients with adult-onset IgA vasculitis (IgAV), mortality risk is also increased, reported first author Alexander Tracy and his colleagues at the University of Birmingham (England).
“Long-term health outcomes of adult-onset IgAV are not well characterized,” the investigators wrote in Annals of Rheumatic Disease. “Most evidence regarding complications of IgAV in adults derives from case reports and case series; there is need for controlled epidemiological studies to address this question.”
The retrospective study compared 2,828 patients with adult-onset IgAV and 10,405 patients with childhood-onset IgAV against sex- and age-matched controls. Patients diagnosed at age 16 years or older were classified as having adult-onset disease. The investigators drew their data from The Health Improvement Network database, which includes 3.6 million active patients from more than 675 general practices in the United Kingdom. Patients in the present study were diagnosed with IgAV between 2005 and 2016. After diagnosis, participant follow-up continued until any of the following occurred: outcome event, patient left practice, death, the practice stopped contributing data, or the study ended. Primary outcomes for adult-onset patients were venous thromboembolism (VTE), ischemic heart disease, hypertension, stage 3-5 CKD, stroke/transient ischemic attack, and all-cause mortality. Primary outcomes for patients with childhood-onset disease were limited to CKD, hypertension, and VTE.
The incidence of childhood-onset IgAV was 27.22 per 100,000 person-years, whereas adult-onset disease was much less common at 2.20 per 100,000 person-years. Mean age at onset of childhood IgAV was 6.68 years. The adult-onset group had a mean age at diagnosis of 38.1 years.
Compared with controls, all patients with IgAV, regardless of onset age, had increased risks of hypertension (adult-onset adjusted hazard ratio, 1.42; P less than .001; childhood-onset aHR, 1.52; P less than .001) and CKD (adult-onset aHR, 1.54; P less than .001; childhood-onset aHR, 1.89; P = .01). Patients with adult-onset IgAV showed increased risk of death, compared with controls (aHR, 1.27; P = .006). No associations were found between IgAV and stroke/transient ischemic attack, VTE, or ischemic heart disease.
“These findings emphasize the importance of blood pressure and renal function monitoring in patients with IgAV,” the investigators concluded. “Our data also suggest that IgAV should not be considered a ‘single-hit’ disease, but that clinicians should monitor for long-term sequelae. Further research is required to clarify the cause of hypertension in patients with IgAV, and to investigate whether such patients suffer from additional long-term sequelae than that are currently unrecognized.”
The investigators reported no funding sources or conflicts or interest.
SOURCE: Tracy A et al. Ann Rheum Dis. 2018 Nov 28. doi: 10.1136/annrheumdis-2018-214142.
IgA vasculitis, also called Henoch-Schönlein purpura, increases risks for hypertension and chronic kidney disease (CKD), according to a retrospective study of more than 13,000 patients with IgAV.
In patients with adult-onset IgA vasculitis (IgAV), mortality risk is also increased, reported first author Alexander Tracy and his colleagues at the University of Birmingham (England).
“Long-term health outcomes of adult-onset IgAV are not well characterized,” the investigators wrote in Annals of Rheumatic Disease. “Most evidence regarding complications of IgAV in adults derives from case reports and case series; there is need for controlled epidemiological studies to address this question.”
The retrospective study compared 2,828 patients with adult-onset IgAV and 10,405 patients with childhood-onset IgAV against sex- and age-matched controls. Patients diagnosed at age 16 years or older were classified as having adult-onset disease. The investigators drew their data from The Health Improvement Network database, which includes 3.6 million active patients from more than 675 general practices in the United Kingdom. Patients in the present study were diagnosed with IgAV between 2005 and 2016. After diagnosis, participant follow-up continued until any of the following occurred: outcome event, patient left practice, death, the practice stopped contributing data, or the study ended. Primary outcomes for adult-onset patients were venous thromboembolism (VTE), ischemic heart disease, hypertension, stage 3-5 CKD, stroke/transient ischemic attack, and all-cause mortality. Primary outcomes for patients with childhood-onset disease were limited to CKD, hypertension, and VTE.
The incidence of childhood-onset IgAV was 27.22 per 100,000 person-years, whereas adult-onset disease was much less common at 2.20 per 100,000 person-years. Mean age at onset of childhood IgAV was 6.68 years. The adult-onset group had a mean age at diagnosis of 38.1 years.
Compared with controls, all patients with IgAV, regardless of onset age, had increased risks of hypertension (adult-onset adjusted hazard ratio, 1.42; P less than .001; childhood-onset aHR, 1.52; P less than .001) and CKD (adult-onset aHR, 1.54; P less than .001; childhood-onset aHR, 1.89; P = .01). Patients with adult-onset IgAV showed increased risk of death, compared with controls (aHR, 1.27; P = .006). No associations were found between IgAV and stroke/transient ischemic attack, VTE, or ischemic heart disease.
“These findings emphasize the importance of blood pressure and renal function monitoring in patients with IgAV,” the investigators concluded. “Our data also suggest that IgAV should not be considered a ‘single-hit’ disease, but that clinicians should monitor for long-term sequelae. Further research is required to clarify the cause of hypertension in patients with IgAV, and to investigate whether such patients suffer from additional long-term sequelae than that are currently unrecognized.”
The investigators reported no funding sources or conflicts or interest.
SOURCE: Tracy A et al. Ann Rheum Dis. 2018 Nov 28. doi: 10.1136/annrheumdis-2018-214142.
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point:
Major finding: There was significantly increased risk of stage 3-5 chronic kidney disease in patients with childhood-onset IgA vasculitis (adjusted hazard ratio, 1.89; P = .01).
Study details: A retrospective study of 2,828 patients with adult-onset IgA vasculitis and 10,405 patients with childhood-onset IgAV, compared with sex-matched and age-matched controls.
Disclosures: No funding sources or conflicts of interest were reported.
Source: Tracy A et al. Ann Rheum Dis. 2018 Nov 28. doi: 10.1136/annrheumdis-2018-214142.
RELIEF: In Behçet’s, apremilast improves oral ulcers for up to 28 weeks
CHICAGO – Apremilast was effective and well tolerated for up to 28 weeks for the treatment of oral ulcers in patients with active Behçet’s disease, based on findings from the randomized, placebo-controlled, phase 3 RELIEF trial.
At baseline, mean oral ulcer counts were 4.2 in 104 patients randomized to receive the oral phosphodiesterase-4 inhibitor and 3.9 in 103 patients in the placebo group. Mean visual analog scale (VAS) pain scores were 61.2 and 60.8 in the two groups, respectively.
The primary study endpoint of area under the curve for total number of oral ulcers over a 12-week period (AUCWk0-12) – a measure that reflects the number of oral ulcers that occur over time and also accounts for the recurring-remitting course of oral ulcers – was achieved. AUCWk0-12 was significantly lower in the apremilast group than in the placebo group (129.54 vs. 222.14, respectively; P less than .0001), Gulen Hatemi, MD, reported at the annual meeting of the American College of Rheumatology.
From baseline to week 12, apremilast treatment also resulted in a significantly lower number of oral ulcers (mean of 1.1 vs. 2.0 for placebo at 12 weeks) and significantly reduced pain from oral ulcers at every visit from week 1 through week 12 of the study, compared with placebo (mean VAS score change from baseline, –40.7 vs. –15.9), said Dr. Hatemi, a professor of medicine at Istanbul University.
“The [12-week] complete response rate ... was 53% in the apremilast group and 22.3% in the placebo group. The [12-week] partial response rate ...was 76% in the apremilast group and 48% in the placebo group,” she said, adding that the efficacy of apremilast was sustained with continued treatment through 28 weeks.
Study participants were adults (mean age, 40 years) with active Behçet’s disease and three or more oral ulcers at randomization or two or more at screening and at randomization. All had been previously treated with at least one nonbiologic medication for oral ulcers and were allowed to have received previous biologic therapies for other disease manifestations. Those with active major organ involvement were excluded.
Treatment included a 30-mg dose of apremilast twice daily for 12 weeks or placebo. After 12 weeks, all patients received apremilast through at least 28 weeks of the 64-week study.
At the 28-week analysis, patients who were initially randomized to placebo and who switched to apremilast after week 12 had benefits comparable with those seen in those randomized to apremilast at the start of the study. A complete response was seen in 59% and 62% of patients in the groups, respectively, and a partial response was seen in 90% and 85%, respectively. Additionally, the mean change in the VAS score for oral ulcer pain in the groups at that time was –40.6 and –41.9, Dr. Hatemi said.
Apremilast was well tolerated in this study; the incidence of adverse events was comparable in the treatment and placebo groups during the 12-week placebo-controlled phase of the study – 78.8% and 71.8%, respectively. The most common events were diarrhea, nausea, headache, and upper respiratory tract infection, she said.
“These were generally mild to moderate, and only two patients had to discontinue the study due to gastrointestinal adverse events,” she said, noting that no new safety signals were observed.
Behçet’s disease is a chronic, relapsing, multisystem inflammatory disorder characterized by recurrent oral ulcers that can be disabling and have a substantial effect on quality of life. These findings, which include efficacy data up to 28 weeks and safety data for at least 100 patients exposed to apremilast for at least 1 year, demonstrate the efficacy of apremilast for the treatment oral ulcers in patients with Behçet’s disease, she said, noting that “the safety findings were consistent with the known safety profile of apremilast.”
The RELIEF study was supported by Celgene. Dr. Hatemi reported receiving grant/research support from Celgene and serving as a speaker for AbbVie, Mustafa Nevzet Pharmaceuticals, and UCB.
SOURCE: Hatemi G et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 2789.
CHICAGO – Apremilast was effective and well tolerated for up to 28 weeks for the treatment of oral ulcers in patients with active Behçet’s disease, based on findings from the randomized, placebo-controlled, phase 3 RELIEF trial.
At baseline, mean oral ulcer counts were 4.2 in 104 patients randomized to receive the oral phosphodiesterase-4 inhibitor and 3.9 in 103 patients in the placebo group. Mean visual analog scale (VAS) pain scores were 61.2 and 60.8 in the two groups, respectively.
