Rheumatology

The Food and Drug Administration has approved the biosimilar infliximab-axxq (Avsola) for various indications, making it the fourth biosimilar of infliximab (Remicade) to be cleared for marketing by the agency.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The tumor necrosis factor inhibitor is indicated for patients with Crohn’s disease or ulcerative colitis who are aged 6 years and older, RA in combination with methotrexate, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis. The approval is based on numerous trials. The most common adverse reactions are infections, infusion-related reactions, headache, and abdominal pain.

Full prescribing information can be found on the FDA website, as can more information about biosimilars.

[email protected]

The Food and Drug Administration has approved the biosimilar infliximab-axxq (Avsola) for various indications, making it the fourth biosimilar of infliximab (Remicade) to be cleared for marketing by the agency.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The tumor necrosis factor inhibitor is indicated for patients with Crohn’s disease or ulcerative colitis who are aged 6 years and older, RA in combination with methotrexate, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis. The approval is based on numerous trials. The most common adverse reactions are infections, infusion-related reactions, headache, and abdominal pain.

Full prescribing information can be found on the FDA website, as can more information about biosimilars.

[email protected]

The Food and Drug Administration has approved the biosimilar infliximab-axxq (Avsola) for various indications, making it the fourth biosimilar of infliximab (Remicade) to be cleared for marketing by the agency.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The tumor necrosis factor inhibitor is indicated for patients with Crohn’s disease or ulcerative colitis who are aged 6 years and older, RA in combination with methotrexate, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis. The approval is based on numerous trials. The most common adverse reactions are infections, infusion-related reactions, headache, and abdominal pain.

Full prescribing information can be found on the FDA website, as can more information about biosimilars.

[email protected]

ATLANTA – Certolizumab pegol, a PEGylated, monoclonal, anti–tumor necrosis factor antibody, reduces recurrent acute anterior uveitis flares and improves disease activity in patients with axial spondyloarthritis, according to findings from the open-label, 96-week, phase 4 C-VIEW study.

Sharon Worcester/MDedge News

When given earlier in the course of disease, the treatment, which is the only Food and Drug Administration–approved tumor necrosis factor inhibitor (TNFi) for the treatment of nonradiographic axial spondyloarthritis (nr-axSpA), also shortens symptom duration, a post hoc analysis of data from the multicenter, phase 3 C-axSpAnd study suggests. The findings from both studies were presented during a session at the annual meeting of the American College of Rheumatology.
 

C-VIEW

In 85 patients with active axSpA who completed 48 weeks of certolizumab pegol therapy in the C-VIEW study, the acute anterior uveitis (AAU) flare incidence over 48 weeks was a mean of 0.2, compared with 1.5 flares per person in the 48 weeks prior to treatment initiation, reported Irene E. van der Horst-Bruinsma, MD, PhD, of Amsterdam University Medical Center. The comparison was adjusted for possible within-patient correlations, flare period (pre- and post baseline), and axSpA disease duration.

This finding, from a preplanned interim analysis, represented a flare incidence of 18.7 versus 146.6 per 100 patient-years, during treatment versus prior to treatment – an 87% reduction – and the difference was statistically significant (P less than .001), Dr. van der Horst-Bruinsma said.

The percentage of patients experiencing one flare was 12.4% during therapy, compared with 64% prior to therapy, and the percentage experiencing two or more flares was 2.2% versus 24.7%, respectively, she said, adding that, in the 13 patients who experienced flares both before and during treatment, the mean flare duration was reduced during treatment (58.4 vs. 97.4 days). A comparison of radiographic and nr-axSpA patients showed similar reductions in flares during versus prior to treatment, going from 144.5 to 19.0 flares per 100 patient-years with radiographic disease and from 158.9 to 17.2 flares per 100 patient-years in nr-axSpA.

Furthermore, after 48 weeks of treatment, disease activity had improved substantially, with mean Ankylosing Spondylitis Disease Activity Score (ASDAS) improving from 3.5 to 2.0 at week 48, 94.2% of patients reaching ASDAS clinical improvement at week 48, and mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score decreasing significantly from 6.5 to 3.3 at week 48.

“ASDAS 20 was reached by 75% of the patients, the ASDAS 40 by 54%, and the ASDAS partial remission criteria were reached by 31% of the patients,” she said.

Study participants were adults with a mean age of 46.5 years and active disease according to Assessment of Spondyloarthritis International Society (ASAS) criteria and a history of recurrent AAU flares (either two or more in total, or one or more in the year prior to study entry). They were HLA-B27 positive, eligible for anti-TNF therapy because they had an inadequate response (or contraindication) to at least two prior NSAIDs, were biologic naive, or had failed to respond to no more than one prior anti-TNF agent. Both radiographic and nr-axSpA patients were included, and of 115 who enrolled, 89 initiated treatment, including 76 with radiographic disease and 13 with nonradiographic disease; 85 completed week 48 of treatment.

Certolizumab pegol was given at a loading dose of 400 mg at weeks 0, 2, and 4, followed by 200 mg every 2 weeks through week 96, and was well tolerated. No new safety signals were identified, Dr. van der Horst-Bruinsma said.

“We know that acute anterior uveitis, an inflammation of ... the uveal tract, is the most common extra-articular manifestation in axial spondyloarthritis,” she said. “It is reported in up to 40% of patients and is associated with significant clinical burden.”

AAU is also strongly associated with the HLA-B27 antigen, therefore patients who do not have ankylosing spondylitis but who are HLA-B27 positive also are at risk, she said, noting that previous studies have shown that TNF inhibitors reduce the incidence of AAU flares in patients with radiographic axSpA (ankylosing spondylitis), but that data in nr-axSpA are scarce.

The aim of C-VIEW was to analyze the impact of certolizumab pegol treatment on AAU flares in patients with active radiographic or nr-axSpA and a recent history of AAU, she said.

“C-VIEW was the first study to examine the impact of certolizumab on the incidence of acute anterior uveitis flares in HLA-B27-positive patients with a recent history of acute anterior uveitis, including patients with nr-axSpA ... and in conclusion we can say that these results indicate that certolizumab is a suitable treatment option for patients with axSpA and a history of recurrent acute anterior uveitis,” she said.

C-axSpAnd

In the pivotal 3-year C-axSpAnd study, which included a 52‑week, double-blind, placebo-controlled period, 159 patients with active nr-axSpA, objective signs of inflammation, and previous failure of at least two NSAIDS were treated with certolizumab pegol, and 158 similar patients received placebo. Both groups received nonbiologic background medication.

The results of the trial, published in Arthritis & Rheumatology in March 2019, showed that adding certolizumab pegol to background medication is superior to adding placebo in patients with active nr-axSpA and led to its FDA approval for axSpA in March 2019, but the effects of symptom duration on outcomes with certolizumab pegol have not been well studied, Jonathan Kay, MD, said at the ACR meeting.

The current post hoc analysis stratified patients based on symptom duration and showed that certolizumab pegol recipients with less than 5 years of symptoms at baseline had improved outcomes at weeks 12 and 52, compared with those who had 5 or more years of symptoms at baseline, said Dr. Kay of UMass Memorial Medical Center and the University of Massachusetts, Worcester.

For example, major improvement in ASDAS at week 52, the primary outcome measure, was achieved by 55% of 80 patients with shorter symptom duration, compared with 39.2% of 79 patients with longer symptom duration, and the ASAS 40 responder rates in the groups, respectively, were 58.5% and 36.7% at 12 weeks and 65% and 48.1% at 52 weeks, he said.

Certolizumab pegol recipients with shorter symptom duration also had greater improvement in BASDAI score, nocturnal spinal pain, fatigue, morning stiffness, and the 36-item Short Form Survey physical component score, he noted.

Using a cutoff of 3 years rather than 5 years, responder rates for major improvement in ASDAS and ASAS 40 were still greater in certolizumab pegol–treated patients with shorter symptom duration: At 52 weeks, 56.4% of 55 patients with less than 3 years of symptoms, compared with 42.3% of 104 with 3 or more years of symptoms, achieved major improvement in ASDAS, and ASAS 40 responder rates were 65.5%, compared with 51.9%, respectively.

Response rates in the placebo arm were low, compared with both certolizumab pegol groups, and no consistent trend in outcomes was observed based on symptom duration in that arm, Dr. Kay noted.

Study subjects were adults with a diagnosis of axSpA, active disease, fulfillment of ASAS classification criteria, and at least 12 months of inflammatory back pain. The trial excluded those with radiographic sacroiliitis meeting the modified New York classification criteria and who had exposure to more than one TNFi prior to baseline or primary failure of any TNFi. As in the C-VIEW study, participants were randomized to receive 400 mg certolizumab pegol at weeks 0, 2, and 4, and then 200 mg every 2 weeks thereafter through week 52.

The findings are notable because patients with axSpA – including radiographic disease and nr-axSpA – often experience delays in diagnosis, which can lead to a delay in treatment and a reduced quality of life because of the back pain, fatigue, and morning stiffness that commonly occur with the disease.

“Women, especially, with axial spondyloarthritis experience a longer delay in diagnosis than do male patients,” Dr. Kay noted.

The findings of this post hoc analysis underscore the risks associated with such a delay. “These results imply that early diagnosis enabling earlier treatment is important for patients with nonradiographic axSpA, as it is for patients with radiographic axSpA,” he concluded.

The C-VIEW and C-axSpAnd studies were funded by UCB. Dr. van der Horst-Bruinsma reported receiving honoraria, consulting fees, and/or research grants from UCB as well as from AbbVie, Bristol-Myers Squibb, Merck, Novartis, and Pfizer. Dr. Kay reported receiving grant/research support from Gilead, Pfizer, and UCB, and consulting fees from AbbVie, Alvotech, Boehringer Ingelheim, Celltrion, Merck, Novartis, Samsung Bioepis, Sandoz, and UCB.

[email protected]

SOURCES: van der Horst-Bruinsma I et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 935; Kay J et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 936.

ATLANTA – Certolizumab pegol, a PEGylated, monoclonal, anti–tumor necrosis factor antibody, reduces recurrent acute anterior uveitis flares and improves disease activity in patients with axial spondyloarthritis, according to findings from the open-label, 96-week, phase 4 C-VIEW study.

Sharon Worcester/MDedge News

When given earlier in the course of disease, the treatment, which is the only Food and Drug Administration–approved tumor necrosis factor inhibitor (TNFi) for the treatment of nonradiographic axial spondyloarthritis (nr-axSpA), also shortens symptom duration, a post hoc analysis of data from the multicenter, phase 3 C-axSpAnd study suggests. The findings from both studies were presented during a session at the annual meeting of the American College of Rheumatology.
 

C-VIEW

In 85 patients with active axSpA who completed 48 weeks of certolizumab pegol therapy in the C-VIEW study, the acute anterior uveitis (AAU) flare incidence over 48 weeks was a mean of 0.2, compared with 1.5 flares per person in the 48 weeks prior to treatment initiation, reported Irene E. van der Horst-Bruinsma, MD, PhD, of Amsterdam University Medical Center. The comparison was adjusted for possible within-patient correlations, flare period (pre- and post baseline), and axSpA disease duration.

This finding, from a preplanned interim analysis, represented a flare incidence of 18.7 versus 146.6 per 100 patient-years, during treatment versus prior to treatment – an 87% reduction – and the difference was statistically significant (P less than .001), Dr. van der Horst-Bruinsma said.

The percentage of patients experiencing one flare was 12.4% during therapy, compared with 64% prior to therapy, and the percentage experiencing two or more flares was 2.2% versus 24.7%, respectively, she said, adding that, in the 13 patients who experienced flares both before and during treatment, the mean flare duration was reduced during treatment (58.4 vs. 97.4 days). A comparison of radiographic and nr-axSpA patients showed similar reductions in flares during versus prior to treatment, going from 144.5 to 19.0 flares per 100 patient-years with radiographic disease and from 158.9 to 17.2 flares per 100 patient-years in nr-axSpA.

Furthermore, after 48 weeks of treatment, disease activity had improved substantially, with mean Ankylosing Spondylitis Disease Activity Score (ASDAS) improving from 3.5 to 2.0 at week 48, 94.2% of patients reaching ASDAS clinical improvement at week 48, and mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score decreasing significantly from 6.5 to 3.3 at week 48.

“ASDAS 20 was reached by 75% of the patients, the ASDAS 40 by 54%, and the ASDAS partial remission criteria were reached by 31% of the patients,” she said.

Study participants were adults with a mean age of 46.5 years and active disease according to Assessment of Spondyloarthritis International Society (ASAS) criteria and a history of recurrent AAU flares (either two or more in total, or one or more in the year prior to study entry). They were HLA-B27 positive, eligible for anti-TNF therapy because they had an inadequate response (or contraindication) to at least two prior NSAIDs, were biologic naive, or had failed to respond to no more than one prior anti-TNF agent. Both radiographic and nr-axSpA patients were included, and of 115 who enrolled, 89 initiated treatment, including 76 with radiographic disease and 13 with nonradiographic disease; 85 completed week 48 of treatment.

Certolizumab pegol was given at a loading dose of 400 mg at weeks 0, 2, and 4, followed by 200 mg every 2 weeks through week 96, and was well tolerated. No new safety signals were identified, Dr. van der Horst-Bruinsma said.

“We know that acute anterior uveitis, an inflammation of ... the uveal tract, is the most common extra-articular manifestation in axial spondyloarthritis,” she said. “It is reported in up to 40% of patients and is associated with significant clinical burden.”

AAU is also strongly associated with the HLA-B27 antigen, therefore patients who do not have ankylosing spondylitis but who are HLA-B27 positive also are at risk, she said, noting that previous studies have shown that TNF inhibitors reduce the incidence of AAU flares in patients with radiographic axSpA (ankylosing spondylitis), but that data in nr-axSpA are scarce.

The aim of C-VIEW was to analyze the impact of certolizumab pegol treatment on AAU flares in patients with active radiographic or nr-axSpA and a recent history of AAU, she said.

“C-VIEW was the first study to examine the impact of certolizumab on the incidence of acute anterior uveitis flares in HLA-B27-positive patients with a recent history of acute anterior uveitis, including patients with nr-axSpA ... and in conclusion we can say that these results indicate that certolizumab is a suitable treatment option for patients with axSpA and a history of recurrent acute anterior uveitis,” she said.

C-axSpAnd

In the pivotal 3-year C-axSpAnd study, which included a 52‑week, double-blind, placebo-controlled period, 159 patients with active nr-axSpA, objective signs of inflammation, and previous failure of at least two NSAIDS were treated with certolizumab pegol, and 158 similar patients received placebo. Both groups received nonbiologic background medication.

The results of the trial, published in Arthritis & Rheumatology in March 2019, showed that adding certolizumab pegol to background medication is superior to adding placebo in patients with active nr-axSpA and led to its FDA approval for axSpA in March 2019, but the effects of symptom duration on outcomes with certolizumab pegol have not been well studied, Jonathan Kay, MD, said at the ACR meeting.

The current post hoc analysis stratified patients based on symptom duration and showed that certolizumab pegol recipients with less than 5 years of symptoms at baseline had improved outcomes at weeks 12 and 52, compared with those who had 5 or more years of symptoms at baseline, said Dr. Kay of UMass Memorial Medical Center and the University of Massachusetts, Worcester.

For example, major improvement in ASDAS at week 52, the primary outcome measure, was achieved by 55% of 80 patients with shorter symptom duration, compared with 39.2% of 79 patients with longer symptom duration, and the ASAS 40 responder rates in the groups, respectively, were 58.5% and 36.7% at 12 weeks and 65% and 48.1% at 52 weeks, he said.

Certolizumab pegol recipients with shorter symptom duration also had greater improvement in BASDAI score, nocturnal spinal pain, fatigue, morning stiffness, and the 36-item Short Form Survey physical component score, he noted.

Using a cutoff of 3 years rather than 5 years, responder rates for major improvement in ASDAS and ASAS 40 were still greater in certolizumab pegol–treated patients with shorter symptom duration: At 52 weeks, 56.4% of 55 patients with less than 3 years of symptoms, compared with 42.3% of 104 with 3 or more years of symptoms, achieved major improvement in ASDAS, and ASAS 40 responder rates were 65.5%, compared with 51.9%, respectively.

Response rates in the placebo arm were low, compared with both certolizumab pegol groups, and no consistent trend in outcomes was observed based on symptom duration in that arm, Dr. Kay noted.

Study subjects were adults with a diagnosis of axSpA, active disease, fulfillment of ASAS classification criteria, and at least 12 months of inflammatory back pain. The trial excluded those with radiographic sacroiliitis meeting the modified New York classification criteria and who had exposure to more than one TNFi prior to baseline or primary failure of any TNFi. As in the C-VIEW study, participants were randomized to receive 400 mg certolizumab pegol at weeks 0, 2, and 4, and then 200 mg every 2 weeks thereafter through week 52.

The findings are notable because patients with axSpA – including radiographic disease and nr-axSpA – often experience delays in diagnosis, which can lead to a delay in treatment and a reduced quality of life because of the back pain, fatigue, and morning stiffness that commonly occur with the disease.

“Women, especially, with axial spondyloarthritis experience a longer delay in diagnosis than do male patients,” Dr. Kay noted.

The findings of this post hoc analysis underscore the risks associated with such a delay. “These results imply that early diagnosis enabling earlier treatment is important for patients with nonradiographic axSpA, as it is for patients with radiographic axSpA,” he concluded.

The C-VIEW and C-axSpAnd studies were funded by UCB. Dr. van der Horst-Bruinsma reported receiving honoraria, consulting fees, and/or research grants from UCB as well as from AbbVie, Bristol-Myers Squibb, Merck, Novartis, and Pfizer. Dr. Kay reported receiving grant/research support from Gilead, Pfizer, and UCB, and consulting fees from AbbVie, Alvotech, Boehringer Ingelheim, Celltrion, Merck, Novartis, Samsung Bioepis, Sandoz, and UCB.

[email protected]

SOURCES: van der Horst-Bruinsma I et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 935; Kay J et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 936.

ATLANTA – Certolizumab pegol, a PEGylated, monoclonal, anti–tumor necrosis factor antibody, reduces recurrent acute anterior uveitis flares and improves disease activity in patients with axial spondyloarthritis, according to findings from the open-label, 96-week, phase 4 C-VIEW study.

Sharon Worcester/MDedge News

When given earlier in the course of disease, the treatment, which is the only Food and Drug Administration–approved tumor necrosis factor inhibitor (TNFi) for the treatment of nonradiographic axial spondyloarthritis (nr-axSpA), also shortens symptom duration, a post hoc analysis of data from the multicenter, phase 3 C-axSpAnd study suggests. The findings from both studies were presented during a session at the annual meeting of the American College of Rheumatology.
 

C-VIEW

In 85 patients with active axSpA who completed 48 weeks of certolizumab pegol therapy in the C-VIEW study, the acute anterior uveitis (AAU) flare incidence over 48 weeks was a mean of 0.2, compared with 1.5 flares per person in the 48 weeks prior to treatment initiation, reported Irene E. van der Horst-Bruinsma, MD, PhD, of Amsterdam University Medical Center. The comparison was adjusted for possible within-patient correlations, flare period (pre- and post baseline), and axSpA disease duration.

This finding, from a preplanned interim analysis, represented a flare incidence of 18.7 versus 146.6 per 100 patient-years, during treatment versus prior to treatment – an 87% reduction – and the difference was statistically significant (P less than .001), Dr. van der Horst-Bruinsma said.

The percentage of patients experiencing one flare was 12.4% during therapy, compared with 64% prior to therapy, and the percentage experiencing two or more flares was 2.2% versus 24.7%, respectively, she said, adding that, in the 13 patients who experienced flares both before and during treatment, the mean flare duration was reduced during treatment (58.4 vs. 97.4 days). A comparison of radiographic and nr-axSpA patients showed similar reductions in flares during versus prior to treatment, going from 144.5 to 19.0 flares per 100 patient-years with radiographic disease and from 158.9 to 17.2 flares per 100 patient-years in nr-axSpA.

Furthermore, after 48 weeks of treatment, disease activity had improved substantially, with mean Ankylosing Spondylitis Disease Activity Score (ASDAS) improving from 3.5 to 2.0 at week 48, 94.2% of patients reaching ASDAS clinical improvement at week 48, and mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score decreasing significantly from 6.5 to 3.3 at week 48.

“ASDAS 20 was reached by 75% of the patients, the ASDAS 40 by 54%, and the ASDAS partial remission criteria were reached by 31% of the patients,” she said.

Study participants were adults with a mean age of 46.5 years and active disease according to Assessment of Spondyloarthritis International Society (ASAS) criteria and a history of recurrent AAU flares (either two or more in total, or one or more in the year prior to study entry). They were HLA-B27 positive, eligible for anti-TNF therapy because they had an inadequate response (or contraindication) to at least two prior NSAIDs, were biologic naive, or had failed to respond to no more than one prior anti-TNF agent. Both radiographic and nr-axSpA patients were included, and of 115 who enrolled, 89 initiated treatment, including 76 with radiographic disease and 13 with nonradiographic disease; 85 completed week 48 of treatment.

Certolizumab pegol was given at a loading dose of 400 mg at weeks 0, 2, and 4, followed by 200 mg every 2 weeks through week 96, and was well tolerated. No new safety signals were identified, Dr. van der Horst-Bruinsma said.

“We know that acute anterior uveitis, an inflammation of ... the uveal tract, is the most common extra-articular manifestation in axial spondyloarthritis,” she said. “It is reported in up to 40% of patients and is associated with significant clinical burden.”

AAU is also strongly associated with the HLA-B27 antigen, therefore patients who do not have ankylosing spondylitis but who are HLA-B27 positive also are at risk, she said, noting that previous studies have shown that TNF inhibitors reduce the incidence of AAU flares in patients with radiographic axSpA (ankylosing spondylitis), but that data in nr-axSpA are scarce.

The aim of C-VIEW was to analyze the impact of certolizumab pegol treatment on AAU flares in patients with active radiographic or nr-axSpA and a recent history of AAU, she said.

“C-VIEW was the first study to examine the impact of certolizumab on the incidence of acute anterior uveitis flares in HLA-B27-positive patients with a recent history of acute anterior uveitis, including patients with nr-axSpA ... and in conclusion we can say that these results indicate that certolizumab is a suitable treatment option for patients with axSpA and a history of recurrent acute anterior uveitis,” she said.

C-axSpAnd

In the pivotal 3-year C-axSpAnd study, which included a 52‑week, double-blind, placebo-controlled period, 159 patients with active nr-axSpA, objective signs of inflammation, and previous failure of at least two NSAIDS were treated with certolizumab pegol, and 158 similar patients received placebo. Both groups received nonbiologic background medication.

The results of the trial, published in Arthritis & Rheumatology in March 2019, showed that adding certolizumab pegol to background medication is superior to adding placebo in patients with active nr-axSpA and led to its FDA approval for axSpA in March 2019, but the effects of symptom duration on outcomes with certolizumab pegol have not been well studied, Jonathan Kay, MD, said at the ACR meeting.

The current post hoc analysis stratified patients based on symptom duration and showed that certolizumab pegol recipients with less than 5 years of symptoms at baseline had improved outcomes at weeks 12 and 52, compared with those who had 5 or more years of symptoms at baseline, said Dr. Kay of UMass Memorial Medical Center and the University of Massachusetts, Worcester.

For example, major improvement in ASDAS at week 52, the primary outcome measure, was achieved by 55% of 80 patients with shorter symptom duration, compared with 39.2% of 79 patients with longer symptom duration, and the ASAS 40 responder rates in the groups, respectively, were 58.5% and 36.7% at 12 weeks and 65% and 48.1% at 52 weeks, he said.

Certolizumab pegol recipients with shorter symptom duration also had greater improvement in BASDAI score, nocturnal spinal pain, fatigue, morning stiffness, and the 36-item Short Form Survey physical component score, he noted.

Using a cutoff of 3 years rather than 5 years, responder rates for major improvement in ASDAS and ASAS 40 were still greater in certolizumab pegol–treated patients with shorter symptom duration: At 52 weeks, 56.4% of 55 patients with less than 3 years of symptoms, compared with 42.3% of 104 with 3 or more years of symptoms, achieved major improvement in ASDAS, and ASAS 40 responder rates were 65.5%, compared with 51.9%, respectively.

Response rates in the placebo arm were low, compared with both certolizumab pegol groups, and no consistent trend in outcomes was observed based on symptom duration in that arm, Dr. Kay noted.

Study subjects were adults with a diagnosis of axSpA, active disease, fulfillment of ASAS classification criteria, and at least 12 months of inflammatory back pain. The trial excluded those with radiographic sacroiliitis meeting the modified New York classification criteria and who had exposure to more than one TNFi prior to baseline or primary failure of any TNFi. As in the C-VIEW study, participants were randomized to receive 400 mg certolizumab pegol at weeks 0, 2, and 4, and then 200 mg every 2 weeks thereafter through week 52.

The findings are notable because patients with axSpA – including radiographic disease and nr-axSpA – often experience delays in diagnosis, which can lead to a delay in treatment and a reduced quality of life because of the back pain, fatigue, and morning stiffness that commonly occur with the disease.

“Women, especially, with axial spondyloarthritis experience a longer delay in diagnosis than do male patients,” Dr. Kay noted.

The findings of this post hoc analysis underscore the risks associated with such a delay. “These results imply that early diagnosis enabling earlier treatment is important for patients with nonradiographic axSpA, as it is for patients with radiographic axSpA,” he concluded.

The C-VIEW and C-axSpAnd studies were funded by UCB. Dr. van der Horst-Bruinsma reported receiving honoraria, consulting fees, and/or research grants from UCB as well as from AbbVie, Bristol-Myers Squibb, Merck, Novartis, and Pfizer. Dr. Kay reported receiving grant/research support from Gilead, Pfizer, and UCB, and consulting fees from AbbVie, Alvotech, Boehringer Ingelheim, Celltrion, Merck, Novartis, Samsung Bioepis, Sandoz, and UCB.

[email protected]

SOURCES: van der Horst-Bruinsma I et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 935; Kay J et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 936.

ATLANTA – Anifrolumab, a human monoclonal antibody that binds the type I interferon receptor subunit 1, was well tolerated and provided clinical benefit in patients with moderate to severe systemic lupus erythematosus (SLE) in the global, phase 3 TULIP-1 and -2 trials.

Sharon Worcester/MDedge News

In TULIP-1, which compared intravenous anifrolumab at doses of 300 or 150 mg and placebo given every 4 weeks for 48 weeks, the primary endpoint of SLE Responder Index (SRI) in the 300 mg versus the placebo group was not met, but in post hoc analyses, numeric improvements at thresholds associated with clinical benefit were observed for several secondary outcomes, Richard A. Furie, MD, a professor of medicine at the Hofstra University/Northwell, Hempstead, N.Y., reported during a plenary session at the annual meeting of the American College of Rheumatology.

The findings were published online Nov. 11 in Lancet Rheumatology.

TULIP-2 compared IV anifrolumab at a dose of 300 mg versus placebo every 4 weeks for 48 weeks and demonstrated the superiority of anifrolumab for multiple efficacy endpoints, including the primary study endpoint of British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA), Eric F. Morand, MD, PhD, reported during a late-breaking abstract session at the meeting.

The double-blind, phase 3 TULIP trials each enrolled seropositive SLE patients with moderate to severe active disease despite standard-of-care therapy (SOC). All patients met ACR criteria, had a SLE Disease Activity Index (SLEDAI)-2K of 6 or greater, and BILAG index scoring showing one or more organ systems with grade A involvement or two or more with grade B. Both trials required stable SOC therapy throughout the study except for mandatory attempts at oral corticosteroid (OCS) tapering for patients who were receiving 10 mg/day or more of prednisone or its equivalent at study entry.

The trials followed a phase 2 trial, reported by Dr. Furie at the 2015 ACR meeting and published in Arthritis & Rheumatology in 2017, which showed “very robust” efficacy of anifrolumab in this setting.

“The burning question for the last 20 years has been, ‘Can type 1 interferon inhibitors actually reduce lupus clinical activity?’ ” Dr. Furie said. “The problem here [is that] you can inhibit interferon-alpha, but there are four other subtypes capable of binding to the interferon receptor.”

Anifrolumab, which was first studied in scleroderma, inhibits the interferon (IFN) receptor, thereby providing broader inhibition than strategies that specifically target interferon-alpha, he explained.

In the phase 2 trial, the primary composite endpoint of SRI response at day 169 and sustained reduction of OCS dose between days 85 and 169 was met by 51.5% of patients receiving 300 mg of anifrolumab versus 26.6% of those receiving placebo.

TULIP-1

The TULIP-1 trial, however, failed to show a significant difference in the primary endpoint of week 52 SRI, although initial analyses showed some numeric benefit with respect to BICLA, OCS dose reductions, and other organ-specific endpoints.

The percentage of SRI responders at week 52 in the double-blind trial was 36.2% in 180 patients who received 300 mg anifrolumab vs. 40.4% in 184 who received placebo (nominal P value = .41), and in a subgroup of patients who had high IFN gene signature (IFNGS) test results, the rates were 35.9% and 39.3% (nominal P value = 0.55), respectively.

Sustained OCS reduction to 7.5 mg/day or less occurred in 41% of anifrolumab and 32.1% of placebo group patients, and a 50% or greater reduction in Cutaneous Lupus Erythematosus Disease Activity Severity Index (CLASI) activity from baseline to week 12 occurred in 41.9% and 24.9%, respectively. The annualized flare rate to week 52 was 0.72 for anifrolumab and 0.60 for placebo.

BICLA response at week 52 was 37.1% with anifrolumab versus 27% with placebo, and a 50% or greater reduction in active joints from baseline to week 52 occurred in 47% versus 32.5% of patients in the groups, respectively.

The 150-mg dose, which was included to provide dose-response data, did not show efficacy in secondary outcomes.

“We see a delta of about 10 percentage points [for BICLA], and about a 15-percentage point change [in swollen and tender joint count] in favor of anifrolumab,” Dr. Furie said. “So why the big difference between phase 2 results and phase 3 results? Well, that led to a year-long interrogation of all the data ... [which revealed that] about 8% of patients were misclassified as nonresponders for [NSAID] use.”

The medication rules in the study automatically required any patient who used a restricted drug, including NSAIDs, to be classified as a nonresponder. That means a patient who took an NSAID for a headache at the beginning of the study, for example, would have been considered a nonresponder regardless of their outcome, he explained.

“This led to a review of all the restricted medication classification rules, and after unblinding, a meeting was convened with SLE experts and the sponsors to actually revise the medication rules just to make them clinically more appropriate. The key analyses were repeated post hoc,” he said.

The difference between the treatment and placebo groups in terms of the week 52 SRI didn’t change much in the post hoc analysis (46.9% vs. 43% of treatment and placebo patients, respectively, met the endpoint). Similarly, SRI rates in the IFNGS test–high subgroup were 48.2% and 41.8%, respectively.

However, more pronounced “shifts to the right,” indicating larger differences favoring anifrolumab over placebo, were seen for OCS dose reduction (48.8% vs. 32.1%), CLASI response (43.6% vs. 24.9%), and BICLA response (48.1% vs. 29.8%).

“For BICLA response, we see a fairly significant change ... with what appears to be a clinically significant delta (about 16 percentage points), and as far as the change in active joints, also very significant in my eyes,” he said.

Also of note, the time to BICLA response sustained to week 52 was improved with anifrolumab (hazard ratio, 1.93), and CLASI response differences emerged early, at about 12 weeks, he said.

The type 1 IFNGS was reduced by a median of 88% to 90% in the anifrolumab groups vs. with placebo, and modest changes in serologies were also noted.

Serious adverse events occurred in 13.9% and 10.8% of patients in the anifrolumab 300- and 150-mg arms, compared with 16.3% in the placebo arm. Herpes zoster was more common in the anifrolumab groups (5.6% for 300 mg and 5.4% for 150 mg vs. 1.6% for placebo).

“But other than that, no major standouts as far as the safety profile,” Dr. Furie said.

The findings, particularly after the medication rules were amended, suggest efficacy of anifrolumab for corticosteroid reductions, skin activity, BICLA, and joint scores, he said, noting that corticosteroid dose reductions are very important for patients, and that BICLA is “actually a very rigorous composite.”

Importantly, the findings also underscore the importance and impact of medication rules, and the critical role that endpoint selection plays in SLE trials.

“We’ve been seeing discordance lately between the SRI and BICLA ... so [there is] still a lot to learn,” he said. “And I think it’s important in evaluating the drug effect to look at the totality of the data.”

TULIP-2

BICLA response, the primary endpoint of TULIP-2, was achieved by 47.8% of 180 patients who received anifrolumab, compared with 31.5% of 182 who received placebo, said Dr. Morand, professor and head of the School of Clinical Sciences at Monash University, Melbourne.

“The effect size was 16.3 percentage points with an adjusted p value of 0.001. Therefore, the primary outcome of this trial was attained,” said Dr. Morand, who also is head of the Monash Health Rheumatology Unit. “Separation between the treatment arms occurred early and was maintained across the progression of the trial.”

Anifrolumab was also superior to placebo for key secondary endpoints, including OCS dose reduction to 7.5 mg/day or less (51.5% vs. 30.2%) and CLASI response (49.0% vs. 25.0%).

“Joint responses did not show a significant difference between the anifrolumab and placebo arms,” he said, adding that the annualized flare rate also did not differ significantly between the groups, but was numerically lower in anifrolumab-treated patients (0.43 vs. 0.64; rate ratio, 0.67; P = .081).

Numeric differences also favored anifrolumab for multiple secondary endpoints, including SRI responses, time to onset of BICLA-sustained response, and time to first flare, he noted.

Further, in patients with high baseline IFNGS, anifrolumab induced neutralization of IFNGS by week 12, with a median suppression of 88.0%, which persisted for the duration of the study; no such effect was seen in the placebo arm.

Serum anti–double stranded DNA also trended toward normalization with anifrolumab.

The safety profile of anifrolumab was similar to that seen in previous trials, including TULIP-1, with herpes zoster occurring more often in those receiving anifrolumab (7.2% vs. 1.1% in the placebo group), Dr. Morand said, noting that “all herpes zoster episodes were cutaneous, all responded to antiviral therapy, and none required [treatment] discontinuation.”

Serious adverse events, including pneumonia and SLE worsening, occurred less frequently in the anifrolumab arm (8.3% vs. 17.0%, respectively), as did adverse events leading to treatment discontinuation (2.8% and 7.1%). One death occurred in the anifrolumab group from community-acquired pneumonia, and few patients (0.6%) developed antidrug antibodies.

No new safety signals were identified, he said, noting that “the findings add to cumulative evidence identifying anifrolumab as a potential new treatment option for SLE.”

“In conclusion, TULIP-2 was a positive phase 3 trial in lupus, and there aren’t many times that that sentence has been spoken,” he said.

The TULIP-1 and -2 trials were sponsored by AstraZeneca. Dr. Furie And Dr. Morand both reported grant/research support and consulting fees from AstraZeneca, as well as speaker’s bureau participation for AstraZeneca.

[email protected]

SOURCES: Furie RA et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1763; Morand EF et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract L17.
 

ATLANTA – Anifrolumab, a human monoclonal antibody that binds the type I interferon receptor subunit 1, was well tolerated and provided clinical benefit in patients with moderate to severe systemic lupus erythematosus (SLE) in the global, phase 3 TULIP-1 and -2 trials.

Sharon Worcester/MDedge News

In TULIP-1, which compared intravenous anifrolumab at doses of 300 or 150 mg and placebo given every 4 weeks for 48 weeks, the primary endpoint of SLE Responder Index (SRI) in the 300 mg versus the placebo group was not met, but in post hoc analyses, numeric improvements at thresholds associated with clinical benefit were observed for several secondary outcomes, Richard A. Furie, MD, a professor of medicine at the Hofstra University/Northwell, Hempstead, N.Y., reported during a plenary session at the annual meeting of the American College of Rheumatology.

The findings were published online Nov. 11 in Lancet Rheumatology.

TULIP-2 compared IV anifrolumab at a dose of 300 mg versus placebo every 4 weeks for 48 weeks and demonstrated the superiority of anifrolumab for multiple efficacy endpoints, including the primary study endpoint of British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA), Eric F. Morand, MD, PhD, reported during a late-breaking abstract session at the meeting.

The double-blind, phase 3 TULIP trials each enrolled seropositive SLE patients with moderate to severe active disease despite standard-of-care therapy (SOC). All patients met ACR criteria, had a SLE Disease Activity Index (SLEDAI)-2K of 6 or greater, and BILAG index scoring showing one or more organ systems with grade A involvement or two or more with grade B. Both trials required stable SOC therapy throughout the study except for mandatory attempts at oral corticosteroid (OCS) tapering for patients who were receiving 10 mg/day or more of prednisone or its equivalent at study entry.

The trials followed a phase 2 trial, reported by Dr. Furie at the 2015 ACR meeting and published in Arthritis & Rheumatology in 2017, which showed “very robust” efficacy of anifrolumab in this setting.

“The burning question for the last 20 years has been, ‘Can type 1 interferon inhibitors actually reduce lupus clinical activity?’ ” Dr. Furie said. “The problem here [is that] you can inhibit interferon-alpha, but there are four other subtypes capable of binding to the interferon receptor.”

Anifrolumab, which was first studied in scleroderma, inhibits the interferon (IFN) receptor, thereby providing broader inhibition than strategies that specifically target interferon-alpha, he explained.

In the phase 2 trial, the primary composite endpoint of SRI response at day 169 and sustained reduction of OCS dose between days 85 and 169 was met by 51.5% of patients receiving 300 mg of anifrolumab versus 26.6% of those receiving placebo.

TULIP-1

The TULIP-1 trial, however, failed to show a significant difference in the primary endpoint of week 52 SRI, although initial analyses showed some numeric benefit with respect to BICLA, OCS dose reductions, and other organ-specific endpoints.

The percentage of SRI responders at week 52 in the double-blind trial was 36.2% in 180 patients who received 300 mg anifrolumab vs. 40.4% in 184 who received placebo (nominal P value = .41), and in a subgroup of patients who had high IFN gene signature (IFNGS) test results, the rates were 35.9% and 39.3% (nominal P value = 0.55), respectively.

Sustained OCS reduction to 7.5 mg/day or less occurred in 41% of anifrolumab and 32.1% of placebo group patients, and a 50% or greater reduction in Cutaneous Lupus Erythematosus Disease Activity Severity Index (CLASI) activity from baseline to week 12 occurred in 41.9% and 24.9%, respectively. The annualized flare rate to week 52 was 0.72 for anifrolumab and 0.60 for placebo.

BICLA response at week 52 was 37.1% with anifrolumab versus 27% with placebo, and a 50% or greater reduction in active joints from baseline to week 52 occurred in 47% versus 32.5% of patients in the groups, respectively.

The 150-mg dose, which was included to provide dose-response data, did not show efficacy in secondary outcomes.

“We see a delta of about 10 percentage points [for BICLA], and about a 15-percentage point change [in swollen and tender joint count] in favor of anifrolumab,” Dr. Furie said. “So why the big difference between phase 2 results and phase 3 results? Well, that led to a year-long interrogation of all the data ... [which revealed that] about 8% of patients were misclassified as nonresponders for [NSAID] use.”

The medication rules in the study automatically required any patient who used a restricted drug, including NSAIDs, to be classified as a nonresponder. That means a patient who took an NSAID for a headache at the beginning of the study, for example, would have been considered a nonresponder regardless of their outcome, he explained.

“This led to a review of all the restricted medication classification rules, and after unblinding, a meeting was convened with SLE experts and the sponsors to actually revise the medication rules just to make them clinically more appropriate. The key analyses were repeated post hoc,” he said.

The difference between the treatment and placebo groups in terms of the week 52 SRI didn’t change much in the post hoc analysis (46.9% vs. 43% of treatment and placebo patients, respectively, met the endpoint). Similarly, SRI rates in the IFNGS test–high subgroup were 48.2% and 41.8%, respectively.

However, more pronounced “shifts to the right,” indicating larger differences favoring anifrolumab over placebo, were seen for OCS dose reduction (48.8% vs. 32.1%), CLASI response (43.6% vs. 24.9%), and BICLA response (48.1% vs. 29.8%).

“For BICLA response, we see a fairly significant change ... with what appears to be a clinically significant delta (about 16 percentage points), and as far as the change in active joints, also very significant in my eyes,” he said.

Also of note, the time to BICLA response sustained to week 52 was improved with anifrolumab (hazard ratio, 1.93), and CLASI response differences emerged early, at about 12 weeks, he said.

The type 1 IFNGS was reduced by a median of 88% to 90% in the anifrolumab groups vs. with placebo, and modest changes in serologies were also noted.

Serious adverse events occurred in 13.9% and 10.8% of patients in the anifrolumab 300- and 150-mg arms, compared with 16.3% in the placebo arm. Herpes zoster was more common in the anifrolumab groups (5.6% for 300 mg and 5.4% for 150 mg vs. 1.6% for placebo).

“But other than that, no major standouts as far as the safety profile,” Dr. Furie said.

The findings, particularly after the medication rules were amended, suggest efficacy of anifrolumab for corticosteroid reductions, skin activity, BICLA, and joint scores, he said, noting that corticosteroid dose reductions are very important for patients, and that BICLA is “actually a very rigorous composite.”

Importantly, the findings also underscore the importance and impact of medication rules, and the critical role that endpoint selection plays in SLE trials.

“We’ve been seeing discordance lately between the SRI and BICLA ... so [there is] still a lot to learn,” he said. “And I think it’s important in evaluating the drug effect to look at the totality of the data.”