The primary study endpoint of area under the curve for total number of oral ulcers over a 12-week period (AUCWk0-12) – a measure that reflects the number of oral ulcers that occur over time and also accounts for the recurring-remitting course of oral ulcers – was achieved. AUCWk0-12 was significantly lower in the apremilast group than in the placebo group (129.54 vs. 222.14, respectively; P less than .0001), Gulen Hatemi, MD, reported at the annual meeting of the American College of Rheumatology.
From baseline to week 12, apremilast treatment also resulted in a significantly lower number of oral ulcers (mean of 1.1 vs. 2.0 for placebo at 12 weeks) and significantly reduced pain from oral ulcers at every visit from week 1 through week 12 of the study, compared with placebo (mean VAS score change from baseline, –40.7 vs. –15.9), said Dr. Hatemi, a professor of medicine at Istanbul University.
“The [12-week] complete response rate ... was 53% in the apremilast group and 22.3% in the placebo group. The [12-week] partial response rate ...was 76% in the apremilast group and 48% in the placebo group,” she said, adding that the efficacy of apremilast was sustained with continued treatment through 28 weeks.
Study participants were adults (mean age, 40 years) with active Behçet’s disease and three or more oral ulcers at randomization or two or more at screening and at randomization. All had been previously treated with at least one nonbiologic medication for oral ulcers and were allowed to have received previous biologic therapies for other disease manifestations. Those with active major organ involvement were excluded.
Treatment included a 30-mg dose of apremilast twice daily for 12 weeks or placebo. After 12 weeks, all patients received apremilast through at least 28 weeks of the 64-week study.
At the 28-week analysis, patients who were initially randomized to placebo and who switched to apremilast after week 12 had benefits comparable with those seen in those randomized to apremilast at the start of the study. A complete response was seen in 59% and 62% of patients in the groups, respectively, and a partial response was seen in 90% and 85%, respectively. Additionally, the mean change in the VAS score for oral ulcer pain in the groups at that time was –40.6 and –41.9, Dr. Hatemi said.
Apremilast was well tolerated in this study; the incidence of adverse events was comparable in the treatment and placebo groups during the 12-week placebo-controlled phase of the study – 78.8% and 71.8%, respectively. The most common events were diarrhea, nausea, headache, and upper respiratory tract infection, she said.
“These were generally mild to moderate, and only two patients had to discontinue the study due to gastrointestinal adverse events,” she said, noting that no new safety signals were observed.
Behçet’s disease is a chronic, relapsing, multisystem inflammatory disorder characterized by recurrent oral ulcers that can be disabling and have a substantial effect on quality of life. These findings, which include efficacy data up to 28 weeks and safety data for at least 100 patients exposed to apremilast for at least 1 year, demonstrate the efficacy of apremilast for the treatment oral ulcers in patients with Behçet’s disease, she said, noting that “the safety findings were consistent with the known safety profile of apremilast.”
The RELIEF study was supported by Celgene. Dr. Hatemi reported receiving grant/research support from Celgene and serving as a speaker for AbbVie, Mustafa Nevzet Pharmaceuticals, and UCB.
SOURCE: Hatemi G et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 2789.
CHICAGO – Apremilast was effective and well tolerated for up to 28 weeks for the treatment of oral ulcers in patients with active Behçet’s disease, based on findings from the randomized, placebo-controlled, phase 3 RELIEF trial.
At baseline, mean oral ulcer counts were 4.2 in 104 patients randomized to receive the oral phosphodiesterase-4 inhibitor and 3.9 in 103 patients in the placebo group. Mean visual analog scale (VAS) pain scores were 61.2 and 60.8 in the two groups, respectively.
The primary study endpoint of area under the curve for total number of oral ulcers over a 12-week period (AUCWk0-12) – a measure that reflects the number of oral ulcers that occur over time and also accounts for the recurring-remitting course of oral ulcers – was achieved. AUCWk0-12 was significantly lower in the apremilast group than in the placebo group (129.54 vs. 222.14, respectively; P less than .0001), Gulen Hatemi, MD, reported at the annual meeting of the American College of Rheumatology.
From baseline to week 12, apremilast treatment also resulted in a significantly lower number of oral ulcers (mean of 1.1 vs. 2.0 for placebo at 12 weeks) and significantly reduced pain from oral ulcers at every visit from week 1 through week 12 of the study, compared with placebo (mean VAS score change from baseline, –40.7 vs. –15.9), said Dr. Hatemi, a professor of medicine at Istanbul University.
“The [12-week] complete response rate ... was 53% in the apremilast group and 22.3% in the placebo group. The [12-week] partial response rate ...was 76% in the apremilast group and 48% in the placebo group,” she said, adding that the efficacy of apremilast was sustained with continued treatment through 28 weeks.
Study participants were adults (mean age, 40 years) with active Behçet’s disease and three or more oral ulcers at randomization or two or more at screening and at randomization. All had been previously treated with at least one nonbiologic medication for oral ulcers and were allowed to have received previous biologic therapies for other disease manifestations. Those with active major organ involvement were excluded.
Treatment included a 30-mg dose of apremilast twice daily for 12 weeks or placebo. After 12 weeks, all patients received apremilast through at least 28 weeks of the 64-week study.
At the 28-week analysis, patients who were initially randomized to placebo and who switched to apremilast after week 12 had benefits comparable with those seen in those randomized to apremilast at the start of the study. A complete response was seen in 59% and 62% of patients in the groups, respectively, and a partial response was seen in 90% and 85%, respectively. Additionally, the mean change in the VAS score for oral ulcer pain in the groups at that time was –40.6 and –41.9, Dr. Hatemi said.
Apremilast was well tolerated in this study; the incidence of adverse events was comparable in the treatment and placebo groups during the 12-week placebo-controlled phase of the study – 78.8% and 71.8%, respectively. The most common events were diarrhea, nausea, headache, and upper respiratory tract infection, she said.
“These were generally mild to moderate, and only two patients had to discontinue the study due to gastrointestinal adverse events,” she said, noting that no new safety signals were observed.
Behçet’s disease is a chronic, relapsing, multisystem inflammatory disorder characterized by recurrent oral ulcers that can be disabling and have a substantial effect on quality of life. These findings, which include efficacy data up to 28 weeks and safety data for at least 100 patients exposed to apremilast for at least 1 year, demonstrate the efficacy of apremilast for the treatment oral ulcers in patients with Behçet’s disease, she said, noting that “the safety findings were consistent with the known safety profile of apremilast.”
The RELIEF study was supported by Celgene. Dr. Hatemi reported receiving grant/research support from Celgene and serving as a speaker for AbbVie, Mustafa Nevzet Pharmaceuticals, and UCB.
SOURCE: Hatemi G et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 2789.
REPORTING FROM THE ACR ANNUAL MEETING
Key clinical point: Apremilast is safe and effective for treating oral ulcers in patients with Behçet’s disease.
Major finding: The AUCWk0-12 was significantly lower with apremilast (129.54) versus placebo (222.14).
Study details: A randomized, placebo-controlled, phase 3 study of 207 patients.
Disclosures: The RELIEF study was supported by Celgene. Dr. Hatemi reported receiving grant/research support from Celgene and serving as a speaker for AbbVie, Mustafa Nevzet Pharmaceuticals, and UCB.
Source: Hatemi G et al. Arthritis Rheumatol. 2018;70(Suppl 10), Abstract 2789
Three drugs disappoint in SSc trials, but show some promise
CHICAGO – Recent randomized, placebo-controlled, phase 3 trials of tocilizumab, abatacept, and riociguat for the treatment of systemic sclerosis each failed to reach its primary endpoint of change from baseline in modified Rodnan Skin Score (mRSS).
Still, findings with respect to secondary endpoints and certain exploratory outcomes suggest each of the agents holds some promise in the systemic sclerosis (SSc) arena, according to the data presented at the annual meeting of the American College of Rheumatology.
Tocilizumab (Actemra)
In the double-blind portion of the phase 3 focuSSced trial of 212 patients with SSc, numerical improvement was observed for the primary endpoint of mean change in mRSS from baseline to week 48 with tocilizumab versus placebo (–6.14 vs. –4.41 points, respectively). The change in the treatment group was comparable with what was seen in the phase 2 faSScinate trial, but the decline in mRSS in the placebo group was much greater in phase 3 than in phase 2, and so the difference between the groups in the current study failed to reach statistical significance (P = .098), reported Dinesh Khanna, MBBS, a professor of medicine and director of the scleroderma program at the University of Michigan, Ann Arbor.
The interleukin-6 (IL-6) receptor–alpha antibody was previously shown in the faSScinate trial to lead to numeric improvements in skin thickening as measured by the mRSS, as well as to clinically meaningful lung function preservation as measured by percent predicted forced vital capacity (FVC).
In the current phase 3 study, key secondary end points also appeared to favor tocilizumab, but since the primary endpoint for mRSS was not met, all other P values cannot be considered statistically significant despite the strength of the evidence and were reported for informational purposes only, he noted.
The median cumulative distribution of change from baseline to week 48 in percent predicted FVC with tocilizumab versus placebo was –0.6 vs. –3.9, respectively (descriptive P = .0015), and the mean change from baseline in FVC at week 48 was –24 mL vs. –190 mL (difference of 167 mL in favor of tocilizumab; descriptive P = .0001).
Time to treatment failure also favored tocilizumab, he said (hazard ratio, 0.63; descriptive P = .082), he said.
Patients were randomly assigned to receive either weekly 162-mg injections of subcutaneous tocilizumab or placebo for 48 weeks. Escape therapy was allowed beginning at week 16 if patients experienced declines in FVC or beginning at week 24 if they experienced worsened mRSS or worsened SSc complications, Dr. Khanna said.
“The key part is that no immunotherapy was allowed. ... So it’s a true randomized, placebo-controlled trial,” he said.
Most (81%) of the patients were women, and they had a mean age of 48 years, mean SSc duration of 23 months, mean mRSS of 20.4 units on a 0-51 scale, and a normal mean percent predicted FVC of 82.1%.