TULIP-2

BICLA response, the primary endpoint of TULIP-2, was achieved by 47.8% of 180 patients who received anifrolumab, compared with 31.5% of 182 who received placebo, said Dr. Morand, professor and head of the School of Clinical Sciences at Monash University, Melbourne.

“The effect size was 16.3 percentage points with an adjusted p value of 0.001. Therefore, the primary outcome of this trial was attained,” said Dr. Morand, who also is head of the Monash Health Rheumatology Unit. “Separation between the treatment arms occurred early and was maintained across the progression of the trial.”

Anifrolumab was also superior to placebo for key secondary endpoints, including OCS dose reduction to 7.5 mg/day or less (51.5% vs. 30.2%) and CLASI response (49.0% vs. 25.0%).

“Joint responses did not show a significant difference between the anifrolumab and placebo arms,” he said, adding that the annualized flare rate also did not differ significantly between the groups, but was numerically lower in anifrolumab-treated patients (0.43 vs. 0.64; rate ratio, 0.67; P = .081).

Numeric differences also favored anifrolumab for multiple secondary endpoints, including SRI responses, time to onset of BICLA-sustained response, and time to first flare, he noted.

Further, in patients with high baseline IFNGS, anifrolumab induced neutralization of IFNGS by week 12, with a median suppression of 88.0%, which persisted for the duration of the study; no such effect was seen in the placebo arm.

Serum anti–double stranded DNA also trended toward normalization with anifrolumab.

The safety profile of anifrolumab was similar to that seen in previous trials, including TULIP-1, with herpes zoster occurring more often in those receiving anifrolumab (7.2% vs. 1.1% in the placebo group), Dr. Morand said, noting that “all herpes zoster episodes were cutaneous, all responded to antiviral therapy, and none required [treatment] discontinuation.”

Serious adverse events, including pneumonia and SLE worsening, occurred less frequently in the anifrolumab arm (8.3% vs. 17.0%, respectively), as did adverse events leading to treatment discontinuation (2.8% and 7.1%). One death occurred in the anifrolumab group from community-acquired pneumonia, and few patients (0.6%) developed antidrug antibodies.

No new safety signals were identified, he said, noting that “the findings add to cumulative evidence identifying anifrolumab as a potential new treatment option for SLE.”

“In conclusion, TULIP-2 was a positive phase 3 trial in lupus, and there aren’t many times that that sentence has been spoken,” he said.

The TULIP-1 and -2 trials were sponsored by AstraZeneca. Dr. Furie And Dr. Morand both reported grant/research support and consulting fees from AstraZeneca, as well as speaker’s bureau participation for AstraZeneca.

[email protected]

SOURCES: Furie RA et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1763; Morand EF et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract L17.
 

ATLANTA – Anifrolumab, a human monoclonal antibody that binds the type I interferon receptor subunit 1, was well tolerated and provided clinical benefit in patients with moderate to severe systemic lupus erythematosus (SLE) in the global, phase 3 TULIP-1 and -2 trials.

Sharon Worcester/MDedge News

In TULIP-1, which compared intravenous anifrolumab at doses of 300 or 150 mg and placebo given every 4 weeks for 48 weeks, the primary endpoint of SLE Responder Index (SRI) in the 300 mg versus the placebo group was not met, but in post hoc analyses, numeric improvements at thresholds associated with clinical benefit were observed for several secondary outcomes, Richard A. Furie, MD, a professor of medicine at the Hofstra University/Northwell, Hempstead, N.Y., reported during a plenary session at the annual meeting of the American College of Rheumatology.

The findings were published online Nov. 11 in Lancet Rheumatology.

TULIP-2 compared IV anifrolumab at a dose of 300 mg versus placebo every 4 weeks for 48 weeks and demonstrated the superiority of anifrolumab for multiple efficacy endpoints, including the primary study endpoint of British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA), Eric F. Morand, MD, PhD, reported during a late-breaking abstract session at the meeting.

The double-blind, phase 3 TULIP trials each enrolled seropositive SLE patients with moderate to severe active disease despite standard-of-care therapy (SOC). All patients met ACR criteria, had a SLE Disease Activity Index (SLEDAI)-2K of 6 or greater, and BILAG index scoring showing one or more organ systems with grade A involvement or two or more with grade B. Both trials required stable SOC therapy throughout the study except for mandatory attempts at oral corticosteroid (OCS) tapering for patients who were receiving 10 mg/day or more of prednisone or its equivalent at study entry.

The trials followed a phase 2 trial, reported by Dr. Furie at the 2015 ACR meeting and published in Arthritis & Rheumatology in 2017, which showed “very robust” efficacy of anifrolumab in this setting.

“The burning question for the last 20 years has been, ‘Can type 1 interferon inhibitors actually reduce lupus clinical activity?’ ” Dr. Furie said. “The problem here [is that] you can inhibit interferon-alpha, but there are four other subtypes capable of binding to the interferon receptor.”

Anifrolumab, which was first studied in scleroderma, inhibits the interferon (IFN) receptor, thereby providing broader inhibition than strategies that specifically target interferon-alpha, he explained.

In the phase 2 trial, the primary composite endpoint of SRI response at day 169 and sustained reduction of OCS dose between days 85 and 169 was met by 51.5% of patients receiving 300 mg of anifrolumab versus 26.6% of those receiving placebo.

TULIP-1

The TULIP-1 trial, however, failed to show a significant difference in the primary endpoint of week 52 SRI, although initial analyses showed some numeric benefit with respect to BICLA, OCS dose reductions, and other organ-specific endpoints.

The percentage of SRI responders at week 52 in the double-blind trial was 36.2% in 180 patients who received 300 mg anifrolumab vs. 40.4% in 184 who received placebo (nominal P value = .41), and in a subgroup of patients who had high IFN gene signature (IFNGS) test results, the rates were 35.9% and 39.3% (nominal P value = 0.55), respectively.

Sustained OCS reduction to 7.5 mg/day or less occurred in 41% of anifrolumab and 32.1% of placebo group patients, and a 50% or greater reduction in Cutaneous Lupus Erythematosus Disease Activity Severity Index (CLASI) activity from baseline to week 12 occurred in 41.9% and 24.9%, respectively. The annualized flare rate to week 52 was 0.72 for anifrolumab and 0.60 for placebo.

BICLA response at week 52 was 37.1% with anifrolumab versus 27% with placebo, and a 50% or greater reduction in active joints from baseline to week 52 occurred in 47% versus 32.5% of patients in the groups, respectively.

The 150-mg dose, which was included to provide dose-response data, did not show efficacy in secondary outcomes.

“We see a delta of about 10 percentage points [for BICLA], and about a 15-percentage point change [in swollen and tender joint count] in favor of anifrolumab,” Dr. Furie said. “So why the big difference between phase 2 results and phase 3 results? Well, that led to a year-long interrogation of all the data ... [which revealed that] about 8% of patients were misclassified as nonresponders for [NSAID] use.”

The medication rules in the study automatically required any patient who used a restricted drug, including NSAIDs, to be classified as a nonresponder. That means a patient who took an NSAID for a headache at the beginning of the study, for example, would have been considered a nonresponder regardless of their outcome, he explained.

“This led to a review of all the restricted medication classification rules, and after unblinding, a meeting was convened with SLE experts and the sponsors to actually revise the medication rules just to make them clinically more appropriate. The key analyses were repeated post hoc,” he said.

The difference between the treatment and placebo groups in terms of the week 52 SRI didn’t change much in the post hoc analysis (46.9% vs. 43% of treatment and placebo patients, respectively, met the endpoint). Similarly, SRI rates in the IFNGS test–high subgroup were 48.2% and 41.8%, respectively.

However, more pronounced “shifts to the right,” indicating larger differences favoring anifrolumab over placebo, were seen for OCS dose reduction (48.8% vs. 32.1%), CLASI response (43.6% vs. 24.9%), and BICLA response (48.1% vs. 29.8%).

“For BICLA response, we see a fairly significant change ... with what appears to be a clinically significant delta (about 16 percentage points), and as far as the change in active joints, also very significant in my eyes,” he said.

Also of note, the time to BICLA response sustained to week 52 was improved with anifrolumab (hazard ratio, 1.93), and CLASI response differences emerged early, at about 12 weeks, he said.

The type 1 IFNGS was reduced by a median of 88% to 90% in the anifrolumab groups vs. with placebo, and modest changes in serologies were also noted.

Serious adverse events occurred in 13.9% and 10.8% of patients in the anifrolumab 300- and 150-mg arms, compared with 16.3% in the placebo arm. Herpes zoster was more common in the anifrolumab groups (5.6% for 300 mg and 5.4% for 150 mg vs. 1.6% for placebo).

“But other than that, no major standouts as far as the safety profile,” Dr. Furie said.

The findings, particularly after the medication rules were amended, suggest efficacy of anifrolumab for corticosteroid reductions, skin activity, BICLA, and joint scores, he said, noting that corticosteroid dose reductions are very important for patients, and that BICLA is “actually a very rigorous composite.”

Importantly, the findings also underscore the importance and impact of medication rules, and the critical role that endpoint selection plays in SLE trials.

“We’ve been seeing discordance lately between the SRI and BICLA ... so [there is] still a lot to learn,” he said. “And I think it’s important in evaluating the drug effect to look at the totality of the data.”

TULIP-2

BICLA response, the primary endpoint of TULIP-2, was achieved by 47.8% of 180 patients who received anifrolumab, compared with 31.5% of 182 who received placebo, said Dr. Morand, professor and head of the School of Clinical Sciences at Monash University, Melbourne.

“The effect size was 16.3 percentage points with an adjusted p value of 0.001. Therefore, the primary outcome of this trial was attained,” said Dr. Morand, who also is head of the Monash Health Rheumatology Unit. “Separation between the treatment arms occurred early and was maintained across the progression of the trial.”

Anifrolumab was also superior to placebo for key secondary endpoints, including OCS dose reduction to 7.5 mg/day or less (51.5% vs. 30.2%) and CLASI response (49.0% vs. 25.0%).

“Joint responses did not show a significant difference between the anifrolumab and placebo arms,” he said, adding that the annualized flare rate also did not differ significantly between the groups, but was numerically lower in anifrolumab-treated patients (0.43 vs. 0.64; rate ratio, 0.67; P = .081).

Numeric differences also favored anifrolumab for multiple secondary endpoints, including SRI responses, time to onset of BICLA-sustained response, and time to first flare, he noted.

Further, in patients with high baseline IFNGS, anifrolumab induced neutralization of IFNGS by week 12, with a median suppression of 88.0%, which persisted for the duration of the study; no such effect was seen in the placebo arm.

Serum anti–double stranded DNA also trended toward normalization with anifrolumab.

The safety profile of anifrolumab was similar to that seen in previous trials, including TULIP-1, with herpes zoster occurring more often in those receiving anifrolumab (7.2% vs. 1.1% in the placebo group), Dr. Morand said, noting that “all herpes zoster episodes were cutaneous, all responded to antiviral therapy, and none required [treatment] discontinuation.”

Serious adverse events, including pneumonia and SLE worsening, occurred less frequently in the anifrolumab arm (8.3% vs. 17.0%, respectively), as did adverse events leading to treatment discontinuation (2.8% and 7.1%). One death occurred in the anifrolumab group from community-acquired pneumonia, and few patients (0.6%) developed antidrug antibodies.

No new safety signals were identified, he said, noting that “the findings add to cumulative evidence identifying anifrolumab as a potential new treatment option for SLE.”

“In conclusion, TULIP-2 was a positive phase 3 trial in lupus, and there aren’t many times that that sentence has been spoken,” he said.

The TULIP-1 and -2 trials were sponsored by AstraZeneca. Dr. Furie And Dr. Morand both reported grant/research support and consulting fees from AstraZeneca, as well as speaker’s bureau participation for AstraZeneca.

[email protected]

SOURCES: Furie RA et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1763; Morand EF et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract L17.
 

Whether patients aged 50 years and older with a displaced femoral neck fracture underwent total hip arthroplasty or hemiarthroplasty had no significant influence on the risk of unplanned secondary hip procedures over 2 years of follow-up. In addition, while functional outcomes modestly favored total hip arthroplasty, the rates of mortality and serious adverse events were similar between the two treatment groups.

Those are key findings from a randomized, multicenter trial of the two procedures that was carried out in 10 countries.

“The American Academy of Orthopedic Surgeons and National Institute for Health and Care Excellence guidelines recommend total hip arthroplasty in all patients with displaced femoral neck fractures who are able to ambulate independently,” a team of investigators led by Mohit Bhandari, MD, and P.J. Devereaux, MD, both from McMaster University, Hamilton, Ont., wrote in a study published in the New England Journal of Medicine. “Our findings suggest that the advantages of total hip arthroplasty may not be compelling. The limited advantages of total hip arthroplasty, as well as the possible higher risk of complications, may be particularly important in regions of the world where total hip arthroplasty is not easily accessible or is cost prohibitive.”

In the Hip Fracture Evaluation With Alternative of Total Hip Arthroplasty Versus Hemiarthroplasty (HEALTH) trial, the researchers randomly assigned 1,495 patients aged 50 years and older who had a displaced femoral neck fracture to undergo either total hip arthroplasty or hemiarthroplasty. They were eligible for the trial only if they had been able to ambulate without the assistance of another person before the hip fracture occurred. The primary endpoint was any unplanned secondary hip procedure within 24 months after the initial surgery. Secondary endpoints included death, serious adverse events, hip-related complications, health-related quality of life, function, and overall health measures. Assessments included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score, pain score, stiffness score, and function score; the European Quality of Life–5 Dimensions utility index score and visual analogue scale; the 12-Item Short Form General Health Survey physical and mental component summary scores; and the Timed Up and Go scores.

The researchers found that the primary endpoint occurred in 7.9% of patients who had been randomly assigned to total hip arthroplasty and in 8.3% of those who had been randomly assigned to hemiarthroplasty (hazard ratio, 0.95; P = .79). As for secondary endpoints, mortality did not differ significantly between the two treatment groups (14.3% in the total hip arthroplasty group vs. 13.1% in the hemiarthroplasty group; P = .48), while serious adverse events occurred in 41.8% of patients in the total hip arthroplasty group versus 36.7% of those in the hemiarthroplasty group (HR, 1.16; P = .13).

In other findings, hip instability or dislocation occurred in 4.7% of patients who were assigned to total hip arthroplasty, compared with 2.4% of those who were assigned to hemiarthroplasty (HR, 2.00), while patients who underwent total hip arthroplasty had superior function as measured by the WOMAC total score, pain score, stiffness score, and function score. “These differences between the treatment groups fell below the threshold for a minimal clinically important difference for WOMAC,” the researchers wrote.

They acknowledged certain limitations of the study, including the fact that patients and endpoint assessors were unblinded in the assessments of function, “which left a possibility of bias.” In addition, 14.9% of patients were lost to follow-up for analysis of the primary endpoint.

In an accompanying editorial, Jan-Erik Gjertsen, MD, wrote that one implication of the HEALTH trial is that hemiarthroplasty may provide a satisfactory results for the majority of elderly patients with hip fractures. “Considering the nearly equal risk of secondary surgical procedures and the modest benefit in functional outcome, should we abandon the use of total hip arthroplasty in the treatment of hip fractures?” asked Dr. Gjertsen, of the department of orthopedic surgery at Haukeland University Hospital in Bergen, Norway (N Engl J Med. 2019 Dec 4. doi:10.1056/NEJMe1913800). “Even if the benefits seem smaller than we previously thought, patients with high physical demands and a long remaining life expectancy should probably still be considered for treatment with total hip arthroplasty. Yet the expected remaining lifetime of those patients who potentially could benefit most from a total hip arthroplasty is much longer than the 2-year follow-up period used in the HEALTH trial. However, the number of secondary procedures after hemiarthroplasty may increase with longer follow-up. Therefore, one hopes that the HEALTH investigators will be able to provide long-term results from their trial in the future.”

The HEALTH trial was supported by grants from the Canadian Institutes of Health, the National Institutes of Health, ZorgOnderzoek Nederland/Medische Wetenschappen, the Sophies Minde Foundation for Orthopedic Research, McMaster Surgical Associates, and Stryker Orthopedics. Dr. Bhandari reported receiving grant support and lecture fees from Sanofi, lecture fees from Pendopharm, and grant support from Acumed and Aphria. Dr. Devereaux reported receiving grant support from Abbott Diagnostics, Boehringer Ingelheim, Philips Healthcare, Roche Diagnostics, and Siemens.

[email protected]

SOURCE: Bhandari M et al. N Engl J Med. 2019 Dec 4. doi: 10.1056/NEJMoa1906190.

Whether patients aged 50 years and older with a displaced femoral neck fracture underwent total hip arthroplasty or hemiarthroplasty had no significant influence on the risk of unplanned secondary hip procedures over 2 years of follow-up. In addition, while functional outcomes modestly favored total hip arthroplasty, the rates of mortality and serious adverse events were similar between the two treatment groups.

Those are key findings from a randomized, multicenter trial of the two procedures that was carried out in 10 countries.

“The American Academy of Orthopedic Surgeons and National Institute for Health and Care Excellence guidelines recommend total hip arthroplasty in all patients with displaced femoral neck fractures who are able to ambulate independently,” a team of investigators led by Mohit Bhandari, MD, and P.J. Devereaux, MD, both from McMaster University, Hamilton, Ont., wrote in a study published in the New England Journal of Medicine. “Our findings suggest that the advantages of total hip arthroplasty may not be compelling. The limited advantages of total hip arthroplasty, as well as the possible higher risk of complications, may be particularly important in regions of the world where total hip arthroplasty is not easily accessible or is cost prohibitive.”

In the Hip Fracture Evaluation With Alternative of Total Hip Arthroplasty Versus Hemiarthroplasty (HEALTH) trial, the researchers randomly assigned 1,495 patients aged 50 years and older who had a displaced femoral neck fracture to undergo either total hip arthroplasty or hemiarthroplasty. They were eligible for the trial only if they had been able to ambulate without the assistance of another person before the hip fracture occurred. The primary endpoint was any unplanned secondary hip procedure within 24 months after the initial surgery. Secondary endpoints included death, serious adverse events, hip-related complications, health-related quality of life, function, and overall health measures. Assessments included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score, pain score, stiffness score, and function score; the European Quality of Life–5 Dimensions utility index score and visual analogue scale; the 12-Item Short Form General Health Survey physical and mental component summary scores; and the Timed Up and Go scores.

The researchers found that the primary endpoint occurred in 7.9% of patients who had been randomly assigned to total hip arthroplasty and in 8.3% of those who had been randomly assigned to hemiarthroplasty (hazard ratio, 0.95; P = .79). As for secondary endpoints, mortality did not differ significantly between the two treatment groups (14.3% in the total hip arthroplasty group vs. 13.1% in the hemiarthroplasty group; P = .48), while serious adverse events occurred in 41.8% of patients in the total hip arthroplasty group versus 36.7% of those in the hemiarthroplasty group (HR, 1.16; P = .13).

In other findings, hip instability or dislocation occurred in 4.7% of patients who were assigned to total hip arthroplasty, compared with 2.4% of those who were assigned to hemiarthroplasty (HR, 2.00), while patients who underwent total hip arthroplasty had superior function as measured by the WOMAC total score, pain score, stiffness score, and function score. “These differences between the treatment groups fell below the threshold for a minimal clinically important difference for WOMAC,” the researchers wrote.

They acknowledged certain limitations of the study, including the fact that patients and endpoint assessors were unblinded in the assessments of function, “which left a possibility of bias.” In addition, 14.9% of patients were lost to follow-up for analysis of the primary endpoint.

In an accompanying editorial, Jan-Erik Gjertsen, MD, wrote that one implication of the HEALTH trial is that hemiarthroplasty may provide a satisfactory results for the majority of elderly patients with hip fractures. “Considering the nearly equal risk of secondary surgical procedures and the modest benefit in functional outcome, should we abandon the use of total hip arthroplasty in the treatment of hip fractures?” asked Dr. Gjertsen, of the department of orthopedic surgery at Haukeland University Hospital in Bergen, Norway (N Engl J Med. 2019 Dec 4. doi:10.1056/NEJMe1913800). “Even if the benefits seem smaller than we previously thought, patients with high physical demands and a long remaining life expectancy should probably still be considered for treatment with total hip arthroplasty. Yet the expected remaining lifetime of those patients who potentially could benefit most from a total hip arthroplasty is much longer than the 2-year follow-up period used in the HEALTH trial. However, the number of secondary procedures after hemiarthroplasty may increase with longer follow-up. Therefore, one hopes that the HEALTH investigators will be able to provide long-term results from their trial in the future.”

The HEALTH trial was supported by grants from the Canadian Institutes of Health, the National Institutes of Health, ZorgOnderzoek Nederland/Medische Wetenschappen, the Sophies Minde Foundation for Orthopedic Research, McMaster Surgical Associates, and Stryker Orthopedics. Dr. Bhandari reported receiving grant support and lecture fees from Sanofi, lecture fees from Pendopharm, and grant support from Acumed and Aphria. Dr. Devereaux reported receiving grant support from Abbott Diagnostics, Boehringer Ingelheim, Philips Healthcare, Roche Diagnostics, and Siemens.

[email protected]

SOURCE: Bhandari M et al. N Engl J Med. 2019 Dec 4. doi: 10.1056/NEJMoa1906190.

Whether patients aged 50 years and older with a displaced femoral neck fracture underwent total hip arthroplasty or hemiarthroplasty had no significant influence on the risk of unplanned secondary hip procedures over 2 years of follow-up. In addition, while functional outcomes modestly favored total hip arthroplasty, the rates of mortality and serious adverse events were similar between the two treatment groups.

Those are key findings from a randomized, multicenter trial of the two procedures that was carried out in 10 countries.

“The American Academy of Orthopedic Surgeons and National Institute for Health and Care Excellence guidelines recommend total hip arthroplasty in all patients with displaced femoral neck fractures who are able to ambulate independently,” a team of investigators led by Mohit Bhandari, MD, and P.J. Devereaux, MD, both from McMaster University, Hamilton, Ont., wrote in a study published in the New England Journal of Medicine. “Our findings suggest that the advantages of total hip arthroplasty may not be compelling. The limited advantages of total hip arthroplasty, as well as the possible higher risk of complications, may be particularly important in regions of the world where total hip arthroplasty is not easily accessible or is cost prohibitive.”

In the Hip Fracture Evaluation With Alternative of Total Hip Arthroplasty Versus Hemiarthroplasty (HEALTH) trial, the researchers randomly assigned 1,495 patients aged 50 years and older who had a displaced femoral neck fracture to undergo either total hip arthroplasty or hemiarthroplasty. They were eligible for the trial only if they had been able to ambulate without the assistance of another person before the hip fracture occurred. The primary endpoint was any unplanned secondary hip procedure within 24 months after the initial surgery. Secondary endpoints included death, serious adverse events, hip-related complications, health-related quality of life, function, and overall health measures. Assessments included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score, pain score, stiffness score, and function score; the European Quality of Life–5 Dimensions utility index score and visual analogue scale; the 12-Item Short Form General Health Survey physical and mental component summary scores; and the Timed Up and Go scores.

The researchers found that the primary endpoint occurred in 7.9% of patients who had been randomly assigned to total hip arthroplasty and in 8.3% of those who had been randomly assigned to hemiarthroplasty (hazard ratio, 0.95; P = .79). As for secondary endpoints, mortality did not differ significantly between the two treatment groups (14.3% in the total hip arthroplasty group vs. 13.1% in the hemiarthroplasty group; P = .48), while serious adverse events occurred in 41.8% of patients in the total hip arthroplasty group versus 36.7% of those in the hemiarthroplasty group (HR, 1.16; P = .13).

In other findings, hip instability or dislocation occurred in 4.7% of patients who were assigned to total hip arthroplasty, compared with 2.4% of those who were assigned to hemiarthroplasty (HR, 2.00), while patients who underwent total hip arthroplasty had superior function as measured by the WOMAC total score, pain score, stiffness score, and function score. “These differences between the treatment groups fell below the threshold for a minimal clinically important difference for WOMAC,” the researchers wrote.

They acknowledged certain limitations of the study, including the fact that patients and endpoint assessors were unblinded in the assessments of function, “which left a possibility of bias.” In addition, 14.9% of patients were lost to follow-up for analysis of the primary endpoint.

In an accompanying editorial, Jan-Erik Gjertsen, MD, wrote that one implication of the HEALTH trial is that hemiarthroplasty may provide a satisfactory results for the majority of elderly patients with hip fractures. “Considering the nearly equal risk of secondary surgical procedures and the modest benefit in functional outcome, should we abandon the use of total hip arthroplasty in the treatment of hip fractures?” asked Dr. Gjertsen, of the department of orthopedic surgery at Haukeland University Hospital in Bergen, Norway (N Engl J Med. 2019 Dec 4. doi:10.1056/NEJMe1913800). “Even if the benefits seem smaller than we previously thought, patients with high physical demands and a long remaining life expectancy should probably still be considered for treatment with total hip arthroplasty. Yet the expected remaining lifetime of those patients who potentially could benefit most from a total hip arthroplasty is much longer than the 2-year follow-up period used in the HEALTH trial. However, the number of secondary procedures after hemiarthroplasty may increase with longer follow-up. Therefore, one hopes that the HEALTH investigators will be able to provide long-term results from their trial in the future.”

The HEALTH trial was supported by grants from the Canadian Institutes of Health, the National Institutes of Health, ZorgOnderzoek Nederland/Medische Wetenschappen, the Sophies Minde Foundation for Orthopedic Research, McMaster Surgical Associates, and Stryker Orthopedics. Dr. Bhandari reported receiving grant support and lecture fees from Sanofi, lecture fees from Pendopharm, and grant support from Acumed and Aphria. Dr. Devereaux reported receiving grant support from Abbott Diagnostics, Boehringer Ingelheim, Philips Healthcare, Roche Diagnostics, and Siemens.

[email protected]

SOURCE: Bhandari M et al. N Engl J Med. 2019 Dec 4. doi: 10.1056/NEJMoa1906190.

ATLANTA – Upadacitinib (Rinvoq), a selective Janus kinase 1 (JAK1) inhibitor, significantly improved the signs and symptoms of active ankylosing spondylitis, compared with placebo, in the randomized, placebo-controlled, phase 2/3 SELECT-AXIS 1 study.

Physical functioning and imaging measures also were improved with upadacitinib in the double-blind, multicenter study, Désirée van der Heijde, MD, PhD, reported at the annual meeting of the American College of Rheumatology.

The findings are notable because patients with ankylosing spondylitis (AS) who have an inadequate response or contraindication to NSAIDs have limited treatment options other than biologic disease-modifying antirheumatic drugs (bDMARDs). The JAK pathway has emerged as a potential therapeutic target in AS, and given its recent approval for the treatment of RA as well as ongoing studies of the agent for several other chronic immune-mediated inflammatory diseases, Dr. van der Heijde and colleagues sought to assess its efficacy and safety in bDMARD-naive patients with active AS.

Of 93 AS patients aged 18 years and older who were randomized to receive 15 mg of upadacitinib daily, 51.6% achieved the primary study endpoint of 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40) at week 14, compared with 25.5% of 94 patients who received placebo, said Dr. van der Heijde, professor of rheumatology at Leiden (the Netherlands) University Medical Center.

The effect was rapid, with a clear difference emerging between the treatment and placebo groups within 2 weeks, she noted.

Significant improvements were also seen with upadacitinib for several key secondary endpoints including change from baseline to week 14 in the Ankylosing Spondylitis Disease Activity Score, Spondyloarthritis Research Consortium of Canada MRI Spine, a 50% improvement of the initial Bath Ankylosing Spondylitis Disease Activity Index (BASDAI 50), ASAS partial remission, and Bath Ankylosing Spondylitis Functional Index.

SELECT-AXIS 1 patients were adults with a mean age of 45 years who were enrolled from 60 sites in 20 countries. All met modified New York criteria for AS based on central reading of radiographs, had a BASDAI score of at least 4, had a patient assessment of total back pain of 4 or greater on a 0-10 scale at screening and baseline, were naive to bDMARDs, and had either an inadequate response to at least two NSAIDs or an intolerance/contraindication to NSAIDs.

Most patients (70.6%) were men, and 76.5% were HLA-B27 positive. Mean symptom duration was 14-15 years, and mean disease duration was 7-8 years, Dr. van der Heijde said, adding that baseline disease characteristics were balanced between the two arms.

All randomized patients received their assigned treatment, and 95.7% completed the study through week 14, including 90 of 94 placebo group patients and 89 of 93 upadacitinib patients.

“Treatment was generally well tolerated,” she said.

The proportions of patients in the treatment and placebo groups, respectively, were similar with respect to adverse events leading to discontinuation (2.2% vs. 3.2%), serious adverse events (1.1% in each group), and infections (20.4% vs. 27.7%). No serious infections, herpes zoster, malignancy, venous thromboembolic events, or deaths were reported. Also, no differences were seen between the groups in relevant laboratory abnormalities, and no new safety finding were observed in comparison with previous upadacitinib studies in other diseases, she noted.

Dr. van der Heijde concluded that “these results support further investigation of upadacitinib for the treatment of ankylosing spondyloarthritis.”

AbbVie, which markets upadacitinib, funded the study. Dr. van der Heijde disclosed financial relationships with AbbVie and 20 other pharmaceutical companies. Many other authors also reported financial relationships with industry, including AbbVie.

[email protected]

SOURCE: van der Heijde D et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 2728.

ATLANTA – Upadacitinib (Rinvoq), a selective Janus kinase 1 (JAK1) inhibitor, significantly improved the signs and symptoms of active ankylosing spondylitis, compared with placebo, in the randomized, placebo-controlled, phase 2/3 SELECT-AXIS 1 study.

Physical functioning and imaging measures also were improved with upadacitinib in the double-blind, multicenter study, Désirée van der Heijde, MD, PhD, reported at the annual meeting of the American College of Rheumatology.

The findings are notable because patients with ankylosing spondylitis (AS) who have an inadequate response or contraindication to NSAIDs have limited treatment options other than biologic disease-modifying antirheumatic drugs (bDMARDs). The JAK pathway has emerged as a potential therapeutic target in AS, and given its recent approval for the treatment of RA as well as ongoing studies of the agent for several other chronic immune-mediated inflammatory diseases, Dr. van der Heijde and colleagues sought to assess its efficacy and safety in bDMARD-naive patients with active AS.

Of 93 AS patients aged 18 years and older who were randomized to receive 15 mg of upadacitinib daily, 51.6% achieved the primary study endpoint of 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40) at week 14, compared with 25.5% of 94 patients who received placebo, said Dr. van der Heijde, professor of rheumatology at Leiden (the Netherlands) University Medical Center.

The effect was rapid, with a clear difference emerging between the treatment and placebo groups within 2 weeks, she noted.

Significant improvements were also seen with upadacitinib for several key secondary endpoints including change from baseline to week 14 in the Ankylosing Spondylitis Disease Activity Score, Spondyloarthritis Research Consortium of Canada MRI Spine, a 50% improvement of the initial Bath Ankylosing Spondylitis Disease Activity Index (BASDAI 50), ASAS partial remission, and Bath Ankylosing Spondylitis Functional Index.

SELECT-AXIS 1 patients were adults with a mean age of 45 years who were enrolled from 60 sites in 20 countries. All met modified New York criteria for AS based on central reading of radiographs, had a BASDAI score of at least 4, had a patient assessment of total back pain of 4 or greater on a 0-10 scale at screening and baseline, were naive to bDMARDs, and had either an inadequate response to at least two NSAIDs or an intolerance/contraindication to NSAIDs.

Most patients (70.6%) were men, and 76.5% were HLA-B27 positive. Mean symptom duration was 14-15 years, and mean disease duration was 7-8 years, Dr. van der Heijde said, adding that baseline disease characteristics were balanced between the two arms.

All randomized patients received their assigned treatment, and 95.7% completed the study through week 14, including 90 of 94 placebo group patients and 89 of 93 upadacitinib patients.

“Treatment was generally well tolerated,” she said.

The proportions of patients in the treatment and placebo groups, respectively, were similar with respect to adverse events leading to discontinuation (2.2% vs. 3.2%), serious adverse events (1.1% in each group), and infections (20.4% vs. 27.7%). No serious infections, herpes zoster, malignancy, venous thromboembolic events, or deaths were reported. Also, no differences were seen between the groups in relevant laboratory abnormalities, and no new safety finding were observed in comparison with previous upadacitinib studies in other diseases, she noted.

Dr. van der Heijde concluded that “these results support further investigation of upadacitinib for the treatment of ankylosing spondyloarthritis.”

AbbVie, which markets upadacitinib, funded the study. Dr. van der Heijde disclosed financial relationships with AbbVie and 20 other pharmaceutical companies. Many other authors also reported financial relationships with industry, including AbbVie.

[email protected]

SOURCE: van der Heijde D et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 2728.

ATLANTA – Upadacitinib (Rinvoq), a selective Janus kinase 1 (JAK1) inhibitor, significantly improved the signs and symptoms of active ankylosing spondylitis, compared with placebo, in the randomized, placebo-controlled, phase 2/3 SELECT-AXIS 1 study.

Physical functioning and imaging measures also were improved with upadacitinib in the double-blind, multicenter study, Désirée van der Heijde, MD, PhD, reported at the annual meeting of the American College of Rheumatology.

The findings are notable because patients with ankylosing spondylitis (AS) who have an inadequate response or contraindication to NSAIDs have limited treatment options other than biologic disease-modifying antirheumatic drugs (bDMARDs). The JAK pathway has emerged as a potential therapeutic target in AS, and given its recent approval for the treatment of RA as well as ongoing studies of the agent for several other chronic immune-mediated inflammatory diseases, Dr. van der Heijde and colleagues sought to assess its efficacy and safety in bDMARD-naive patients with active AS.

Of 93 AS patients aged 18 years and older who were randomized to receive 15 mg of upadacitinib daily, 51.6% achieved the primary study endpoint of 40% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS 40) at week 14, compared with 25.5% of 94 patients who received placebo, said Dr. van der Heijde, professor of rheumatology at Leiden (the Netherlands) University Medical Center.

The effect was rapid, with a clear difference emerging between the treatment and placebo groups within 2 weeks, she noted.

Significant improvements were also seen with upadacitinib for several key secondary endpoints including change from baseline to week 14 in the Ankylosing Spondylitis Disease Activity Score, Spondyloarthritis Research Consortium of Canada MRI Spine, a 50% improvement of the initial Bath Ankylosing Spondylitis Disease Activity Index (BASDAI 50), ASAS partial remission, and Bath Ankylosing Spondylitis Functional Index.

SELECT-AXIS 1 patients were adults with a mean age of 45 years who were enrolled from 60 sites in 20 countries. All met modified New York criteria for AS based on central reading of radiographs, had a BASDAI score of at least 4, had a patient assessment of total back pain of 4 or greater on a 0-10 scale at screening and baseline, were naive to bDMARDs, and had either an inadequate response to at least two NSAIDs or an intolerance/contraindication to NSAIDs.

Most patients (70.6%) were men, and 76.5% were HLA-B27 positive. Mean symptom duration was 14-15 years, and mean disease duration was 7-8 years, Dr. van der Heijde said, adding that baseline disease characteristics were balanced between the two arms.

All randomized patients received their assigned treatment, and 95.7% completed the study through week 14, including 90 of 94 placebo group patients and 89 of 93 upadacitinib patients.

“Treatment was generally well tolerated,” she said.

The proportions of patients in the treatment and placebo groups, respectively, were similar with respect to adverse events leading to discontinuation (2.2% vs. 3.2%), serious adverse events (1.1% in each group), and infections (20.4% vs. 27.7%). No serious infections, herpes zoster, malignancy, venous thromboembolic events, or deaths were reported. Also, no differences were seen between the groups in relevant laboratory abnormalities, and no new safety finding were observed in comparison with previous upadacitinib studies in other diseases, she noted.

Dr. van der Heijde concluded that “these results support further investigation of upadacitinib for the treatment of ankylosing spondyloarthritis.”

AbbVie, which markets upadacitinib, funded the study. Dr. van der Heijde disclosed financial relationships with AbbVie and 20 other pharmaceutical companies. Many other authors also reported financial relationships with industry, including AbbVie.

[email protected]

SOURCE: van der Heijde D et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 2728.

Most tricyclic antidepressants (TCAs) have US Food and Drug Administration approval for treatment of depression and anxiety disorders, but they are also a viable off-label option that should be considered by clinicians in specialties beyond psychiatry, especially for treating pain syndromes. Given the ongoing epidemic of opioid use disorder, increasing attention has been drawn to alternative strategies for chronic pain management, renewing an interest in the use of TCAs.

This review summarizes the pharmacologic properties of TCAs, their potential indications in conditions other than depression, and safety considerations.

BRIEF HISTORY OF TRICYCLICS

TCAs were originally designed in the 1950s and marketed later for treating depression. Due to their adverse effects and lethality in overdose quantities, over time they have been largely replaced by selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in depression management. However, TCAs have been applied to conditions other than depression with varying degrees of efficacy and safety.

TCA PHARMACOLOGY

TCAs are absorbed in the small intestine and undergo first-pass metabolism in the liver. They bind extensively to proteins, leading to interactions with other protein-bound drugs. They are widely distributed throughout the systemic circulation because they are highly lipophilic, resulting in systemic effects including central nervous system manifestations.

Peak plasma concentration is at about 2 to 6 hours, and elimination half-life is around 24 hours for most agents, providing a long duration of action. Clearance depends on cytochrome P450 oxidative enzymes.¹

MECHANISMS OF ACTION

TCAs inhibit reuptake of norepinephrine and serotonin, resulting in accumulation of these neurotransmitters in the presynaptic cleft. They also block postsynaptic histamine, alpha-adrenergic, and muscarinic-acetylcholine receptors, causing a variety of adverse effects, including dry mouth, confusion, cognitive impairment, hypotension, orthostasis, blurred vision, urinary retention, drowsiness, and sedation.¹

Research suggests that TCAs relieve pain centrally through a descending pathway that inhibits transmission of pain signals in the spinal cord, as well as peripherally through complex anti-neuroimmune actions.² Norepinephrine appears to play a more important role in this process than serotonin, although both are deemed necessary for the “dual action” often cited in pain management,¹ which is also the rationale for widespread use of SNRIs to control pain.

Table 1 compares neurotransmitter reuptake mechanisms, adverse effect profiles, and typical dosages for depression for commonly prescribed TCAs.

POTENTIAL USES

Headache and migraine

TCAs have been shown to be effective for managing and preventing chronic headache syndromes.^3,4 Amitriptyline has been the most studied of the TCAs for both chronic daily and episodic migraine headache, showing the most efficacy among diverse drug classes (angiotensin II receptor blockers, anticonvulsants, beta-blockers, SSRIs) compared with placebo. However, in head-to-head trials, amitriptyline was no more effective than SSRIs, venlafaxine, topiramate, or propranolol.⁴ Jackson et al⁴ suggested that prophylactic medication choices should be tailored to patient characteristics and expected adverse effects, and specifically recommended that TCAs—particularly amitriptyline—be reserved for patients who have both migraine and depression.

Neuropathic pain

Neuropathic pain is defined as pain secondary to a lesion or disease of the somatosensory nervous system⁵ and is the pathomechanistic component of a number of conditions, including postherpetic neuralgia,⁶ diabetic and nondiabetic painful polyneuropathy,⁷ posttraumatic or postsurgical neuropathic pain⁸ (including plexus avulsion and complex regional pain syndrome⁹), central poststroke pain,¹⁰ spinal cord injury pain,¹¹ and multiple sclerosis-associated pain.¹²

As a group, TCAs appear to have a role as first-line agents for managing these varied neuropathic pain syndromes. In a recent meta-analysis,¹³ 16 (89%) of 18 placebo-controlled trials of TCAs (mainly amitriptyline at 25–150 mg/day) for these pain conditions were positive, with a combined number needed to treat of 3.6, suggesting a role for TCAs in these conditions. Of note, the TCAs desipramine¹⁴ and nortriptyline¹⁵ have demonstrated little evidence of efficacy in neuropathic pain syndromes.

Chronic low back pain

Chronic low back pain is a leading cause of loss of work, excessive healthcare expenditure, and disability in the United States. It can be due to numerous spinal conditions, including degenerative disk disease, spinal stenosis, lumbar spondylosis, and spinal arthropathy.

TCAs have been used to treat chronic low back pain for decades and have been repeatedly shown to be more effective than placebo in reducing pain severity.^16,17 A double-blind controlled trial¹⁸ from 1999 compared the effects of the TCA maprotiline (up to 150 mg daily), the SSRI paroxetine (up to 30 mg daily), and placebo and found a statistically significant reduction in back pain with maprotiline compared with paroxetine and placebo. However, a 2008 meta-analysis suggested little evidence that TCAs were superior to placebo.¹⁹

Evidence of TCA efficacy for back pain was reported in 2018 with a well-designed 6-month double-blind randomized controlled trial²⁰ comparing low-dose amitriptyline (25 mg) with an active comparator (benztropine 1 mg). The authors reported that amitriptyline was effective in reducing pain and pain-related disability without incurring serious adverse effects. They suggested continued use of TCAs for chronic low back pain if complicated with pain-related disability, insomnia, depression, or other comorbidity, although they called for further large-scale studies. They also cautioned that patients started the trial with symptoms similar to the adverse effects of TCAs themselves; this has implications for monitoring of symptoms as well as TCA adverse effects while using these drugs.