“HAQ-DI showed moderate disability of 1.2,” he noted.
Safety in the study was consistent with that seen in prior tocilizumab studies; no new safety signals were identified. Serious adverse events occurred in 13% and 17% of tocilizumab and placebo group patients , respectively, and serious infections were reported by 7% and 2%.
Although clinically meaningful and consistent differences in FVC favoring tocilizumab were shown in this study, the primary endpoint was not met, Dr. Khanna said.
“There were no statistically significant differences, largely driven by unexpected improvement in the placebo group, which was different than what we found in [the faSScinate] trial,” he said, noting, however, that the FVC findings in the current study were clinically meaningful.
Also, in a separate presentation at the meeting, he explained that the differences favoring tocilizumab were statistically significant when patient-level data from the trial were analyzed based on the ACR Composite Response Index in Systemic Sclerosis (CRISS). Those findings provide validation of the novel outcomes measure, he said.
Abatacept (Orencia)
Dr. Khanna also reported results of the 12-month, double-blind, randomized, placebo-controlled phase 2 ASSET trial of abatacept, which showed no significant difference in mRSS in patients with early diffuse cutaneous SSc (dfSSc) who were treated with 125 mg of the recombinant fusion protein weekly and those who received placebo. However, certain secondary outcomes favored abatacept. No concomitant immunotherapy was allowed.
The adjusted mean decrease in the mRSS among patients who completed the 12-month treatment period was –6.24 vs. –4.49 in 34 patients in the abatacept group and 35 in the placebo group, respectively (P = .28).
The secondary outcome measures of mean change in Health Assessment Questionnaire Disability Index (HAQ-DI), patients global assessment, physician global assessment, and ACR CRISS scores were statistically significant or showed numerical results favoring abatacept over placebo: mean decrease in HAQ-DI, –0.17 vs. –0.11 (P = .05), respectively; mean change in physician global assessment scores, –1.30 vs. –0.35 (P = .03); median ACR CRISS index, 0.68 vs. 0.01 (P = .03), decline in percent predicted FVC of 4.13% and 1.34% (P = .11).
Escape therapy was allowed at 6 months for worsening SSc, but it did not change the outcomes trajectory, he said. A larger proportion of placebo vs. abatacept subjects required escape immunosuppressive therapy (36% vs. 16%; P = .03).
Patients were enrolled between 2014 and 2018 at 27 U.S., Canadian, and U.K. sites. At baseline, participants had a mean age of 49 years, 75% were women, and mean disease duration was very short at 1.59 years, with 60% having disease duration of 18 months or less. The mean baseline mRSS was 22.4, mean percent predicted FVC was 85.3%, and mean HAQ-DI was 1.0.
Compliance with both treatments was greater than 98%. Abatacept was well tolerated with comparable adverse events (AEs), serious AEs, and AEs of special interest such as infections and malignancies between treatments, Dr. Khanna said, noting that two deaths occurred in the abatacept group (caused by scleroderma renal crisis in both cases at days 11 and 46) and one occurred in a placebo group patient who experienced sudden cardiac arrest at day 310.
Of note, mRSS showed large variability, despite recruiting an early dcSSc population, Dr. Khanna said.
The finding with respect to the primary outcome is consistent with other recent trials because of improvement in mRSS that’s part of the natural history of the disease, including the tocilizumab findings that he reported at the meeting. The findings with respect to secondary endpoints and safety show promise.
“Stay tuned for robust ongoing work on the relationship between clinical changes and ongoing mechanistic work,” he said.
Riociguat (Adempas)
Similarly, in the randomized, placebo-controlled phase 2b RISE-SSc study comparing riociguat and placebo for early dcSSc, the primary efficacy endpoint of mean change in mRSS did not reach statistical significance, but exploratory data suggested that the soluble guanylate cyclase stimulator prevented disease progression in patients with early dcSSc, reported Oliver Distler, MD, head of the connective tissue diseases program at University Hospital Zurich (Switzerland).
The mean mRSS at baseline was comparable in 60 patients randomized to receive riociguat and 61 in the placebo group (16.8 and 16.71, respectively). These mean values at week 52 dropped to 14.63 vs. 15.73, respectively (P = .08).
“So it was close, but it didn’t reach significance,” he said.
The difference in the mRSS progression rate, however, suggested significant effects favoring riociguat (descriptive P = .02), he said.
Further, mean change from baseline to week 52 in percent predicted FVC was not different overall between the groups, but a large difference favoring riociguat was seen among patients with scleroderma interstitial lung disease at baseline (mean change of –2.7 vs. –8.9), he said.
No differences were seen between the groups in HAQ-DI or patient and physician global assessment. The proportion of patients with probability of improvement at 52 weeks as measured using ACR CRISS was also the same at 18% in both treatment arms, he noted, ”but the CRISS is designed more for assessing disease regression than for assessing prevention of progression.”
Treatment was, however, well tolerated. At week 52, fewer serious adverse events occurred with riociguat group than in the placebo group (15% vs. 25%, respectively), and no new safety signals were observed, he said.
Riociguat has previously shown antifibrotic effects in animal models and efficacy in patients with pulmonary arterial hypertension associated with connective tissue disease, so it was hypothesized that patients with dcSSc might benefit from riociguat therapy, Dr. Distler explained.
Study subjects had very early dcSSc (duration of 18 months or less; mean of 9 months), mRSS of 10-22 units, FVC of 45% predicted or greater, and diffusion capacity of the lung for carbon monoxide of at least 40% of predicted at screening.
Riociguat was given at an individually adjusted dose between 0.5 mg and 2.5 mg three times daily.
The findings demonstrate a numeric decrease in mRSS over time with riociguat versus placebo and a prevention of progression with riociguat; the failure to reach the primary endpoint may be related to the small study size and the higher than expected regression rate in the placebo group, Dr. Distler said.
Dr. Khanna is a consultant to Roche/Genentech and Bayer, which markets riociguat, and other companies. He has received research grants from Bayer, Bristol-Myers Squibb (which markets abatacept), and Pfizer. The ASSET trial he presented was sponsored by an National Institutes of Health/National Institute of Allergy and Infectious Diseases Clinical ACE grant and an investigator-initiated grant by Bristol-Myers Squibb. Dr. Distler has a consultancy relationship and/or has received research funding from Bayer, Roche/Genentech, and other companies. In addition, he has a patent on mir-29 for the treatment of systemic sclerosis.
SOURCES: Khanna D et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 898 and Abstract 900; Distler O et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 903.
CHICAGO – Recent randomized, placebo-controlled, phase 3 trials of tocilizumab, abatacept, and riociguat for the treatment of systemic sclerosis each failed to reach its primary endpoint of change from baseline in modified Rodnan Skin Score (mRSS).
Still, findings with respect to secondary endpoints and certain exploratory outcomes suggest each of the agents holds some promise in the systemic sclerosis (SSc) arena, according to the data presented at the annual meeting of the American College of Rheumatology.
Tocilizumab (Actemra)
In the double-blind portion of the phase 3 focuSSced trial of 212 patients with SSc, numerical improvement was observed for the primary endpoint of mean change in mRSS from baseline to week 48 with tocilizumab versus placebo (–6.14 vs. –4.41 points, respectively). The change in the treatment group was comparable with what was seen in the phase 2 faSScinate trial, but the decline in mRSS in the placebo group was much greater in phase 3 than in phase 2, and so the difference between the groups in the current study failed to reach statistical significance (P = .098), reported Dinesh Khanna, MBBS, a professor of medicine and director of the scleroderma program at the University of Michigan, Ann Arbor.
The interleukin-6 (IL-6) receptor–alpha antibody was previously shown in the faSScinate trial to lead to numeric improvements in skin thickening as measured by the mRSS, as well as to clinically meaningful lung function preservation as measured by percent predicted forced vital capacity (FVC).
In the current phase 3 study, key secondary end points also appeared to favor tocilizumab, but since the primary endpoint for mRSS was not met, all other P values cannot be considered statistically significant despite the strength of the evidence and were reported for informational purposes only, he noted.
The median cumulative distribution of change from baseline to week 48 in percent predicted FVC with tocilizumab versus placebo was –0.6 vs. –3.9, respectively (descriptive P = .0015), and the mean change from baseline in FVC at week 48 was –24 mL vs. –190 mL (difference of 167 mL in favor of tocilizumab; descriptive P = .0001).
Time to treatment failure also favored tocilizumab, he said (hazard ratio, 0.63; descriptive P = .082), he said.
Patients were randomly assigned to receive either weekly 162-mg injections of subcutaneous tocilizumab or placebo for 48 weeks. Escape therapy was allowed beginning at week 16 if patients experienced declines in FVC or beginning at week 24 if they experienced worsened mRSS or worsened SSc complications, Dr. Khanna said.
“The key part is that no immunotherapy was allowed. ... So it’s a true randomized, placebo-controlled trial,” he said.
Most (81%) of the patients were women, and they had a mean age of 48 years, mean SSc duration of 23 months, mean mRSS of 20.4 units on a 0-51 scale, and a normal mean percent predicted FVC of 82.1%.
“HAQ-DI showed moderate disability of 1.2,” he noted.
Safety in the study was consistent with that seen in prior tocilizumab studies; no new safety signals were identified. Serious adverse events occurred in 13% and 17% of tocilizumab and placebo group patients , respectively, and serious infections were reported by 7% and 2%.
Although clinically meaningful and consistent differences in FVC favoring tocilizumab were shown in this study, the primary endpoint was not met, Dr. Khanna said.
“There were no statistically significant differences, largely driven by unexpected improvement in the placebo group, which was different than what we found in [the faSScinate] trial,” he said, noting, however, that the FVC findings in the current study were clinically meaningful.
Also, in a separate presentation at the meeting, he explained that the differences favoring tocilizumab were statistically significant when patient-level data from the trial were analyzed based on the ACR Composite Response Index in Systemic Sclerosis (CRISS). Those findings provide validation of the novel outcomes measure, he said.