Fibromyalgia is a common, frustrating, noninflammatory pain syndrome characterized by diffuse hyperalgesia and multiple comorbidities.²¹ Although sleep hygiene, exercise, cognitive-behavioral therapy, some gabapentinoids (pregabalin), and a combination of these therapies have demonstrated efficacy, TCAs also offer robust benefits.

A meta-analysis of 9 placebo-controlled TCA trials showed large effect sizes for pain reduction, fatigue reduction, improved sleep quality, and reduced stiffness and tenderness, with the most significant of these improvements being for sleep.²² A separate meta-analysis calculated that the number needed to treat with amitriptyline for a positive outcome is 4.9.²³ Recent systematic reviews have supported these findings, listing TCAs as second-line agents after pregabalin, duloxetine, and milnacipran.²⁴

Of note, TCA monotherapy rarely produces a complete response in patients with moderate to severe fibromyalgia, chronic widespread pain, or significant comorbidities (depression, anxiety). Supplementation with cognitive-behavioral therapy, physical therapy, functional restoration, and other modalities is strongly recommended.

Abdominal and gastrointestinal pain

TCAs have been applied to a number of gastrointestinal syndromes with or without pain. Patients with irritable bowel syndrome have long been known to benefit from TCAs; the number needed to treat for symptomatic benefit over placebo is 3.5.^25,26

Although there is no substantial evidence that TCAs are useful in reducing active inflammation in inflammatory bowel disease, a study involving 81 patients found that residual noninflammatory gastrointestinal symptoms (such as diarrhea and pain) responded to TCAs, including nortriptyline and amitriptyline, with greater benefit for ulcerative colitis than for Crohn disease.²⁷

TCAs have also shown prophylactic benefit in cyclic vomiting syndrome, with a clinical response in over 75% of patients in controlled cohort studies.²⁸

The efficacy of TCAs in other abdominal or gastrointestinal syndromes is unclear or modest at best.²⁹ However, few alternative treatments exist for these conditions. Amitriptyline may help symptoms of functional dyspepsia,³⁰ but nortriptyline has proven ineffective in gastroparesis.³¹ Nonetheless, some authors²⁹ suggest considering TCAs on an individualized basis, with proper monitoring, in many if not most functional gastrointestinal disorders, especially when paired with behavioral therapies.

Pelvic and urogynecologic symptoms

Chronic pelvic pain affects up to 24% of women³² and 5% to 10% of men.³³ TCAs have shown efficacy in treating chronic pelvic pain with or without comorbid depression.³⁴ Amitriptyline and to a lesser extent nortriptyline are the TCAs most often prescribed. Pain relief appears to be independent of antidepressant effects and may be achieved at low doses; initial dosing ranges from 10 to 25 mg at bedtime, which may be increased to 100 mg as tolerated.³⁴

Based on a randomized, double-blind trial,³⁵ amitriptyline was recommended as a treatment option for interstitial cystitis or bladder pain, with the greatest symptom improvement in patients tolerating a daily dose of 50 mg.

Another study³⁶ randomized 56 women with chronic pelvic pain to amitriptyline or  gabapentin, or a combination of the drugs for 24 months. Although each regimen resulted in significant reduction in pain, fewer adverse effects occurred with gabapentin than amitriptyline. Poor compliance and early discontinuation of amitriptyline were common due to anticholinergic effects.

In small uncontrolled studies,³⁷ about half of women with chronic pelvic pain became pain-free after 8 weeks of treatment with nortriptyline and imipramine.

Randomized controlled studies are needed to confirm potential benefits of TCAs in chronic urologic and pelvic pain.

Insomnia

Insomnia affects 23% to 56% of people in the United States, Europe, and Asia³⁸ and is the reason for more than 5.5 million primary care visits annually.³⁹ TCAs (especially doxepin, maprotiline, and amitriptyline⁴⁰) have been shown to be an effective treatment, with an 82% increase in somnolence compared with placebo, as well as measurably improved total sleep time, enhanced sleep efficiency, reduced latency to persistent sleep, and decreased wake times after sleep onset.³⁸

Dosing should be kept at a minimum to minimize harsh anticholinergic effects and avoid daytime sedation. Patients should be advised to take new doses or dose escalations earlier in the night to ensure less hangover sedation the next morning.

For patients with insomnia and comorbid depression, the American Academy of Sleep Medicine suggests the addition of a low dose (eg, 10–25 mg) of a TCA at nighttime to complement preexisting, full-dose, non-TCA antidepressants, while monitoring for serotonin syndrome and other potential but exceedingly rare drug-drug interactions.⁴¹

Psychiatric indications other than depression

Beyond the known benefits in major depressive disorder, TCAs have been shown to be effective for obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, bulimia nervosa, and childhood enuresis.⁴² Given the shortage of mental health clinicians and the high prevalence of these conditions, nonpsychiatrist physicians should be familiar with the therapeutic potential of TCAs for these indications.

ADVERSE EFFECTS

Adverse effects vary among TCAs. Common ones include blurred vision, dry mouth, constipation, urinary retention, hypotension, tachycardia, tremor, weight gain, and sexual dysfunction.⁴³ Tertiary amines are generally more sedating than secondary amines and cause more anticholinergic effects (Table 1).

Despite widespread perceptions that TCAs are less tolerable than newer antidepressants, studies repeatedly suggest that they have an adverse-effect burden similar to that of SSRIs and SNRIs, although SSRIs have a greater tendency to produce nausea, whereas TCAs are more likely to cause constipation.⁴⁴

Discontinuation syndrome

Abrupt discontinuation or unintentionally missed doses of TCAs have been associated with a discontinuation syndrome in about 40% of users.⁴⁵ Patients should be warned about this possibility and the syndrome’s potential effects: dizziness, insomnia, headaches, nausea, vomiting, flulike achiness, and restlessness. Rebound depression, anxiety, panic, or other psychiatric symptoms may also occur. Symptoms generally present within 2 to 5 days after dose discontinuation and last 7 to 14 days.⁴⁵

However, all TCAs have a long half-life, allowing for sufficient coverage with once-daily dosing and thus carry a lower risk of discontinuation syndrome than many other antidepressants (78% with venlafaxine; 55% with paroxetine).⁴⁵

To discontinue therapy safely, the dosage should be reduced gradually. As is pharmacologically expected, the greatest likelihood of discontinuation syndrome is associated with longer duration of continuous treatment.

CONTRAINDICATIONS

Cardiac conduction abnormalities

TCAs should not be prescribed to patients who have right bundle branch block, a severe electrolyte disturbance, or other cardiac conduction deficit or arrhythmia that can prolong the QTc interval and elevate the risk of lethal arrhythmia.^46,47 Cardiac effects from TCAs are largely dose-dependent. Nevertheless, a baseline electrocardiogram can be obtained to assess cardiac risk, and dose escalation can proceed if results are normal (eg, appropriate conduction intervals, QTc ≤ 450 ms).

Advanced age

For elderly patients, TCAs should be prescribed with caution and sometimes not at all,⁴⁸ because anticholinergic effects may worsen preexisting urinary retention (including benign prostatic hyperplasia), narrow-angle glaucoma, imbalance and gait issues, and cognitive impairment and dementia. Dehydration and orthostatic hypotension are contraindications for TCAs, as they may precipitate falls or hypotensive shock.

Epilepsy

TCAs should also be used with caution in patients with epilepsy, as they lower the seizure threshold.

Concomitant monoamine oxidase inhibitor treatment

Giving TCAs together with monoamine oxidase inhibitor antidepressants should be avoided, given the risk of hypertensive crisis.

Suicide risk

TCAs are dangerous and potentially lethal in overdose and so should not be prescribed to suicidal or otherwise impulsive patients.

Pregnancy

TCAs are in pregnancy risk category C (animal studies show adverse effects on fetus; no adequate or well-controlled studies in humans; potential benefits may warrant use despite risks). Using TCAs during pregnancy has very rarely led to neonatal withdrawal such as irritability, jitteriness, and convulsions, as well as fetal QTc interval prolongation.⁴⁹

The American College of Obstetricians and Gynecologists recommends that therapy for depression during pregnancy be individualized, incorporating the expertise of the patient’s mental health clinician, obstetrician, primary healthcare provider, and pediatrician. In general, they recommend that TCAs should be avoided if possible and that alternatives such as SSRIs or SNRIs should be considered.⁵⁰

TCAs are excreted in breast milk, but they have not been detected in the serum of nursing infants, and no adverse events have been reported.

OVERDOSE IS HIGHLY DANGEROUS

Severe morbidity and death are associated with TCA overdose, characterized by  convulsions, cardiac arrest, and coma (the “3 Cs”). These dangers occur at much higher rates with TCAs than with other antidepressants.⁴³ Signs and symptoms of toxicity develop rapidly, usually within the first hour of overdose. Manifestations of overdose include prolonged QTc, cardiac arrhythmias, tachycardia, hypertension, severe hypotension, agitation, seizures, central nervous system depression, hallucinations, seizures, and coma.

Overdose management includes activated charcoal, seizure control, cardioversion, hydration, electrolyte stabilization, and other intensive care.

OFF-LABEL TCA MANAGEMENT

Dosing recommendations for off-label use of TCAs vary based on the condition, the medication, and the suggestions of individual authors and researchers. In general, dosing ranges for pain and other nondepression indications may be lower than for severe depression (Table 2).¹

As with any pharmacologic titration, monitoring for rate-limiting adverse effects is recommended. We suggest caution, tailoring the approach to the patient, and routinely assessing for adverse effects and other safety considerations.

In addition, we strongly recommend supplementing TCA therapy with nonpharmacologic strategies such as lifestyle changes, dietary modifications, exercise, physical therapy, and mental health optimization.

Most tricyclic antidepressants (TCAs) have US Food and Drug Administration approval for treatment of depression and anxiety disorders, but they are also a viable off-label option that should be considered by clinicians in specialties beyond psychiatry, especially for treating pain syndromes. Given the ongoing epidemic of opioid use disorder, increasing attention has been drawn to alternative strategies for chronic pain management, renewing an interest in the use of TCAs.

This review summarizes the pharmacologic properties of TCAs, their potential indications in conditions other than depression, and safety considerations.

BRIEF HISTORY OF TRICYCLICS

TCAs were originally designed in the 1950s and marketed later for treating depression. Due to their adverse effects and lethality in overdose quantities, over time they have been largely replaced by selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in depression management. However, TCAs have been applied to conditions other than depression with varying degrees of efficacy and safety.

TCA PHARMACOLOGY

TCAs are absorbed in the small intestine and undergo first-pass metabolism in the liver. They bind extensively to proteins, leading to interactions with other protein-bound drugs. They are widely distributed throughout the systemic circulation because they are highly lipophilic, resulting in systemic effects including central nervous system manifestations.

Peak plasma concentration is at about 2 to 6 hours, and elimination half-life is around 24 hours for most agents, providing a long duration of action. Clearance depends on cytochrome P450 oxidative enzymes.¹

MECHANISMS OF ACTION

TCAs inhibit reuptake of norepinephrine and serotonin, resulting in accumulation of these neurotransmitters in the presynaptic cleft. They also block postsynaptic histamine, alpha-adrenergic, and muscarinic-acetylcholine receptors, causing a variety of adverse effects, including dry mouth, confusion, cognitive impairment, hypotension, orthostasis, blurred vision, urinary retention, drowsiness, and sedation.¹

Research suggests that TCAs relieve pain centrally through a descending pathway that inhibits transmission of pain signals in the spinal cord, as well as peripherally through complex anti-neuroimmune actions.² Norepinephrine appears to play a more important role in this process than serotonin, although both are deemed necessary for the “dual action” often cited in pain management,¹ which is also the rationale for widespread use of SNRIs to control pain.

Table 1 compares neurotransmitter reuptake mechanisms, adverse effect profiles, and typical dosages for depression for commonly prescribed TCAs.

POTENTIAL USES

Headache and migraine

TCAs have been shown to be effective for managing and preventing chronic headache syndromes.^3,4 Amitriptyline has been the most studied of the TCAs for both chronic daily and episodic migraine headache, showing the most efficacy among diverse drug classes (angiotensin II receptor blockers, anticonvulsants, beta-blockers, SSRIs) compared with placebo. However, in head-to-head trials, amitriptyline was no more effective than SSRIs, venlafaxine, topiramate, or propranolol.⁴ Jackson et al⁴ suggested that prophylactic medication choices should be tailored to patient characteristics and expected adverse effects, and specifically recommended that TCAs—particularly amitriptyline—be reserved for patients who have both migraine and depression.

Neuropathic pain

Neuropathic pain is defined as pain secondary to a lesion or disease of the somatosensory nervous system⁵ and is the pathomechanistic component of a number of conditions, including postherpetic neuralgia,⁶ diabetic and nondiabetic painful polyneuropathy,⁷ posttraumatic or postsurgical neuropathic pain⁸ (including plexus avulsion and complex regional pain syndrome⁹), central poststroke pain,¹⁰ spinal cord injury pain,¹¹ and multiple sclerosis-associated pain.¹²

As a group, TCAs appear to have a role as first-line agents for managing these varied neuropathic pain syndromes. In a recent meta-analysis,¹³ 16 (89%) of 18 placebo-controlled trials of TCAs (mainly amitriptyline at 25–150 mg/day) for these pain conditions were positive, with a combined number needed to treat of 3.6, suggesting a role for TCAs in these conditions. Of note, the TCAs desipramine¹⁴ and nortriptyline¹⁵ have demonstrated little evidence of efficacy in neuropathic pain syndromes.

Chronic low back pain

Chronic low back pain is a leading cause of loss of work, excessive healthcare expenditure, and disability in the United States. It can be due to numerous spinal conditions, including degenerative disk disease, spinal stenosis, lumbar spondylosis, and spinal arthropathy.

TCAs have been used to treat chronic low back pain for decades and have been repeatedly shown to be more effective than placebo in reducing pain severity.^16,17 A double-blind controlled trial¹⁸ from 1999 compared the effects of the TCA maprotiline (up to 150 mg daily), the SSRI paroxetine (up to 30 mg daily), and placebo and found a statistically significant reduction in back pain with maprotiline compared with paroxetine and placebo. However, a 2008 meta-analysis suggested little evidence that TCAs were superior to placebo.¹⁹

Evidence of TCA efficacy for back pain was reported in 2018 with a well-designed 6-month double-blind randomized controlled trial²⁰ comparing low-dose amitriptyline (25 mg) with an active comparator (benztropine 1 mg). The authors reported that amitriptyline was effective in reducing pain and pain-related disability without incurring serious adverse effects. They suggested continued use of TCAs for chronic low back pain if complicated with pain-related disability, insomnia, depression, or other comorbidity, although they called for further large-scale studies. They also cautioned that patients started the trial with symptoms similar to the adverse effects of TCAs themselves; this has implications for monitoring of symptoms as well as TCA adverse effects while using these drugs.

Fibromyalgia is a common, frustrating, noninflammatory pain syndrome characterized by diffuse hyperalgesia and multiple comorbidities.²¹ Although sleep hygiene, exercise, cognitive-behavioral therapy, some gabapentinoids (pregabalin), and a combination of these therapies have demonstrated efficacy, TCAs also offer robust benefits.

A meta-analysis of 9 placebo-controlled TCA trials showed large effect sizes for pain reduction, fatigue reduction, improved sleep quality, and reduced stiffness and tenderness, with the most significant of these improvements being for sleep.²² A separate meta-analysis calculated that the number needed to treat with amitriptyline for a positive outcome is 4.9.²³ Recent systematic reviews have supported these findings, listing TCAs as second-line agents after pregabalin, duloxetine, and milnacipran.²⁴

Of note, TCA monotherapy rarely produces a complete response in patients with moderate to severe fibromyalgia, chronic widespread pain, or significant comorbidities (depression, anxiety). Supplementation with cognitive-behavioral therapy, physical therapy, functional restoration, and other modalities is strongly recommended.

Abdominal and gastrointestinal pain

TCAs have been applied to a number of gastrointestinal syndromes with or without pain. Patients with irritable bowel syndrome have long been known to benefit from TCAs; the number needed to treat for symptomatic benefit over placebo is 3.5.^25,26

Although there is no substantial evidence that TCAs are useful in reducing active inflammation in inflammatory bowel disease, a study involving 81 patients found that residual noninflammatory gastrointestinal symptoms (such as diarrhea and pain) responded to TCAs, including nortriptyline and amitriptyline, with greater benefit for ulcerative colitis than for Crohn disease.²⁷

TCAs have also shown prophylactic benefit in cyclic vomiting syndrome, with a clinical response in over 75% of patients in controlled cohort studies.²⁸

The efficacy of TCAs in other abdominal or gastrointestinal syndromes is unclear or modest at best.²⁹ However, few alternative treatments exist for these conditions. Amitriptyline may help symptoms of functional dyspepsia,³⁰ but nortriptyline has proven ineffective in gastroparesis.³¹ Nonetheless, some authors²⁹ suggest considering TCAs on an individualized basis, with proper monitoring, in many if not most functional gastrointestinal disorders, especially when paired with behavioral therapies.

Pelvic and urogynecologic symptoms

Chronic pelvic pain affects up to 24% of women³² and 5% to 10% of men.³³ TCAs have shown efficacy in treating chronic pelvic pain with or without comorbid depression.³⁴ Amitriptyline and to a lesser extent nortriptyline are the TCAs most often prescribed. Pain relief appears to be independent of antidepressant effects and may be achieved at low doses; initial dosing ranges from 10 to 25 mg at bedtime, which may be increased to 100 mg as tolerated.³⁴

Based on a randomized, double-blind trial,³⁵ amitriptyline was recommended as a treatment option for interstitial cystitis or bladder pain, with the greatest symptom improvement in patients tolerating a daily dose of 50 mg.

Another study³⁶ randomized 56 women with chronic pelvic pain to amitriptyline or  gabapentin, or a combination of the drugs for 24 months. Although each regimen resulted in significant reduction in pain, fewer adverse effects occurred with gabapentin than amitriptyline. Poor compliance and early discontinuation of amitriptyline were common due to anticholinergic effects.

In small uncontrolled studies,³⁷ about half of women with chronic pelvic pain became pain-free after 8 weeks of treatment with nortriptyline and imipramine.

Randomized controlled studies are needed to confirm potential benefits of TCAs in chronic urologic and pelvic pain.

Insomnia

Insomnia affects 23% to 56% of people in the United States, Europe, and Asia³⁸ and is the reason for more than 5.5 million primary care visits annually.³⁹ TCAs (especially doxepin, maprotiline, and amitriptyline⁴⁰) have been shown to be an effective treatment, with an 82% increase in somnolence compared with placebo, as well as measurably improved total sleep time, enhanced sleep efficiency, reduced latency to persistent sleep, and decreased wake times after sleep onset.³⁸

Dosing should be kept at a minimum to minimize harsh anticholinergic effects and avoid daytime sedation. Patients should be advised to take new doses or dose escalations earlier in the night to ensure less hangover sedation the next morning.

For patients with insomnia and comorbid depression, the American Academy of Sleep Medicine suggests the addition of a low dose (eg, 10–25 mg) of a TCA at nighttime to complement preexisting, full-dose, non-TCA antidepressants, while monitoring for serotonin syndrome and other potential but exceedingly rare drug-drug interactions.⁴¹

Psychiatric indications other than depression

Beyond the known benefits in major depressive disorder, TCAs have been shown to be effective for obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, bulimia nervosa, and childhood enuresis.⁴² Given the shortage of mental health clinicians and the high prevalence of these conditions, nonpsychiatrist physicians should be familiar with the therapeutic potential of TCAs for these indications.

ADVERSE EFFECTS

Adverse effects vary among TCAs. Common ones include blurred vision, dry mouth, constipation, urinary retention, hypotension, tachycardia, tremor, weight gain, and sexual dysfunction.⁴³ Tertiary amines are generally more sedating than secondary amines and cause more anticholinergic effects (Table 1).

Despite widespread perceptions that TCAs are less tolerable than newer antidepressants, studies repeatedly suggest that they have an adverse-effect burden similar to that of SSRIs and SNRIs, although SSRIs have a greater tendency to produce nausea, whereas TCAs are more likely to cause constipation.⁴⁴

Discontinuation syndrome

Abrupt discontinuation or unintentionally missed doses of TCAs have been associated with a discontinuation syndrome in about 40% of users.⁴⁵ Patients should be warned about this possibility and the syndrome’s potential effects: dizziness, insomnia, headaches, nausea, vomiting, flulike achiness, and restlessness. Rebound depression, anxiety, panic, or other psychiatric symptoms may also occur. Symptoms generally present within 2 to 5 days after dose discontinuation and last 7 to 14 days.⁴⁵

However, all TCAs have a long half-life, allowing for sufficient coverage with once-daily dosing and thus carry a lower risk of discontinuation syndrome than many other antidepressants (78% with venlafaxine; 55% with paroxetine).⁴⁵

To discontinue therapy safely, the dosage should be reduced gradually. As is pharmacologically expected, the greatest likelihood of discontinuation syndrome is associated with longer duration of continuous treatment.

CONTRAINDICATIONS

Cardiac conduction abnormalities

TCAs should not be prescribed to patients who have right bundle branch block, a severe electrolyte disturbance, or other cardiac conduction deficit or arrhythmia that can prolong the QTc interval and elevate the risk of lethal arrhythmia.^46,47 Cardiac effects from TCAs are largely dose-dependent. Nevertheless, a baseline electrocardiogram can be obtained to assess cardiac risk, and dose escalation can proceed if results are normal (eg, appropriate conduction intervals, QTc ≤ 450 ms).

Advanced age

For elderly patients, TCAs should be prescribed with caution and sometimes not at all,⁴⁸ because anticholinergic effects may worsen preexisting urinary retention (including benign prostatic hyperplasia), narrow-angle glaucoma, imbalance and gait issues, and cognitive impairment and dementia. Dehydration and orthostatic hypotension are contraindications for TCAs, as they may precipitate falls or hypotensive shock.

Epilepsy

TCAs should also be used with caution in patients with epilepsy, as they lower the seizure threshold.

Concomitant monoamine oxidase inhibitor treatment

Giving TCAs together with monoamine oxidase inhibitor antidepressants should be avoided, given the risk of hypertensive crisis.

Suicide risk

TCAs are dangerous and potentially lethal in overdose and so should not be prescribed to suicidal or otherwise impulsive patients.

Pregnancy

TCAs are in pregnancy risk category C (animal studies show adverse effects on fetus; no adequate or well-controlled studies in humans; potential benefits may warrant use despite risks). Using TCAs during pregnancy has very rarely led to neonatal withdrawal such as irritability, jitteriness, and convulsions, as well as fetal QTc interval prolongation.⁴⁹

The American College of Obstetricians and Gynecologists recommends that therapy for depression during pregnancy be individualized, incorporating the expertise of the patient’s mental health clinician, obstetrician, primary healthcare provider, and pediatrician. In general, they recommend that TCAs should be avoided if possible and that alternatives such as SSRIs or SNRIs should be considered.⁵⁰

TCAs are excreted in breast milk, but they have not been detected in the serum of nursing infants, and no adverse events have been reported.

OVERDOSE IS HIGHLY DANGEROUS

Severe morbidity and death are associated with TCA overdose, characterized by  convulsions, cardiac arrest, and coma (the “3 Cs”). These dangers occur at much higher rates with TCAs than with other antidepressants.⁴³ Signs and symptoms of toxicity develop rapidly, usually within the first hour of overdose. Manifestations of overdose include prolonged QTc, cardiac arrhythmias, tachycardia, hypertension, severe hypotension, agitation, seizures, central nervous system depression, hallucinations, seizures, and coma.

Overdose management includes activated charcoal, seizure control, cardioversion, hydration, electrolyte stabilization, and other intensive care.

OFF-LABEL TCA MANAGEMENT

Dosing recommendations for off-label use of TCAs vary based on the condition, the medication, and the suggestions of individual authors and researchers. In general, dosing ranges for pain and other nondepression indications may be lower than for severe depression (Table 2).¹

As with any pharmacologic titration, monitoring for rate-limiting adverse effects is recommended. We suggest caution, tailoring the approach to the patient, and routinely assessing for adverse effects and other safety considerations.

In addition, we strongly recommend supplementing TCA therapy with nonpharmacologic strategies such as lifestyle changes, dietary modifications, exercise, physical therapy, and mental health optimization.

Most tricyclic antidepressants (TCAs) have US Food and Drug Administration approval for treatment of depression and anxiety disorders, but they are also a viable off-label option that should be considered by clinicians in specialties beyond psychiatry, especially for treating pain syndromes. Given the ongoing epidemic of opioid use disorder, increasing attention has been drawn to alternative strategies for chronic pain management, renewing an interest in the use of TCAs.

This review summarizes the pharmacologic properties of TCAs, their potential indications in conditions other than depression, and safety considerations.

BRIEF HISTORY OF TRICYCLICS

TCAs were originally designed in the 1950s and marketed later for treating depression. Due to their adverse effects and lethality in overdose quantities, over time they have been largely replaced by selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in depression management. However, TCAs have been applied to conditions other than depression with varying degrees of efficacy and safety.

TCA PHARMACOLOGY

TCAs are absorbed in the small intestine and undergo first-pass metabolism in the liver. They bind extensively to proteins, leading to interactions with other protein-bound drugs. They are widely distributed throughout the systemic circulation because they are highly lipophilic, resulting in systemic effects including central nervous system manifestations.

Peak plasma concentration is at about 2 to 6 hours, and elimination half-life is around 24 hours for most agents, providing a long duration of action. Clearance depends on cytochrome P450 oxidative enzymes.¹

MECHANISMS OF ACTION

TCAs inhibit reuptake of norepinephrine and serotonin, resulting in accumulation of these neurotransmitters in the presynaptic cleft. They also block postsynaptic histamine, alpha-adrenergic, and muscarinic-acetylcholine receptors, causing a variety of adverse effects, including dry mouth, confusion, cognitive impairment, hypotension, orthostasis, blurred vision, urinary retention, drowsiness, and sedation.¹

Research suggests that TCAs relieve pain centrally through a descending pathway that inhibits transmission of pain signals in the spinal cord, as well as peripherally through complex anti-neuroimmune actions.² Norepinephrine appears to play a more important role in this process than serotonin, although both are deemed necessary for the “dual action” often cited in pain management,¹ which is also the rationale for widespread use of SNRIs to control pain.

Table 1 compares neurotransmitter reuptake mechanisms, adverse effect profiles, and typical dosages for depression for commonly prescribed TCAs.

POTENTIAL USES

Headache and migraine

TCAs have been shown to be effective for managing and preventing chronic headache syndromes.^3,4 Amitriptyline has been the most studied of the TCAs for both chronic daily and episodic migraine headache, showing the most efficacy among diverse drug classes (angiotensin II receptor blockers, anticonvulsants, beta-blockers, SSRIs) compared with placebo. However, in head-to-head trials, amitriptyline was no more effective than SSRIs, venlafaxine, topiramate, or propranolol.⁴ Jackson et al⁴ suggested that prophylactic medication choices should be tailored to patient characteristics and expected adverse effects, and specifically recommended that TCAs—particularly amitriptyline—be reserved for patients who have both migraine and depression.

Neuropathic pain

Neuropathic pain is defined as pain secondary to a lesion or disease of the somatosensory nervous system⁵ and is the pathomechanistic component of a number of conditions, including postherpetic neuralgia,⁶ diabetic and nondiabetic painful polyneuropathy,⁷ posttraumatic or postsurgical neuropathic pain⁸ (including plexus avulsion and complex regional pain syndrome⁹), central poststroke pain,¹⁰ spinal cord injury pain,¹¹ and multiple sclerosis-associated pain.¹²

As a group, TCAs appear to have a role as first-line agents for managing these varied neuropathic pain syndromes. In a recent meta-analysis,¹³ 16 (89%) of 18 placebo-controlled trials of TCAs (mainly amitriptyline at 25–150 mg/day) for these pain conditions were positive, with a combined number needed to treat of 3.6, suggesting a role for TCAs in these conditions. Of note, the TCAs desipramine¹⁴ and nortriptyline¹⁵ have demonstrated little evidence of efficacy in neuropathic pain syndromes.

Chronic low back pain

Chronic low back pain is a leading cause of loss of work, excessive healthcare expenditure, and disability in the United States. It can be due to numerous spinal conditions, including degenerative disk disease, spinal stenosis, lumbar spondylosis, and spinal arthropathy.

TCAs have been used to treat chronic low back pain for decades and have been repeatedly shown to be more effective than placebo in reducing pain severity.^16,17 A double-blind controlled trial¹⁸ from 1999 compared the effects of the TCA maprotiline (up to 150 mg daily), the SSRI paroxetine (up to 30 mg daily), and placebo and found a statistically significant reduction in back pain with maprotiline compared with paroxetine and placebo. However, a 2008 meta-analysis suggested little evidence that TCAs were superior to placebo.¹⁹

Evidence of TCA efficacy for back pain was reported in 2018 with a well-designed 6-month double-blind randomized controlled trial²⁰ comparing low-dose amitriptyline (25 mg) with an active comparator (benztropine 1 mg). The authors reported that amitriptyline was effective in reducing pain and pain-related disability without incurring serious adverse effects. They suggested continued use of TCAs for chronic low back pain if complicated with pain-related disability, insomnia, depression, or other comorbidity, although they called for further large-scale studies. They also cautioned that patients started the trial with symptoms similar to the adverse effects of TCAs themselves; this has implications for monitoring of symptoms as well as TCA adverse effects while using these drugs.

Fibromyalgia is a common, frustrating, noninflammatory pain syndrome characterized by diffuse hyperalgesia and multiple comorbidities.²¹ Although sleep hygiene, exercise, cognitive-behavioral therapy, some gabapentinoids (pregabalin), and a combination of these therapies have demonstrated efficacy, TCAs also offer robust benefits.

A meta-analysis of 9 placebo-controlled TCA trials showed large effect sizes for pain reduction, fatigue reduction, improved sleep quality, and reduced stiffness and tenderness, with the most significant of these improvements being for sleep.²² A separate meta-analysis calculated that the number needed to treat with amitriptyline for a positive outcome is 4.9.²³ Recent systematic reviews have supported these findings, listing TCAs as second-line agents after pregabalin, duloxetine, and milnacipran.²⁴

Of note, TCA monotherapy rarely produces a complete response in patients with moderate to severe fibromyalgia, chronic widespread pain, or significant comorbidities (depression, anxiety). Supplementation with cognitive-behavioral therapy, physical therapy, functional restoration, and other modalities is strongly recommended.

Abdominal and gastrointestinal pain

TCAs have been applied to a number of gastrointestinal syndromes with or without pain. Patients with irritable bowel syndrome have long been known to benefit from TCAs; the number needed to treat for symptomatic benefit over placebo is 3.5.^25,26

Although there is no substantial evidence that TCAs are useful in reducing active inflammation in inflammatory bowel disease, a study involving 81 patients found that residual noninflammatory gastrointestinal symptoms (such as diarrhea and pain) responded to TCAs, including nortriptyline and amitriptyline, with greater benefit for ulcerative colitis than for Crohn disease.²⁷

TCAs have also shown prophylactic benefit in cyclic vomiting syndrome, with a clinical response in over 75% of patients in controlled cohort studies.²⁸

The efficacy of TCAs in other abdominal or gastrointestinal syndromes is unclear or modest at best.²⁹ However, few alternative treatments exist for these conditions. Amitriptyline may help symptoms of functional dyspepsia,³⁰ but nortriptyline has proven ineffective in gastroparesis.³¹ Nonetheless, some authors²⁹ suggest considering TCAs on an individualized basis, with proper monitoring, in many if not most functional gastrointestinal disorders, especially when paired with behavioral therapies.

Pelvic and urogynecologic symptoms

Chronic pelvic pain affects up to 24% of women³² and 5% to 10% of men.³³ TCAs have shown efficacy in treating chronic pelvic pain with or without comorbid depression.³⁴ Amitriptyline and to a lesser extent nortriptyline are the TCAs most often prescribed. Pain relief appears to be independent of antidepressant effects and may be achieved at low doses; initial dosing ranges from 10 to 25 mg at bedtime, which may be increased to 100 mg as tolerated.³⁴

Based on a randomized, double-blind trial,³⁵ amitriptyline was recommended as a treatment option for interstitial cystitis or bladder pain, with the greatest symptom improvement in patients tolerating a daily dose of 50 mg.

Another study³⁶ randomized 56 women with chronic pelvic pain to amitriptyline or  gabapentin, or a combination of the drugs for 24 months. Although each regimen resulted in significant reduction in pain, fewer adverse effects occurred with gabapentin than amitriptyline. Poor compliance and early discontinuation of amitriptyline were common due to anticholinergic effects.

In small uncontrolled studies,³⁷ about half of women with chronic pelvic pain became pain-free after 8 weeks of treatment with nortriptyline and imipramine.

Randomized controlled studies are needed to confirm potential benefits of TCAs in chronic urologic and pelvic pain.

Insomnia

Insomnia affects 23% to 56% of people in the United States, Europe, and Asia³⁸ and is the reason for more than 5.5 million primary care visits annually.³⁹ TCAs (especially doxepin, maprotiline, and amitriptyline⁴⁰) have been shown to be an effective treatment, with an 82% increase in somnolence compared with placebo, as well as measurably improved total sleep time, enhanced sleep efficiency, reduced latency to persistent sleep, and decreased wake times after sleep onset.³⁸

Dosing should be kept at a minimum to minimize harsh anticholinergic effects and avoid daytime sedation. Patients should be advised to take new doses or dose escalations earlier in the night to ensure less hangover sedation the next morning.

For patients with insomnia and comorbid depression, the American Academy of Sleep Medicine suggests the addition of a low dose (eg, 10–25 mg) of a TCA at nighttime to complement preexisting, full-dose, non-TCA antidepressants, while monitoring for serotonin syndrome and other potential but exceedingly rare drug-drug interactions.⁴¹

Psychiatric indications other than depression

Beyond the known benefits in major depressive disorder, TCAs have been shown to be effective for obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, bulimia nervosa, and childhood enuresis.⁴² Given the shortage of mental health clinicians and the high prevalence of these conditions, nonpsychiatrist physicians should be familiar with the therapeutic potential of TCAs for these indications.

ADVERSE EFFECTS

Adverse effects vary among TCAs. Common ones include blurred vision, dry mouth, constipation, urinary retention, hypotension, tachycardia, tremor, weight gain, and sexual dysfunction.⁴³ Tertiary amines are generally more sedating than secondary amines and cause more anticholinergic effects (Table 1).

Despite widespread perceptions that TCAs are less tolerable than newer antidepressants, studies repeatedly suggest that they have an adverse-effect burden similar to that of SSRIs and SNRIs, although SSRIs have a greater tendency to produce nausea, whereas TCAs are more likely to cause constipation.⁴⁴

Discontinuation syndrome

Abrupt discontinuation or unintentionally missed doses of TCAs have been associated with a discontinuation syndrome in about 40% of users.⁴⁵ Patients should be warned about this possibility and the syndrome’s potential effects: dizziness, insomnia, headaches, nausea, vomiting, flulike achiness, and restlessness. Rebound depression, anxiety, panic, or other psychiatric symptoms may also occur. Symptoms generally present within 2 to 5 days after dose discontinuation and last 7 to 14 days.⁴⁵

However, all TCAs have a long half-life, allowing for sufficient coverage with once-daily dosing and thus carry a lower risk of discontinuation syndrome than many other antidepressants (78% with venlafaxine; 55% with paroxetine).⁴⁵

To discontinue therapy safely, the dosage should be reduced gradually. As is pharmacologically expected, the greatest likelihood of discontinuation syndrome is associated with longer duration of continuous treatment.

CONTRAINDICATIONS

Cardiac conduction abnormalities

TCAs should not be prescribed to patients who have right bundle branch block, a severe electrolyte disturbance, or other cardiac conduction deficit or arrhythmia that can prolong the QTc interval and elevate the risk of lethal arrhythmia.^46,47 Cardiac effects from TCAs are largely dose-dependent. Nevertheless, a baseline electrocardiogram can be obtained to assess cardiac risk, and dose escalation can proceed if results are normal (eg, appropriate conduction intervals, QTc ≤ 450 ms).

Advanced age

For elderly patients, TCAs should be prescribed with caution and sometimes not at all,⁴⁸ because anticholinergic effects may worsen preexisting urinary retention (including benign prostatic hyperplasia), narrow-angle glaucoma, imbalance and gait issues, and cognitive impairment and dementia. Dehydration and orthostatic hypotension are contraindications for TCAs, as they may precipitate falls or hypotensive shock.

Epilepsy

TCAs should also be used with caution in patients with epilepsy, as they lower the seizure threshold.

Concomitant monoamine oxidase inhibitor treatment

Giving TCAs together with monoamine oxidase inhibitor antidepressants should be avoided, given the risk of hypertensive crisis.

Suicide risk

TCAs are dangerous and potentially lethal in overdose and so should not be prescribed to suicidal or otherwise impulsive patients.

Pregnancy

TCAs are in pregnancy risk category C (animal studies show adverse effects on fetus; no adequate or well-controlled studies in humans; potential benefits may warrant use despite risks). Using TCAs during pregnancy has very rarely led to neonatal withdrawal such as irritability, jitteriness, and convulsions, as well as fetal QTc interval prolongation.⁴⁹

The American College of Obstetricians and Gynecologists recommends that therapy for depression during pregnancy be individualized, incorporating the expertise of the patient’s mental health clinician, obstetrician, primary healthcare provider, and pediatrician. In general, they recommend that TCAs should be avoided if possible and that alternatives such as SSRIs or SNRIs should be considered.⁵⁰

TCAs are excreted in breast milk, but they have not been detected in the serum of nursing infants, and no adverse events have been reported.

OVERDOSE IS HIGHLY DANGEROUS

Severe morbidity and death are associated with TCA overdose, characterized by  convulsions, cardiac arrest, and coma (the “3 Cs”). These dangers occur at much higher rates with TCAs than with other antidepressants.⁴³ Signs and symptoms of toxicity develop rapidly, usually within the first hour of overdose. Manifestations of overdose include prolonged QTc, cardiac arrhythmias, tachycardia, hypertension, severe hypotension, agitation, seizures, central nervous system depression, hallucinations, seizures, and coma.

Overdose management includes activated charcoal, seizure control, cardioversion, hydration, electrolyte stabilization, and other intensive care.

OFF-LABEL TCA MANAGEMENT

Dosing recommendations for off-label use of TCAs vary based on the condition, the medication, and the suggestions of individual authors and researchers. In general, dosing ranges for pain and other nondepression indications may be lower than for severe depression (Table 2).¹

As with any pharmacologic titration, monitoring for rate-limiting adverse effects is recommended. We suggest caution, tailoring the approach to the patient, and routinely assessing for adverse effects and other safety considerations.

In addition, we strongly recommend supplementing TCA therapy with nonpharmacologic strategies such as lifestyle changes, dietary modifications, exercise, physical therapy, and mental health optimization.

In no way do I minimize the value of the imprimatur of FDA approval stating a drug, after appropriate preclinical and clinical studies, is deemed safe and effective. Whatever the agency’s shortcomings, the story of thalidomide (a drug never approved by the FDA) gives credence to the value of having a robust approval process. Arguments will likely continue forever as to whether the agency errs on the side of being too permissive or too restrictive in its approval process.

Nonetheless, I believe there are valid clinical reasons why we should continue to prescribe FDA-approved medications for nonapproved indications. In my practice, I treat some conditions that are sufficiently uncommon or heterogeneous in expression that large-scale clinical trials are logistically hard to carry out or deemed financially unviable by the corporate sponsor, even though clinical experience has informed us of a reasonable likelihood of efficacy. Sometimes drugs have “failed” in clinical trials, but experience and post hoc subset analysis of data have indicated a likely positive response in certain patients.

Although a drug that has been FDA approved has passed significant safety testing, the patients exposed to the drug when it was evaluated for treating a certain disease may be strikingly different from patients who have a different disease—the age, sex, comorbidities, and coprescribed medications may all differ significantly in the population of patients with the “off-label” disorder. Hence, appropriate caution is warranted, and if relevant, this should be explained to patients before giving them the medication.

In this issue of the Journal, 2 papers address the use of medications in an “off-label” manner. Schneider and colleagues discuss several frequent clinical uses of tricyclic antidepressants for reasons other than depression, and Modesto-Lowe and colleagues review the more controversial use of gabapentin in patients with alcohol use disorder. The hoped-for benefits in both circumstances are symptomatic, and both benefits and side effects are dose-related in ways not necessarily coinciding with those in the FDA-labeled indications.

My experience in using tricyclics as adjunctive treatment for fibromyalgia is that patients are quite sensitive to some of the side effects of the drugs (eg, oral dryness and fatigue), even in low doses. Moreover, we should expect only modest benefits, which should be explicitly described to the patient: improved quality of sleep with resultant decreased fatigue (while we watch closely for worsened fatigue from too-high dosing) and a modest reduction in pain over time as part of a multimodality treatment plan. I often find that practitioners who are less familiar with the use of these medications in this setting tend to start at lowish (but higher than often tolerated) doses, have patients take the medication too close to bedtime (resulting in some morning hangover sensation), fail to discuss the timing and degree of expected pain relief, don’t titrate the dose over time, and are not aware of the different responses that patients may experience with different medications within the same class. As with all prescribed medications, the benefits and ill effects must be frequently assessed, and particularly with these medications, one must be willing to discontinue them if appropriate outcomes are not achieved.