Abatacept (Orencia)
Dr. Khanna also reported results of the 12-month, double-blind, randomized, placebo-controlled phase 2 ASSET trial of abatacept, which showed no significant difference in mRSS in patients with early diffuse cutaneous SSc (dfSSc) who were treated with 125 mg of the recombinant fusion protein weekly and those who received placebo. However, certain secondary outcomes favored abatacept. No concomitant immunotherapy was allowed.
The adjusted mean decrease in the mRSS among patients who completed the 12-month treatment period was –6.24 vs. –4.49 in 34 patients in the abatacept group and 35 in the placebo group, respectively (P = .28).
The secondary outcome measures of mean change in Health Assessment Questionnaire Disability Index (HAQ-DI), patients global assessment, physician global assessment, and ACR CRISS scores were statistically significant or showed numerical results favoring abatacept over placebo: mean decrease in HAQ-DI, –0.17 vs. –0.11 (P = .05), respectively; mean change in physician global assessment scores, –1.30 vs. –0.35 (P = .03); median ACR CRISS index, 0.68 vs. 0.01 (P = .03), decline in percent predicted FVC of 4.13% and 1.34% (P = .11).
Escape therapy was allowed at 6 months for worsening SSc, but it did not change the outcomes trajectory, he said. A larger proportion of placebo vs. abatacept subjects required escape immunosuppressive therapy (36% vs. 16%; P = .03).
Patients were enrolled between 2014 and 2018 at 27 U.S., Canadian, and U.K. sites. At baseline, participants had a mean age of 49 years, 75% were women, and mean disease duration was very short at 1.59 years, with 60% having disease duration of 18 months or less. The mean baseline mRSS was 22.4, mean percent predicted FVC was 85.3%, and mean HAQ-DI was 1.0.
Compliance with both treatments was greater than 98%. Abatacept was well tolerated with comparable adverse events (AEs), serious AEs, and AEs of special interest such as infections and malignancies between treatments, Dr. Khanna said, noting that two deaths occurred in the abatacept group (caused by scleroderma renal crisis in both cases at days 11 and 46) and one occurred in a placebo group patient who experienced sudden cardiac arrest at day 310.
Of note, mRSS showed large variability, despite recruiting an early dcSSc population, Dr. Khanna said.
The finding with respect to the primary outcome is consistent with other recent trials because of improvement in mRSS that’s part of the natural history of the disease, including the tocilizumab findings that he reported at the meeting. The findings with respect to secondary endpoints and safety show promise.
“Stay tuned for robust ongoing work on the relationship between clinical changes and ongoing mechanistic work,” he said.
Riociguat (Adempas)
Similarly, in the randomized, placebo-controlled phase 2b RISE-SSc study comparing riociguat and placebo for early dcSSc, the primary efficacy endpoint of mean change in mRSS did not reach statistical significance, but exploratory data suggested that the soluble guanylate cyclase stimulator prevented disease progression in patients with early dcSSc, reported Oliver Distler, MD, head of the connective tissue diseases program at University Hospital Zurich (Switzerland).
The mean mRSS at baseline was comparable in 60 patients randomized to receive riociguat and 61 in the placebo group (16.8 and 16.71, respectively). These mean values at week 52 dropped to 14.63 vs. 15.73, respectively (P = .08).
“So it was close, but it didn’t reach significance,” he said.
The difference in the mRSS progression rate, however, suggested significant effects favoring riociguat (descriptive P = .02), he said.
Further, mean change from baseline to week 52 in percent predicted FVC was not different overall between the groups, but a large difference favoring riociguat was seen among patients with scleroderma interstitial lung disease at baseline (mean change of –2.7 vs. –8.9), he said.
No differences were seen between the groups in HAQ-DI or patient and physician global assessment. The proportion of patients with probability of improvement at 52 weeks as measured using ACR CRISS was also the same at 18% in both treatment arms, he noted, ”but the CRISS is designed more for assessing disease regression than for assessing prevention of progression.”
Treatment was, however, well tolerated. At week 52, fewer serious adverse events occurred with riociguat group than in the placebo group (15% vs. 25%, respectively), and no new safety signals were observed, he said.
Riociguat has previously shown antifibrotic effects in animal models and efficacy in patients with pulmonary arterial hypertension associated with connective tissue disease, so it was hypothesized that patients with dcSSc might benefit from riociguat therapy, Dr. Distler explained.
Study subjects had very early dcSSc (duration of 18 months or less; mean of 9 months), mRSS of 10-22 units, FVC of 45% predicted or greater, and diffusion capacity of the lung for carbon monoxide of at least 40% of predicted at screening.
Riociguat was given at an individually adjusted dose between 0.5 mg and 2.5 mg three times daily.
The findings demonstrate a numeric decrease in mRSS over time with riociguat versus placebo and a prevention of progression with riociguat; the failure to reach the primary endpoint may be related to the small study size and the higher than expected regression rate in the placebo group, Dr. Distler said.
Dr. Khanna is a consultant to Roche/Genentech and Bayer, which markets riociguat, and other companies. He has received research grants from Bayer, Bristol-Myers Squibb (which markets abatacept), and Pfizer. The ASSET trial he presented was sponsored by an National Institutes of Health/National Institute of Allergy and Infectious Diseases Clinical ACE grant and an investigator-initiated grant by Bristol-Myers Squibb. Dr. Distler has a consultancy relationship and/or has received research funding from Bayer, Roche/Genentech, and other companies. In addition, he has a patent on mir-29 for the treatment of systemic sclerosis.
SOURCES: Khanna D et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 898 and Abstract 900; Distler O et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 903.
CHICAGO – Recent randomized, placebo-controlled, phase 3 trials of tocilizumab, abatacept, and riociguat for the treatment of systemic sclerosis each failed to reach its primary endpoint of change from baseline in modified Rodnan Skin Score (mRSS).
Still, findings with respect to secondary endpoints and certain exploratory outcomes suggest each of the agents holds some promise in the systemic sclerosis (SSc) arena, according to the data presented at the annual meeting of the American College of Rheumatology.
Tocilizumab (Actemra)
In the double-blind portion of the phase 3 focuSSced trial of 212 patients with SSc, numerical improvement was observed for the primary endpoint of mean change in mRSS from baseline to week 48 with tocilizumab versus placebo (–6.14 vs. –4.41 points, respectively). The change in the treatment group was comparable with what was seen in the phase 2 faSScinate trial, but the decline in mRSS in the placebo group was much greater in phase 3 than in phase 2, and so the difference between the groups in the current study failed to reach statistical significance (P = .098), reported Dinesh Khanna, MBBS, a professor of medicine and director of the scleroderma program at the University of Michigan, Ann Arbor.
The interleukin-6 (IL-6) receptor–alpha antibody was previously shown in the faSScinate trial to lead to numeric improvements in skin thickening as measured by the mRSS, as well as to clinically meaningful lung function preservation as measured by percent predicted forced vital capacity (FVC).
In the current phase 3 study, key secondary end points also appeared to favor tocilizumab, but since the primary endpoint for mRSS was not met, all other P values cannot be considered statistically significant despite the strength of the evidence and were reported for informational purposes only, he noted.
The median cumulative distribution of change from baseline to week 48 in percent predicted FVC with tocilizumab versus placebo was –0.6 vs. –3.9, respectively (descriptive P = .0015), and the mean change from baseline in FVC at week 48 was –24 mL vs. –190 mL (difference of 167 mL in favor of tocilizumab; descriptive P = .0001).
Time to treatment failure also favored tocilizumab, he said (hazard ratio, 0.63; descriptive P = .082), he said.
Patients were randomly assigned to receive either weekly 162-mg injections of subcutaneous tocilizumab or placebo for 48 weeks. Escape therapy was allowed beginning at week 16 if patients experienced declines in FVC or beginning at week 24 if they experienced worsened mRSS or worsened SSc complications, Dr. Khanna said.
“The key part is that no immunotherapy was allowed. ... So it’s a true randomized, placebo-controlled trial,” he said.
Most (81%) of the patients were women, and they had a mean age of 48 years, mean SSc duration of 23 months, mean mRSS of 20.4 units on a 0-51 scale, and a normal mean percent predicted FVC of 82.1%.
“HAQ-DI showed moderate disability of 1.2,” he noted.
Safety in the study was consistent with that seen in prior tocilizumab studies; no new safety signals were identified. Serious adverse events occurred in 13% and 17% of tocilizumab and placebo group patients , respectively, and serious infections were reported by 7% and 2%.
Although clinically meaningful and consistent differences in FVC favoring tocilizumab were shown in this study, the primary endpoint was not met, Dr. Khanna said.
“There were no statistically significant differences, largely driven by unexpected improvement in the placebo group, which was different than what we found in [the faSScinate] trial,” he said, noting, however, that the FVC findings in the current study were clinically meaningful.
Also, in a separate presentation at the meeting, he explained that the differences favoring tocilizumab were statistically significant when patient-level data from the trial were analyzed based on the ACR Composite Response Index in Systemic Sclerosis (CRISS). Those findings provide validation of the novel outcomes measure, he said.
Abatacept (Orencia)
Dr. Khanna also reported results of the 12-month, double-blind, randomized, placebo-controlled phase 2 ASSET trial of abatacept, which showed no significant difference in mRSS in patients with early diffuse cutaneous SSc (dfSSc) who were treated with 125 mg of the recombinant fusion protein weekly and those who received placebo. However, certain secondary outcomes favored abatacept. No concomitant immunotherapy was allowed.
The adjusted mean decrease in the mRSS among patients who completed the 12-month treatment period was –6.24 vs. –4.49 in 34 patients in the abatacept group and 35 in the placebo group, respectively (P = .28).
The secondary outcome measures of mean change in Health Assessment Questionnaire Disability Index (HAQ-DI), patients global assessment, physician global assessment, and ACR CRISS scores were statistically significant or showed numerical results favoring abatacept over placebo: mean decrease in HAQ-DI, –0.17 vs. –0.11 (P = .05), respectively; mean change in physician global assessment scores, –1.30 vs. –0.35 (P = .03); median ACR CRISS index, 0.68 vs. 0.01 (P = .03), decline in percent predicted FVC of 4.13% and 1.34% (P = .11).