“Off-label” should not imply off the table as a therapeutic option. But it is incumbent on us to devote sufficient time to explain to each patient the anticipated side effects and hoped-for benefits, particularly since in most cases, we and our patients cannot refer to the results of definitive phase 3 clinical trials or patient online information sites that are totally relevant, reliable, data supported, and FDA reviewed.

In no way do I minimize the value of the imprimatur of FDA approval stating a drug, after appropriate preclinical and clinical studies, is deemed safe and effective. Whatever the agency’s shortcomings, the story of thalidomide (a drug never approved by the FDA) gives credence to the value of having a robust approval process. Arguments will likely continue forever as to whether the agency errs on the side of being too permissive or too restrictive in its approval process.

Nonetheless, I believe there are valid clinical reasons why we should continue to prescribe FDA-approved medications for nonapproved indications. In my practice, I treat some conditions that are sufficiently uncommon or heterogeneous in expression that large-scale clinical trials are logistically hard to carry out or deemed financially unviable by the corporate sponsor, even though clinical experience has informed us of a reasonable likelihood of efficacy. Sometimes drugs have “failed” in clinical trials, but experience and post hoc subset analysis of data have indicated a likely positive response in certain patients.

Although a drug that has been FDA approved has passed significant safety testing, the patients exposed to the drug when it was evaluated for treating a certain disease may be strikingly different from patients who have a different disease—the age, sex, comorbidities, and coprescribed medications may all differ significantly in the population of patients with the “off-label” disorder. Hence, appropriate caution is warranted, and if relevant, this should be explained to patients before giving them the medication.

In this issue of the Journal, 2 papers address the use of medications in an “off-label” manner. Schneider and colleagues discuss several frequent clinical uses of tricyclic antidepressants for reasons other than depression, and Modesto-Lowe and colleagues review the more controversial use of gabapentin in patients with alcohol use disorder. The hoped-for benefits in both circumstances are symptomatic, and both benefits and side effects are dose-related in ways not necessarily coinciding with those in the FDA-labeled indications.

My experience in using tricyclics as adjunctive treatment for fibromyalgia is that patients are quite sensitive to some of the side effects of the drugs (eg, oral dryness and fatigue), even in low doses. Moreover, we should expect only modest benefits, which should be explicitly described to the patient: improved quality of sleep with resultant decreased fatigue (while we watch closely for worsened fatigue from too-high dosing) and a modest reduction in pain over time as part of a multimodality treatment plan. I often find that practitioners who are less familiar with the use of these medications in this setting tend to start at lowish (but higher than often tolerated) doses, have patients take the medication too close to bedtime (resulting in some morning hangover sensation), fail to discuss the timing and degree of expected pain relief, don’t titrate the dose over time, and are not aware of the different responses that patients may experience with different medications within the same class. As with all prescribed medications, the benefits and ill effects must be frequently assessed, and particularly with these medications, one must be willing to discontinue them if appropriate outcomes are not achieved.

“Off-label” should not imply off the table as a therapeutic option. But it is incumbent on us to devote sufficient time to explain to each patient the anticipated side effects and hoped-for benefits, particularly since in most cases, we and our patients cannot refer to the results of definitive phase 3 clinical trials or patient online information sites that are totally relevant, reliable, data supported, and FDA reviewed.

In no way do I minimize the value of the imprimatur of FDA approval stating a drug, after appropriate preclinical and clinical studies, is deemed safe and effective. Whatever the agency’s shortcomings, the story of thalidomide (a drug never approved by the FDA) gives credence to the value of having a robust approval process. Arguments will likely continue forever as to whether the agency errs on the side of being too permissive or too restrictive in its approval process.

Nonetheless, I believe there are valid clinical reasons why we should continue to prescribe FDA-approved medications for nonapproved indications. In my practice, I treat some conditions that are sufficiently uncommon or heterogeneous in expression that large-scale clinical trials are logistically hard to carry out or deemed financially unviable by the corporate sponsor, even though clinical experience has informed us of a reasonable likelihood of efficacy. Sometimes drugs have “failed” in clinical trials, but experience and post hoc subset analysis of data have indicated a likely positive response in certain patients.

Although a drug that has been FDA approved has passed significant safety testing, the patients exposed to the drug when it was evaluated for treating a certain disease may be strikingly different from patients who have a different disease—the age, sex, comorbidities, and coprescribed medications may all differ significantly in the population of patients with the “off-label” disorder. Hence, appropriate caution is warranted, and if relevant, this should be explained to patients before giving them the medication.

In this issue of the Journal, 2 papers address the use of medications in an “off-label” manner. Schneider and colleagues discuss several frequent clinical uses of tricyclic antidepressants for reasons other than depression, and Modesto-Lowe and colleagues review the more controversial use of gabapentin in patients with alcohol use disorder. The hoped-for benefits in both circumstances are symptomatic, and both benefits and side effects are dose-related in ways not necessarily coinciding with those in the FDA-labeled indications.

My experience in using tricyclics as adjunctive treatment for fibromyalgia is that patients are quite sensitive to some of the side effects of the drugs (eg, oral dryness and fatigue), even in low doses. Moreover, we should expect only modest benefits, which should be explicitly described to the patient: improved quality of sleep with resultant decreased fatigue (while we watch closely for worsened fatigue from too-high dosing) and a modest reduction in pain over time as part of a multimodality treatment plan. I often find that practitioners who are less familiar with the use of these medications in this setting tend to start at lowish (but higher than often tolerated) doses, have patients take the medication too close to bedtime (resulting in some morning hangover sensation), fail to discuss the timing and degree of expected pain relief, don’t titrate the dose over time, and are not aware of the different responses that patients may experience with different medications within the same class. As with all prescribed medications, the benefits and ill effects must be frequently assessed, and particularly with these medications, one must be willing to discontinue them if appropriate outcomes are not achieved.

“Off-label” should not imply off the table as a therapeutic option. But it is incumbent on us to devote sufficient time to explain to each patient the anticipated side effects and hoped-for benefits, particularly since in most cases, we and our patients cannot refer to the results of definitive phase 3 clinical trials or patient online information sites that are totally relevant, reliable, data supported, and FDA reviewed.

Here are 5 articles from the December issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Sustainable weight loss seen 5 years after endoscopic sleeve gastroplasty

To take the posttest, go to: https://bit.ly/37lteRX
Expires May 16, 2020

2. PT beats steroid injections for knee OA

To take the posttest, go to: https://bit.ly/2KIWKY6
Expires May 17, 2020

3. Better screening needed to reduce pregnancy-related overdose, death

To take the posttest, go to: https://bit.ly/2XEZyuG
Expires May 17, 2020

4. Meta-analysis finds no link between PPI use and risk of dementia

To take the posttest, go to: https://bit.ly/2Xzs7JM
Expires June 3, 2020

5. Study: Cardiac biomarkers predicted CV events in CAP

To take the posttest, go to: https://bit.ly/33bAH2u
Expires August 13, 2020

Here are 5 articles from the December issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Sustainable weight loss seen 5 years after endoscopic sleeve gastroplasty

To take the posttest, go to: https://bit.ly/37lteRX
Expires May 16, 2020

2. PT beats steroid injections for knee OA

To take the posttest, go to: https://bit.ly/2KIWKY6
Expires May 17, 2020

3. Better screening needed to reduce pregnancy-related overdose, death

To take the posttest, go to: https://bit.ly/2XEZyuG
Expires May 17, 2020

4. Meta-analysis finds no link between PPI use and risk of dementia

To take the posttest, go to: https://bit.ly/2Xzs7JM
Expires June 3, 2020

5. Study: Cardiac biomarkers predicted CV events in CAP

To take the posttest, go to: https://bit.ly/33bAH2u
Expires August 13, 2020

Here are 5 articles from the December issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Sustainable weight loss seen 5 years after endoscopic sleeve gastroplasty

To take the posttest, go to: https://bit.ly/37lteRX
Expires May 16, 2020

2. PT beats steroid injections for knee OA

To take the posttest, go to: https://bit.ly/2KIWKY6
Expires May 17, 2020

3. Better screening needed to reduce pregnancy-related overdose, death

To take the posttest, go to: https://bit.ly/2XEZyuG
Expires May 17, 2020

4. Meta-analysis finds no link between PPI use and risk of dementia

To take the posttest, go to: https://bit.ly/2Xzs7JM
Expires June 3, 2020

5. Study: Cardiac biomarkers predicted CV events in CAP

To take the posttest, go to: https://bit.ly/33bAH2u
Expires August 13, 2020

MADRID – The risk of serious adverse events in patients on certolizumab varies considerably across indications for use of the biologic, with differential disease-related rates of systemic corticosteroid use and obesity having a big impact, Andrew Blauvelt, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/MDedge News

He presented a comprehensive analysis of safety data from all 49 clinical trials of the tumor necrosis factor inhibitor for its approved indications. The data set included 11,317 patients who received certolizumab for a collective 21,695 person-years in 27 trials in rheumatoid arthritis patients, 5 in psoriasis, 15 for Crohn’s disease, and one trial each for axial spondyloarthritis and psoriatic arthritis.

“It’s not real-world data, but it is a large group of patients [studied] over many years,” noted Dr. Blauvelt, a dermatologist and president of the Oregon Medical Research Center, Portland.

As a renowned authority on psoriasis, he was part of a multidisciplinary expert panel commissioned by UCB to analyze serious adverse events in the complete clinical trials experience involving the company’s tumor necrosis factor inhibitor certolizumab (Cimzia). The panel included experts from rheumatology, gastroenterology, epidemiology, and other disciplines.

The key takeaway: “When you think about the serious side effects of the drug, you have to think about what the indication is, whether the patients are on systemic corticosteroids, and whether they’re heavy or not,” Dr. Blauvelt said.

Take, for example, the risk of serious infections requiring treatment with intravenous antibiotics. The incidence rates ranged from a low of 1.5 per 100 patient-years in psoriasis patients on certolizumab to a high of 5.97 in those with Crohn’s disease, with rates of 3.44 cases per 100 patient-years among rheumatoid arthritis patients and 1.64-1.67 in those with psoriatic arthritis and ankylosing spondylitis, respectively. Patients with Crohn’s disease were 2.22-fold more likely than were those with rheumatoid arthritis to experience a serious infection during their clinical trial experience on certolizumab. In contrast, psoriasis patients had a 52% relative risk reduction and those with psoriatic arthritis were 31% less likely to develop a serious infection compared with those with rheumatoid arthritis.

The explanation for these highly variable serious infection rates lies in part on the huge differences in the concurrent use of systemic corticosteroids with certolizumab across indications. A mere 3.3% of psoriasis patients were also on steroids, compared with 46.2% of rheumatoid arthritis patients, 50.8% of those with ankylosing spondylitis, and about 25% of the Crohn’s disease and psoriatic arthritis patients, he noted.

Advanced age was independently associated with increased risk of serious infections. Patients aged 65 or older were 1.68-fold more likely to experience this event than were those under age 45. And patients whose disease duration was 10 years or more at baseline had a 1.36-fold increased serious infection risk compared with those who had less than a 1-year-long disease history, independent of which disease they had.

The prevalence of baseline obesity varied by indication. The mean body mass index was 30.1 kg/m² in the psoriasis patients, 29.8 kg/m² in those with psoriatic arthritis, lowest at 24 kg/m² in Crohn’s disease patients, and a bit over 27 kg/m² in those with rheumatoid arthritis or ankylosing spondylitis.

Obesity alone was not an independent risk factor for serious infection in certolizumab-treated patients; however, the combination of a BMI of 30 kg/m² or more plus systemic corticosteroid use was associated with a greater risk than with steroids alone.

Based upon a multivariate regression analysis adjusted for age, sex, indication, disease duration, use of methotrexate, and prior use of other TNF inhibitors, the investigators calculated that in patients with Crohn’s disease 16.6% of serious infections in patients on certolizumab were attributable to systemic corticosteroid use.
 

Risks of major adverse cardiovascular events and cancer on certolizumab

The risk of major adverse cardiovascular events (MACE) while on certolizumab ranged from a high of 0.62 MACE events per 100 patient-years in the rheumatoid arthritis population to a low of 0.1 per 100 patient-years in patients treated for Crohn’s disease or ankylosing spondylitis. Psoriasis and psoriatic arthritis patients had MACE rates of 0.27 and 0.54, respectively.

Obesity was independently associated with increased risk of an acute MI and other MACEs. So was advanced age. No surprises there. The investigators calculated that 16.7% of MACEs in patients on certolizumab were attributable to obesity and another 20.9% were attributable to use of systemic corticosteroids.

The incidence rate for all malignancies, including nonmelanoma skin cancer, ranged from a low of 0.46 cases per 100 patient-years in the psoriatic arthritis cohort on certolizumab to a high of 0.93 in those with rheumatoid arthritis, with rates of 0.68, 0.73, and 0.51 in patients with psoriasis, Crohn’s disease, and ankylosing spondylitis, respectively.

Neither systemic corticosteroids, obesity, disease duration, or prior exposure to a TNF inhibitor was linked to increased risk of cancer in patients on certolizumab. The standout risk factor was age: Patients who were 65 or older at baseline were 11.4-fold more likely to develop cancer during participation in their clinical trial than were those younger than 45. Those who were 45 to 65 years old were 4.3-fold more likely to be diagnosed with a malignancy than were those younger than age 45.

Of note, concomitant use of methotrexate was associated with a statistically significant 28% reduction in malignancy risk.

Dr. Blauvelt reported serving as a consultant to and receiving research funding from UCB, the study sponsor, as well as more than two dozen other pharmaceutical companies.

[email protected]

SOURCE: Blauvelt A. EADV Congress, Abstract FC04.06.

MADRID – The risk of serious adverse events in patients on certolizumab varies considerably across indications for use of the biologic, with differential disease-related rates of systemic corticosteroid use and obesity having a big impact, Andrew Blauvelt, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/MDedge News

He presented a comprehensive analysis of safety data from all 49 clinical trials of the tumor necrosis factor inhibitor for its approved indications. The data set included 11,317 patients who received certolizumab for a collective 21,695 person-years in 27 trials in rheumatoid arthritis patients, 5 in psoriasis, 15 for Crohn’s disease, and one trial each for axial spondyloarthritis and psoriatic arthritis.

“It’s not real-world data, but it is a large group of patients [studied] over many years,” noted Dr. Blauvelt, a dermatologist and president of the Oregon Medical Research Center, Portland.

As a renowned authority on psoriasis, he was part of a multidisciplinary expert panel commissioned by UCB to analyze serious adverse events in the complete clinical trials experience involving the company’s tumor necrosis factor inhibitor certolizumab (Cimzia). The panel included experts from rheumatology, gastroenterology, epidemiology, and other disciplines.

The key takeaway: “When you think about the serious side effects of the drug, you have to think about what the indication is, whether the patients are on systemic corticosteroids, and whether they’re heavy or not,” Dr. Blauvelt said.

Take, for example, the risk of serious infections requiring treatment with intravenous antibiotics. The incidence rates ranged from a low of 1.5 per 100 patient-years in psoriasis patients on certolizumab to a high of 5.97 in those with Crohn’s disease, with rates of 3.44 cases per 100 patient-years among rheumatoid arthritis patients and 1.64-1.67 in those with psoriatic arthritis and ankylosing spondylitis, respectively. Patients with Crohn’s disease were 2.22-fold more likely than were those with rheumatoid arthritis to experience a serious infection during their clinical trial experience on certolizumab. In contrast, psoriasis patients had a 52% relative risk reduction and those with psoriatic arthritis were 31% less likely to develop a serious infection compared with those with rheumatoid arthritis.

The explanation for these highly variable serious infection rates lies in part on the huge differences in the concurrent use of systemic corticosteroids with certolizumab across indications. A mere 3.3% of psoriasis patients were also on steroids, compared with 46.2% of rheumatoid arthritis patients, 50.8% of those with ankylosing spondylitis, and about 25% of the Crohn’s disease and psoriatic arthritis patients, he noted.

Advanced age was independently associated with increased risk of serious infections. Patients aged 65 or older were 1.68-fold more likely to experience this event than were those under age 45. And patients whose disease duration was 10 years or more at baseline had a 1.36-fold increased serious infection risk compared with those who had less than a 1-year-long disease history, independent of which disease they had.

The prevalence of baseline obesity varied by indication. The mean body mass index was 30.1 kg/m² in the psoriasis patients, 29.8 kg/m² in those with psoriatic arthritis, lowest at 24 kg/m² in Crohn’s disease patients, and a bit over 27 kg/m² in those with rheumatoid arthritis or ankylosing spondylitis.

Obesity alone was not an independent risk factor for serious infection in certolizumab-treated patients; however, the combination of a BMI of 30 kg/m² or more plus systemic corticosteroid use was associated with a greater risk than with steroids alone.

Based upon a multivariate regression analysis adjusted for age, sex, indication, disease duration, use of methotrexate, and prior use of other TNF inhibitors, the investigators calculated that in patients with Crohn’s disease 16.6% of serious infections in patients on certolizumab were attributable to systemic corticosteroid use.
 

Risks of major adverse cardiovascular events and cancer on certolizumab

The risk of major adverse cardiovascular events (MACE) while on certolizumab ranged from a high of 0.62 MACE events per 100 patient-years in the rheumatoid arthritis population to a low of 0.1 per 100 patient-years in patients treated for Crohn’s disease or ankylosing spondylitis. Psoriasis and psoriatic arthritis patients had MACE rates of 0.27 and 0.54, respectively.

Obesity was independently associated with increased risk of an acute MI and other MACEs. So was advanced age. No surprises there. The investigators calculated that 16.7% of MACEs in patients on certolizumab were attributable to obesity and another 20.9% were attributable to use of systemic corticosteroids.

The incidence rate for all malignancies, including nonmelanoma skin cancer, ranged from a low of 0.46 cases per 100 patient-years in the psoriatic arthritis cohort on certolizumab to a high of 0.93 in those with rheumatoid arthritis, with rates of 0.68, 0.73, and 0.51 in patients with psoriasis, Crohn’s disease, and ankylosing spondylitis, respectively.

Neither systemic corticosteroids, obesity, disease duration, or prior exposure to a TNF inhibitor was linked to increased risk of cancer in patients on certolizumab. The standout risk factor was age: Patients who were 65 or older at baseline were 11.4-fold more likely to develop cancer during participation in their clinical trial than were those younger than 45. Those who were 45 to 65 years old were 4.3-fold more likely to be diagnosed with a malignancy than were those younger than age 45.

Of note, concomitant use of methotrexate was associated with a statistically significant 28% reduction in malignancy risk.

Dr. Blauvelt reported serving as a consultant to and receiving research funding from UCB, the study sponsor, as well as more than two dozen other pharmaceutical companies.

[email protected]

SOURCE: Blauvelt A. EADV Congress, Abstract FC04.06.

MADRID – The risk of serious adverse events in patients on certolizumab varies considerably across indications for use of the biologic, with differential disease-related rates of systemic corticosteroid use and obesity having a big impact, Andrew Blauvelt, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/MDedge News

He presented a comprehensive analysis of safety data from all 49 clinical trials of the tumor necrosis factor inhibitor for its approved indications. The data set included 11,317 patients who received certolizumab for a collective 21,695 person-years in 27 trials in rheumatoid arthritis patients, 5 in psoriasis, 15 for Crohn’s disease, and one trial each for axial spondyloarthritis and psoriatic arthritis.

“It’s not real-world data, but it is a large group of patients [studied] over many years,” noted Dr. Blauvelt, a dermatologist and president of the Oregon Medical Research Center, Portland.

As a renowned authority on psoriasis, he was part of a multidisciplinary expert panel commissioned by UCB to analyze serious adverse events in the complete clinical trials experience involving the company’s tumor necrosis factor inhibitor certolizumab (Cimzia). The panel included experts from rheumatology, gastroenterology, epidemiology, and other disciplines.

The key takeaway: “When you think about the serious side effects of the drug, you have to think about what the indication is, whether the patients are on systemic corticosteroids, and whether they’re heavy or not,” Dr. Blauvelt said.

Take, for example, the risk of serious infections requiring treatment with intravenous antibiotics. The incidence rates ranged from a low of 1.5 per 100 patient-years in psoriasis patients on certolizumab to a high of 5.97 in those with Crohn’s disease, with rates of 3.44 cases per 100 patient-years among rheumatoid arthritis patients and 1.64-1.67 in those with psoriatic arthritis and ankylosing spondylitis, respectively. Patients with Crohn’s disease were 2.22-fold more likely than were those with rheumatoid arthritis to experience a serious infection during their clinical trial experience on certolizumab. In contrast, psoriasis patients had a 52% relative risk reduction and those with psoriatic arthritis were 31% less likely to develop a serious infection compared with those with rheumatoid arthritis.

The explanation for these highly variable serious infection rates lies in part on the huge differences in the concurrent use of systemic corticosteroids with certolizumab across indications. A mere 3.3% of psoriasis patients were also on steroids, compared with 46.2% of rheumatoid arthritis patients, 50.8% of those with ankylosing spondylitis, and about 25% of the Crohn’s disease and psoriatic arthritis patients, he noted.