Escape therapy was allowed at 6 months for worsening SSc, but it did not change the outcomes trajectory, he said. A larger proportion of placebo vs. abatacept subjects required escape immunosuppressive therapy (36% vs. 16%; P = .03).
Patients were enrolled between 2014 and 2018 at 27 U.S., Canadian, and U.K. sites. At baseline, participants had a mean age of 49 years, 75% were women, and mean disease duration was very short at 1.59 years, with 60% having disease duration of 18 months or less. The mean baseline mRSS was 22.4, mean percent predicted FVC was 85.3%, and mean HAQ-DI was 1.0.
Compliance with both treatments was greater than 98%. Abatacept was well tolerated with comparable adverse events (AEs), serious AEs, and AEs of special interest such as infections and malignancies between treatments, Dr. Khanna said, noting that two deaths occurred in the abatacept group (caused by scleroderma renal crisis in both cases at days 11 and 46) and one occurred in a placebo group patient who experienced sudden cardiac arrest at day 310.
Of note, mRSS showed large variability, despite recruiting an early dcSSc population, Dr. Khanna said.
The finding with respect to the primary outcome is consistent with other recent trials because of improvement in mRSS that’s part of the natural history of the disease, including the tocilizumab findings that he reported at the meeting. The findings with respect to secondary endpoints and safety show promise.
“Stay tuned for robust ongoing work on the relationship between clinical changes and ongoing mechanistic work,” he said.
Riociguat (Adempas)
Similarly, in the randomized, placebo-controlled phase 2b RISE-SSc study comparing riociguat and placebo for early dcSSc, the primary efficacy endpoint of mean change in mRSS did not reach statistical significance, but exploratory data suggested that the soluble guanylate cyclase stimulator prevented disease progression in patients with early dcSSc, reported Oliver Distler, MD, head of the connective tissue diseases program at University Hospital Zurich (Switzerland).
The mean mRSS at baseline was comparable in 60 patients randomized to receive riociguat and 61 in the placebo group (16.8 and 16.71, respectively). These mean values at week 52 dropped to 14.63 vs. 15.73, respectively (P = .08).
“So it was close, but it didn’t reach significance,” he said.
The difference in the mRSS progression rate, however, suggested significant effects favoring riociguat (descriptive P = .02), he said.
Further, mean change from baseline to week 52 in percent predicted FVC was not different overall between the groups, but a large difference favoring riociguat was seen among patients with scleroderma interstitial lung disease at baseline (mean change of –2.7 vs. –8.9), he said.
No differences were seen between the groups in HAQ-DI or patient and physician global assessment. The proportion of patients with probability of improvement at 52 weeks as measured using ACR CRISS was also the same at 18% in both treatment arms, he noted, ”but the CRISS is designed more for assessing disease regression than for assessing prevention of progression.”
Treatment was, however, well tolerated. At week 52, fewer serious adverse events occurred with riociguat group than in the placebo group (15% vs. 25%, respectively), and no new safety signals were observed, he said.
Riociguat has previously shown antifibrotic effects in animal models and efficacy in patients with pulmonary arterial hypertension associated with connective tissue disease, so it was hypothesized that patients with dcSSc might benefit from riociguat therapy, Dr. Distler explained.
Study subjects had very early dcSSc (duration of 18 months or less; mean of 9 months), mRSS of 10-22 units, FVC of 45% predicted or greater, and diffusion capacity of the lung for carbon monoxide of at least 40% of predicted at screening.
Riociguat was given at an individually adjusted dose between 0.5 mg and 2.5 mg three times daily.
The findings demonstrate a numeric decrease in mRSS over time with riociguat versus placebo and a prevention of progression with riociguat; the failure to reach the primary endpoint may be related to the small study size and the higher than expected regression rate in the placebo group, Dr. Distler said.
Dr. Khanna is a consultant to Roche/Genentech and Bayer, which markets riociguat, and other companies. He has received research grants from Bayer, Bristol-Myers Squibb (which markets abatacept), and Pfizer. The ASSET trial he presented was sponsored by an National Institutes of Health/National Institute of Allergy and Infectious Diseases Clinical ACE grant and an investigator-initiated grant by Bristol-Myers Squibb. Dr. Distler has a consultancy relationship and/or has received research funding from Bayer, Roche/Genentech, and other companies. In addition, he has a patent on mir-29 for the treatment of systemic sclerosis.
SOURCES: Khanna D et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 898 and Abstract 900; Distler O et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 903.
REPORTING FROM THE ACR ANNUAL MEETING
ACR CRISS: A way forward for scleroderma treatment trials?
CHICAGO – At least three phase 3 randomized scleroderma treatment trials presented at the annual meeting of the American College of Rheumatology failed to meet modified Rodnan Skin Score–based primary endpoints, but a different story emerged when data from the trials were analyzed using the novel ACR Composite Response Index in Systemic Sclerosis (CRISS).
The differences highlight the limitations of individual outcome measures like the modified Rodnan Skin Score (mRSS) and underscore the need for new measures that capture the complexity of systemic sclerosis (SSc) and are more sensitive to changes in disease severity, according to Robert Spiera, MD, director of the vasculitis and scleroderma program at the Hospital for Special Surgery in New York.
Such measures are needed to better assess the effects of treatment interventions in scleroderma trials, Dr. Spiera said in an interview.
The ACR CRISS
Development of the ACR CRISS was led by Dinesh Khanna, MBBS, a professor of medicine and director of the scleroderma program at the University of Michigan, Ann Arbor. He and his colleagues described the measure in 2016 (Arthritis Rheumatol. 2016 Feb;68[2]:299-311. doi: 10.1002/art.39501).
Its use involves a two-step process of identifying any significant disease worsening or new end-organ damage, and then calculating the probability of patient improvement after 1 year of treatment on a 0- to 1-point scale based on changes from baseline in five variables: the mRSS, percent predicted forced vital capacity (FVC), patient and physician global assessments, and the Health Assessment Questionnaire Disability Index (HAQ-DI).
A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Of note, subjects with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.
To devise the CRISS, the investigators compiled 150 patient profiles with standardized clinical outcome elements using patients with diffuse cutaneous systemic sclerosis (dcSSc). The profiles were assessed by 40 scleroderma experts who rated patient improvement or lack thereof over 12 months.
Using the 79% of profiles for which a consensus was reached, the investigators “fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to follow-up were entered as covariates,” they explained.
This led to the selection of the five measures included in the final version, which was found to have sensitivity of 0.982 and specificity of 0.931. When evaluated in a previously completed 1-year randomized controlled trial, the index differentiated the effect of methotrexate from the effect of placebo (P = .02), they reported.
Based on these findings, the ACR board of directors granted “provisional” endorsement of the CRISS for use in SSc clinical studies, signifying that it had been quantitatively validated using patient data, but had not undergone validation using an external data set.
New data presented at the 2018 ACR meeting will likely lead to full approval of the measure once the studies validating the measure are published, according to Dr. Spiera.
The focuSSced study of tocilizumab
For example, in the phase 3 focuSSced study comparing the interleukin-6 (IL-6) receptor–alpha antibody tocilizumab (Actemra) with placebo in patients with SSc, the primary endpoint of mean change from baseline in mRSS was not met (–6.14 vs. –4.41 points with tocilizumab vs. placebo, respectively; P = .098), Dr. Khanna said during a report of findings from the double-blind portion of the study.
However, when the CRISS was applied and its performance prospectively assessed as an exploratory outcome at week 48 in the focuSSced trial, the differences between the groups were statistically significant. Dr. Khanna reported those findings in a separate presentation at the meeting, noting that they marked the first prospective evaluation of the ACR CRISS in a phase 3 trial in SSc.
The CRISS was applied – using a blinded review of adverse events and serious adverse events to complete step 1 – in all patients who received study treatment, stratified by baseline IL-6 levels.
Of 104 patients in the tocilizumab arm and 106 in the placebo arm, 6 and 13 patients, respectively, had cardio-pulmonary-renal involvement and therefore received a score of 0.
Using the ACR CRISS as a continuous measure, scores favored tocilizumab over placebo at week 48 with a median increase of 0.89 vs. 0.25 points (P = .023), and using the binary form of CRISS, 51% vs. 37% of patients in the treatment and placebo arms achieved the score cutoff of 0.60 or higher at week 48 (P = .035), he said.
“The focuSSced study validates the ACR CRISS endpoint for the first time in an independent prospective clinical trial and highlights the importance of step 1 as an indicator of reduced organ progression during 48 weeks of treatment,” Dr. Khanna concluded.
The ASSET trial of abatacept
Dr. Khanna also reported results from the 12-month phase 2 ASSET trial comparing abatacept (Orencia) and placebo in early dcSSc.
Again, the change from baseline in mRSS – the primary endpoint of the study – did not differ significantly with treatment vs. placebo (–6.24 vs. –4.49; P = .28).
And again, as presented separately in a poster session at ACR, application of CRISS at 12 months – a secondary outcome measure in the trial – showed a significant difference between the groups.
The investigators prospectively performed step 1 of the CRISS using a case report form. Of 63 patients with complete data available for relevant outcomes at 12 months, 10 (5 in each group) had cardio-pulmonary-renal involvement and thus were given a score of 0.
Overall, there was evidence of significantly improved CRISS scores in the abatacept group vs. the placebo group (P = .03), he said.
Most of the individual CRISS variables, except HAQ-DI and patient global assessment, had statistically significant correlations with the CRISS, he noted, adding that “although the degree of correlation is high between the mRSS and CRISS, there is evidence that CRISS may be more sensitive to clinically meaningful treatment changes than the standard skin score endpoint.”
“This suggests further validation of CRISS as an independent primary endpoint for scleroderma clinical trials,” he concluded.
The phase 2b RISE-SSc study of riociguat
As in the focuSSced and ASSET studies, the primary efficacy endpoint of mean change from baseline in mRSS was not met in the randomized, double-blind, placebo-controlled RISE-SSc study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator riociguat (Adempas) vs. placebo in 121 patients with early dcSSc, reported Oliver Distler, MD, a professor at University Hospital Zurich.
The mean change in mRSS at 52 weeks was 2.25 vs. 0.97 with riociguat vs. placebo, respectively (P = .08), although the difference in mRSS progression rate showed significant effects favoring riociguat (P = .02), he noted.
In this study, however, the proportion of patients with ACR CRISS probability of improvement (score of 0.60 or higher) at week 52 – a secondary study outcome – was the same at 18% in both arms, Dr. Distler said.
In a way, it’s helpful that the CRISS findings as well as the mRSS outcome in the RISE-SSc study were negative because it shows that “not everything comes up positive using the CRISS,” Dr. Spiera said.
An open-label extension trial of lenabasum
In the open-label extension of a phase 2 trial of lenabasum, Dr. Spiera and his colleagues also found the CRISS useful for assessing response in 36 patients. Lenabasum is a synthetic, nonimunosuppressive, selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses.
The agent continued to demonstrate acceptable safety and tolerability in dcSSc with no severe or serious adverse events or study discontinuations related to treatment during 12 months of open-label extension dosing, both from baseline and from the start of the extension, they reported in a poster at the ACR meeting. These assessments were based on ACR CRISS score, mRSS, physician global assessment, and multiple patient-reported outcomes.
The median CRISS score was 92% at week 52, and mRSS declined by a mean of 9.4 points (41.3% from baseline). More than a third of patients (35%) achieved a low mRSS of 10 or less.
The investigators noted, however, that definitive attribution of the findings to lenabasum is limited by the use of background therapy, the potential for spontaneous improvement in patients, and open-label dosing.
Evaluating immunosuppressive therapy in SSc
In another study presented at the ACR meeting, Boyang Zheng, MD, a second-year rheumatology fellow at McGill University in Montreal and his colleagues evaluated the effect of current immunosuppressive therapy on the ACR CRISS in 301 adult dcSSc patients without prior immunosuppression who were part of the Canadian Scleroderma Research Group (CSRG) registry.
Patients newly treated with methotrexate, azathioprine, mycophenolate and/or cyclophosphamide for at least 2 years (47 patients) were considered “exposed patients,” and untreated patients with at least the same follow-up duration were considered control subjects (254 patients).
Inverse probability of treatment weighting (IPTW) was performed to balance potential confounders in the two groups, including age, sex, disease duration, and CRISS variables, in an effort “to create a statistical cohort that would resemble a randomized, controlled trial,” Dr Zheng explained.
Prior to IPTW, treated patients trended towards more improvement after 1 year, but with “unimpressive absolute values.”
“But [after IPTW], when you look at overall CRISS at 1 year, more of the treated patients had actually improved – 23% vs. 11.8% in the untreated patients. After adjusting for age, sex, and disease duration, immunosuppression was associated with an almost twofold higher likelihood of improvement, although this was not statistically significant,” he said.
“Most importantly, after our balancing in the statistical cohort – so after balancing and adjusting for covariates ... immunosuppression use was still associated with a higher likelihood of improving [with an] odds ratio of 1.85 and P-value of 0.018,” he said.
The treated patients were sicker, and the CRISS was still able to capture individual patient improvement, he added.
Though limited by the observational design and the fact that “IPTW balancing cannot correct for all possible confounders,” the findings “provide novel evidence to support the use of immunosuppression in diffuse systemic sclerosis, and this reassures us in our current practice; it provides evidence that the CRISS seems to have better sensitivity to change than the mean of individual disease measures,” he said.
However, it also shows that “we have a long way to go to have better treatment for our patients,” he added, noting that only a minority (23%) of the patients in this study improved on the CRISS.
Moving forward in systemic sclerosis
Indeed, in order to move forward in developing better treatment for SSc, it is important to have the best possible means for assessing the effects of the potential new treatments, Dr. Spiera said.
“The mRSS is a good, reliable outcome measure in terms of intra- and inter-rater reliability, and we know it has meaning in the real world; in a patient with rapidly progressive skin thickening and a skin score that is getting higher and higher, we know they have worse prognosis in terms of function and even survival,” he said. “On the other hand, it’s just one piece of this very complicated story when you’re dealing with patients with systemic sclerosis, some of whom can have important internal organ involvement and not even have skin involvement.”
The main challenge with the skin score is how it performs in clinical trials when it comes to demonstrating whether a drug works, he added.
“This is particularly relevant in an era where our better understanding of the disease has led to candidate therapeutic agents that we have reason to think might work, but where clinical trials haven’t shown a significant difference between the groups using the skin score.”
Conversely, there have been studies in which skin scores improve, but the patient is doing terribly, he noted.
“That patient would not be [shown to be] doing well using the CRISS,” he said, explaining that the complex formula used to determine the CRISS score, which is “heavily weighted toward skin score,” allows for an overall score that is “greater than the sum of its parts.” That is, if a patient is improving in multiple domains indicating that the patient is responding to therapy, more credit is given for each of those parts.
“So my sense, and I think it’s the consensus in the community of clinical investigators, is that the skin score is not adequately sensitive to change in the context of a trial and doesn’t capture the disease holistically enough to be the optimal measure for scleroderma clinical trials,” he said. “We think the CRISS score works better in terms of capturing improvement in the course of a trial, and also in capturing other outcomes that are really, really important to patients and to their physicians, like disability or lung function.”
The hope is that, given the evidence, regulatory agencies will look favorably on the ACR CRISS as an outcome measure in clinical trials moving forward, and that understanding of its use and value will increase across the rheumatology community, he said.
Dr. Spiera has received research grants, consulting fees, and/or other payments from many companies involved in SSc treatments, including Roche/Genentech, which markets tocilizumab, and Corbus Pharmaceuticals, which is developing lenabasum.
Dr. Khanna is a consultant to Roche/Genentech and Bayer, which markets riociguat, and other companies. He has received research grants from Bayer, Bristol-Myers Squibb (which markets abatacept), and Pfizer. The ASSET trial he presented was sponsored by an NIH/NIAID Clinical ACE grant and an investigator-initiated grant by Bristol-Myers Squibb.
Dr. Distler has a consultancy relationship and/or has received research funding from Bayer, Roche/Genentech, and other companies. He also has a patent for a treatment for systemic sclerosis.
Dr. Zheng reported having no disclosures.
CHICAGO – At least three phase 3 randomized scleroderma treatment trials presented at the annual meeting of the American College of Rheumatology failed to meet modified Rodnan Skin Score–based primary endpoints, but a different story emerged when data from the trials were analyzed using the novel ACR Composite Response Index in Systemic Sclerosis (CRISS).
The differences highlight the limitations of individual outcome measures like the modified Rodnan Skin Score (mRSS) and underscore the need for new measures that capture the complexity of systemic sclerosis (SSc) and are more sensitive to changes in disease severity, according to Robert Spiera, MD, director of the vasculitis and scleroderma program at the Hospital for Special Surgery in New York.
Such measures are needed to better assess the effects of treatment interventions in scleroderma trials, Dr. Spiera said in an interview.
The ACR CRISS
Development of the ACR CRISS was led by Dinesh Khanna, MBBS, a professor of medicine and director of the scleroderma program at the University of Michigan, Ann Arbor. He and his colleagues described the measure in 2016 (Arthritis Rheumatol. 2016 Feb;68[2]:299-311. doi: 10.1002/art.39501).
Its use involves a two-step process of identifying any significant disease worsening or new end-organ damage, and then calculating the probability of patient improvement after 1 year of treatment on a 0- to 1-point scale based on changes from baseline in five variables: the mRSS, percent predicted forced vital capacity (FVC), patient and physician global assessments, and the Health Assessment Questionnaire Disability Index (HAQ-DI).
A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Of note, subjects with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.
To devise the CRISS, the investigators compiled 150 patient profiles with standardized clinical outcome elements using patients with diffuse cutaneous systemic sclerosis (dcSSc). The profiles were assessed by 40 scleroderma experts who rated patient improvement or lack thereof over 12 months.
Using the 79% of profiles for which a consensus was reached, the investigators “fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to follow-up were entered as covariates,” they explained.
This led to the selection of the five measures included in the final version, which was found to have sensitivity of 0.982 and specificity of 0.931. When evaluated in a previously completed 1-year randomized controlled trial, the index differentiated the effect of methotrexate from the effect of placebo (P = .02), they reported.
Based on these findings, the ACR board of directors granted “provisional” endorsement of the CRISS for use in SSc clinical studies, signifying that it had been quantitatively validated using patient data, but had not undergone validation using an external data set.
New data presented at the 2018 ACR meeting will likely lead to full approval of the measure once the studies validating the measure are published, according to Dr. Spiera.
The focuSSced study of tocilizumab
For example, in the phase 3 focuSSced study comparing the interleukin-6 (IL-6) receptor–alpha antibody tocilizumab (Actemra) with placebo in patients with SSc, the primary endpoint of mean change from baseline in mRSS was not met (–6.14 vs. –4.41 points with tocilizumab vs. placebo, respectively; P = .098), Dr. Khanna said during a report of findings from the double-blind portion of the study.
However, when the CRISS was applied and its performance prospectively assessed as an exploratory outcome at week 48 in the focuSSced trial, the differences between the groups were statistically significant. Dr. Khanna reported those findings in a separate presentation at the meeting, noting that they marked the first prospective evaluation of the ACR CRISS in a phase 3 trial in SSc.
The CRISS was applied – using a blinded review of adverse events and serious adverse events to complete step 1 – in all patients who received study treatment, stratified by baseline IL-6 levels.
Of 104 patients in the tocilizumab arm and 106 in the placebo arm, 6 and 13 patients, respectively, had cardio-pulmonary-renal involvement and therefore received a score of 0.