Advanced age was independently associated with increased risk of serious infections. Patients aged 65 or older were 1.68-fold more likely to experience this event than were those under age 45. And patients whose disease duration was 10 years or more at baseline had a 1.36-fold increased serious infection risk compared with those who had less than a 1-year-long disease history, independent of which disease they had.

The prevalence of baseline obesity varied by indication. The mean body mass index was 30.1 kg/m² in the psoriasis patients, 29.8 kg/m² in those with psoriatic arthritis, lowest at 24 kg/m² in Crohn’s disease patients, and a bit over 27 kg/m² in those with rheumatoid arthritis or ankylosing spondylitis.

Obesity alone was not an independent risk factor for serious infection in certolizumab-treated patients; however, the combination of a BMI of 30 kg/m² or more plus systemic corticosteroid use was associated with a greater risk than with steroids alone.

Based upon a multivariate regression analysis adjusted for age, sex, indication, disease duration, use of methotrexate, and prior use of other TNF inhibitors, the investigators calculated that in patients with Crohn’s disease 16.6% of serious infections in patients on certolizumab were attributable to systemic corticosteroid use.
 

Risks of major adverse cardiovascular events and cancer on certolizumab

The risk of major adverse cardiovascular events (MACE) while on certolizumab ranged from a high of 0.62 MACE events per 100 patient-years in the rheumatoid arthritis population to a low of 0.1 per 100 patient-years in patients treated for Crohn’s disease or ankylosing spondylitis. Psoriasis and psoriatic arthritis patients had MACE rates of 0.27 and 0.54, respectively.

Obesity was independently associated with increased risk of an acute MI and other MACEs. So was advanced age. No surprises there. The investigators calculated that 16.7% of MACEs in patients on certolizumab were attributable to obesity and another 20.9% were attributable to use of systemic corticosteroids.

The incidence rate for all malignancies, including nonmelanoma skin cancer, ranged from a low of 0.46 cases per 100 patient-years in the psoriatic arthritis cohort on certolizumab to a high of 0.93 in those with rheumatoid arthritis, with rates of 0.68, 0.73, and 0.51 in patients with psoriasis, Crohn’s disease, and ankylosing spondylitis, respectively.

Neither systemic corticosteroids, obesity, disease duration, or prior exposure to a TNF inhibitor was linked to increased risk of cancer in patients on certolizumab. The standout risk factor was age: Patients who were 65 or older at baseline were 11.4-fold more likely to develop cancer during participation in their clinical trial than were those younger than 45. Those who were 45 to 65 years old were 4.3-fold more likely to be diagnosed with a malignancy than were those younger than age 45.

Of note, concomitant use of methotrexate was associated with a statistically significant 28% reduction in malignancy risk.

Dr. Blauvelt reported serving as a consultant to and receiving research funding from UCB, the study sponsor, as well as more than two dozen other pharmaceutical companies.

[email protected]

SOURCE: Blauvelt A. EADV Congress, Abstract FC04.06.

ATLANTA – New guidelines for management of osteoarthritis of the hand, knee, and hip from the American College of Rheumatology and the Arthritis Foundation lay out a wide range of treatment options without an algorithm or hierarchy, making strong recommendations for nondrug interventions and for tailoring plans to individual patient-level factors.

Jeff Craven/MDedge News

Since the ACR last released OA management guidelines in 2012, a number of recommendations have been added, changed, and removed, and the structure of the guidelines has also changed. For instance, the new OA guidelines include a broad list of management options, Sharon L. Kolasinski, MD, chair of the ACR guidelines panel and professor of clinical medicine in the division of rheumatology at the University of Pennsylvania, Philadelphia, said in a presentation at the annual meeting of the American College of Rheumatology.

“The new guideline emphasizes comprehensive management of patients with OA, rather than a stepwise algorithm in a linear manner,” she said.

There is also no hierarchy to the recommendations, apart from the strength of the recommendation. “For any individual patient, a single option may be chosen at a particular time point, perhaps with or without other options, and may be reused in the future. For a given intervention, there might be a period of time over which it’s useful, and then the option might be changed,” Dr. Kolasinski noted.

Dr. Kolasinski advised making treatment decisions based on a patient’s disease severity, whether the patient uses medical devices, and in consideration of patient risk factors. “A history of injuries, surgical history, access to care, personal beliefs and preferences should all be brought to bear on decision making for osteoarthritis management,” she said.

The guidelines also advise considering a patient’s overall well-being and factors related to a patient’s perception of pain and function, such as mood disorders, altered sleep, chronic pain, impaired coping measures, and stress level. “Comprehensive management requires a broad assessment of how pain and function are affecting the patient with OA as a whole and recognizing that multiple options are available. They might be used in combination or change over time,” Dr. Kolasinski said.

The new guidelines place a strong emphasis on educational, behavioral, psychosocial, mind-body, and physical approaches. There are strong recommendations for the use of exercise, including aerobic, strengthening, neuromuscular, and aquatic exercise. Weight loss also carries a strong recommendation for patients with hip and knee OA, with a focus on group-based exercise, education, fitness and exercise goals, and a multidisciplinary approach using self-efficacy and self-management programs. The panels made a strong recommendation for tai chi to improve hip and knee OA. There are also strong recommendations for orthoses; aids and assistive devices such as canes, first carpometacarpal (CMC) orthoses, and tibiofemoral knee braces. Other interventions, such as Kinesio tape for first CMC joint and knee OA, hand orthoses, and patellofemoral knee braces, carried a conditional recommendation. Other conditional recommendations made by the panel were for acupuncture, thermal interventions, and radiofrequency ablation for patients with knee OA. Balance training for hip and knee OA, yoga for knee OA, and cognitive-behavioral therapy all were conditionally recommended by the panel.

The panel strongly recommended against the use of transcutaneous nerve stimulation for hip and knee OA, Dr. Kolasinski noted. The panel also conditionally recommended against use of modified shoes and pulsed vibration therapy in knee OA; lateral or medial wedged insoles, massage, and manual therapy with exercise in hip or knee OA; and iontophoresis in first CMC OA.

Jeff Craven/MDedge News

Recommendations for, against pharmacologic approaches

The ACR has changed conditional recommendations for topical NSAIDs for knee and hand OA, oral NSAIDs, and intra-articular steroids for knee and hip OA into strong recommendations for the 2019 guidelines, Dr. Kolasinski said. While the 2012 guidelines conditionally recommended against topical capsaicin for knee OA, the new guidelines conditionally recommend it.

Other pharmacologic conditional recommendations included topical NSAIDs, chondroitin sulfate, and intra-articular corticosteroid injections for hand OA, acetaminophen, and duloxetine for knee OA.

With the new recommendations come changes that some rheumatologists and health care providers may find controversial. “I think that the practicing rheumatologist may be surprised that we have a recommendation against the use of hyaluronic acid in the knee as a conditional recommendation,” Dr. Kolasinski said. “The assessment of the literature at this point really reveals that there is equivalence between intra-articular hyaluronic acid injection and intra-articular saline injection, and so it was the feeling of the panel that, really, this was worth changing the recommendation from the 2012 guideline.”

The panel made strong recommendations against use of the following pharmacologic interventions:

• Bisphosphonates.
• Glucosamine sulfate.
• Combination glucosamine sulfate-chondroitin sulfate products.
• Hydroxychloroquine.
• Methotrexate.
• Intra-articular hyaluronic acid injections in hip OA.
• Chondroitin sulfate, platelet-rich plasma injections, and stem cell injections in hip and knee OA.
• Tumor necrosis factor (TNF) inhibitors.
• Interleukin-1–receptor antagonists.

Additionally, the panel made a conditional recommendation against topical capsaicin on the hand, colchicine, fish oil, vitamin D, intra-articular hyaluronic acid injections in the first CMC, and intra-articular botulinum toxin and prolotherapy in hip and knee OA.

The panel did not recommend for or against use of yoga for hip and hand OA, topical lidocaine, pregabalin, gabapentin, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors apart from duloxetine, tricyclic antidepressants, and anti-nerve growth factor agents.

While the panel conditionally recommended against use of opioids, they made a conditional recommendation for use of tramadol opioids, and there was “a heated discussion about that distinction,” Dr. Neogi noted in a discussion session at the meeting. “There was a recent observational study that indicated that tramadol may have an increased risk of [all-cause] mortality, but there are lots of issues of confounding by indication in that study.”

The patient panel also raised strong concerns about the ACR and the Arthritis Foundation coming out against opioids for OA management in their guidelines. “They don’t want to damn opioids, but they’re also concerned about a specialty society coming out strongly against opioids in the concern that their physicians may limit their access to opioids if they’re in a situation where nothing else is helping them,” Dr. Neogi said.

Dr. Kolasinski noted the guidelines will be published online in Arthritis & Rheumatology in December, and will appear in print in February of next year.

Dr. Kolasinski reported no relevant financial disclosures. Dr. Neogi reported relationships with EMD Serono, Merck, and Pfizer.

ATLANTA – New guidelines for management of osteoarthritis of the hand, knee, and hip from the American College of Rheumatology and the Arthritis Foundation lay out a wide range of treatment options without an algorithm or hierarchy, making strong recommendations for nondrug interventions and for tailoring plans to individual patient-level factors.

Jeff Craven/MDedge News

Since the ACR last released OA management guidelines in 2012, a number of recommendations have been added, changed, and removed, and the structure of the guidelines has also changed. For instance, the new OA guidelines include a broad list of management options, Sharon L. Kolasinski, MD, chair of the ACR guidelines panel and professor of clinical medicine in the division of rheumatology at the University of Pennsylvania, Philadelphia, said in a presentation at the annual meeting of the American College of Rheumatology.

“The new guideline emphasizes comprehensive management of patients with OA, rather than a stepwise algorithm in a linear manner,” she said.

There is also no hierarchy to the recommendations, apart from the strength of the recommendation. “For any individual patient, a single option may be chosen at a particular time point, perhaps with or without other options, and may be reused in the future. For a given intervention, there might be a period of time over which it’s useful, and then the option might be changed,” Dr. Kolasinski noted.

Dr. Kolasinski advised making treatment decisions based on a patient’s disease severity, whether the patient uses medical devices, and in consideration of patient risk factors. “A history of injuries, surgical history, access to care, personal beliefs and preferences should all be brought to bear on decision making for osteoarthritis management,” she said.

The guidelines also advise considering a patient’s overall well-being and factors related to a patient’s perception of pain and function, such as mood disorders, altered sleep, chronic pain, impaired coping measures, and stress level. “Comprehensive management requires a broad assessment of how pain and function are affecting the patient with OA as a whole and recognizing that multiple options are available. They might be used in combination or change over time,” Dr. Kolasinski said.

The new guidelines place a strong emphasis on educational, behavioral, psychosocial, mind-body, and physical approaches. There are strong recommendations for the use of exercise, including aerobic, strengthening, neuromuscular, and aquatic exercise. Weight loss also carries a strong recommendation for patients with hip and knee OA, with a focus on group-based exercise, education, fitness and exercise goals, and a multidisciplinary approach using self-efficacy and self-management programs. The panels made a strong recommendation for tai chi to improve hip and knee OA. There are also strong recommendations for orthoses; aids and assistive devices such as canes, first carpometacarpal (CMC) orthoses, and tibiofemoral knee braces. Other interventions, such as Kinesio tape for first CMC joint and knee OA, hand orthoses, and patellofemoral knee braces, carried a conditional recommendation. Other conditional recommendations made by the panel were for acupuncture, thermal interventions, and radiofrequency ablation for patients with knee OA. Balance training for hip and knee OA, yoga for knee OA, and cognitive-behavioral therapy all were conditionally recommended by the panel.

The panel strongly recommended against the use of transcutaneous nerve stimulation for hip and knee OA, Dr. Kolasinski noted. The panel also conditionally recommended against use of modified shoes and pulsed vibration therapy in knee OA; lateral or medial wedged insoles, massage, and manual therapy with exercise in hip or knee OA; and iontophoresis in first CMC OA.

Jeff Craven/MDedge News

Recommendations for, against pharmacologic approaches

The ACR has changed conditional recommendations for topical NSAIDs for knee and hand OA, oral NSAIDs, and intra-articular steroids for knee and hip OA into strong recommendations for the 2019 guidelines, Dr. Kolasinski said. While the 2012 guidelines conditionally recommended against topical capsaicin for knee OA, the new guidelines conditionally recommend it.

Other pharmacologic conditional recommendations included topical NSAIDs, chondroitin sulfate, and intra-articular corticosteroid injections for hand OA, acetaminophen, and duloxetine for knee OA.

With the new recommendations come changes that some rheumatologists and health care providers may find controversial. “I think that the practicing rheumatologist may be surprised that we have a recommendation against the use of hyaluronic acid in the knee as a conditional recommendation,” Dr. Kolasinski said. “The assessment of the literature at this point really reveals that there is equivalence between intra-articular hyaluronic acid injection and intra-articular saline injection, and so it was the feeling of the panel that, really, this was worth changing the recommendation from the 2012 guideline.”

The panel made strong recommendations against use of the following pharmacologic interventions:

• Bisphosphonates.
• Glucosamine sulfate.
• Combination glucosamine sulfate-chondroitin sulfate products.
• Hydroxychloroquine.
• Methotrexate.
• Intra-articular hyaluronic acid injections in hip OA.
• Chondroitin sulfate, platelet-rich plasma injections, and stem cell injections in hip and knee OA.
• Tumor necrosis factor (TNF) inhibitors.
• Interleukin-1–receptor antagonists.

Additionally, the panel made a conditional recommendation against topical capsaicin on the hand, colchicine, fish oil, vitamin D, intra-articular hyaluronic acid injections in the first CMC, and intra-articular botulinum toxin and prolotherapy in hip and knee OA.

The panel did not recommend for or against use of yoga for hip and hand OA, topical lidocaine, pregabalin, gabapentin, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors apart from duloxetine, tricyclic antidepressants, and anti-nerve growth factor agents.

While the panel conditionally recommended against use of opioids, they made a conditional recommendation for use of tramadol opioids, and there was “a heated discussion about that distinction,” Dr. Neogi noted in a discussion session at the meeting. “There was a recent observational study that indicated that tramadol may have an increased risk of [all-cause] mortality, but there are lots of issues of confounding by indication in that study.”

The patient panel also raised strong concerns about the ACR and the Arthritis Foundation coming out against opioids for OA management in their guidelines. “They don’t want to damn opioids, but they’re also concerned about a specialty society coming out strongly against opioids in the concern that their physicians may limit their access to opioids if they’re in a situation where nothing else is helping them,” Dr. Neogi said.

Dr. Kolasinski noted the guidelines will be published online in Arthritis & Rheumatology in December, and will appear in print in February of next year.

Dr. Kolasinski reported no relevant financial disclosures. Dr. Neogi reported relationships with EMD Serono, Merck, and Pfizer.

ATLANTA – New guidelines for management of osteoarthritis of the hand, knee, and hip from the American College of Rheumatology and the Arthritis Foundation lay out a wide range of treatment options without an algorithm or hierarchy, making strong recommendations for nondrug interventions and for tailoring plans to individual patient-level factors.

Jeff Craven/MDedge News

Since the ACR last released OA management guidelines in 2012, a number of recommendations have been added, changed, and removed, and the structure of the guidelines has also changed. For instance, the new OA guidelines include a broad list of management options, Sharon L. Kolasinski, MD, chair of the ACR guidelines panel and professor of clinical medicine in the division of rheumatology at the University of Pennsylvania, Philadelphia, said in a presentation at the annual meeting of the American College of Rheumatology.

“The new guideline emphasizes comprehensive management of patients with OA, rather than a stepwise algorithm in a linear manner,” she said.

There is also no hierarchy to the recommendations, apart from the strength of the recommendation. “For any individual patient, a single option may be chosen at a particular time point, perhaps with or without other options, and may be reused in the future. For a given intervention, there might be a period of time over which it’s useful, and then the option might be changed,” Dr. Kolasinski noted.

Dr. Kolasinski advised making treatment decisions based on a patient’s disease severity, whether the patient uses medical devices, and in consideration of patient risk factors. “A history of injuries, surgical history, access to care, personal beliefs and preferences should all be brought to bear on decision making for osteoarthritis management,” she said.

The guidelines also advise considering a patient’s overall well-being and factors related to a patient’s perception of pain and function, such as mood disorders, altered sleep, chronic pain, impaired coping measures, and stress level. “Comprehensive management requires a broad assessment of how pain and function are affecting the patient with OA as a whole and recognizing that multiple options are available. They might be used in combination or change over time,” Dr. Kolasinski said.

The new guidelines place a strong emphasis on educational, behavioral, psychosocial, mind-body, and physical approaches. There are strong recommendations for the use of exercise, including aerobic, strengthening, neuromuscular, and aquatic exercise. Weight loss also carries a strong recommendation for patients with hip and knee OA, with a focus on group-based exercise, education, fitness and exercise goals, and a multidisciplinary approach using self-efficacy and self-management programs. The panels made a strong recommendation for tai chi to improve hip and knee OA. There are also strong recommendations for orthoses; aids and assistive devices such as canes, first carpometacarpal (CMC) orthoses, and tibiofemoral knee braces. Other interventions, such as Kinesio tape for first CMC joint and knee OA, hand orthoses, and patellofemoral knee braces, carried a conditional recommendation. Other conditional recommendations made by the panel were for acupuncture, thermal interventions, and radiofrequency ablation for patients with knee OA. Balance training for hip and knee OA, yoga for knee OA, and cognitive-behavioral therapy all were conditionally recommended by the panel.

The panel strongly recommended against the use of transcutaneous nerve stimulation for hip and knee OA, Dr. Kolasinski noted. The panel also conditionally recommended against use of modified shoes and pulsed vibration therapy in knee OA; lateral or medial wedged insoles, massage, and manual therapy with exercise in hip or knee OA; and iontophoresis in first CMC OA.

Jeff Craven/MDedge News

Recommendations for, against pharmacologic approaches

The ACR has changed conditional recommendations for topical NSAIDs for knee and hand OA, oral NSAIDs, and intra-articular steroids for knee and hip OA into strong recommendations for the 2019 guidelines, Dr. Kolasinski said. While the 2012 guidelines conditionally recommended against topical capsaicin for knee OA, the new guidelines conditionally recommend it.

Other pharmacologic conditional recommendations included topical NSAIDs, chondroitin sulfate, and intra-articular corticosteroid injections for hand OA, acetaminophen, and duloxetine for knee OA.

With the new recommendations come changes that some rheumatologists and health care providers may find controversial. “I think that the practicing rheumatologist may be surprised that we have a recommendation against the use of hyaluronic acid in the knee as a conditional recommendation,” Dr. Kolasinski said. “The assessment of the literature at this point really reveals that there is equivalence between intra-articular hyaluronic acid injection and intra-articular saline injection, and so it was the feeling of the panel that, really, this was worth changing the recommendation from the 2012 guideline.”

The panel made strong recommendations against use of the following pharmacologic interventions:

• Bisphosphonates.
• Glucosamine sulfate.
• Combination glucosamine sulfate-chondroitin sulfate products.
• Hydroxychloroquine.
• Methotrexate.
• Intra-articular hyaluronic acid injections in hip OA.
• Chondroitin sulfate, platelet-rich plasma injections, and stem cell injections in hip and knee OA.
• Tumor necrosis factor (TNF) inhibitors.
• Interleukin-1–receptor antagonists.

Additionally, the panel made a conditional recommendation against topical capsaicin on the hand, colchicine, fish oil, vitamin D, intra-articular hyaluronic acid injections in the first CMC, and intra-articular botulinum toxin and prolotherapy in hip and knee OA.

The panel did not recommend for or against use of yoga for hip and hand OA, topical lidocaine, pregabalin, gabapentin, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors apart from duloxetine, tricyclic antidepressants, and anti-nerve growth factor agents.

While the panel conditionally recommended against use of opioids, they made a conditional recommendation for use of tramadol opioids, and there was “a heated discussion about that distinction,” Dr. Neogi noted in a discussion session at the meeting. “There was a recent observational study that indicated that tramadol may have an increased risk of [all-cause] mortality, but there are lots of issues of confounding by indication in that study.”

The patient panel also raised strong concerns about the ACR and the Arthritis Foundation coming out against opioids for OA management in their guidelines. “They don’t want to damn opioids, but they’re also concerned about a specialty society coming out strongly against opioids in the concern that their physicians may limit their access to opioids if they’re in a situation where nothing else is helping them,” Dr. Neogi said.

Dr. Kolasinski noted the guidelines will be published online in Arthritis & Rheumatology in December, and will appear in print in February of next year.

Dr. Kolasinski reported no relevant financial disclosures. Dr. Neogi reported relationships with EMD Serono, Merck, and Pfizer.