Using the ACR CRISS as a continuous measure, scores favored tocilizumab over placebo at week 48 with a median increase of 0.89 vs. 0.25 points (P = .023), and using the binary form of CRISS, 51% vs. 37% of patients in the treatment and placebo arms achieved the score cutoff of 0.60 or higher at week 48 (P = .035), he said.
“The focuSSced study validates the ACR CRISS endpoint for the first time in an independent prospective clinical trial and highlights the importance of step 1 as an indicator of reduced organ progression during 48 weeks of treatment,” Dr. Khanna concluded.
The ASSET trial of abatacept
Dr. Khanna also reported results from the 12-month phase 2 ASSET trial comparing abatacept (Orencia) and placebo in early dcSSc.
Again, the change from baseline in mRSS – the primary endpoint of the study – did not differ significantly with treatment vs. placebo (–6.24 vs. –4.49; P = .28).
And again, as presented separately in a poster session at ACR, application of CRISS at 12 months – a secondary outcome measure in the trial – showed a significant difference between the groups.
The investigators prospectively performed step 1 of the CRISS using a case report form. Of 63 patients with complete data available for relevant outcomes at 12 months, 10 (5 in each group) had cardio-pulmonary-renal involvement and thus were given a score of 0.
Overall, there was evidence of significantly improved CRISS scores in the abatacept group vs. the placebo group (P = .03), he said.
Most of the individual CRISS variables, except HAQ-DI and patient global assessment, had statistically significant correlations with the CRISS, he noted, adding that “although the degree of correlation is high between the mRSS and CRISS, there is evidence that CRISS may be more sensitive to clinically meaningful treatment changes than the standard skin score endpoint.”
“This suggests further validation of CRISS as an independent primary endpoint for scleroderma clinical trials,” he concluded.
The phase 2b RISE-SSc study of riociguat
As in the focuSSced and ASSET studies, the primary efficacy endpoint of mean change from baseline in mRSS was not met in the randomized, double-blind, placebo-controlled RISE-SSc study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator riociguat (Adempas) vs. placebo in 121 patients with early dcSSc, reported Oliver Distler, MD, a professor at University Hospital Zurich.
The mean change in mRSS at 52 weeks was 2.25 vs. 0.97 with riociguat vs. placebo, respectively (P = .08), although the difference in mRSS progression rate showed significant effects favoring riociguat (P = .02), he noted.
In this study, however, the proportion of patients with ACR CRISS probability of improvement (score of 0.60 or higher) at week 52 – a secondary study outcome – was the same at 18% in both arms, Dr. Distler said.
In a way, it’s helpful that the CRISS findings as well as the mRSS outcome in the RISE-SSc study were negative because it shows that “not everything comes up positive using the CRISS,” Dr. Spiera said.
An open-label extension trial of lenabasum
In the open-label extension of a phase 2 trial of lenabasum, Dr. Spiera and his colleagues also found the CRISS useful for assessing response in 36 patients. Lenabasum is a synthetic, nonimunosuppressive, selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses.
The agent continued to demonstrate acceptable safety and tolerability in dcSSc with no severe or serious adverse events or study discontinuations related to treatment during 12 months of open-label extension dosing, both from baseline and from the start of the extension, they reported in a poster at the ACR meeting. These assessments were based on ACR CRISS score, mRSS, physician global assessment, and multiple patient-reported outcomes.
The median CRISS score was 92% at week 52, and mRSS declined by a mean of 9.4 points (41.3% from baseline). More than a third of patients (35%) achieved a low mRSS of 10 or less.
The investigators noted, however, that definitive attribution of the findings to lenabasum is limited by the use of background therapy, the potential for spontaneous improvement in patients, and open-label dosing.
Evaluating immunosuppressive therapy in SSc
In another study presented at the ACR meeting, Boyang Zheng, MD, a second-year rheumatology fellow at McGill University in Montreal and his colleagues evaluated the effect of current immunosuppressive therapy on the ACR CRISS in 301 adult dcSSc patients without prior immunosuppression who were part of the Canadian Scleroderma Research Group (CSRG) registry.
Patients newly treated with methotrexate, azathioprine, mycophenolate and/or cyclophosphamide for at least 2 years (47 patients) were considered “exposed patients,” and untreated patients with at least the same follow-up duration were considered control subjects (254 patients).
Inverse probability of treatment weighting (IPTW) was performed to balance potential confounders in the two groups, including age, sex, disease duration, and CRISS variables, in an effort “to create a statistical cohort that would resemble a randomized, controlled trial,” Dr Zheng explained.
Prior to IPTW, treated patients trended towards more improvement after 1 year, but with “unimpressive absolute values.”
“But [after IPTW], when you look at overall CRISS at 1 year, more of the treated patients had actually improved – 23% vs. 11.8% in the untreated patients. After adjusting for age, sex, and disease duration, immunosuppression was associated with an almost twofold higher likelihood of improvement, although this was not statistically significant,” he said.
“Most importantly, after our balancing in the statistical cohort – so after balancing and adjusting for covariates ... immunosuppression use was still associated with a higher likelihood of improving [with an] odds ratio of 1.85 and P-value of 0.018,” he said.
The treated patients were sicker, and the CRISS was still able to capture individual patient improvement, he added.
Though limited by the observational design and the fact that “IPTW balancing cannot correct for all possible confounders,” the findings “provide novel evidence to support the use of immunosuppression in diffuse systemic sclerosis, and this reassures us in our current practice; it provides evidence that the CRISS seems to have better sensitivity to change than the mean of individual disease measures,” he said.
However, it also shows that “we have a long way to go to have better treatment for our patients,” he added, noting that only a minority (23%) of the patients in this study improved on the CRISS.
Moving forward in systemic sclerosis
Indeed, in order to move forward in developing better treatment for SSc, it is important to have the best possible means for assessing the effects of the potential new treatments, Dr. Spiera said.
“The mRSS is a good, reliable outcome measure in terms of intra- and inter-rater reliability, and we know it has meaning in the real world; in a patient with rapidly progressive skin thickening and a skin score that is getting higher and higher, we know they have worse prognosis in terms of function and even survival,” he said. “On the other hand, it’s just one piece of this very complicated story when you’re dealing with patients with systemic sclerosis, some of whom can have important internal organ involvement and not even have skin involvement.”
The main challenge with the skin score is how it performs in clinical trials when it comes to demonstrating whether a drug works, he added.
“This is particularly relevant in an era where our better understanding of the disease has led to candidate therapeutic agents that we have reason to think might work, but where clinical trials haven’t shown a significant difference between the groups using the skin score.”
Conversely, there have been studies in which skin scores improve, but the patient is doing terribly, he noted.
“That patient would not be [shown to be] doing well using the CRISS,” he said, explaining that the complex formula used to determine the CRISS score, which is “heavily weighted toward skin score,” allows for an overall score that is “greater than the sum of its parts.” That is, if a patient is improving in multiple domains indicating that the patient is responding to therapy, more credit is given for each of those parts.
“So my sense, and I think it’s the consensus in the community of clinical investigators, is that the skin score is not adequately sensitive to change in the context of a trial and doesn’t capture the disease holistically enough to be the optimal measure for scleroderma clinical trials,” he said. “We think the CRISS score works better in terms of capturing improvement in the course of a trial, and also in capturing other outcomes that are really, really important to patients and to their physicians, like disability or lung function.”
The hope is that, given the evidence, regulatory agencies will look favorably on the ACR CRISS as an outcome measure in clinical trials moving forward, and that understanding of its use and value will increase across the rheumatology community, he said.
Dr. Spiera has received research grants, consulting fees, and/or other payments from many companies involved in SSc treatments, including Roche/Genentech, which markets tocilizumab, and Corbus Pharmaceuticals, which is developing lenabasum.
Dr. Khanna is a consultant to Roche/Genentech and Bayer, which markets riociguat, and other companies. He has received research grants from Bayer, Bristol-Myers Squibb (which markets abatacept), and Pfizer. The ASSET trial he presented was sponsored by an NIH/NIAID Clinical ACE grant and an investigator-initiated grant by Bristol-Myers Squibb.
Dr. Distler has a consultancy relationship and/or has received research funding from Bayer, Roche/Genentech, and other companies. He also has a patent for a treatment for systemic sclerosis.
Dr. Zheng reported having no disclosures.
CHICAGO – At least three phase 3 randomized scleroderma treatment trials presented at the annual meeting of the American College of Rheumatology failed to meet modified Rodnan Skin Score–based primary endpoints, but a different story emerged when data from the trials were analyzed using the novel ACR Composite Response Index in Systemic Sclerosis (CRISS).
The differences highlight the limitations of individual outcome measures like the modified Rodnan Skin Score (mRSS) and underscore the need for new measures that capture the complexity of systemic sclerosis (SSc) and are more sensitive to changes in disease severity, according to Robert Spiera, MD, director of the vasculitis and scleroderma program at the Hospital for Special Surgery in New York.
Such measures are needed to better assess the effects of treatment interventions in scleroderma trials, Dr. Spiera said in an interview.
The ACR CRISS
Development of the ACR CRISS was led by Dinesh Khanna, MBBS, a professor of medicine and director of the scleroderma program at the University of Michigan, Ann Arbor. He and his colleagues described the measure in 2016 (Arthritis Rheumatol. 2016 Feb;68[2]:299-311. doi: 10.1002/art.39501).
Its use involves a two-step process of identifying any significant disease worsening or new end-organ damage, and then calculating the probability of patient improvement after 1 year of treatment on a 0- to 1-point scale based on changes from baseline in five variables: the mRSS, percent predicted forced vital capacity (FVC), patient and physician global assessments, and the Health Assessment Questionnaire Disability Index (HAQ-DI).
A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Of note, subjects with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.
To devise the CRISS, the investigators compiled 150 patient profiles with standardized clinical outcome elements using patients with diffuse cutaneous systemic sclerosis (dcSSc). The profiles were assessed by 40 scleroderma experts who rated patient improvement or lack thereof over 12 months.
Using the 79% of profiles for which a consensus was reached, the investigators “fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to follow-up were entered as covariates,” they explained.
This led to the selection of the five measures included in the final version, which was found to have sensitivity of 0.982 and specificity of 0.931. When evaluated in a previously completed 1-year randomized controlled trial, the index differentiated the effect of methotrexate from the effect of placebo (P = .02), they reported.
Based on these findings, the ACR board of directors granted “provisional” endorsement of the CRISS for use in SSc clinical studies, signifying that it had been quantitatively validated using patient data, but had not undergone validation using an external data set.
New data presented at the 2018 ACR meeting will likely lead to full approval of the measure once the studies validating the measure are published, according to Dr. Spiera.
The focuSSced study of tocilizumab
For example, in the phase 3 focuSSced study comparing the interleukin-6 (IL-6) receptor–alpha antibody tocilizumab (Actemra) with placebo in patients with SSc, the primary endpoint of mean change from baseline in mRSS was not met (–6.14 vs. –4.41 points with tocilizumab vs. placebo, respectively; P = .098), Dr. Khanna said during a report of findings from the double-blind portion of the study.
However, when the CRISS was applied and its performance prospectively assessed as an exploratory outcome at week 48 in the focuSSced trial, the differences between the groups were statistically significant. Dr. Khanna reported those findings in a separate presentation at the meeting, noting that they marked the first prospective evaluation of the ACR CRISS in a phase 3 trial in SSc.
The CRISS was applied – using a blinded review of adverse events and serious adverse events to complete step 1 – in all patients who received study treatment, stratified by baseline IL-6 levels.
Of 104 patients in the tocilizumab arm and 106 in the placebo arm, 6 and 13 patients, respectively, had cardio-pulmonary-renal involvement and therefore received a score of 0.
Using the ACR CRISS as a continuous measure, scores favored tocilizumab over placebo at week 48 with a median increase of 0.89 vs. 0.25 points (P = .023), and using the binary form of CRISS, 51% vs. 37% of patients in the treatment and placebo arms achieved the score cutoff of 0.60 or higher at week 48 (P = .035), he said.
“The focuSSced study validates the ACR CRISS endpoint for the first time in an independent prospective clinical trial and highlights the importance of step 1 as an indicator of reduced organ progression during 48 weeks of treatment,” Dr. Khanna concluded.
The ASSET trial of abatacept
Dr. Khanna also reported results from the 12-month phase 2 ASSET trial comparing abatacept (Orencia) and placebo in early dcSSc.
Again, the change from baseline in mRSS – the primary endpoint of the study – did not differ significantly with treatment vs. placebo (–6.24 vs. –4.49; P = .28).
And again, as presented separately in a poster session at ACR, application of CRISS at 12 months – a secondary outcome measure in the trial – showed a significant difference between the groups.
The investigators prospectively performed step 1 of the CRISS using a case report form. Of 63 patients with complete data available for relevant outcomes at 12 months, 10 (5 in each group) had cardio-pulmonary-renal involvement and thus were given a score of 0.
Overall, there was evidence of significantly improved CRISS scores in the abatacept group vs. the placebo group (P = .03), he said.
Most of the individual CRISS variables, except HAQ-DI and patient global assessment, had statistically significant correlations with the CRISS, he noted, adding that “although the degree of correlation is high between the mRSS and CRISS, there is evidence that CRISS may be more sensitive to clinically meaningful treatment changes than the standard skin score endpoint.”
“This suggests further validation of CRISS as an independent primary endpoint for scleroderma clinical trials,” he concluded.
The phase 2b RISE-SSc study of riociguat
As in the focuSSced and ASSET studies, the primary efficacy endpoint of mean change from baseline in mRSS was not met in the randomized, double-blind, placebo-controlled RISE-SSc study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator riociguat (Adempas) vs. placebo in 121 patients with early dcSSc, reported Oliver Distler, MD, a professor at University Hospital Zurich.
The mean change in mRSS at 52 weeks was 2.25 vs. 0.97 with riociguat vs. placebo, respectively (P = .08), although the difference in mRSS progression rate showed significant effects favoring riociguat (P = .02), he noted.
In this study, however, the proportion of patients with ACR CRISS probability of improvement (score of 0.60 or higher) at week 52 – a secondary study outcome – was the same at 18% in both arms, Dr. Distler said.
In a way, it’s helpful that the CRISS findings as well as the mRSS outcome in the RISE-SSc study were negative because it shows that “not everything comes up positive using the CRISS,” Dr. Spiera said.
An open-label extension trial of lenabasum
In the open-label extension of a phase 2 trial of lenabasum, Dr. Spiera and his colleagues also found the CRISS useful for assessing response in 36 patients. Lenabasum is a synthetic, nonimunosuppressive, selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses.
The agent continued to demonstrate acceptable safety and tolerability in dcSSc with no severe or serious adverse events or study discontinuations related to treatment during 12 months of open-label extension dosing, both from baseline and from the start of the extension, they reported in a poster at the ACR meeting. These assessments were based on ACR CRISS score, mRSS, physician global assessment, and multiple patient-reported outcomes.
The median CRISS score was 92% at week 52, and mRSS declined by a mean of 9.4 points (41.3% from baseline). More than a third of patients (35%) achieved a low mRSS of 10 or less.
The investigators noted, however, that definitive attribution of the findings to lenabasum is limited by the use of background therapy, the potential for spontaneous improvement in patients, and open-label dosing.
Evaluating immunosuppressive therapy in SSc
In another study presented at the ACR meeting, Boyang Zheng, MD, a second-year rheumatology fellow at McGill University in Montreal and his colleagues evaluated the effect of current immunosuppressive therapy on the ACR CRISS in 301 adult dcSSc patients without prior immunosuppression who were part of the Canadian Scleroderma Research Group (CSRG) registry.
Patients newly treated with methotrexate, azathioprine, mycophenolate and/or cyclophosphamide for at least 2 years (47 patients) were considered “exposed patients,” and untreated patients with at least the same follow-up duration were considered control subjects (254 patients).
Inverse probability of treatment weighting (IPTW) was performed to balance potential confounders in the two groups, including age, sex, disease duration, and CRISS variables, in an effort “to create a statistical cohort that would resemble a randomized, controlled trial,” Dr Zheng explained.
Prior to IPTW, treated patients trended towards more improvement after 1 year, but with “unimpressive absolute values.”
“But [after IPTW], when you look at overall CRISS at 1 year, more of the treated patients had actually improved – 23% vs. 11.8% in the untreated patients. After adjusting for age, sex, and disease duration, immunosuppression was associated with an almost twofold higher likelihood of improvement, although this was not statistically significant,” he said.
“Most importantly, after our balancing in the statistical cohort – so after balancing and adjusting for covariates ... immunosuppression use was still associated with a higher likelihood of improving [with an] odds ratio of 1.85 and P-value of 0.018,” he said.
The treated patients were sicker, and the CRISS was still able to capture individual patient improvement, he added.
Though limited by the observational design and the fact that “IPTW balancing cannot correct for all possible confounders,” the findings “provide novel evidence to support the use of immunosuppression in diffuse systemic sclerosis, and this reassures us in our current practice; it provides evidence that the CRISS seems to have better sensitivity to change than the mean of individual disease measures,” he said.
However, it also shows that “we have a long way to go to have better treatment for our patients,” he added, noting that only a minority (23%) of the patients in this study improved on the CRISS.
Moving forward in systemic sclerosis
Indeed, in order to move forward in developing better treatment for SSc, it is important to have the best possible means for assessing the effects of the potential new treatments, Dr. Spiera said.
“The mRSS is a good, reliable outcome measure in terms of intra- and inter-rater reliability, and we know it has meaning in the real world; in a patient with rapidly progressive skin thickening and a skin score that is getting higher and higher, we know they have worse prognosis in terms of function and even survival,” he said. “On the other hand, it’s just one piece of this very complicated story when you’re dealing with patients with systemic sclerosis, some of whom can have important internal organ involvement and not even have skin involvement.”
The main challenge with the skin score is how it performs in clinical trials when it comes to demonstrating whether a drug works, he added.
“This is particularly relevant in an era where our better understanding of the disease has led to candidate therapeutic agents that we have reason to think might work, but where clinical trials haven’t shown a significant difference between the groups using the skin score.”
Conversely, there have been studies in which skin scores improve, but the patient is doing terribly, he noted.
“That patient would not be [shown to be] doing well using the CRISS,” he said, explaining that the complex formula used to determine the CRISS score, which is “heavily weighted toward skin score,” allows for an overall score that is “greater than the sum of its parts.” That is, if a patient is improving in multiple domains indicating that the patient is responding to therapy, more credit is given for each of those parts.
“So my sense, and I think it’s the consensus in the community of clinical investigators, is that the skin score is not adequately sensitive to change in the context of a trial and doesn’t capture the disease holistically enough to be the optimal measure for scleroderma clinical trials,” he said. “We think the CRISS score works better in terms of capturing improvement in the course of a trial, and also in capturing other outcomes that are really, really important to patients and to their physicians, like disability or lung function.”
The hope is that, given the evidence, regulatory agencies will look favorably on the ACR CRISS as an outcome measure in clinical trials moving forward, and that understanding of its use and value will increase across the rheumatology community, he said.
Dr. Spiera has received research grants, consulting fees, and/or other payments from many companies involved in SSc treatments, including Roche/Genentech, which markets tocilizumab, and Corbus Pharmaceuticals, which is developing lenabasum.
Dr. Khanna is a consultant to Roche/Genentech and Bayer, which markets riociguat, and other companies. He has received research grants from Bayer, Bristol-Myers Squibb (which markets abatacept), and Pfizer. The ASSET trial he presented was sponsored by an NIH/NIAID Clinical ACE grant and an investigator-initiated grant by Bristol-Myers Squibb.
Dr. Distler has a consultancy relationship and/or has received research funding from Bayer, Roche/Genentech, and other companies. He also has a patent for a treatment for systemic sclerosis.
Dr. Zheng reported having no disclosures.
REPORTING FROM THE ACR ANNUAL MEETING